Differential modulation of glucocorticoid action by FK506 in A549 cells.

PubMed Central

Croxtall, Jamie D; Paul-Clark, Mark; Van Hal, Peter Th W

2003-01-01

Glucocorticoids inhibit the release of eicosanoid pro-inflammatory mediators. The immunosuppressant FK506 is known to enhance many aspects of glucocorticoid action. In the present study we show that FK506 (1 microM or 10 microM) inhibits the release of arachidonic acid and prostaglandin E2 from A549 cells and also inhibits their proliferation. Simultaneous treatment of FK506 together with the glucocorticoids dexamethasone, methyl-prednisolone, fluticasone or mometasone (10 nM) enhances the growth inhibitory effect of these steroids. Furthermore, the simultaneous use of FK506 and these glucocorticoids similarly results in enhanced inhibition of arachidonic acid release. When pretreated for 2 h, FK506 enhances glucocorticoid inhibition of COX2 (cyclo-oxygenase 2) expression. However, when administered simultaneously, FK506 blocks glucocorticoid inhibition of COX2 expression. Nuclear uptake of glucocorticoid receptors mediated by glucocorticoids is also blocked by the simultaneous administration of FK506. These results suggest that the effect of simultaneous treatment of FK506 with glucocorticoids differs significantly from that where pre-treatment of the immunosuppressant is used. Recently, immunophilin interchange has been identified as a first step in glucocorticoid receptor activation following ligand activation. We show here that the FKB51 (FK506-binding protein 51)-FKB52 switch is differentially regulated by glucocorticoid and FK506 treatment strategy. PMID:12948397

Improvement of FK506 Production in the High-Yielding Strain Streptomyces sp. RM7011 by Engineering the Supply of Allylmalonyl-CoA Through a Combination of Genetic and Chemical Approach.

PubMed

Mo, SangJoon; Lee, Sung-Kwon; Jin, Ying-Yu; Suh, Joo-Won

2016-02-01

FK506, a widely used immunosuppressant, is a 23-membered polyketide macrolide that is produced by several Streptomyces species. FK506 high-yielding strain Streptomyces sp. RM7011 was developed from the discovered Streptomyces sp. KCCM 11116P by random mutagenesis in our previous study. The results of transcript expression analysis showed that the transcription levels of tcsA, B, C, and D were increased in Streptomyces sp. RM7011 by 2.1-, 3.1-, 3.3-, and 4.1- fold, respectively, compared with Streptomyces sp. KCCM 11116P. The overexpression of tcsABCD genes in Streptomyces sp. RM7011 gave rise to approximately 2.5-fold (238.1 μg/ml) increase in the level of FK506 production compared with that of Streptomyces sp. RM7011. When vinyl pentanoate was added into the culture broth of Streptomyces sp. RM7011, the level of FK506 production was approximately 2.2-fold (207.7 μg/ml) higher than that of the unsupplemented fermentation. Furthermore, supplementing the culture broth of Streptomyces sp. RM7011 expressing tcsABCD genes with vinyl pentanoate resulted in an additional 1.7-fold improvement in the FK506 titer (498.1 μg/ml) compared with that observed under nonsupplemented condition. Overall, the level of FK506 production was increased approximately 5.2-fold by engineering the supply of allylmalonyl-CoA in the high-yielding strain Streptomyces sp. RM7011, using a combination of overexpressing tcsABCD genes and adding vinyl pentanoate, as compared with Streptomyces sp. RM7011 (95.3 μg/ml). Moreover, among the three precursors analyzed, pentanoate was the most effective precursor, supporting the highest titer of FK506 in the FK506 high-yielding strain Streptomyces sp. RM7011.

Diverse effects of FK506 on the apoptosis of hepatocytes and infiltrating lymphocytes in an allografted rat liver.

PubMed

Moriuchi, Hiroki; Kamohara, Yukio; Eguchi, Susumu; Gu, Weili; Fujioka, Hikaru; Yamamoto, Takao; Tajima, Yoshitsugu; Kanematsu, Takashi; Koji, Takehiko

2011-05-01

The current study investigated whether FK506 (FK) regulates the apoptotic systems in allografted rat liver and the contribution of Fas/Fas-ligand system and Bcl-2 family during acute rejection. The recipients were divided into three groups, the allo, the allo-FK, and the syn group. Rats were euthanized 1, 3, 5, and 7 d after OLT. Apoptotic activity was explored using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. The expression of Fas/Fas-ligand and Bcl-2/Bax in the grafted livers was investigated by Western blotting and immunohistochemistry. The apoptotic index (AI) of hepatocytes in the allo-FK group was less than that in the allo group. Fas in the allo group was more intense than that in the allo-FK group in the periportal areas on day 1 and 3, while Bcl-2 in the allo group was less intense than that in the allo-FK group in the pericaval areas at all time-points after OLT. FK provides beneficial antiapoptotic effects on hepatocytes in the grafted rat livers through both the down-regulation of Fas expression in the periportal areas and the up-regulation of Bcl-2 expression in the pericaval areas. Copyright © 2011 Elsevier Inc. All rights reserved.

Cyclosporin A and tacrolimus (FK506) suppress expression of inducible nitric oxide synthase in vitro by different mechanisms

PubMed Central

Dusting, Gregory J; Akita, Kazuhiro; Hickey, Haruyo; Smith, Melanie; Gurevich, Vladimir

1999-01-01

The effects of the immunosuppressant drugs cyclosporin A and tacrolimus (FK506) on nitric oxide synthesis were examined in a murine macrophage cell line (J774) and rat vascular smooth muscle cells (VSMC) in culture for 24 and 48 h, respectively.Cyclosporin A (0.01–10 μM) inhibited by up to 90% accumulation of nitrite induced by lipopolysaccharide (LPS) in both cell lines, but FK506 (0.01–10 μM) had a weaker effect on nitrite accumulation in these cells. Cyclosporin A and FK506 (at 1 μM) also significantly inhibited nitrite production induced by recombinant murine interferon-γ (rIFNγ) and recombinant murine interleukin-1β (rIL-1β) in J774 and VSMC, respectively.In J774 cells, cyclosporin A (but not FK506) at 1 μM was inhibitory when co-incubated with the inducing agents but not when the cells were treated with the immunosuppressant before or after the inducer. In VSMC, nitrite production was inhibited by co-incubation of cyclosporin A or FK506 with the inducer, or when the immunosuppressants were pre-incubated with cells. In contrast, N-monomethyl L-arginine (NMMA) abolished nitrite production when incubated with either cell type during or after addition of inducing agent, but not if cells were preincubated with NMMA.RNA extracted from treated J774 and VSMC was subjected to reverse transcription–polymerase chain reaction (RT–PCR). Cyclosporin A, but not FK506, suppressed expression of mRNA for NOS2 in a concentration-dependent manner when co-incubated with LPS.The fact that the potency difference between cyclosporin A and FK506 for NO suppression is the opposite to that for inhibition of interleukin-2 generation suggests that the immunosuppressants act in J774 macrophages and VSMC through intracellular mechanisms that differ from those elucidated in T-cells. Cyclosporin A suppresses NOS2 gene transcription, but FK506 acts post-transcriptionally to suppress NO generation in VSMC.Taken together the present data suggest that therapeutic concentrations of cyclosporin A, but not FK506, might well suppress NO production, but FK506 would not have this effect. Suppression of NO might contribute to the side effects of hypertension and nephrotoxicity associated with long-term use of cyclosporin A to prevent transplant rejection. PMID:10510443

Physiological stimuli evoke two forms of endocytosis in bovine chromaffin cells.

PubMed

Chan, S A; Smith, C

2001-12-15

1. Exocytosis and endocytosis were measured following single, or trains of, simulated action potentials (sAP) in bovine adrenal chromaffin cells. Catecholamine secretion was measured by oxidative amperometry and cell membrane turnover was measured by voltage clamp cell capacitance measurements. 2. The sAPs evoked inward Na(+) and Ca(2+) currents that were statistically identical to those evoked by native action potential waveforms. On average, a single secretory granule underwent fusion following sAP stimulation. An equivalent amount of membrane was then quickly internalised (tau = 560 ms). 3. Stimulation with sAP trains revealed a biphasic relationship between cell firing rate and endocytic activity. At basal stimulus frequencies (single to 0.5 Hz) cells exhibited a robust membrane internalisation that then diminished as firing increased to intermediate levels (1.9 and 6 Hz). However at the higher stimulation rates (10 and 16 Hz) endocytic activity rebounded and was again able to effectively maintain cell surface near pre-stimulus levels. 4. Treatment with cyclosporin A and FK506, inhibitors of the phosphatase calcineurin, left endocytosis characteristics unaltered at the lower basal stimulus levels, but blocked the resurgence in endocytosis seen in control cells at higher sAP frequencies. 5. Based on these findings we propose that, under physiological electrical stimulation, chromaffin cells internalise membrane via two distinct pathways that are separable. One is prevalent at basal stimulus frequencies, is lessened with increased firing, and is insensitive to cyclosporin A and FK506. A second endocytic form is activated by increased firing frequencies, and is selectively blocked by cyclosporin A and FK506.

Toxicity prediction of PHDDs and phenols in the light of nucleic acid bases and DNA base pair interaction.

PubMed

Mondal Roy, Sutapa; Roy, Debesh R; Sahoo, Suban K

2015-11-01

The applicability of Density Functional Theory (DFT) based descriptors for the development of quantitative structure-toxicity relationships (QSTR) is assessed for two different series of toxic aromatic compounds, viz., polyhalogenated dibenzo-p-dioxins (PHDDs) and phenols (PHs). A series of 20 compounds each for PHDDs and PHs with their experimental toxicities (IC50 and IGC50) is chosen in the present study to develop DFT based efficient quantum chemical parameters (QCPs) for explaining the toxin potential of the considered compounds. A systematic analysis to find out the electron donation/acceptance nature of these selected compounds with the considered model biosystems, viz., nucleic acid (NA) bases and DNA base pairs, is performed to identify potential QCPs. Accordingly, PHDDs is found to be electron acceptors whereas phenols as donors, during their interaction with biosystems. Two parameter regression model is carried out comprising global charge transfer (ΔN), and local Fukui Function's for nucleophilic attack (fk(+)) for PHDDs and the same for electrophilic attack (fk(-)) in case of PHs. It is heartening to note that our chosen descriptors, viz, charge transfer (ΔN) and Fukui Function (fk(±)) plays a crucial role by explaining more than 90% of the observed toxic behavior (in terms of correlation-coefficient, R) of PHDDs and PHs. The developed QCPs, viz., ΔN and fk(±) can be added as the new descriptors in the QSTR parlance. Copyright © 2015 Elsevier Inc. All rights reserved.

Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats.

PubMed

Rubert, Mercedes; Montero, Mercedes; Guede, David; Caeiro, Jose-Ramón; Martín-Fernández, Marta; Díaz-Curiel, Manuel; de la Piedra, Concepción

2015-06-01

The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on bone mass, femoral microstructure, femoral biomechanical properties, and bone remodeling in healthy adult male rats. Forty-eight 5-month-old male Wistar rats were used. CsA (2 mg/kg/day), FK-506 (3 mg/kg/day), RAPA (1.25 mg/kg/day), or water (0.5 ml/rat/day, control group) were administered orally for 3 months. After sacrifice, mean values of immunosuppressants in blood were: CsA (670.4 ng/ml), FK-506 (19.2 ng/ml), and RAPA (4.8 ng/ml). Levels of biochemical parameters were normal in all groups. Femoral BMD was decreased in FK-506 and RAPA groups and lumbar BMD in FK-506 group. Trabecular volume fraction (BV/TV) decreased only in FK-506 group. RAPA and CsA affected femoral cortical structure, but FK-506 did not. FK-506 produced an increase in bone remodeling, and CsA a decrease. FK-506 group showed a decrease in biomechanical parameters relative to all groups. RAPA group showed a decrease in ultimate stress vs control group, and CsA group presented an increase in biomechanical parameters versus control group. We found that administration of both RAPA and FK-506 as monotherapy for healthy rats produced osteopenia. CsA treatment only produces slight damages in the cortical zone of the femur.

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

Schuster, Susanne, E-mail: Susanne.Schuster@medizin.uni-leipzig.de; Penke, Melanie; Gorski, Theresa

Background: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC). Here, we investigated the effects of NAMPT inhibition by its specific inhibitor FK866 on the viability of hepatocarcinoma cells and analyzed the effects of FK866 on the nutrient sensor AMPK and mTOR complex1more » (mTORC1) signaling. Results: FK866 markedly decreased NAMPT activity and NAD content in hepatocarcinoma cells (Huh7 cells, Hep3B cells) and led to delayed ATP reduction which was associated with increased cell death. These effects could be abrogated by administration of nicotinamide mononucleotide (NMN), the enzyme product of NAMPT. Our results demonstrated a dysregulation of the AMPK/mTOR pathway in hepatocarcinoma cells compared to non-cancerous hepatocytes with a higher expression of mTOR and a lower AMPKα activation in hepatocarcinoma cells. We found that NAMPT inhibition by FK866 significantly activated AMPKα and inhibited the activation of mTOR and its downstream targets p70S6 kinase and 4E-BP1 in hepatocarcinoma cells. Non-cancerous hepatocytes were less sensitive to FK866 and did not show changes in AMPK/mTOR signaling after FK866 treatment. Conclusion: Taken together, these findings reveal an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of hepatocarcinoma cells and suggest NAMPT inhibition as a potential treatment option for HCC. - Highlights: • FK866 increases cell death in p53-deficient hepatocarcinoma cells. • AMPK/mTOR signaling is dysregulated in hepatocarcinoma cells. • FK866-induced NAMPT inhibition activates AMPKα and downregulates mTOR signaling. • NMN abrogates the effects of FK866-induced NAMPT inhibition. • Non-cancerous human hepatocytes are less sensitive to FK866.« less

In vitro activity of FK037, a new parenteral cephalosporin, against anaerobic bacteria.

PubMed Central

Kato, N; Kato, H; Tanaka, Y; Bando, K; Watanabe, K; Ueno, K

1993-01-01

The activity of FK037, a new parenteral cephalosporin, was compared with those of cefpirome, ceftazidime, and flomoxef against 322 recent clinical isolates of anaerobic bacteria. A fastidious facultative anaerobe, Gardnerella vaginalis, was also studied. FK037 inhibited 90% of isolates of Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Clostridium perfringens, Mobiluncus spp., G. vaginalis, and Porphyromonas gingivalis at < or = 0.78 micrograms/ml. The MICs of FK037 for 50 and 90% of Bacteroides fragilis isolates were 25 and > 200 micrograms/ml, respectively; the activity of FK037 was comparable to those of cefpirome and ceftazidime but lower than that of flomoxef. The activity of FK037 against Fusobacterium nucleatum, Fusobacterium varium, and Bilophila wadsworthia decreased when inoculum size was increased from 10(6) to 10(8) CFU/ml. Little influence of inoculum size on the activity of FK037 was observed for other isolates tested. Medium pH affected the activity of FK037 against F. varium (MICs at pHs 5 and 7, 3.13 and 100 micrograms/ml, respectively) and Bacteroides gracilis (MICs at pHs 5 and 7, 12.5 and 1.56 micrograms/ml, respectively) but not against other organisms tested. FK037 was less resistant than flomoxef to hydrolysis by beta-lactamase group 2e derived from B. fragilis GAI 0558 and GAI 10150. PMID:8517721

Successful treatment of dry eye in two patients with chronic graft-versus-host disease with systemic administration of FK506 and corticosteroids.

PubMed

Ogawa, Y; Okamoto, S; Kuwana, M; Mori, T; Watanabe, R; Nakajima, T; Yamada, M; Mashima, Y; Tsubota, K; Oguchi, Y

2001-05-01

We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids. A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time. Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

Mechanism of tacrolimus-induced chronic renal fibrosis following transplantation is regulated by ox-LDL and its receptor, LOX-1

PubMed Central

Deng, Shi; Jin, Tao; Zhang, Li; Bu, Hong; Zhang, Peng

2016-01-01

Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long-term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK-52E, were cultured either with oxidized low-density lipoprotein (ox-LDL), FK506, ox-LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin-like ox-LDL receptor-1 (LOX-1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis-associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague-Dawley rats were divided randomly into four groups, which included a high-fat group, FK506 group, high-fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox-LDL, ROS, and the expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX-1 markedly reduced the levels of TGF-β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation. PMID:27633115

Application of a combined approach involving classical random mutagenesis and metabolic engineering to enhance FK506 production in Streptomyces sp. RM7011.

PubMed

Mo, SangJoon; Lee, Sung-Kwon; Jin, Ying-Yu; Oh, Chung-Hun; Suh, Joo-Won

2013-04-01

FK506 production by a mutant strain (Streptomyces sp. RM7011) induced by N-methyl-N'-nitro-N-nitrosoguanidine and ultraviolet mutagenesis was improved by 11.63-fold (94.24 mg/l) compared to that of the wild-type strain. Among three different metabolic pathways involved in the biosynthesis of methylmalonyl-CoA, only expression of propionyl-CoA carboxylase (PCC) pathway led to a 1.75-fold and 2.5-fold increase in FK506 production and the methylmalonyl-CoA pool, respectively, compared to those of the RM7011 strain. Lipase activity of the high FK506 producer mutant increased in direct proportion to the increase in FK506 yield, from low detection level up to 43.1 U/ml (12.6-fold). The level of specific FK506 production and lipase activity was improved by enhancing the supply of lipase inducers. This improvement was approximately 1.88-fold (71.5 mg/g) with the supplementation of 5 mM Tween 80, which is the probable effective stimulator in lipase production, to the R2YE medium. When 5 mM vinyl propionate was added as a precursor for PCC pathway to R2YE medium, the specific production of FK506 increased approximately 1.9-fold (71.61 mg/g) compared to that under the non-supplemented condition. Moreover, in the presence of 5 mM Tween 80, the specific FK506 production was approximately 2.2-fold (157.44 mg/g) higher than that when only vinyl propionate was added to the R2YE medium. In particular, PCC expression in Streptomyces sp. RM7011 (RM7011/pSJ1003) together with vinyl propionate feeding resulted in an increase in the FK506 titer to as much as 1.6-fold (251.9 mg/g) compared with that in RM7011/pSE34 in R2YE medium with 5 mM Tween 80 supplementation, indicating that the vinyl propionate is more catabolized to propionate by stimulated lipase activity on Tween 80, that propionyl-CoA yielded from propionate generates methylmalonyl-CoA, and that the PCC pathway plays a key role in increasing the methylmalonyl-CoA pool for FK506 biosynthesis in RM7011 strain. Overall, these results show that a combined approach involving classical random mutation and metabolic engineering can be applied to supply the limiting factor for FK506 biosynthesis, and vinyl propionate could be successfully used as a precursor of important methylmalonyl-CoA building blocks.

Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus.

PubMed

Harrison, S; Reddy, S; Page, C P; Spina, D

1998-12-01

We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.

HEPATOTROPHIC EFFECTS OF FK506 IN DOGS1

PubMed Central

Starzl, Thomas E.; Porter, Kendrick A.; Mazzaferro, Vincenzo; Todo, Satoru; Fung, John; Francavilla, Antonio

2010-01-01

Portacaval shunt (Eck fistula) in dogs causes hepatocyte atrophy and organelle disruption, as well as tripling of hepatocyte mitoses. After submitting dogs to this procedure, FK506 was infused into the tied-off left portal vein. The size, anatomic quality, and replication of hepatocytes were enhanced in the portion of liver infused with FK506, with a significant spillover effect in the noninfused portion. These hepatotrophic qualities of FK506 may explain part of FK506’s efficacy for the treatment of chronic liver rejection. Also, the observations support a trial with this drug for the treatment of autoimmune liver diseases because, in addition to turning off the immunologic genesis of such disorders, repair and regeneration of the damaged liver may be augmented. Finally, these hepatrophic qualities are part of an emerging spectrum of biologic effects caused by drugs that may modulate the enzyme cis-trans peptidyl-prolyl isomerase (PPIase), the principal constituent of the cytosolic binding sites of FK506, repamycin, cyclosporine, and presumably other immunosuppressive drugs as yet undiscovered. PMID:1702912

Fifth Fundamental Catalogue (FK5). Part 1: Basic fundamental stars (Fricke, Schwan, and Lederle 1988): Documentation for the machine-readable version

NASA Technical Reports Server (NTRS)

Warren, Wayne H., Jr.

1990-01-01

The machine-readable version of the catalog, as it is currently being distributed from the Astronomical Data Center, is described. The Basic FK5 provides improved mean positions and proper motions for the 1535 classical fundamental stars that had been included in the FK3 and FK4 catalogs. The machine version of the catalog contains the positions and proper motions of the Basic FK5 stars for the epochs and equinoxes J2000.0 and B1950.0, the mean epochs of individual observed right ascensions and declinations used to determine the final positions, and the mean errors of the final positions and proper motions for the reported epochs. The cross identifications to other designations used for the FK5 stars that are given in the published catalog were not included in the original machine versions, but the Durchmusterung numbers have been added at the Astronomical Data Center.

Physiological stimuli evoke two forms of endocytosis in bovine chromaffin cells

PubMed Central

Chan, Shyue-An; Smith, Corey

2001-01-01

Exocytosis and endocytosis were measured following single, or trains of, simulated action potentials (sAP) in bovine adrenal chromaffin cells. Catecholamine secretion was measured by oxidative amperometry and cell membrane turnover was measured by voltage clamp cell capacitance measurements. The sAPs evoked inward Na+ and Ca2+ currents that were statistically identical to those evoked by native action potential waveforms. On average, a single secretory granule underwent fusion following sAP stimulation. An equivalent amount of membrane was then quickly internalised (τ = 560 ms). Stimulation with sAP trains revealed a biphasic relationship between cell firing rate and endocytic activity. At basal stimulus frequencies (single to 0.5 Hz) cells exhibited a robust membrane internalisation that then diminished as firing increased to intermediate levels (1.9 and 6 Hz). However at the higher stimulation rates (10 and 16 Hz) endocytic activity rebounded and was again able to effectively maintain cell surface near pre-stimulus levels. Treatment with cyclosporin A and FK506, inhibitors of the phosphatase calcineurin, left endocytosis characteristics unaltered at the lower basal stimulus levels, but blocked the resurgence in endocytosis seen in control cells at higher sAP frequencies. Based on these findings we propose that, under physiological electrical stimulation, chromaffin cells internalise membrane via two distinct pathways that are separable. One is prevalent at basal stimulus frequencies, is lessened with increased firing, and is insensitive to cyclosporin A and FK506. A second endocytic form is activated by increased firing frequencies, and is selectively blocked by cyclosporin A and FK506. PMID:11744761

Comparative proteomic and metabolomic analysis of Streptomyces tsukubaensis reveals the metabolic mechanism of FK506 overproduction by feeding soybean oil.

PubMed

Wang, Jun; Liu, Huanhuan; Huang, Di; Jin, Lina; Wang, Cheng; Wen, Jianping

2017-03-01

FK506 (tacrolimus) is a 23-membered polyketide macrolide that possesses powerful immunosuppressant activity. In this study, feeding soybean oil into the fermentation culture of Streptomyces tsukubaensis improved FK506 production by 88.8%. To decipher the overproduction mechanism, comparative proteomic and metabolomic analysis was carried out. A total of 72 protein spots with differential expression in the two-dimensional gel electrophoresis (2-DE) were identified by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF-MS), and 66 intracellular metabolites were measured by gas chromatography-mass spectrometer (GC-MS). The analysis of proteome and metabolome indicated that feeding soybean oil as a supplementary carbon source could not only strengthen the FK506 precursor metabolism and energy metabolism but also tune the pathways related to transcriptional regulation, translation, and stress response, suggesting a better intracellular metabolic environment for the synthesis of FK506. Based on these analyses, 20 key metabolites and precursors of FK506 were supplemented into the soybean oil medium. Among them, lysine, citric acid, shikimic acid, and malonic acid performed excellently for promoting the FK506 production and biomass. Especially, the addition of malonic acid achieved the highest FK506 production, which was 1.56-fold of that in soybean oil medium and 3.05-fold of that in initial medium. This report represented the first comprehensive study on the comparative proteomics and metabolomics applied in S. tsukubaensis, and it would be a rational guidance to further strengthen the FK506 production.

Rayleigh-Sommerfield Diffraction vs Fresnel-Kirchhoff, Fourier Propagation and Poisson's Spot

NASA Technical Reports Server (NTRS)

Lucke, Robert L.

2004-01-01

The boundary conditions imposed on the diffraction problem in order to obtain the Fresnel-Kirchhoff (FK) solution are well-known to be mathematically inconsistent and to be violated by the solution when the observation point is close to the diffracting screen 1-3. These problems are absent in the Rayleigh-Sommerfeld (RS) solution. The difference between RS and FK is in the inclination factor and is usually immaterial because the inclination factor is approximated by unity. But when this approximation is not valid, FK can lead to unacceptable answers. Calculating the on-axis intensity of Poisson s spot provides a critical test, a test passed by RS and failed by FK. FK fails because (a) convergence of the integral depends on how it is evaluated and (b) when the convergence problem is xed, the predicted amplitude at points near the obscuring disk is not consistent with the assumed boundary conditions.

Treatment of Refractory Filamentary Keratitis With Autologous Serum Tears.

PubMed

Read, Sarah P; Rodriguez, Marianeli; Dubovy, Sander; Karp, Carol L; Galor, Anat

2017-09-01

To report a case of filamentary keratitis (FK) successfully treated with autologous serum tears and to review the pathogenesis and management of FK. Case report including high-resolution anterior segment optical coherence tomography and filament histopathology. A 61-year-old Hispanic man presented with pain and photophobia of the right eye. He was found to have a corneal epithelial defect and a small peripheral infiltrate 4 months after Laser Assisted in situ Keratomileusis. After resolution of the epithelial defect, he developed FK. Over a 4-month period, conservative management with aggressive lubrication, lid hygiene, topical corticosteroids, topical cyclosporine, bandage contact lenses, and oral doxycycline failed to resolve the corneal filaments. Notably, treatment with 20% autologous serum tears, four times daily, led to a sustained resolution of the FK within 1 week. This case demonstrates the complexity of FK management and introduces autologous serum tears as a viable management option when conservative approaches to this condition fail.

Insulin Inhibits Nrf2 Gene Expression via Heterogeneous Nuclear Ribonucleoprotein F/K in Diabetic Mice

PubMed Central

Ghosh, Anindya; Abdo, Shaaban; Zhao, Shuiling; Wu, Chin-Han; Shi, Yixuan; Lo, Chao-Sheng; Chenier, Isabelle; Alquier, Thierry; Filep, Janos G.; Ingelfinger, Julie R.; Zhang, Shao-Ling

2017-01-01

Oxidative stress induces endogenous antioxidants via nuclear factor erythroid 2–related factor 2 (Nrf2), potentially preventing tissue injury. We investigated whether insulin affects renal Nrf2 expression in type 1 diabetes (T1D) and studied its underlying mechanism. Insulin normalized hyperglycemia, hypertension, oxidative stress, and renal injury; inhibited renal Nrf2 and angiotensinogen (Agt) gene expression; and upregulated heterogeneous nuclear ribonucleoprotein F and K (hnRNP F and hnRNP K) expression in Akita mice with T1D. In immortalized rat renal proximal tubular cells, insulin suppressed Nrf2 and Agt but stimulated hnRNP F and hnRNP K gene transcription in high glucose via p44/42 mitogen-activated protein kinase signaling. Transfection with small interfering RNAs of p44/42 MAPK, hnRNP F, or hnRNP K blocked insulin inhibition of Nrf2 gene transcription. Insulin curbed Nrf2 promoter activity via a specific DNA-responsive element that binds hnRNP F/K, and hnRNP F/K overexpression curtailed Nrf2 promoter activity. In hyperinsulinemic-euglycemic mice, renal Nrf2 and Agt expression was downregulated, whereas hnRNP F/K expression was upregulated. Thus, the beneficial actions of insulin in diabetic nephropathy appear to be mediated, in part, by suppressing renal Nrf2 and Agt gene transcription and preventing Nrf2 stimulation of Agt expression via hnRNP F/K. These findings identify hnRNP F/K and Nrf2 as potential therapeutic targets in diabetes. PMID:28324005

Mast Cell Activation Protects Cornea by Promoting Neutrophil Infiltration via Stimulating ICAM-1 and Vascular Dilation in Fungal Keratitis.

PubMed

Xie, Yanting; Zhang, Hongmin; Liu, Susu; Chen, Guoming; He, Siyu; Li, Zhijie; Wang, Liya

2018-05-30

The role of mast cells (MCs) in fungal infection is largely unknown. This study was to explore a protective role and mechanism of MCs in fungal keratitis. Experimental fungal keratitis (FK) mouse model was developed. Mice untreated (UT) or receiving corneal wound without fungal infection (Mock) were used as controls. Large number of connective tissue MCs was found in normal mice. MC activation with degranulation was largely observed, and the percentage of degranulated/total cells was high in FK. Dilated limbal vasculature with increased permeability, as well as largely infiltrated neutrophils with stimulated ICAM-1 protein levels were observed in corneas of FK mice, when compared with Mock and UT mice. Interestingly, pretreatment with cromolyn sodium (Block) significantly blocked MC degranulation, dramatically suppressed vascular dilation and permeability, and markedly reduced neutrophil infiltration with lower ICAM-1 levels in FK mice at 6-24 hours. Furthermore, the Block mice manifested prolonged disease course, increased pathological damage, and vigorous fungus growth, with much higher corneal perforation rate than FK mice at 72 h. These findings reveal a novel phenomenon that MCs play a vital role in protecting cornea against fungal infection through degranulation that promotes neutrophil infiltration via stimulating ICAM-1 production and limbal vascular dilation and permeability.

Gene Expression ‏‏‏‏Profiles of BAD and Bcl-xL in the CA1 Region of the Hippocampus Following Global Ischemic/Reperfusion and FK-506 Administration.

PubMed

Badr, Ramak; Hashemi, Mehrdad; Javadi, Gholamreza; Movafagh, Abolfazl; Mahdian, Reza

2015-12-01

The hippocampus is a tiny nub in the mammalian brain that is involved in forming, organizing, and storing memories. Global cerebral ischemia (GCI) and reperfusion induced apoptosis lead to cell injury and death. FK-506 is a strong immunosuppressant drug that has neuroprotective effects on the hypoxic-ischemic effects of brain damage. BAD and Bcl-xL are pro-apoptotic and anti-apoptotic genes, respectively. These genes belong to The B-cell lymphoma-2 (Bcl-2) family. In this study, we assessed the neurotrophic properties of FK-506 on expression of the BAD and Bcl-xL genes in the hippocampus following global ischemia and reperfusion. In the present experimental study, adult male Wistar rats were obtained and housed under standard conditions in the Tehran University of Medical Science in Iran. Rats were equally distributed in groups of three among the following groups: normal control, treated-1 (ischemia/reperfusion), and treated-2 (ischemia/reperfusion followed by FK-506). Global ischemia was induced for animals in the treated-1 and treated-2 groups. In treated-2, two doses of FK-506 were injected: one dose as an IV injection immediately after reperfusion and another as an intra-peritoneal (IP) injection after 48 hours. Then, the hippocampus tissue was removed after anaesthetizing the rats. RNA was isolated, cDNA was synthesized, and real-time PCR was performed. Finally, the obtained data were analyzed statistically (P value ˂ 0.05). The quantitative results of real-time PCR show that the mRNA expression ratio of Bcl-xL down-regulated was 0.75 ± 0.06 in the ischemia/reperfusion group versus 1.57 ± 0.09 in the control group (P value < 0.001), whereas Bcl-xL gene expression was greater in the ischemia/reperfusion +FK506 group (1.93 ± 0.15) than in the ischemia/reperfusion group. Moreover, the mRNA expression ratio of BAD up-regulated in the ischemia/reperfusion + FK506 group was 3.65 ± 0.49 compared to Normal control (1.39 ± 0.09) and Ischemia/reperfusion + FK506 was 1.09 ± 0.20 (P value < 0.001). The analysis of the pro-apoptotic gene to anti-apoptotic gene expression ratio (BAD /Bcl-xL) confirmed that expression of the pro-apoptotic gene significantly decreased (P value ˂ 0.001) under the ischemia/reperfusion condition. In contrast, the expression of the anti-apoptotic gene increased after administration of FK-506 (P value ˂ 0.001).

Synergistic effects of Isatis tinctoria L. and tacrolimus in the prevention of acute heart rejection in mice.

PubMed

Wang, Yongzhi; Qin, Qing; Chen, Jibing; Kuang, Xiaocong; Xia, Junjie; Xie, Baiyi; Wang, Feng; Liang, Hua; Qi, Zhongquan

2009-12-01

Although immunosuppressive treatments are available for acute cardiac rejection no viable treatment exists for long-term cardiac graft failure. Moreover, the extended use of calcineurin inhibitor immunosuppressants, the mainstay of current treatment for cardiac transplantation, leads to significant side effects such as nephrotoxicity and an increased risk of cardiac disease. Because some agents used in Traditional Chinese Medicine (TCM) have strong immunosuppressive effects coupled with low toxicity, we investigated the effect of Compound K (K), the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., either as a single treatment or combined with tacrolimus (FK-506) on acute cardiac allograft rejection. We compared the ability of K alone, or in combination with FK-506, to inhibit acute heart transplant rejection both in vitro and in vivo. We found that the inhibition of lymphocyte proliferation was positively correlated with K concentration. K significantly reduced IL-2 and IFN-gamma expression levels and significantly inhibited lymphocyte proliferation in both a lymphocyte transformation test and a mixed lymphocyte reaction (MLR). We also found that the inhibitory effect of a combination of K and a sub-therapeutic dose of FK-506 (SubFK-506) was stronger than that of full-dose FK-506 alone. Oral administration of K reduced acute cardiac allograft rejection in mice and had no apparent toxicity. In vivo, the immunosuppressive effect of K combined with a half-dose of FK-506 was equivalent to that of a full-dose of FK-506 alone. K combined with a half-dose of FK-506 reduced the expression levels of IL-2 and IFN-gamma (both within the graft and in the recipients' serum) more effectively than a full-dose of FK-506. These results show that K has significant immunosuppressive effects both in vitro and in vivo. When used as a combination therapy with FK-506 we see a powerful inhibition of rejection with no obvious toxic side effects. The mechanism of action is postulated to involve the inhibition of IL-2 and IFN-gamma expressions by lymphocytes, rather than the activation of Tr1 cells via the production of IL-10.

Reversion of the P-glycoprotein-mediated multidrug resistance of cancer cells by FK-506 derivatives.

PubMed

Jachez, B; Boesch, D; Grassberger, M A; Loor, F

1993-04-01

FK-506 is a resistance-modulating agent (RMA) for tumor cells whose multidrug resistance (MDR) involves a P-glycoprotein (Pgp)-mediated anti-cancer drug efflux. The family of FK-506 relatives and derivatives includes analogs which display a whole range of chemosensitizing strengths, from no detectable RMA activity to a complete reversion of the MDR phenotype. Similarly, FK-506 analogs display a whole range of immunosuppressive activities, including inactive ones. FK-506 was compared for RMA activity with 11 FK-506 analogs which were at least 20-fold less active than FK-506 for the inhibition of the bi-directional mixed lymphocyte reaction displayed the whole range of RMA activity. One such strong RMA derivative of FK-506 (SDZ 280-629) was further shown able to restore completely daunomycin retention by highly resistant MDR P388 tumor cells.

Nephelauxetic effect and 〈r(k)〉₄f radial integrals of Tm³⁺ in crystals.

PubMed

Petrov, Dimitar

2015-12-05

Bonding and covalency parameters have been evaluated from the nephelauxetic ratios βk=Fk (crystal)/Fk (free ion), with k=2, 4, 6, for 24 halide and chalcogenide crystals containing Tm(3+) ions. The radial expectation values for 4f electrons 〈r(k)〉4f of Tm(3+) ion in certain complex oxides, fluorides, and a sulfide have been determined by means of experimental Slater parameter shifts ΔFk relative to the Fk values for the free ion Tm IV. The 〈r(k)〉1f values derived in the dielectric screening model have been compared with those computed by different types of 4f wave functions as well as with other estimates. Copyright © 2015 Elsevier B.V. All rights reserved.

Results from Evaluation of Representative ASME AG-1 Section FK Radial Flow Dimple Pleated HEPA Filters Under Elevated Conditions - 12002

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

Giffin, Paxton K.; Parsons, Michael S.; Rickert, Jaime G.

The American Society of Mechanical Engineers (ASME) has recently added Section FK establishing requirements for radial flow HEPA filters to the Code on Nuclear Air and Gas Treatment (AG-1). Section FK filters are expected to be a major element in the HEPA filtration systems across the US Department of Energy (DOE) complex. Radial flow filters have been used in Europe for some time, however a limited amount of performance evaluation data exists with respect to these new AG-1 Section FK units. In consultation with a technical working group, the Institute for Clean Energy Technology (ICET) at Mississippi State University (MSU)hasmore » evaluated a series of representative AG-1 Section FK dimple pleated radial flow HEPA filters. The effects of elevated relative humidity and temperature conditions on these filters are particularly concerning. Results from the evaluation of Section FK filters under ambient conditions have been presented at the 2011 waste management conference. Additions to the previous test stand to enable high temperature and high humidity testing, a review of the equipment used, the steps taken to characterize the new additions, and the filter test results are presented in this study. Test filters were evaluated at a volumetric flow rate of 56.6 m{sup 3}/min (2000 cfm) and were challenged under ambient conditions with Alumina, Al(OH){sub 3}, until reaching a differential pressure of 1 kPa (4 in. w.c.), at which time the filters were tested, unchallenged with aerosol, at 54 deg. C (130 deg. F) for approximately 1 hour. At the end of that hour water was sprayed near the heat source to maximize vaporization exposing the filter to an elevated relative humidity up to 95%. Collected data include differential pressure, temperature, relative humidity, and volumetric flow rate versus time. (authors)« less

Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats.

PubMed

Okuda, Keiji; Fu, Hai Ying; Matsuzaki, Takashi; Araki, Ryo; Tsuchida, Shota; Thanikachalam, Punniyakoti V; Fukuta, Tatsuya; Asai, Tomohiro; Yamato, Masaki; Sanada, Shoji; Asanuma, Hiroshi; Asano, Yoshihiro; Asakura, Masanori; Hanawa, Haruo; Hao, Hiroyuki; Oku, Naoto; Takashima, Seiji; Kitakaze, Masafumi; Sakata, Yasushi; Minamino, Tetsuo

2016-01-01

Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.

Regulation of Steroid Hormone Receptor Function By the 52-kDa FK506-Binding Protein (FKBP52)

PubMed Central

Sivils, Jeffrey C.; Storer, Cheryl L.; Galigniana, Mario D.; Cox, Marc B.

2011-01-01

The large FK506-binding protein FKBP52 has been characterized as an important positive regulator of androgen, glucocorticoid and progesterone receptor signaling pathways. FKBP52 associates with receptor-Hsp90 complexes and is proposed to have roles in both receptor hormone binding and receptor subcellular localization. Data from biochemical and cellular studies has been corroborated in whole animal models as fkbp52-deficient male and female mice display characteristics of androgen, glucocorticoid and/or progesterone insensitivity. FKBP52 receptor specificity and the specific phenotypes displayed by the fkbp52-deficient mice have firmly established FKBP52 as a promising target for the treatment of a variety of hormone-dependent diseases. Recent studies demonstrated that the FKBP52 FK1 domain and the proline-rich loop within this domain are functionally important for FKBP52 regulation of receptor function. Based on these data, efforts are currently underway to target the FKBP52 FK1 domain and the proline-rich loop with small molecule inhibitors. PMID:21511531

Signature of chaos in the 4 f -core-excited states for highly-charged tungsten ions

NASA Astrophysics Data System (ADS)

Safronova, Ulyana; Safronova, Alla

2014-05-01

We evaluate radiative and autoionizing transition rates in highly charged W ions in search for the signature of chaos. In particularly, previously published results for Ag-like W27+, Tm-like W5+, and Yb-like W4+ ions as well as newly obtained for I-like W21+, Xe-like W20+, Cs-like W19+, and La-like W17+ ions (with ground configuration [Kr] 4d10 4fk with k = 7, 8, 9, and 11, respectively) are considered that were calculated using the multiconfiguration relativistic Hebrew University Lawrence Livermore Atomic Code (HULLAC code) and the Hartree-Fock-Relativistic method (COWAN code). The main emphasis was on verification of Gaussian statistics of rates as a function of transition energy. There was no evidence of such statistics for above mentioned previously published results as well as for the transitions between the excited and autoionizing states for newly calculated results. However, we did find the Gaussian profile for the transitions between excited states such as the [Kr] 4d10 4fk - [Kr] 4d10 4f k - 1 5 d transitions , for newly calculated W ions. This work is supported in part by DOE under NNSA Cooperative Agreement DE-NA0001984.

Origin of the Allyl Group in FK506 Biosynthesis*

PubMed Central

Goranovič, Dušan; Kosec, Gregor; Mrak, Peter; Fujs, Štefan; Horvat, Jaka; Kuščer, Enej; Kopitar, Gregor; Petković, Hrvoje

2010-01-01

FK506 (tacrolimus) is a secondary metabolite with a potent immunosuppressive activity, currently registered for use as immunosuppressant after organ transplantation. FK506 and FK520 are biogenetically related natural products that are synthesized by combined polyketide synthase/nonribosomal peptide synthetase systems. The entire gene cluster for biosynthesis of FK520 from Streptomyces hygroscopicus var. ascomyceticus has been cloned and sequenced. On the other hand, the FK506 gene cluster from Streptomyces sp. MA6548 (ATCC55098) was sequenced only partially, and it was reasonable to expect that additional genes would be required for the provision of substrate supply. Here we report the identification of a previously unknown region of the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488 containing genes encoding the provision of unusual building blocks for FK506 biosynthesis as well as a regulatory gene. Among others, we identified a group of genes encoding biosynthesis of the extender unit that forms the allyl group at carbon 21 of FK506. Interestingly, we have identified a small independent diketide synthase system involved in the biosynthesis of the allyl group. Inactivation of one of these genes, encoding an unusual ketosynthase domain, resulted in an FK506 nonproducing strain, and the production was restored when a synthetic analog of the allylmalonyl-CoA extender unit was added to the cultivation medium. Based on our results, we propose a biosynthetic pathway for the provision of an unusual five-carbon extender unit, which is carried out by a novel diketide synthase complex. PMID:20194504

Differences in the distribution and characteristics of tachykinin NK1 binding sites between human and guinea pig lung.

PubMed Central

Walsh, D A; Salmon, M; Featherstone, R; Wharton, J; Church, M K; Polak, J M

1994-01-01

1. The distribution and characteristics of tachykinin NK1 binding sites have been compared in human and guinea pig lung using quantitative in vitro receptor autoradiography with [125I]-Bolton Hunter-labelled substance P ([125I]-BH-SP). In addition, the effects on these sites of ovalbumin sensitization and challenge have been determined in guinea pig lung. 2. [125I]-BH-SP bound specifically and with high affinity to microvascular endothelium in both human and guinea pig lung, but to bronchial smooth muscle and pulmonary artery media in only guinea pig lung. 3. Specific binding of [125I]-BH-SP to guinea pig bronchial smooth muscle was positively correlated with airway diameter in the range 150-800 microns and was less dense in trachea than in main bronchi. 4. [125I]-BH-SP binding was inhibited by tachykinins with rank orders of affinity of SP > NKA > NKB (human microvessels) and SP > NKA = NKB (guinea pig bronchi and pulmonary arteries). NKA displayed a higher affinity for [125I]-BH-SP binding sites in human microvessels than in guinea pig tissues (P < 0.0001), indicating differences in selectivity for tachykinins between human and guinea pig NK1 receptors. 5. In both human and guinea pig lung, [125I]-BH-SP binding was inhibited by the specific tachykinin receptor antagonists FK888 (NK1 selective antagonist) and FK224 (mixed NK1/NK2 antagonist), with FK888 displaying equal affinity to SP and > 500 times higher affinity than FK224. SP, NKA, NKB and FK888 exhibited similar affinities for [125I]-BH-SP binding sites in both guinea pig arteries and bronchi.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 2 PMID:7534186

Coupling of conformational transitions in the N-terminal domain of the 51-kDa FK506-binding protein (FKBP51) near its site of interaction with the steroid receptor proteins

DOE PAGES

LeMaster, David M.; Mustafi, Sourajit M.; Brecher, Matthew; ...

2015-05-07

Interchanging Leu-119 for Pro-119 at the tip of the β 4-β 5 loop in the first FK506 binding domain (FK1) of the FKBP51 and FKBP52 proteins, respectively, has been reported to largely reverse the inhibitory (FKBP51) or stimulatory (FKBP52) effects of these co-chaperones on the transcriptional activity of glucocorticoid and androgen receptor-protein complexes. Previous NMR relaxation studies have identified exchange line broadening, indicative of submillisecond conformational motion, throughout the β 4-β 5 loop in the FK1 domain of FKBP51, which are suppressed by the FKBP52-like L119P substitution. This substitution also attenuates exchange line broadening in the underlying β 2 andmore » β 3a strands that is centered near a bifurcated main chain hydrogen bond interaction between these two strands. The present study demonstrates that these exchange line broadening effects arise from two distinct coupled conformational transitions, and the transition within the β 2 and β 3a strands samples a transient conformation that resembles the crystal structures of the selectively inhibited FK1 domain of FKBP51 recently reported. Although the crystal structures for their series of inhibitors were interpreted as evidence for an induced fit mechanism of association, the presence of a similar conformation being significantly populated in the unliganded FKBP51 domain is more consistent with a conformational selection binding process. As a result, the contrastingly reduced conformational plasticity of the corresponding FK1 domain of FKBP52 is consistent with the current model in which FKBP51 binds to both the apo- and hormone-bound forms of the steroid receptor to modulate its affinity for ligand, whereas FKBP52 binds selectively to the latter state.« less

Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery.

PubMed

Knock, Greg A; Shaifta, Yasin; Snetkov, Vladimir A; Vowles, Benjamin; Drndarski, Svetlana; Ward, Jeremy P T; Aaronson, Philip I

2008-02-01

We investigated the role of src family kinases (srcFK) in agonist-mediated Ca2+-sensitization in pulmonary artery and whether this involves interaction with the rho/rho-kinase pathway. Intra-pulmonary arteries (IPAs) and cultured pulmonary artery smooth muscle cells (PASMC) were obtained from rat. Expression of srcFK was determined at the mRNA and protein levels. Ca2+-sensitization was induced by prostaglandin F(2 alpha) (PGF(2 alpha)) in alpha-toxin-permeabilized IPAs. Phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light-chain-20 (MLC20) and translocation of rho-kinase in response to PGF(2 alpha) were also determined. Nine srcFK were expressed at the mRNA level, including src, fyn, and yes, and PGF(2 alpha) enhanced phosphorylation of three srcFK proteins at tyr-416. In alpha-toxin-permeabilized IPAs, PGF(2 alpha) enhanced the Ca2+-induced contraction (pCa 6.9) approximately three-fold. This enhancement was inhibited by the srcFK blockers SU6656 and PP2 and by the rho-kinase inhibitor Y27632. Y27632, but not SU6656 or PP2, also inhibited the underlying pCa 6.9 contraction. PGF(2 alpha) enhanced phosphorylation of MYPT-1 at thr-697 and thr-855 and of MLC20 at ser-19. This enhancement, but not the underlying basal phosphorylation, was inhibited by SU6656. Y27632 suppressed both basal and PGF(2 alpha)-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF(2 alpha) triggered translocation of rho-kinase in PASMC, and this was inhibited by SU6656. srcFK are activated by PGF(2 alpha) in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via rho-kinase translocation and phosphorylation of MYPT-1.

Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery

PubMed Central

Knock, Greg A.; Shaifta, Yasin; Snetkov, Vladimir A.; Vowles, Benjamin; Drndarski, Svetlana; Ward, Jeremy P.T.; Aaronson, Philip I.

2008-01-01

Abstract Aims We investigated the role of src family kinases (srcFK) in agonist-mediated Ca2+-sensitization in pulmonary artery and whether this involves interaction with the rho/rho-kinase pathway. Methods and results Intra-pulmonary arteries (IPAs) and cultured pulmonary artery smooth muscle cells (PASMC) were obtained from rat. Expression of srcFK was determined at the mRNA and protein levels. Ca2+-sensitization was induced by prostaglandin F2α (PGF2α) in α-toxin-permeabilized IPAs. Phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light-chain-20 (MLC20) and translocation of rho-kinase in response to PGF2α were also determined. Nine srcFK were expressed at the mRNA level, including src, fyn, and yes, and PGF2α enhanced phosphorylation of three srcFK proteins at tyr-416. In α-toxin-permeabilized IPAs, PGF2α enhanced the Ca2+-induced contraction (pCa 6.9) approximately three-fold. This enhancement was inhibited by the srcFK blockers SU6656 and PP2 and by the rho-kinase inhibitor Y27632. Y27632, but not SU6656 or PP2, also inhibited the underlying pCa 6.9 contraction. PGF2α enhanced phosphorylation of MYPT-1 at thr-697 and thr-855 and of MLC20 at ser-19. This enhancement, but not the underlying basal phosphorylation, was inhibited by SU6656. Y27632 suppressed both basal and PGF2α-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF2α triggered translocation of rho-kinase in PASMC, and this was inhibited by SU6656. Conclusions srcFK are activated by PGF2α in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via rho-kinase translocation and phosphorylation of MYPT-1. PMID:18032393

FK506 biosynthesis is regulated by two positive regulatory elements in Streptomyces tsukubaensis

PubMed Central

2012-01-01

Background FK506 (Tacrolimus) is an important immunosuppressant, produced by industrial biosynthetic processes using various Streptomyces species. Considering the complex structure of FK506, it is reasonable to expect complex regulatory networks controlling its biosynthesis. Regulatory elements, present in gene clusters can have a profound influence on the final yield of target product and can play an important role in development of industrial bioprocesses. Results Three putative regulatory elements, namely fkbR, belonging to the LysR-type family, fkbN, a large ATP-binding regulator of the LuxR family (LAL-type) and allN, a homologue of AsnC family regulatory proteins, were identified in the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488, a progenitor of industrial strains used for production of FK506. Inactivation of fkbN caused a complete disruption of FK506 biosynthesis, while inactivation of fkbR resulted in about 80% reduction of FK506 yield. No functional role in the regulation of the FK506 gene cluster has been observed for the allN gene. Using RT-PCR and a reporter system based on a chalcone synthase rppA, we demonstrated, that in the wild type as well as in fkbN- and fkbR-inactivated strains, fkbR is transcribed in all stages of cultivation, even before the onset of FK506 production, whereas fkbN expression is initiated approximately with the initiation of FK506 production. Surprisingly, inactivation of fkbN (or fkbR) does not abolish the transcription of the genes in the FK506 gene cluster in general, but may reduce expression of some of the tested biosynthetic genes. Finally, introduction of a second copy of the fkbR or fkbN genes under the control of the strong ermE* promoter into the wild type strain resulted in 30% and 55% of yield improvement, respectively. Conclusions Our results clearly demonstrate the positive regulatory role of fkbR and fkbN genes in FK506 biosynthesis in S. tsukubaensis NRRL 18488. We have shown that regulatory mechanisms can differ substantially from other, even apparently closely similar FK506-producing strains, reported in literature. Finally, we have demonstrated the potential of these genetically modified strains of S. tsukubaensis for improving the yield of fermentative processes for production of FK506. PMID:23083511

Structural Modeling and Response of Command, Control and Communication Shelter Systems for Event DICE THROW.

DTIC Science & Technology

1980-03-01

Construction ... ........... ... 71 7 FkAEC"IWAG FitAZbL~ai-am naJ" LIST OF ILLUSTRATIONS (CONT’D) Figure Page 2.26 Grid Point System for AN/TRC-145...systems consists of a basic shelter structure whose side walls are of sandwich construction with internal stiffeners. Channel extrusions along each...free edge of the shelter provide additional strength and stiffening. The shelters contain electronic equipment racks of open framework construction using

Corn Silk Extract and Its Bioactive Peptide Ameliorated Lipopolysaccharide-Induced Inflammation in Mice via the Nuclear Factor-κB Signaling Pathway.

PubMed

Ho, Tin-Yun; Li, Chia-Cheng; Lo, Hsin-Yi; Chen, Feng-Yuan; Hsiang, Chien-Yun

2017-02-01

Bioactive peptides derived from foods have shown beneficial anti-inflammatory potential. Inhibitory κB kinase-β (IKKβ) plays a crucial role in the activation of nuclear factor-κB (NF-κB), a transcription factor involved in inflammation. Here we applied proteomic and bioinformatics approaches to identify anti-inflammatory peptides that target IKKβ from corn silk. Corn silk extract significantly suppressed lipopolysaccharide (LPS)-induced NF-κB activities [(1.7 ± 0.2)-fold vs (3.0 ± 0.6)-fold, p < 0.05] in cells. Trypsin hydrolysate of corn silk also suppressed LPS-induced NF-κB activities [(1.1 ± 0.3)-fold vs 3.3 ± 0.5 fold, p < 0.01]. In addition, both corn silk extract and trypsin hydrolysate significantly inhibited LPS-induced interleukin-1β (IL-1β) production by 58.3 ± 4.5 and 55.1 ± 7.4%, respectively. A novel peptide, FK2, docked into the ATP-binding pocket of IKKβ, was further identified from trypsin hydrolysis of corn silk. FK2 inhibited IKKβ activities, IκB phosphorylation, and subsequent NF-κB activation [(2.3 ± 0.4)-fold vs (5.5 ± 0.4)-fold, p < 0.001]. Moreover, FK2 significantly reduced NF-κB-driven luminescent signals in organs by 5-11-fold and suppressed LPS-induced NF-κB activities and IL-β production in tissues. In conclusion, our findings indicated that corn silk displayed anti-inflammatory abilities. In addition, we first identified an anti-inflammatory peptide FK2 from corn silk. Moreover, the anti-inflammatory effect of FK2 might be through IKKβ-NF-κB signaling pathways.

Improved oral absorption of tacrolimus by a solid dispersion with hypromellose and sodium lauryl sulfate.

PubMed

Jung, Hyuck Jun; Ahn, Hye In; Park, Ji Yeon; Ho, Myoung Jin; Lee, Dae Ro; Cho, Ha Ra; Park, Jun Seo; Choi, Yong Seok; Kang, Myung Joo

2016-02-01

A novel surfactant-incorporated hydroxypropyl methylcellulose (HPMC) solid dispersion (SD) system was constructed in order to facilitate the release rate and oral absorption of tacrolimus (FK506), a poorly water-soluble immunosuppressant. Several emulsifiers including sodium lauryl sulfate (SLS), as drug release promotors, were employed with HPMC to fabricate SD using the solvent wetting method. The solid state characteristics using differential scanning calorimetry and X-ray powder diffraction, revealed that FK506 was molecularly distributed within all dispersions in amorphous form. The dissolution rates of FK506 in SLS-incorporated SDs were much higher than those in SDs prepared with HPMC alone, and even with stearoyl polyoxyl-32 glycerides or tocopheryl polyethylene glycol 1000 succinate. In particular, the greatest dissolution enhancement was obtained from the SD consisting of the drug, HPMC, and SLS in a weight ratio of 1:1:3, providing a 50-fold higher drug concentration within 15 min, compared with HPMC SD. In vivo absorption study in rats demonstrates that the optimized formula remarkably increased the oral absorption of FK506, providing about 4.0-fold greater bioavailability (p<0.05) compared with the marketed product (Prograf®, Astellas Pharma). These data suggest that a novel SLS/HPMC SD may be an advantageous dosage form of FK506, boosting the dissolution and absorption in gastrointestinal tract. Copyright © 2015 Elsevier B.V. All rights reserved.

[Effects of ciclosporin and tacrolimus on replication of hepatitis B virus in vitro: a comparative study].

PubMed

Xia, Wei-liang; Xie, Hai-yang; Shen, Yan; Wu, Li-ming; Zhang, Feng; Zheng, Shu-sen

2006-01-10

To investigate the effects of ciclosporin (CsA) and tacrolimus (FK506) on replication of hepatitis B virus (HBV) in vitro. HBV genome permanently transfected human liver cancer cells of the line HepG2.2.15 were cultured. CsA and FK506 at different concentrations were added into the culture fluid so as to identify the nontoxic concentrations by MTT method. Then the HepG2.2.15 cells were treated by CsA and FK506 at different nontoxic concentrations respectively for 4 days. ELISA was used to detect the HB surface antigen (HBsAg) and HB e antigen (HBeAg) in the supernatant. The relative replication level of HBV DNA was detected by slot blot analysis. MTT method confirmed that the nontoxic concentrations of CsA and FK506 were 0-40.0 microg/ml and 0-400 ng/ml respectively. After the treatment of CsA at the concentration of 1.3, 2.5, and 5.0 microg/ml, in comparison to the control group, the suppression rates of HBsAg expression in the HepG2.2.15 cells were 16.5% +/- 9.4%, 21.5% +/- 8.9%, and 33.1% +/- 5.3% respectively (all P < 0.05); the suppression rates of HBeAg expression in the HepG2.2.15 cells were 7.8% +/- 2.2%, 11.0% +/- 2.3%, and 20.8% +/- 1.5% respectively (all P < 0.05); and the HBV DNA replication levels were 56 +/- 16, 42 +/- 11, and 40 +/- 10 respectively (P > 0.05, P < 0.05, and P > 0.05). However, FK506 at different nontoxic concentrations showed no significant inhibitory effect on the levels of HBsAg, HBeAg, and HBV DNA. CsA dose-dependently inhibits the HBV replication in vitro, and FK506 does not exercise similar effects.

Tachykinin antagonist FK224 inhibits neurokinin A-, substance P- and capsaicin-induced human bronchial contraction.

PubMed

Honda, I; Kohrogi, H; Yamaguchi, T; Hamamoto, J; Hirata, N; Iwagoe, H; Fujii, K; Goto, E; Ando, M

1997-01-01

To determine the roles of endogenously released tachykinins (substance P [SP] and neurokinin A [NKA]) in the human bronchial tissues, we studied the effects of tachykinin antagonist FK224 on bronchial smooth muscle contraction induced by SP, NKA and capsaicin in an organ bath. FK224 (10(-6) M and 10(-5) M, respectively) significantly inhibited NKA-induced contraction and 10(-5) M FK224 shifted the dose-response curve to more than one log unit higher concentration. Because SP- and capsaicin-induced contractions were small, we pretreated the tissues with the neutral endopeptidase inhibitor phosphoramidon (10(-5) M), which inhibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10(-5) M) significantly inhibited SP-induced contraction and it shifted the dose-response curves to about one log unit higher concentration. FK224 (10(-5) M) also significantly inhibited capsaicin-induced contraction and it shifted the dose-response curves to more than one log unit higher concentration. In contrast, FK224 (10(-5) M) did not affect on acetylcholine-, histamine-, and leukotriene D4-induced contraction. These results suggest that FK224 is a tachykinin receptor antagonist in the human bronchial smooth muscle, and that capsaicin-induced contraction is due to endogenously released tachykinin-like substances in the human bronchus.

Readability of Spine-Related Patient Education Materials From Leading Orthopedic Academic Centers.

PubMed

Ryu, Justine H; Yi, Paul H

2016-05-01

Cross-sectional analysis of online spine-related patient education materials from leading academic centers. To assess the readability levels of spine surgery-related patient education materials available on the websites of academic orthopedic surgery departments. The Internet is becoming an increasingly popular resource for patient education. Yet many previous studies have found that Internet-based orthopedic-related patient education materials from subspecialty societies are written at a level too difficult for the average American; however, no prior study has assessed the readability of spine surgery-related patient educational materials from leading academic centers. All spine surgery-related articles from the online patient education libraries of the top five US News & World Report-ranked orthopedic institutions were assessed for readability using the Flesch-Kincaid (FK) readability test. Mean readability levels of articles amongst the five academic institutions and articles were compared. We also determined the number of articles with readability levels at or below the recommended sixth- or eight-grade levels. Intraobserver and interobserver reliability of readability assessment were assessed. A total of 122 articles were reviewed. The mean overall FK grade level was 11.4; the difference in mean FK grade level between each department varied significantly (range, 9.3-13.4; P < 0.0001). Twenty-three articles (18.9%) had a readability level at or below the eighth grade level, and only one (0.8%) was at or below the sixth grade level. Intraobserver and interobserver reliability were both excellent (intraclass correlation coefficient of 1 for both). Online patient education materials related to spine from academic orthopedic centers are written at a level too high for the average patient, consistent with spine surgery-related patient education materials provided by the American Academy of Orthopaedic Surgeons and spine subspecialty societies. This study highlights the potential difficulties patients might have in reading and comprehending the information in publicly available education materials related to spine. N/A.

Engraftment versus immunosuppression: cost-benefit analysis of immunosuppression after intrahepatic murine islet transplantation.

PubMed

Marzorati, Simona; Melzi, Raffaella; Citro, Antonio; Cantarelli, Elisa; Mercalli, Alessia; Scavini, Marina; Piemonti, Lorenzo

2014-05-27

Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects. To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx. RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection. IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.

Minimizers with Bounded Action for the High-Dimensional Frenkel-Kontorova Model

NASA Astrophysics Data System (ADS)

Miao, Xue-Qing; Wang, Ya-Nan; Qin, Wen-Xin

In Aubry-Mather theory for monotone twist maps or for one-dimensional Frenkel-Kontorova (FK) model with nearest neighbor interactions, each global minimizer (minimal energy configuration) is naturally Birkhoff. However, this is not true for the one-dimensional FK model with non-nearest neighbor interactions or for the high-dimensional FK model. In this paper, we study the Birkhoff property of minimizers with bounded action for the high-dimensional FK model.

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

PubMed Central

Hultsch, T; Albers, M W; Schreiber, S L; Hohman, R J

1991-01-01

Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism. Images PMID:1712484

FK-3000 isolated from Stephania delavayi Diels. inhibits MDA-MB-231 cell proliferation by decreasing NF-κB phosphorylation and COX-2 expression.

PubMed

Xu, Hong De; Cho, Soon-Chang; Bang, Mi-Ae; Bae, Chun-Sik; Choi, Yeonshik; Li, Yong-Chun; Lim, Seung-Kil; Shim, Jaegal; Park, Dae-Hun

2015-01-01

The World Health Organization (WHO) has reported that cancer is one of the most prevalent diseases and a leading cause of death worldwide. Many anticancer drug development studies have been pursued over the last few decades and several viable drugs have been discovered, such as paclitaxel, topotecan and irinotecan. Previously, our research group uncovered the cytocidal and cytostatic effects of the plant Stephania delavayi Diels. In this study, we determined the active chemical to be 6,7-di-O-acetylsinococuline (FK-3000). The FK-3000 half maximal inhibitory concentration (IC50) in MDA-MB-231 breast carcinoma cells at 48 h was 0.52 µg/ml and it induced apoptosis in a dose- and time-dependent manner. FK-3000 suppressed NF-κB nuclear translocation, decreased NF-κB phosphorylation, and decreased COX-2 protein expression. MDA-MB-231 xenografted mice were treated with FK-3000, Taxol, or their combination for 21 days. The tumor size was smallest in the co-treatment group, indicating that FK-3000 may have a synergistic effect with Taxol. FK-3000 treatment showed no adverse effects on blood cell counts, serum protein levels, or pathology. These studies demonstrate that FK-3000, isolated from S. delavayi Diels., is a promising, pathway-specific anticancer agent that exhibits low toxicity.

Frequency-Wavenumber (F-K) Processing for Infrasound Distributed Arrays

DTIC Science & Technology

2012-10-01

UNCLASSIFIED Approved for public release; distribution is unlimited (U) Frequency-Wavenumber (F-K) Processing for Infrasound Distributed...have conventionally been used to detect infrasound . Pipe arrays, used in conjunction with microbarometers, provide noise reduction by averaging wind...signals. This is especially true for infrasound and low-frequency acoustic sources of tactical interest in the 1 to 100 Hz range. The work described

Immunosuppressive macrolides of the type FK 506: a novel class of topical agents for treatment of skin diseases?

PubMed

Meingassner, J G; Stütz, A

1992-06-01

The immunosuppressive macrolide antibiotics FK 506 and rapamycin were tested for topical activity in experimental allergic contact dermatitis of farm pigs. This species was used because pig skin, in comparison to rodent skin, resembles human skin more closely. For comparison, cyclosporine A (CyA), which is orally but not topically active in patients with skin disease, dexamethasone, and clobetasol propionate were used. Treatment was performed twice, 30 min and 6 h after elicitation of challenge reaction. Topical application of 0.4 to 0.04% FK 506 caused a pronounced inhibition of inflammatory skin reactions of hypersensitivity to dinitrofluorobenzene. The treatment response was similar to the activity of 0.13% clobetasole. Dexamethasone (1.2%) was less active than clobetasol. In contrast, rapamycin and CyA were inactive at concentrations of 1.2 and 10%, respectively. Because the pig data on corticosteroids and cyclosporine A are in agreement with clinical findings, these studies indicate that immunosuppressive macrolides of the type FK 506 may be useful drugs for the topical treatment of human skin diseases that respond to local corticosteroids and oral treatment with cyclosporine A.

Routine parallel diagnosis of malaria using microscopy and the malaria rapid diagnostic test SD 05FK60: the experience of Médecins Sans Frontières in Myanmar.

PubMed

Kosack, Cara S; Naing, Wint Thu; Piriou, Erwan; Shanks, Leslie

2013-05-21

Malaria rapid diagnostic tests (RDTs) are commonly used in Médecins Sans Frontières (MSF) programmes to detect acute malaria infection. Programmes in regions with both Plasmodium falciparum and non-falciparum malaria (i.e. Plasmodium ovale, Plasmodium malariae and Plasmodium vivax) use a three-band P. falciparum/Pan test such as the SD Bioline Malaria Ag P.f/Pan 05FK60 (Standard Diagnostics, Kyonggi, Republic of Korea), hereafter referred to as SD 05FK60, as used by the MSF-Holland clinics in Rakhine state, Myanmar. In spite of published reports of generally good test performance, medical and paramedical staff on the ground often doubt the diagnostic accuracy of these RDTs. Parallel testing with malaria microscopy and RDT was conducted at two clinics in Rakhine state, Myanmar, for a period of 14 months as a programmatic response due to doubts and concerns of medical and paramedical staff into malaria RDTs. A total of 2,585 blood samples from non-pregnant suspected malaria patients were examined by the SD 05FK60 RDT and microscopy at two clinics in Myanmar from October 2010 to December 2011. The reference standard microscopy diagnosed 531 P. falciparum and 587 P. vivax or P. malariae mono-infections. The overall sensitivity for P. falciparum detection by the SD 05FK60 was 90.2% (95% CI: 87.4-92.6) and for P. vivax/P. malariae 79.4% (95% CI: 75.9-82.6). The overall specificity for P. falciparum detection by the SD 05FK60 was 98.5% (95% CI: 97.7-99.1) and for P. vivax/P. malariae 98.7% (95% CI: 97.9-99.2). The sensitivity for P. falciparum was >91% for parasitaemia levels of >100-1,000 parasites/μl and increased for P. vivax/P. malariae with the parasitaemia level but was overall lower than for P. falciparum 25/408 and 13/420 cases, respectively, of P. falciparum and non-falciparum malaria were missed by the RDT. In field conditions in Myanmar, the SD 05FK60 malaria RDT performed consistent with other reports. The test detected malaria caused by P. vivax/P. malariae to a lesser extent than P. falciparum infection. Sensitivity improved with increasing parasitaemia level, however even at higher levels some infections were missed. The SD 05FK60 is adequate for use in settings where high quality microscopy is not available.

TSOS and TSOS-FK hybrid methods for modelling the propagation of seismic waves

NASA Astrophysics Data System (ADS)

Ma, Jian; Yang, Dinghui; Tong, Ping; Ma, Xiao

2018-05-01

We develop a new time-space optimized symplectic (TSOS) method for numerically solving elastic wave equations in heterogeneous isotropic media. We use the phase-preserving symplectic partitioned Runge-Kutta method to evaluate the time derivatives and optimized explicit finite-difference (FD) schemes to discretize the space derivatives. We introduce the averaged medium scheme into the TSOS method to further increase its capability of dealing with heterogeneous media and match the boundary-modified scheme for implementing free-surface boundary conditions and the auxiliary differential equation complex frequency-shifted perfectly matched layer (ADE CFS-PML) non-reflecting boundaries with the TSOS method. A comparison of the TSOS method with analytical solutions and standard FD schemes indicates that the waveform generated by the TSOS method is more similar to the analytic solution and has a smaller error than other FD methods, which illustrates the efficiency and accuracy of the TSOS method. Subsequently, we focus on the calculation of synthetic seismograms for teleseismic P- or S-waves entering and propagating in the local heterogeneous region of interest. To improve the computational efficiency, we successfully combine the TSOS method with the frequency-wavenumber (FK) method and apply the ADE CFS-PML to absorb the scattered waves caused by the regional heterogeneity. The TSOS-FK hybrid method is benchmarked against semi-analytical solutions provided by the FK method for a 1-D layered model. Several numerical experiments, including a vertical cross-section of the Chinese capital area crustal model, illustrate that the TSOS-FK hybrid method works well for modelling waves propagating in complex heterogeneous media and remains stable for long-time computation. These numerical examples also show that the TSOS-FK method can tackle the converted and scattered waves of the teleseismic plane waves caused by local heterogeneity. Thus, the TSOS and TSOS-FK methods proposed in this study present an essential tool for the joint inversion of local, regional, and teleseismic waveform data.

A systematic review of propulsion from the flutter kick - What can we learn from the dolphin kick?

PubMed

Andersen, Jordan T; Sanders, Ross H

2018-09-01

Propulsion, one of the most important factors in front crawl swimming performance, is generated from both the upper and lower limbs, yet little is known about the mechanisms of propulsion from the alternating movements of the lower limbs in the flutter kick (FK). The purpose of this systematic review was to review the literature relating to the mechanisms of propulsion from FK in front crawl. There was limited information about the mechanisms of propulsion in FK. Since movements of the lower limbs are similar between FK and the dolphin kick (DK), mechanisms of propulsion from DK were reviewed to better understand propulsion from FK. Recent evidence suggests that propulsion in DK is generated in conjunction with formation and shedding of vortices. Similar vortex structures have been observed in FK. Visualisation and simulation techniques, such as particle image velocimetry (PIV) and computational fluid dynamics (CFD), are non-invasive tools that can effectively model water flow without impacting swimming technique. These technologies allow researchers to estimate the acceleration of water and, consequently, the propulsive reaction forces acting on the swimmer. Future research should use these technologies to investigate propulsion from FK.

The NAMPT inhibitor FK866 reverts the damage in spinal cord injury

PubMed Central

2012-01-01

Background Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting. Methods We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI. Results Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity. We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866. Conclusions Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors. PMID:22490786

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-01-01

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

FK506 protects against articular cartilage collagenous extra-cellular matrix degradation.

PubMed

Siebelt, M; van der Windt, A E; Groen, H C; Sandker, M; Waarsing, J H; Müller, C; de Jong, M; Jahr, H; Weinans, H

2014-04-01

Osteoarthritis (OA) is a non-rheumatologic joint disease characterized by progressive degeneration of the cartilage extra-cellular matrix (ECM), enhanced subchondral bone remodeling, activation of synovial macrophages and osteophyte growth. Inhibition of calcineurin (Cn) activity through tacrolimus (FK506) in in vitro monolayer chondrocytes exerts positive effects on ECM marker expression. This study therefore investigated the effects of FK506 on anabolic and catabolic markers of osteoarthritic chondrocytes in 2D and 3D in vitro cultures, and its therapeutic effects in an in vivo rat model of OA. Effects of high and low doses of FK506 on anabolic (QPCR/histochemistry) and catabolic (QPCR) markers were evaluated in vitro on isolated (2D) and ECM-embedded chondrocytes (explants, 3D pellets). Severe cartilage damage was induced unilaterally in rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with FK506 orally and compared to twenty untreated controls. Subchondral cortical and trabecular bone changes (longitudinal microCT) and macrophage activation (SPECT/CT) were measured. Articular cartilage was analyzed ex vivo using contrast enhanced microCT and histology. FK506 treatment of osteoarthritic chondrocytes in vitro induced anabolic (mainly collagens) and reduced catabolic ECM marker expression. In line with this, FK506 treatment clearly protected ECM integrity in vivo by markedly decreasing subchondral sclerosis, less development of subchondral pores, depletion of synovial macrophage activation and lower osteophyte growth. FK506 protected cartilage matrix integrity in vitro and in vivo. Additionally, FK506 treatment in vivo reduced OA-like responses in different articular joint tissues and thereby makes Cn an interesting target for therapeutic intervention of OA. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Characterization of a gene cluster responsible for the biosynthesis of anticancer agent FK228 in Chromobacterium violaceum No. 968.

PubMed

Cheng, Yi-Qiang; Yang, Min; Matter, Andrea M

2007-06-01

A gene cluster responsible for the biosynthesis of anticancer agent FK228 has been identified, cloned, and partially characterized in Chromobacterium violaceum no. 968. First, a genome-scanning approach was applied to identify three distinctive C. violaceum no. 968 genomic DNA clones that code for portions of nonribosomal peptide synthetase and polyketide synthase. Next, a gene replacement system developed originally for Pseudomonas aeruginosa was adapted to inactivate the genomic DNA-associated candidate natural product biosynthetic genes in vivo with high efficiency. Inactivation of a nonribosomal peptide synthetase-encoding gene completely abolished FK228 production in mutant strains. Subsequently, the entire FK228 biosynthetic gene cluster was cloned and sequenced. This gene cluster is predicted to encompass a 36.4-kb DNA region that includes 14 genes. The products of nine biosynthetic genes are proposed to constitute an unusual hybrid nonribosomal peptide synthetase-polyketide synthase-nonribosomal peptide synthetase assembly line including accessory activities for the biosynthesis of FK228. In particular, a putative flavin adenine dinucleotide-dependent pyridine nucleotide-disulfide oxidoreductase is proposed to catalyze disulfide bond formation between two sulfhydryl groups of cysteine residues as the final step in FK228 biosynthesis. Acquisition of the FK228 biosynthetic gene cluster and acclimation of an efficient genetic system should enable genetic engineering of the FK228 biosynthetic pathway in C. violaceum no. 968 for the generation of structural analogs as anticancer drug candidates.

Modulation of interleukin-1 secretion by immunosuppressive drugs, alone and in combination.

PubMed

Reisman, L; Lin, W G; Martinelli, G P

1995-03-01

This study evaluates the ability of the immunosuppressive drugs dexamethasone, cyclosporine, FK506 and rapamycin, alone and in combination to suppress interleukin-1 beta (IL-1 beta) secretion in vitro by THP-1 cells when stimulated by lipopolysaccharide. All four drugs, when added to cell culture medium at therapeutic concentrations, significantly decrease secretion of the monokine to well below control levels. However, only dexamethasone completely suppresses IL-1 beta secretion in a dose-dependent fashion. Cyclosporine, FK506 and rapamycin only partially suppress secretion of IL-1 beta at concentrations within their therapeutic ranges and increasing concentrations of the drugs do not result in further suppression of secretion. Likewise, the combination of any two of these three drugs does not provide any additional suppressive effect. Dexamethasone, however, when added in increasing concentrations in combination with any of the other drugs, results in further suppression of IL-1 secretion in a dose-dependent fashion. These data suggest that cyclosporine, FK506 and rapamycin all share a common effect on the production of IL-1 beta, different from that of dexamethasone.

Effectiveness of minocycline and FK506 alone and in combination on enhanced behavioral and biochemical recovery from spinal cord injury in rats.

PubMed

Ahmad, Mohammad; Zakaria, Abdulrahim; Almutairi, Khalid M

2016-06-01

Injury to the spinal cord results in immediate physical damage (primary injury) followed by a prolonged posttraumatic inflammatory disorder (secondary injury). The present study aimed to investigate the neuroprotective effects of minocycline and FK506 (Tacrolimus) individually and in combination on recovery from experimental spinal cord injury (SCI). Young adult male rats were subjected to experimental SCI by weight compression method. Minocycline (50mg/kg) and FK506 (1mg/kg) were administered orally in combination and individually to the SCI group daily for three weeks. During these three weeks, the recovery was measured using behavioral motor parameters (including BBB, Tarlov and other scorings) every other day for 29days after SCI. Thereafter, the animals were sacrificed and the segment of the spinal cord centered at the injury site was removed for the histopathological studies as well as for biochemical analysis of monoamines such as 5-hydroxytryptamine (5-HT) and 5-hydroxy-indolacetic acid (5-HIAA) and some oxidative stress indices, such as thiobarbituric acid-reactive substances (TBARS), total glutathione (GSH) and myeloperoxidase (MPO). All behavioral results indicated that both drugs induced significant recovery from SCI with respect to time. The biochemical and histopathological results supported the behavioral findings, revealing significant recovery in the regeneration of the injured spinal tissues, the monoamine levels, and the oxidative stress indices. Overall, the effects of the tested drugs for SCI recovery were as follows: FK506+minocycline>minocycline>FK506 in all studied parameters. Thus, minocycline and FK506 may prove to be a potential therapy cocktail to treat acute SCI. However, further studies are warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Reconstruction of living bilayer human skin equivalent utilizing human fibrin as a scaffold.

PubMed

Mazlyzam, A L; Aminuddin, B S; Fuzina, N H; Norhayati, M M; Fauziah, O; Isa, M R; Saim, L; Ruszymah, B H I

2007-05-01

Our aim of this study was to develop a new methodology for constructing a bilayer human skin equivalent to create a more clinical compliance skin graft composite for the treatment of various skin defects. We utilized human plasma derived fibrin as the scaffold for the development of a living bilayer human skin equivalent: fibrin-fibroblast and fibrin-keratinocyte (B-FF/FK SE). Skin cells from six consented patients were culture-expanded to passage 1. For B-FF/FK SE formation, human fibroblasts were embedded in human fibrin matrix and subsequently another layer of human keratinocytes in human fibrin matrix was stacked on top. The B-FF/FK SE was then transplanted to athymic mice model for 4 weeks to evaluate its regeneration and clinical performance. The in vivo B-FF/FK SE has similar properties as native human skin by histological analysis and expression of basal Keratin 14 gene in the epidermal layer and Collagen type I gene in the dermal layer. Electron microscopy analysis of in vivo B-FF/FK SE showed well-formed and continuous epidermal-dermal junction. We have successfully developed a technique to engineer living bilayer human skin equivalent using human fibrin matrix. The utilization of culture-expanded human skin cells and fibrin matrix from human blood will allow a fully autologous human skin equivalent construction.

Diet-induced dermatitis response of hairless rats to systemic treatment with cyclosporin A (Sandimmun), cyclosporin H and FK506.

PubMed

Bavandi, A; Meingassner, J G; Becker, S

1992-11-01

Weaned hairless rats were fed a diet deficient in fat, magnesium and folacin. After approximately 1 week, an erythematous dermatitis developed which was associated with extreme generalized pruritus. Scratching led to excoriations and hemorrhagic crusting. The acute stage (pruritic rash) resolved after several days and was followed by sporadic non-itching relapses. Subsequent to the onset of symptoms, rats were treated orally, once daily for 3 days with CyA, CyH or FK506. The immunosuppressants CyA and FK506 caused a dose-dependent inhibition of symptoms in contrast to CyH. The immediate clinical response was associated with changes in blood histamine, white blood cell counts and histological parameters. Since CyH is known to lack immunosuppressive activity, these results may indicate that the cutaneous changes induced by the nutritional deficiency are associated with immunological abnormalities. The results may also indicate mechanisms influenced by CyA and FK506 but not by CyH; for example, release of chemical mediators from inflammatory cells.

Multiple Restrictions of Human Immunodeficiency Virus Type 1 in Feline Cells▿

PubMed Central

Münk, Carsten; Zielonka, Jörg; Constabel, Hannelore; Kloke, Björn-Philipp; Rengstl, Benjamin; Battenberg, Marion; Bonci, Francesca; Pistello, Mauro; Löchelt, Martin; Cichutek, Klaus

2007-01-01

The productive replication of human immunodeficiency virus type 1 (HIV-1) occurs exclusively in defined cells of human or chimpanzee origin, explaining why heterologous animal models for HIV replication, pathogenesis, vaccination, and therapy are not available. This lack of an animal model for HIV-1 studies prompted us to examine the susceptibility of feline cells in order to evaluate the cat (Felis catus) as an animal model for studying HIV-1. Here, we report that feline cell lines harbor multiple restrictions with respect to HIV-1 replication. The feline CD4 receptor does not permit virus infection. Feline T-cell lines MYA-1 and FeT-1C showed postentry restrictions resulting in low HIV-1 luciferase reporter activity and low expression of viral Gag-Pol proteins when pseudotyped vectors were used. Feline fibroblastic CrFK and KE-R cells, expressing human CD4 and CCR5, were very permissive for viral entry and HIV-long terminal repeat-driven expression but failed to support spreading infection. KE-R cells displayed a profound block with respect to release of HIV-1 particles. In contrast, CrFK cells allowed very efficient particle production; however, the CrFK cell-derived HIV-1 particles had low specific infectivity. We subsequently identified feline apolipoprotein B-editing catalytic polypeptide 3 (feAPOBEC3) proteins as active inhibitors of HIV-1 particle infectivity. CrFK cells express at least three different APOBEC3s: APOBEC3C, APOBEC3H, and APOBEC3CH. While the feAPOBEC3C did not significantly inhibit HIV-1, the feAPOBEC3H and feAPOBEC3CH induced G to A hypermutations of the viral cDNA and reduced the infectivity ∼10- to ∼40-fold. PMID:17459941

Activation of calcineurin in human failing heart ventricle by endothelin-1, angiotensin II and urotensin II

PubMed Central

Li, Joan; Wang, Jianchun; Russell, Fraser D; Molenaar, Peter

2005-01-01

The calcineurin (CaN) enzyme–transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 μM, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. ET-1 increased contractile force in all 13 patients (P<0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P>0.1). FK506 had no effect on contractile force (P=0.12). ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKCɛ compared to samples incubated without PKCɛ. Endogenous cardiostimulants which activate Gαq-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate. PMID:15821752

Conformational Entropy of FK506 Binding to FKBP12 Determined by Nuclear Magnetic Resonance Relaxation and Molecular Dynamics Simulations.

PubMed

Solomentsev, Gleb; Diehl, Carl; Akke, Mikael

2018-03-06

FKBP12 (FK506 binding protein 12 kDa) is an important drug target. Nuclear magnetic resonance (NMR) order parameters, describing amplitudes of motion on the pico- to nanosecond time scale, can provide estimates of changes in conformational entropy upon ligand binding. Here we report backbone and methyl-axis order parameters of the apo and FK506-bound forms of FKBP12, based on 15 N and 2 H NMR relaxation. Binding of FK506 to FKBP12 results in localized changes in order parameters, notably for the backbone of residues E54 and I56 and the side chains of I56, I90, and I91, all positioned in the binding site. The order parameters increase slightly upon FK506 binding, indicating an unfavorable entropic contribution to binding of TΔ S = -18 ± 2 kJ/mol at 293 K. Molecular dynamics simulations indicate a change in conformational entropy, associated with all dihedral angles, of TΔ S = -26 ± 9 kJ/mol. Both these values are significant compared to the total entropy of binding determined by isothermal titration calorimetry and referenced to a reactant concentration of 1 mM ( TΔ S = -29 ± 1 kJ/mol). Our results reveal subtle differences in the response to ligand binding compared to that of the previously studied rapamycin-FKBP12 complex, despite the high degree of structural homology between the two complexes and their nearly identical ligand-FKBP12 interactions. These results highlight the delicate dependence of protein dynamics on drug interactions, which goes beyond the view provided by static structures, and reinforce the notion that protein conformational entropy can make important contributions to the free energy of ligand binding.

Tolerogenic β2-glycoprotein I DNA vaccine and FK506 as an adjuvant attenuates experimental obstetric antiphospholipid syndrome.

PubMed

Chao, Ya-Hsuan; Chen, Der-Yuan; Lan, Joung-Liang; Tang, Kuo-Tung; Lin, Chi-Chien

2018-01-01

DNA vaccines have recently emerged as a therapeutic agent for treating autoimmune diseases, such as multiple sclerosis. Antiphospholipid antibody syndrome (APS) is an autoimmune disease characterized by β2-glycoprotein I (β2-GPI)-targeting antiphospholipid antibodies (APAs) and vascular thrombosis or obstetrical complications. To examine the therapeutic potential of a β2-GPI DNA vaccine, we administered a vaccine mixed with FK506 as an adjuvant to a mouse model of obstetric APS. First, the pCMV3-β2-GPI DNA vaccine, which encodes the full-length human β2-GPI gene, was constructed. Then, we administered the β2-GPI DNA vaccine in 0.1 ml of saline, mixed with or without 100 μg of FK506, intramuscularly to the mice on days 28, 35 and 42. Blood titers of the anti-β2-GPI antibody, platelet counts, activated partial thromboplastin times (aPTTs), and the percentage of fetal loss were measured. We also stimulated murine splenic T cells ex vivo with β2-GPI and determined the T helper cell proportion and cytokine secretion. The administration of the β2-GPI DNA vaccine mixed with FK506 reduced the blood IgG anti-β2-GPI antibody titers and suppressed APS manifestations in mice. The combination also suppressed interferon-γ and interleukin (IL)-17A secretion but increased the Treg cell proportion and IL-10 secretion in murine splenic T cells following ex vivo stimulation with β2-GPI. Our results demonstrated the therapeutic efficacy of a β2-GPI DNA vaccine and FK506 as an adjuvant in a murine model of obstetric APS. Possible mechanisms include the inhibition of Th1 and Th17 responses and the up-regulation of Treg cells.

Tolerogenic β2-glycoprotein I DNA vaccine and FK506 as an adjuvant attenuates experimental obstetric antiphospholipid syndrome

PubMed Central

Chen, Der-Yuan; Lan, Joung-Liang; Tang, Kuo-Tung; Lin, Chi-Chien

2018-01-01

DNA vaccines have recently emerged as a therapeutic agent for treating autoimmune diseases, such as multiple sclerosis. Antiphospholipid antibody syndrome (APS) is an autoimmune disease characterized by β2-glycoprotein I (β2-GPI)-targeting antiphospholipid antibodies (APAs) and vascular thrombosis or obstetrical complications. To examine the therapeutic potential of a β2-GPI DNA vaccine, we administered a vaccine mixed with FK506 as an adjuvant to a mouse model of obstetric APS. First, the pCMV3-β2-GPI DNA vaccine, which encodes the full-length human β2-GPI gene, was constructed. Then, we administered the β2-GPI DNA vaccine in 0.1 ml of saline, mixed with or without 100 μg of FK506, intramuscularly to the mice on days 28, 35 and 42. Blood titers of the anti-β2-GPI antibody, platelet counts, activated partial thromboplastin times (aPTTs), and the percentage of fetal loss were measured. We also stimulated murine splenic T cells ex vivo with β2-GPI and determined the T helper cell proportion and cytokine secretion. The administration of the β2-GPI DNA vaccine mixed with FK506 reduced the blood IgG anti-β2-GPI antibody titers and suppressed APS manifestations in mice. The combination also suppressed interferon-γ and interleukin (IL)-17A secretion but increased the Treg cell proportion and IL-10 secretion in murine splenic T cells following ex vivo stimulation with β2-GPI. Our results demonstrated the therapeutic efficacy of a β2-GPI DNA vaccine and FK506 as an adjuvant in a murine model of obstetric APS. Possible mechanisms include the inhibition of Th1 and Th17 responses and the up-regulation of Treg cells. PMID:29894515

Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models

PubMed Central

Shen, Xiujin; Jiang, Hong; Ying, Meike; Xie, Zhoutao; Li, Xiayu; Wang, Haibing; Zhao, Jie; Lin, Chuan; Wang, Yucheng; Feng, Shi; Shen, Jia; Weng, Chunhua; Lin, Weiqiang; Wang, Huiping; Zhou, Qin; Bi, Yan; Li, Meng; Wang, Lingyan; Zhu, Tongyu; Huang, Xiaoru; Lan, Hui-Yao; Zhou, Jing; Chen, Jianghua

2016-01-01

Podocyte injury and the appearance of proteinuria are features of minimal-change disease (MCD). Cyclosporin A (CsA) and tacrolimus (FK506) has been reported to reduce proteinuria in patients with nephrotic syndrome, but mechanisms remain unknown. We, therefore, investigated the protective mechanisms of CsA and FK506 on proteinuria in a rat model of MCD induced by puromycin aminonucleoside (PAN) and in vitro cultured mouse podocytes. Our results showed that CsA and FK506 treatment decreased proteinuria via a mechanism associated to a reduction in the foot-process fusion and desmin, and a recovery of synaptopodin and podocin. In PAN-treated mouse podocytes, pre-incubation with CsA and FK506 restored the distribution of the actin cytoskeleton, increased the expression of synaptopodin and podocin, improved podocyte viability, and reduced the migrating activities of podocytes. Treatment with CsA and FK506 also inhibited PAN-induced podocytes apoptosis, which was associated with the induction of Bcl-xL and inhibition of Bax, cleaved caspase 3, and cleaved PARP expression. Further studies revealed that CsA and FK506 inhibited PAN-induced p38 and JNK signaling, thereby protecting podocytes from PAN-induced injury. In conclusion, CsA and FK506 inhibit proteinuria by protecting against PAN-induced podocyte injury, which may be associated with inhibition of the MAPK signaling pathway. PMID:27580845

Inhibition of NAMPT pathway by FK866 activates the function of p53 in HEK293T cells

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

Thakur, Basant Kumar, E-mail: thakur.basant@mh-hannover.de; Department of Molecular Hematopoiesis, Hannover Medical School, Carl Neuberg Str-1, 30625 Hannover; Dittrich, Tino

2012-08-03

Highlights: Black-Right-Pointing-Pointer In 293T cells, p53 is considered to be inactive due to its interaction with the large T-antigen. Black-Right-Pointing-Pointer Acetylation of p53 at lysine 382 is important for its functional activation. Black-Right-Pointing-Pointer First evidence to document the presence of a functional p53 in 293T cells. Black-Right-Pointing-Pointer Inhibition of NAMPT/SIRT pathway by FK866 in 293T cells increases the functional activity of p53. Black-Right-Pointing-Pointer This activation of p53 involves reversible acetylation of p53 at lysine 382. -- Abstract: Inactivation of p53 protein by endogenous and exogenous carcinogens is involved in the pathogenesis of different human malignancies. In cancer associated with SV-40more » DNA tumor virus, p53 is considered to be non-functional mainly due to its interaction with the large T-antigen. Using the 293T cell line (HEK293 cells transformed with large T antigen) as a model, we provide evidence that p53 is one of the critical downstream targets involved in FK866-mediated killing of 293T cells. A reduced rate of apoptosis and an increased number of cells in S-phase was accompanied after knockdown of p53 in these cells. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway. Additionally, knockdown of p53 attenuated the effect of FK866 on cell proliferation, apoptosis, and cell cycle arrest. The data presented here shed light on two important facts: (1) that p53 in 293T cells is active in the presence of FK866, an inhibitor of NAMPT pathway; (2) the apoptosis induced by FK866 in 293T cells is associated with increased acetylation of p53 at Lys382, which is required for the functional activity of p53.« less

Cochlearoids F-K: Phenolic meroterpenoids from the fungus Ganoderma cochlear and their renoprotective activity.

PubMed

Wang, Xin-Long; Zhou, Feng-Jiao; Dou, Man; Yan, Yong-Ming; Wang, Shu-Mei; Di, Lei; Cheng, Yong-Xian

2016-11-15

Ganoderma mushrooms are of great nutritious and medicinal values. This study was designed to characterize compounds from the fruiting bodies of Ganoderma cochlear and investigate their protective effects against kidney disorders. Six novel meroterpenoids cochlearoids F-K (1-6) were isolated by utilizing phytochemical approaches. Their structures were identified on the basis of extensive spectroscopic data and calculation methods. Biological evaluation shows that compounds 1-4 and 6 exhibit potent inhibitory activity on fibronectin overproduction in TGF-β1-induced HKC-8 cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radial integrals 4f and nephelauxetic effect of Nd3+ in crystals.

PubMed

Petrov, D; Angelov, B

2014-01-24

The radial expectation values 4f,k=2, 4, 6, for oxygen- or halogen- coordinated Nd(3+) ions in 25 crystals have been obtained from experimental Slater parameter shifts ΔFk=Fk (free ion) - Fk (crystal) by means of the dielectric screening model. The 4f values found by this new approach are compatible with those computed by relativistic 4f wave functions. The nephelauxetic ratios βk in respect to the free ion Nd IV have been also determined and related to covalency and bonding parameters. Copyright © 2013 Elsevier B.V. All rights reserved.

Liver, kidney, and thoracic organ transplantation under FK 506.

PubMed Central

Todo, S; Fung, J J; Starzl, T E; Tzakis, A; Demetris, A J; Kormos, R; Jain, A; Alessiani, M; Takaya, S; Shapiro, R

1990-01-01

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506 and the immunosuppressive mechanisms resemble those of cyclosporine, our preliminary observations suggest that FK 506 may have a more advantageous therapeutic index. PMID:1697743

Fortuin-Kasteleyn and damage-spreading transitions in random-bond Ising lattices

NASA Astrophysics Data System (ADS)

Lundow, P. H.; Campbell, I. A.

2012-10-01

The Fortuin-Kasteleyn and heat-bath damage-spreading temperatures TFK(p) and TDS(p) are studied on random-bond Ising models of dimensions 2-5 and as functions of the ferromagnetic interaction probability p; the conjecture that TDS(p)˜TFK(p) is tested. It follows from a statement by Nishimori that in any such system, exact coordinates can be given for the intersection point between the Fortuin-Kasteleyn TFK(p) transition line and the Nishimori line [pNL,FK,TNL,FK]. There are no finite-size corrections for this intersection point. In dimension 3, at the intersection concentration [pNL,FK], the damage spreading TDS(p) is found to be equal to TFK(p) to within 0.1%. For the other dimensions, however, TDS(p) is observed to be systematically a few percent lower than TFK(p).

Mode separation in frequency-wavenumber domain through compressed sensing of far-field Lamb waves

NASA Astrophysics Data System (ADS)

Gao, Fei; Zeng, Liang; Lin, Jing; Luo, Zhi

2017-07-01

This method based on Lamb waves shows great potential for long-range damage detection. Mode superposition resulting from multi-modal and dispersive characteristics makes signal interpretation and damage feature extraction difficult. Mode separation in the frequency-wavenumber (f-k) domain using a 1D sparse sensing array is a promising solution. However, due to the lack of prior knowledge about damage location, this method based on 1D linear measurement, for the mode extraction of arbitrary reflections caused by defects that are not in line with the sensor array, is restricted. In this paper, an improved compressed sensing method under the far-field assumption is established, which is beneficial to the reconstruction of reflections in the f-k domain. Hence, multiple components consisting of structure and damage features could be recovered via a limited number of measurements. Subsequently, a mode sweeping process based on theoretical dispersion curves has been designed for mode characterization and direction of arrival estimation. Moreover, 2D f-k filtering and inverse transforms are applied to the reconstructed f-k distribution in order to extract the purified mode of interest. As a result, overlapping waveforms can be separated and the direction of defects can be estimated. A uniform linear sensor array consisting of 16 laser excitations is finally employed for experimental investigations and the results demonstrate the efficiency of the proposed method.

Refinement of the experimental dynamic structure factor for liquid para-hydrogen and ortho-deuterium using semi-classical quantum simulation.

PubMed

Smith, Kyle K G; Poulsen, Jens Aage; Cunsolo, A; Rossky, Peter J

2014-01-21

The dynamic structure factor of liquid para-hydrogen and ortho-deuterium in corresponding thermodynamic states (T = 20.0 K, n = 21.24 nm(-3)) and (T = 23.0 K, n = 24.61 nm(-3)), respectively, has been computed by both the Feynman-Kleinert linearized path-integral (FK-LPI) and Ring-Polymer Molecular Dynamics (RPMD) methods and compared with Inelastic X Ray Scattering spectra. The combined use of computational and experimental methods enabled us to reduce experimental uncertainties in the determination of the true sample spectrum. Furthermore, the refined experimental spectrum of para-hydrogen and ortho-deuterium is consistently reproduced by both FK-LPI and RPMD results at momentum transfers lower than 12.8 nm(-1). At larger momentum transfers the FK-LPI results agree with experiment much better for ortho-deuterium than for para-hydrogen. More specifically we found that for k ∼ 20.0 nm(-1) para-hydrogen provides a test case for improved approximations to quantum dynamics.

Local Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance Induction Protocol

DTIC Science & Technology

2016-10-01

Chimerism Vascularized Composite Allograft Tolerance Induction Protocol PRINCIPAL INVESTIGATORS: Dr. Curtis L. Cetrulo CONTRACTING ORGANIZATION...Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance...tacrolimus, FK506, vascularized composite allografts , immune rejection, preclinical, transplant, nonhuman primate model, degradable polymer, tyrosine

Therapeutic effects of combination using glucosamine plus tacrolimus (FK-506) on the development of atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Kim, C-H; Cheong, K A; Park, C D; Lee, A-Y

2012-05-01

Tacrolimus (FK-506) has been found to exhibit potent inhibitory effects on spontaneously developed dermatitis. We previously showed that glucosamine prevents the development of Atopic dermatitis (AD)-like skin lesions in NC/Nga mice. The aims of our study were to investigate the synergistic therapeutic efficacy of combination of glucosamine plus FK-506 in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 8 were used for treatment with glucosamine (500 mg/kg) alone, FK-506 (1.0 mg/kg) or in combination. The synergistic effects of combination therapy were evaluated by dermatitis scores, skin histology and immunological parameters such as IgE, Th2-mediated cytokines and chemokines, CD3(+) T cells and CLA(+) T cells. Combined therapy using glucosamine plus FK-506 improved the development of AD-like skin lesions as exemplified by a significant decrease in total skin symptom severity scores. The suppression of dermatitis by combined therapy was accompanied by a decrease in the plasma level of IgE and in the splenic level of IL-5, IL-13, TARC and eotaxin. Histological finding indicated that the dermal infiltration of inflammatory cells including mast cells and eosinophils was greatly reduced. Particularly, immunohistological evaluation reveals a reduction in CD3(+) T cells and CLA(+) cells in the combined therapy. Our findings suggest that combination therapy of glucosamine plus FK-506 was more synergistic efficacy than single-modality treatment with either alone to improve the development of established dermatitis in NC/Nga mice model. This combined immunosuppressive therapy may provide an effective therapeutic strategy for the treatment of AD. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

Relationship between negative differential thermal resistance and asymmetry segment size

NASA Astrophysics Data System (ADS)

Kong, Peng; Hu, Tao; Hu, Ke; Jiang, Zhenhua; Tang, Yi

2018-03-01

Negative differential thermal resistance (NDTR) was investigated in a system consisting of two dissimilar anharmonic lattices exemplified by Frenkel-Kontorova (FK) lattices and Fremi-Pasta-Ulam (FPU) lattices (FK-FPU). The previous theoretical and numerical simulations show the dependence of NDTR are the coupling constant, interface and system size, but we find the segment size also to be an important element. It’s interesting that NDTR region depends on FK segment size rather than FPU segment size in this coupling FK-FPU model. Remarkably, we could observe that NDTR appears in the strong interface coupling strength case which is not NDTR in previous studies. The results are conducive to further developments in designing and fabricating thermal devices.

FK506: therapeutic effects on lupus dermatoses in autoimmune-prone MRL/Mp-lpr/lpr mice.

PubMed

Furukawa, F; Imamura, S; Takigawa, M

1995-01-01

The effects of FK506, a new immunosuppressive agent, on the development of lupus dermatoses were investigated in the autoimmune-prone MRL/Mp-lpr/lpr (MRL/lpr) mouse, which is an animal model for the spontaneous development of skin lesions similar to those of human lupus erythematosus (LE). FK506 reduced the incidence of skin lesions, lupus nephritis, the titre of serum anti-double-stranded DNA antibodies and the massive T cell proliferation. The incidence and magnitude of IgG deposition at the dermoepidermal junction were not changed. These results suggest that FK506 is a promising immunosuppressive agent for the control of autoimmune skin diseases.

Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

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

Zawawi, M.S.F.; Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005; Dharmapatni, A.A.S.S.K.

2012-10-19

Highlights: Black-Right-Pointing-Pointer Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. Black-Right-Pointing-Pointer Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. Black-Right-Pointing-Pointer FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway inmore » osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcR{gamma}) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin ({beta}3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p < 0.05) reduced the expression of NFATc1, CathK, OSCAR, FcR{gamma}, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p < 0.05) decreased CathK, OSCAR, FcR{gamma}, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.« less

Diverse structures, functions and uses of FK506 binding proteins.

PubMed

Bonner, Julia Maeve; Boulianne, Gabrielle L

2017-10-01

FK506 (Tacrolimus), isolated from Streptomyces tsukubaenis is a powerful immunosuppressant shown to inhibit T cell activation. FK506 mediated immunosuppression requires the formation of a complex between FK506, a FK506 binding protein (FKBP) and calcineurin. Numerous FKBPs have been identified in a wide range of species, from single celled organisms to humans. FKBPs show peptidylprolyl cis/trans isomerase (PPIase) activity and have been shown to affect a wide range of cellular processes including protein folding, receptor signaling and apoptosis. FKBPs also affect numerous biological functions in addition to immunosuppression including regulation of cardiac function, neuronal function and development and have been implicated in several diseases including cardiac disease, cancer and neurodegenerative diseases such as Alzheimer's disease. More recently, FKBPs have proven useful as molecular tools for studying protein interactions, localization and functions. This review provides an overview of the current state of knowledge of FKBPs and their numerous biological functions and uses. Copyright © 2017 Elsevier Inc. All rights reserved.

Coronal Abundances In Xi Boo A, Abundances in the Corona of FK Aqr and the Origin of Cosmic Ray

NASA Technical Reports Server (NTRS)

Drake, Jeremy; Oliversen, Ronald J. (Technical Monitor)

2002-01-01

Both Xi Boo A and FK Agr observations have been acquired, reduced and analysed. The results of the Xi Boo A study were published in ApJ (Drake, J.J., Kashyap, V., 2001, Up, 547, 428). Work is ongoing to determine the coronet metallicity of FK Aqr based on EUVE spectra and DO photometer data, using the techniques developed in the Drake & Kashyap paper. Preliminary synthetic spectra for FK Aqr have been developed, and further work to heap define the hot plasma emission measure distribution is underway. Progress on spectral analysis has been hampered following the post-doctoral scientist, Vinay Kashyap, taking up new position. A suitable replacement has been difficult to find, but new hire is expected shortly. However, good progress has been made on analysis of DO photometric variations in FK Age, with a publication now ready (Kashyap, V., Drake, J.J., Guedel, M., Audard, M.) for submission to a mainstream astrophysical journal.

Process optimization by use of design of experiments: Application for liposomalization of FK506.

PubMed

Toyota, Hiroyasu; Asai, Tomohiro; Oku, Naoto

2017-05-01

Design of experiments (DoE) can accelerate the optimization of drug formulations, especially complexed formulas such as those of drugs, using delivery systems. Administration of FK506 encapsulated in liposomes (FK506 liposomes) is an effective approach to treat acute stroke in animal studies. To provide FK506 liposomes as a brain protective agent, it is necessary to manufacture these liposomes with good reproducibility. The objective of this study was to confirm the usefulness of DoE for the process-optimization study of FK506 liposomes. The Box-Behnken design was used to evaluate the effect of the process parameters on the properties of FK506 liposomes. The results of multiple regression analysis showed that there was interaction between the hydration temperature and the freeze-thaw cycle on both the particle size and encapsulation efficiency. An increase in the PBS hydration volume resulted in an increase in encapsulation efficiency. Process parameters had no effect on the ζ-potential. The multiple regression equation showed good predictability of the particle size and the encapsulation efficiency. These results indicated that manufacturing conditions must be taken into consideration to prepare liposomes with desirable properties. DoE would thus be promising approach to optimize the conditions for the manufacturing of liposomes. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of tacrolimus and erythropoietin in experimental spinal cord lesion in rats: functional and histological evaluation

PubMed Central

de Mesquita Coutinho, P R; Cristante, A F; de Barros Filho, T E P; Ferreira, R; dos Santos, G B

2016-01-01

Study design: Experimental study with rats. Objective: To evaluate functional and histological effects of tacrolimus (FK 506) and erythropoietin (EPO) after experimental spinal cord contusion injury (SCI). Setting: Brazil. Methods: Wistar rats (n=60) were submitted to SCI with the NYU Impactor system. The control group received saline; the EPO group received EPO; the group EPO+FK 506 received EPO associated with tacrolimus and the group FK 506 received tacrolimus only. The Sham group underwent SCI, but did not receive any drug. Locomotor function was evaluated after SCI by BBB (Basso, Beattie and Bresnahan) weekly and by the motor-evoked potential test in 42 days. The spinal cord was histologically evaluated. Results: There was a significant difference between treated and the control groups from the seventh day on for BBB scores, with no difference between the groups EPO and EPO+FK 506 by the end of the study. There were significant differences between groups for necrosis and bleeding, but not for hiperemia, degeneration and cellular infiltrate. Axon neuron count was different between all groups (P=0.001), between EPO+FK 506 and FK 506 (P=0.011) and between EPO+FK 506 and Sham (P=0.002). Amplitude was significantly different between all groups except between control and sham. For latency, there was no difference. Conclusions: This study did not reveal significant differences in the recovery of locomotor function, or in the histological and electrophysiological analysis in animals treated with EPO and tacrolimus after thoracic SCI. PMID:26481712

Acetone as biomarker for ketosis buildup capability--a study in healthy individuals under combined high fat and starvation diets.

PubMed

Prabhakar, Amlendu; Quach, Ashley; Zhang, Haojiong; Terrera, Mirna; Jackemeyer, David; Xian, Xiaojun; Tsow, Francis; Tao, Nongjian; Forzani, Erica S

2015-04-22

Ketogenic diets are high fat and low carbohydrate or very low carbohydrate diets, which render high production of ketones upon consumption known as nutritional ketosis (NK). Ketosis is also produced during fasting periods, which is known as fasting ketosis (FK). Recently, the combinations of NK and FK, as well as NK alone, have been used as resources for weight loss management and treatment of epilepsy. A crossover study design was applied to 11 healthy individuals, who maintained moderately sedentary lifestyle, and consumed three types of diet randomly assigned over a three-week period. All participants completed the diets in a randomized and counterbalanced fashion. Each weekly diet protocol included three phases: Phase 1 - A mixed diet with ratio of fat: (carbohydrate + protein) by mass of 0.18 or the equivalence of 29% energy from fat from Day 1 to Day 5. Phase 2- A mixed or a high-fat diet with ratio of fat: (carbohydrate + protein) by mass of approximately 0.18, 1.63, or 3.80 on Day 6 or the equivalence of 29%, 79%, or 90% energy from fat, respectively. Phase 3 - A fasting diet with no calorie intake on Day 7. Caloric intake from diets on Day 1 to Day 6 was equal to each individual's energy expenditure. On Day 7, ketone buildup from FK was measured. A statistically significant effect of Phase 2 (Day 6) diet was found on FK of Day 7, as indicated by repeated analysis of variance (ANOVA), F(2,20) = 6.73, p < 0.0058. Using a Fisher LDS pair-wise comparison, higher significant levels of acetone buildup were found for diets with 79% fat content and 90% fat content vs. 29% fat content (with p = 0.00159**, and 0.04435**, respectively), with no significant difference between diets with 79% fat content and 90% fat content. In addition, independent of the diet, a significantly higher ketone buildup capability of subjects with higher resting energy expenditure (R(2) = 0.92), and lower body mass index (R(2) = 0.71) was observed during FK.

Fibrose kystique atypique

PubMed Central

Schram, Carrie A.

2012-01-01

Résumé Objectif Passer en revue le diagnostic des patients atteints de fibrose kystique (FK) atypique. Sources des données On a procédé à une recension exhaustive dans MEDLINE (de 1950 à la troisième semaine de mai 2009), dans MEDLINE In-Process and Other Non-Indexed Citations and Cases (de 1950 à la troisième semaine de 2009) et dans EMBASE (de 1980 à la quatrième semaine de mars 2009). On a aussi passé en revue le site web de Fibrose kystique Canada et on a consulté son plus récent rapport des inscriptions de données sur les patients. Message principal La FK atypique est une forme moins intense du trouble de la FK, qui est associée à des mutations du gène régulateur de la conductance transmembranaire de la fibrose kystique. Au lieu d’avoir les symptômes classiques, les personnes atteintes d’une FK atypique pourraient avoir une légère dysfonction d’un seul système organique et avoir ou non des concentrations de chlorure élevées dans la sueur. La FK atypique est un trouble très diversifié affectant différents systèmes organiques à divers degrés. Les symptômes du patient peuvent aussi fluctuer avec le temps; par ailleurs, certains signes et symptômes cliniques touchant les systèmes respiratoire, gastro-intestinal, endocrinien et métabolique et génito-urinaire devraient signaler aux médecins la possibilité d’une FK. Les patients atteints d’une FK atypique ont moins d’hospitalisations durant l’enfance que ceux qui ont une FK classique et le diagnostic peut passer inaperçu pendant de nombreuses années, parfois même jusqu’à l’âge adulte. Conclusion Même si les patients atteints d’une FK atypique ont une espérance de vie plus longue que les personnes atteintes de la forme classique, les issues à long terme pour de nombreuses personnes qui ont la forme atypique sont inconnues. Il est important de conseiller les patients à propos de la possibilité d’une manifestation future de la maladie. Renseigner les patients à propos de la FK peut les aider à comprendre leurs symptômes, à modifier leur mode de vie pour optimiser leur santé, à réduire l’incidence des complications et à recevoir au besoin du counseling sur la planification familiale.

Rapidly rotating single late-type giants: New FK Comae stars?

NASA Technical Reports Server (NTRS)

Fekel, Francis C.

1986-01-01

A group of rapidly rotating single late-type giants was found from surveys of chromospherically active stars. These stars have V sin I's ranging from 6 to 46 km/sec, modest ultraviolet emission line fluxes, and strong H alpha absorption lines. Although certainly chromospherically active, their characteristics are much less extreme than those of FK Com and one or two other similar systems. One possible explanation for the newly identified systems is that they have evolved from stars similar to FK Com. The chromospheric activity and rotation of single giant stars like FK Com would be expected to decrease with time as they do in single dwarfs. Alternatively, this newly identified group may have evolved from single rapidly rotating A, or early F stars.

Expression of an engineered synthetic cry2Aa (D42/K63F/K64P) gene of Bacillus thuringiensis in marker free transgenic tobacco facilitated full-protection from cotton leaf worm (S. littoralis) at very low concentration.

PubMed

Gayen, Srimonta; Mandal, Chandi Charan; Samanta, Milan Kumar; Dey, Avishek; Sen, Soumitra Kumar

2016-04-01

Emergence of resistant insects limits the sustainability of Bacillus thuringiensis (Bt) transgenic crop plants for insect management. Beside this, the presence of unwanted marker gene(s) in the transgenic crops is also a major environmental and health concern. Thus, development of marker free transgenic crop plants expressing a new class of toxin having a different mortality mechanism is necessary for resistance management. In a previous study, we generated an engineered Cry2Aa (D42/K63F/K64P) toxin which has a different mortality mechanism as compared to first generation Bt toxin Cry1A, and this engineered toxin was found to enhance 4.1-6.6-fold toxicity against major lepidopteran insect pests of crop plants. In the present study, we have tested the potency of this engineered synthetic Cry2Aa (D42/K63F/K64P) toxin as a candidate in the development of insect resistant transgenic tobacco plants. Simultaneously, we have eliminated the selectable marker gene from the Cry2Aa (D42/K63F/K64P) expressing tobacco plants by exploiting the Cre/lox mediated recombination methodology, and successfully developed marker free T2 transgenic tobacco plants expressing the engineered Cry2Aa toxin. Realtime and western blot analysis demonstrated the expression of engineered toxin gene in transgenic plants. Insect feeding assays revealed that the marker free T2 progeny of transgenic plants expressing Cry2Aa (D42/K63F/K64P) toxin showed 82-92 and 52-61 % mortality to cotton leaf worm (CLW) and cotton bollworm (CBW) respectively. Thus, this engineered Cry2Aa toxin could be useful for the generation of insect resistant transgenic Bt lines which will protect the crop damages caused by different insect pests such as CLW and CBW.

Readability of arthroscopy-related patient education materials from the American Academy of Orthopaedic Surgeons and Arthroscopy Association of North America Web sites.

PubMed

Yi, Paul H; Ganta, Abhishek; Hussein, Khalil I; Frank, Rachel M; Jawa, Andrew

2013-06-01

We sought to assess the readability levels of arthroscopy-related patient education materials available on the Web sites of the American Academy of Orthopaedic Surgeons (AAOS) and the Arthroscopy Association of North America (AANA). We identified all articles related to arthroscopy available in 2012 from the online patient education libraries of AAOS and AANA. After performing follow-up editing, we assessed each article with the Flesch-Kincaid (FK) readability test. Mean readability levels of the articles from the AAOS Web site and the AANA Web site were compared. We also determined the number of articles with readability levels at or below the eighth-grade level (the average reading ability of the US adult population) and sixth-grade level (the widely recommended level for patient education materials). Intraobserver reliability and interobserver reliability of FK grade assessment were evaluated. A total of 62 articles were reviewed (43 from AAOS and 19 from AANA). The mean overall FK grade level was 10.2 (range, 5.2 to 12). The AAOS articles had a mean FK grade level of 9.6 (range, 5.2 to 12), whereas the AANA articles had a mean FK grade level of 11.4 (range, 8.7 to 12); the difference was significant (P < .0001). Only 3 articles had a readability level at or below the eighth-grade level and only 1 was at or below the sixth-grade level; all were from AAOS. Intraobserver reliability and interobserver reliability were excellent (intraclass correlation coefficient of 1 for both). Online patient education materials related to arthroscopy from AAOS and AANA may be written at a level too difficult for a large portion of the patient population to comprehend. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

The effect of the immunophilin ligands rapamycin and FK506 on proliferation of mast cells and other hematopoietic cell lines.

PubMed Central

Hultsch, T; Martin, R; Hohman, R J

1992-01-01

The immunosuppressive drugs FK506 and cyclosporin A have an identical spectrum of activities with respect to IgE receptor (Fc epsilon RI)-mediated exocytosis from mast cells and T cell receptor-mediated transcription of IL-2. These findings suggest a common step in receptor-mediated signal transduction leading to exocytosis and transcription and imply that immunosuppressive drugs target specific signal transduction pathways, rather than specific cell types. This hypothesis is supported by studies on the effect of rapamycin on IL-3 dependent proliferation of the rodent mast cell line PT18. Rapamycin inhibits proliferation of PT18 cells, achieving a plateau of 80% inhibition at 1 nM. This inhibition is prevented in a competitive manner by FK506, a structural analogue of rapamycin. Proliferation of rat basophilic leukemia cells and WEHI-3 cells was also inhibited, at doses comparable to those shown previously to inhibit IL-2-dependent proliferation of cytotoxic T lymphocyte line (CTLL) cells. In contrast, proliferation of A-431 cells, a epidermoid cell line, was not affected by rapamycin. DNA histograms indicate that complexes formed between the rapamycin-FK506-binding protein (FKBP) and rapamycin arrest-proliferating PT18 cells in the G0/G1-phase. It is concluded that FKBP-rapamycin complexes may inhibit proliferative signals emanating from IL-3 receptors, resulting in growth arrest of cytokine-dependent, hematopoietic cells. PMID:1384815

Mapping of the immunophilin-immunosuppressant site of interaction on calcineurin.

PubMed

Husi, H; Luyten, M A; Zurini, M G

1994-05-13

The interaction of the immunosuppressive complexes cyclosporin A-cyclophilin A and FK506 binding protein-FK506 with the Ca(2+)- and calmodulin-dependent protein phosphatase calcineurin has been investigated by means of photoaffinity labeling and chemical cross-linking. Photolabeling of purified bovine brain calcineurin with the affinity label [O-[4-[4-(1-diazo-2,2,2-trifluoroethyl)benzoyl]aminobutanoyl]-D- serine8]cyclosporin in the presence of cyclophilin A results, in addition to the labeling of cyclophilin itself, in the transfer of some of the chemical probe to both the catalytic subunit A and the regulatory subunit B of calcineurin. Chemical cross-linking studies with disuccinimidyl suberate in the presence of either cyclophilin A, B, or C in complex with cyclosporin A or FK506 binding protein-FK506 result on the other hand in the apparently exclusive and strictly immunosuppressant-dependent formation of covalent immunophilin-calcineurin B subunit products. Cross-linking of immunophilins to calcineurin B subunit requires the presence of subunit A. In the present study, using a set of recombinant maltose-binding protein fusion products representing different stretches of the catalytic subunit A, we were able to map the minimal calcineurin A sequence necessary for immunophilin-ligand-calcineurin B interaction to occur.

Diclofenac sodium, 0.1% (Voltaren Ophtha), versus sodium chloride, 5%, in the treatment of filamentary keratitis.

PubMed

Avisar, R; Robinson, A; Appel, I; Yassur, Y; Weinberger, D

2000-03-01

To compare the efficacy and short-term safety of diclofenac sodium, 0.1% (Voltaren Ophtha; Ciba-Vision) and of sodium chloride, 5% ophthalmic solution, in the treatment of filamentary keratitis (FK) in patients with dry-eye syndrome due to secondary Sjögren's syndrome. Thirty-two patients (64 eyes) with dry-eye syndrome due to secondary Sjögren' syndrome were enrolled in a randomized study (patients and authors were aware of which medication was being used). All patients had FK. Sixteen patients were treated with sodium chloride, 5% drops, and 16 patients received diclofenac sodium, 0.1% eyedrops. Treatment regimen included instillation of 1 drop, 4 times a day for 28 days, for both groups. Clinical assessment was performed once a week during the study period. Data on the efficacy and safety of the different therapeutic regimens were collected and compared. Both medications achieved disappearance of filaments at the end of the study. Treatment with diclofenac sodium, 0.1%, revealed a significantly more rapid improvement of the clinical symptoms as compared with sodium chloride, 5%. No significant adverse effects were observed in both groups. Diclofenac sodium, 0.1%, may be an effective and safe topical therapy in patients with FK caused by secondary Sjögren's disease.

How accessible was information about H1N1 flu? Literacy assessments of CDC guidance documents for different audiences.

PubMed

Lagassé, Lisa P; Rimal, Rajiv N; Smith, Katherine C; Storey, J Douglas; Rhoades, Elizabeth; Barnett, Daniel J; Omer, Saad B; Links, Jonathan

2011-01-01

We assessed the literacy level and readability of online communications about H1N1/09 influenza issued by the Centers for Disease Control and Prevention (CDC) during the first month of outbreak. Documents were classified as targeting one of six audiences ranging in technical expertise. Flesch-Kincaid (FK) measure assessed literacy level for each group of documents. ANOVA models tested for differences in FK scores across target audiences and over time. Readability was assessed for documents targeting non-technical audiences using the Suitability Assessment of Materials (SAM). Overall, there was a main-effect by audience, F(5, 82) = 29.72, P<.001, but FK scores did not vary over time, F(2, 82) = .34, P>.05. A time-by-audience interaction was significant, F(10, 82) = 2.11, P<.05. Documents targeting non-technical audiences were found to be text-heavy and densely-formatted. The vocabulary and writing style were found to adequately reflect audience needs. The reading level of CDC guidance documents about H1N1/09 influenza varied appropriately according to the intended audience; sub-optimal formatting and layout may have rendered some text difficult to comprehend.

Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of clonogenic resistance in breast cancer cells by combined cisplatin and FK228.

PubMed

Pluchino, Lenora Ann; Choudhary, Shambhunath; Wang, Hwa-Chain Robert

2016-10-10

Safe and effective combination chemotherapy regimens against breast cancer are lacking. We used our cellular system, consisting of the non-cancerous human breast epithelial MCF10A cell line and its derived tumorigenic, oncogenic H-Ras-expressing, MCF10A-Ras cell line, to investigate the effectiveness of a combination chemotherapy regimen in treating breast cancer cells using two FDA-approved agents, cisplatin and FK228. Cisplatin and FK228 significantly, synergistically, and preferentially induced death and reduced drug resistance of MCF10A-Ras versus MCF10A cells. The ERK-Nox-ROS pathway played a major role in both synergistic cell death induction and GSH-level reduction, which contributed to the synergistic suppression of drug resistance in cells. Enhancement of the Ras-ERK-Nox pathway by combined cisplatin and FK228 significantly increased ROS levels, leading to induction of death, reduction of drug resistance, and induction of DNA damage and oxidation in cancerous MCF10A-Ras cells. Furthermore, synergistic induction of cell death and reduction of drug resistance by combined cisplatin and FK228 in breast cells is independent of their estrogen receptor status. Our study suggests that combined cisplatin and FK228 should be considered in clinical trials as a new regimen for therapeutic control of breast cancers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Improved Plane-Wave Ultrasound Beamforming by Incorporating Angular Weighting and Coherent Compounding in Fourier Domain.

PubMed

Chen, Chuan; Hendriks, Gijs A G M; van Sloun, Ruud J G; Hansen, Hendrik H G; de Korte, Chris L

2018-05-01

In this paper, a novel processing framework is introduced for Fourier-domain beamforming of plane-wave ultrasound data, which incorporates coherent compounding and angular weighting in the Fourier domain. Angular weighting implies spectral weighting by a 2-D steering-angle-dependent filtering template. The design of this filter is also optimized as part of this paper. Two widely used Fourier-domain plane-wave ultrasound beamforming methods, i.e., Lu's f-k and Stolt's f-k methods, were integrated in the framework. To enable coherent compounding in Fourier domain for the Stolt's f-k method, the original Stolt's f-k method was modified to achieve alignment of the spectra for different steering angles in k-space. The performance of the framework was compared for both methods with and without angular weighting using experimentally obtained data sets (phantom and in vivo), and data sets (phantom) provided by the IEEE IUS 2016 plane-wave beamforming challenge. The addition of angular weighting enhanced the image contrast while preserving image resolution. This resulted in images of equal quality as those obtained by conventionally used delay-and-sum (DAS) beamforming with apodization and coherent compounding. Given the lower computational load of the proposed framework compared to DAS, to our knowledge it can, therefore, be concluded that it outperforms commonly used beamforming methods such as Stolt's f-k, Lu's f-k, and DAS.

Application of a New Ensemble Conserving Quantum Dynamics Simulation Algorithm to Liquid para-Hydrogen and ortho-Deuterium

DOE PAGES

Smith, Kyle K.G.; Poulsen, Jens Aage; Nyman, Gunnar; ...

2015-06-30

Here, we apply the Feynman-Kleinert Quasi-Classical Wigner (FK-QCW) method developed in our previous work [Smith et al., J. Chem. Phys. 142, 244112 (2015)] for the determination of the dynamic structure factor of liquid para-hydrogen and ortho-deuterium at state points of (T = 20.0 K, n = 21.24 nm -3) and (T = 23.0 K, n = 24.61 nm -3), respectively. When applied to this challenging system, it is shown that this new FK-QCW method consistently reproduces the experimental dynamic structure factor reported by Smith et al. [J. Chem. Phys. 140, 034501 (2014)] for all momentum transfers considered. Moreover, this showsmore » that FK-QCW provides a substantial improvement over the Feynman-Kleinert linearized path-integral method, in which purely classical dynamics are used. Furthermore, for small momentum transfers, it is shown that FK-QCW provides nearly the same results as ring-polymer molecular dynamics (RPMD), thus suggesting that FK-QCW provides a potentially more appealing algorithm than RPMD since it is not formally limited to correlation functions involving linear operators.« less

Application of a New Ensemble Conserving Quantum Dynamics Simulation Algorithm to Liquid para-Hydrogen and ortho-Deuterium

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

Smith, Kyle K.G.; Poulsen, Jens Aage; Nyman, Gunnar

Here, we apply the Feynman-Kleinert Quasi-Classical Wigner (FK-QCW) method developed in our previous work [Smith et al., J. Chem. Phys. 142, 244112 (2015)] for the determination of the dynamic structure factor of liquid para-hydrogen and ortho-deuterium at state points of (T = 20.0 K, n = 21.24 nm -3) and (T = 23.0 K, n = 24.61 nm -3), respectively. When applied to this challenging system, it is shown that this new FK-QCW method consistently reproduces the experimental dynamic structure factor reported by Smith et al. [J. Chem. Phys. 140, 034501 (2014)] for all momentum transfers considered. Moreover, this showsmore » that FK-QCW provides a substantial improvement over the Feynman-Kleinert linearized path-integral method, in which purely classical dynamics are used. Furthermore, for small momentum transfers, it is shown that FK-QCW provides nearly the same results as ring-polymer molecular dynamics (RPMD), thus suggesting that FK-QCW provides a potentially more appealing algorithm than RPMD since it is not formally limited to correlation functions involving linear operators.« less

Application of a new ensemble conserving quantum dynamics simulation algorithm to liquid para-hydrogen and ortho-deuterium

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

Smith, Kyle K. G., E-mail: kylesmith@utexas.edu; Poulsen, Jens Aage, E-mail: jens72@chem.gu.se; Nyman, Gunnar, E-mail: nyman@chem.gu.se

We apply the Feynman-Kleinert Quasi-Classical Wigner (FK-QCW) method developed in our previous work [Smith et al., J. Chem. Phys. 142, 244112 (2015)] for the determination of the dynamic structure factor of liquid para-hydrogen and ortho-deuterium at state points of (T = 20.0 K, n = 21.24 nm{sup −3}) and (T = 23.0 K, n = 24.61 nm{sup −3}), respectively. When applied to this challenging system, it is shown that this new FK-QCW method consistently reproduces the experimental dynamic structure factor reported by Smith et al. [J. Chem. Phys. 140, 034501 (2014)] for all momentum transfers considered. This shows that FK-QCWmore » provides a substantial improvement over the Feynman-Kleinert linearized path-integral method, in which purely classical dynamics are used. Furthermore, for small momentum transfers, it is shown that FK-QCW provides nearly the same results as ring-polymer molecular dynamics (RPMD), thus suggesting that FK-QCW provides a potentially more appealing algorithm than RPMD since it is not formally limited to correlation functions involving linear operators.« less

Chaos and Chaos Control of the Frenkel-Kontorova Model with Dichotomous Noise

NASA Astrophysics Data System (ADS)

Lei, Youming; Zheng, Fan; Shao, Xizhen

Chaos and chaos control of the Frenkel-Kontorova (FK) model with dichotomous noise are studied theoretically and numerically. The threshold conditions for the onset of chaos in the FK model are firstly derived by applying the random Melnikov method with a mean-square criterion to the soliton equation, which is a fundamental topological mode of the FK model and accounts for its nonlinear phenomena. We found that dichotomous noise can induce stochastic chaos in the FK model, and the threshold of noise amplitude for the onset of chaos increases with the increase of its transition rate. Then the analytical criterion of chaos control is obtained by means of the time-delay feedback method. Since the time-delay feedback control raises the threshold of noise amplitude for the onset of chaos, chaos in the FK model is effectively suppressed. Through numerical simulations including the mean top Lyapunov exponent and the safe basin, we demonstrate the validity of the analytical predictions of chaos. Furthermore, time histories and phase portraits are utilized to verify the effectiveness of the proposed control.

Application of a new ensemble conserving quantum dynamics simulation algorithm to liquid para-hydrogen and ortho-deuterium.

PubMed

Smith, Kyle K G; Poulsen, Jens Aage; Nyman, Gunnar; Cunsolo, Alessandro; Rossky, Peter J

2015-06-28

We apply the Feynman-Kleinert Quasi-Classical Wigner (FK-QCW) method developed in our previous work [Smith et al., J. Chem. Phys. 142, 244112 (2015)] for the determination of the dynamic structure factor of liquid para-hydrogen and ortho-deuterium at state points of (T = 20.0 K, n = 21.24 nm(-3)) and (T = 23.0 K, n = 24.61 nm(-3)), respectively. When applied to this challenging system, it is shown that this new FK-QCW method consistently reproduces the experimental dynamic structure factor reported by Smith et al. [J. Chem. Phys. 140, 034501 (2014)] for all momentum transfers considered. This shows that FK-QCW provides a substantial improvement over the Feynman-Kleinert linearized path-integral method, in which purely classical dynamics are used. Furthermore, for small momentum transfers, it is shown that FK-QCW provides nearly the same results as ring-polymer molecular dynamics (RPMD), thus suggesting that FK-QCW provides a potentially more appealing algorithm than RPMD since it is not formally limited to correlation functions involving linear operators.

Persistent C II absorption in the normal type Ia supernova 2002fk

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

Cartier, Régis; Zelaya, Paula; Hamuy, Mario

2014-07-01

We present well-sampled UBVRIJHK photometry of SN 2002fk starting 12 days before maximum light through 122 days after peak brightness, along with a series of 15 optical spectra from –4 to +95 days since maximum. Our observations show the presence of C II lines in the early-time spectra of SN 2002fk, expanding at 11,000 km s{sup –1} and persisting until 8 days past maximum light with a velocity of ∼9000 km s{sup –1}. SN 2002fk is characterized by a small velocity gradient of v-dot {sub Si} {sub II}=26 km s{sup –1} day{sup –1}, possibly caused by an off-center explosion withmore » the ignition region oriented toward the observer. The connection between the viewing angle of an off-center explosion and the presence of C II in the early-time spectrum suggests that the observation of C II could be also due to a viewing angle effect. Adopting the Cepheid distance to NGC 1309 we provide the first H {sub 0} value based on near-infrared (near-IR) measurements of a Type Ia supernova (SN) between 63.0 ± 0.8 (±3.4 systematic) and 66.7 ± 1.0 (±3.5 systematic) km s{sup –1} Mpc{sup –1}, depending on the absolute magnitude/decline rate relationship adopted. It appears that the near-IR yields somewhat lower (6%-9%) H {sub 0} values than the optical. It is essential to further examine this issue by (1) expanding the sample of high-quality near-IR light curves of SNe in the Hubble flow, and (2) increasing the number of nearby SNe with near-IR SN light curves and precise Cepheid distances, which affords the promise to deliver a more precise determination of H {sub 0}.« less

Refinement of the experimental dynamic structure factor for liquid para-hydrogen and ortho-deuterium using semi-classical quantum simulation

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

Smith, Kyle K. G., E-mail: kylesmith@utexas.edu; Rossky, Peter J., E-mail: peter.rossky@austin.utexas.edu; Poulsen, Jens Aage, E-mail: jens72@chem.gu.se

The dynamic structure factor of liquid para-hydrogen and ortho-deuterium in corresponding thermodynamic states (T = 20.0 K, n = 21.24 nm{sup −3}) and (T = 23.0 K, n = 24.61 nm{sup −3}), respectively, has been computed by both the Feynman-Kleinert linearized path-integral (FK-LPI) and Ring-Polymer Molecular Dynamics (RPMD) methods and compared with Inelastic X Ray Scattering spectra. The combined use of computational and experimental methods enabled us to reduce experimental uncertainties in the determination of the true sample spectrum. Furthermore, the refined experimental spectrum of para-hydrogen and ortho-deuterium is consistently reproduced by both FK-LPI and RPMD results at momentum transfers lower than 12.8 nm{sup −1}.more » At larger momentum transfers the FK-LPI results agree with experiment much better for ortho-deuterium than for para-hydrogen. More specifically we found that for k ∼ 20.0 nm{sup −1} para-hydrogen provides a test case for improved approximations to quantum dynamics.« less

Asymptotic dynamics in perturbative quantum gravity and BMS supertranslations

NASA Astrophysics Data System (ADS)

Choi, Sangmin; Kol, Uri; Akhoury, Ratindranath

2018-01-01

Recently it has been shown that infrared divergences in the conventional S-matrix elements of gauge and gravitational theories arise from a violation of the conservation laws associated with large gauge symmetries. These infrared divergences can be cured by using the Faddeev-Kulish (FK) asymptotic states as the basis for S-matrix elements. Motivated by this connection, we study the action of BMS supertranslations on the FK asymptotic states of perturbative quantum gravity. We compute the BMS charge of the FK states and show that it characterizes the superselection sector to which the state belongs. Conservation of the BMS charge then implies that there is no transition between different superselection sectors, hence showing that the FK graviton clouds implement the necessary transition induced by the scattering process.

Rotation Period Determination for 8994 Kashkashian, (25980) 2001 FK53 and (29128) 1985 RA1

NASA Astrophysics Data System (ADS)

Papini, Riccardo; Franco, Lorenzo; Marchini, Alessandro; Cicali, Cristina; Poggialini, Anna; Salvaggio, Fabio

2018-01-01

Photometric observations of three main-belt asteroids were made from the Astronomical Observatory of the University of Siena (Italy) in order to determine their rotation periods. For 8994 Kashkashian, we found a period of 11.761 ± 0.001 h with an amplitude of 0.24 ± 0.01 mag. For (25980) 2001 FK53 the period was 2.762 ± 0.002 h with an amplitude of 0.10 ± 0.02 mag. For (29128) 1985 RA1 we found a period of 5.056 ± 0.004 h with an amplitude of 0.18 ± 0.04 mag.

Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans.

PubMed

Chen, Ying-Lien; Lehman, Virginia N; Averette, Anna F; Perfect, John R; Heitman, Joseph

2013-01-01

The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.

Report of Investigation: Lieutenant General John F. Mulholland U.S. Army (Redacted)

DTIC Science & Technology

2014-06-09

unprofessional ... I’m just venting ... but you guys have pissed me the f--k off.2 One complainant stated he infonned Maj Gen Laster he believed LTG...L TG Mulh<.)lland) needed to stop as he was bein g unprofessional and remarked he was just venting but "you guys have pissed me the f--k off...course of his career. (b) (6) (b) (7)(() (b) 161 !bl (7l(CJoffered similar testimoJ1yto . ­ testified L TG Mulholland stated the team ··had pissed me

Synergy, Pharmacodynamics, and Time-Sequenced Ultrastructural Changes of the Interaction between Nikkomycin Z and the Echinocandin FK463 against Aspergillus fumigatus

PubMed Central

Chiou, Christine C.; Mavrogiorgos, Nikolaos; Tillem, Elizabeth; Hector, Richard; Walsh, Thomas J.

2001-01-01

We investigated the potential synergy between two cell wall-active agents, the echinocandin FK463 (FK) and the chitin synthase inhibitor nikkomycin Z (NZ), against 16 isolates of filamentous fungi. Susceptibility testing was performed with a broth macrodilution procedure by NCCLS methods. The median minimal effective concentration (MEC) of FK against all Aspergillus species was 0.25 μg/ml (range, 0.05 to 0.5 μg/ml). For Fusarium solani and Rhizopus oryzae, MECs of FK were >512 μg/ml. The median MEC of NZ against Aspergillus fumigatus was 32 μg/ml (range, 8 to 64 μg/ml), and that against R. oryzae was 0.5 μg/ml (range, 0.06 to 2 μg/ml); however, for the other Aspergillus species, as well as F. solani, MECs were >512 μg/ml. A checkerboard inhibitory assay demonstrated synergy against A. fumigatus (median fractional inhibitory concentration index = 0.312 [range, 0.15 to 0.475]). The effect was additive to indifferent against R. oryzae and indifferent against other Aspergillus spp. and F. solani. We further investigated the pharmacodynamics of hyphal damage by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and examined the time-sequenced changes in hyphal ultrastructure. Significant synergistic hyphal damage was demonstrated with the combination of NZ (2 to 32 μg/ml) and FK (0.03 to 0.5 μg/ml) over a wide range of concentrations (P < 0.001). The synergistic effect was most pronounced after 12 h of incubation and was sustained through 24 h. Time-sequenced light and electron microscopic studies demonstrated that structural alterations of hyphae were profound, with marked transformation of hyphae to blastospore-like structures, in the presence of FK plus NZ, while fungi treated with a single drug showed partial recovery at 24 h. The methods used in this study may be applicable to elucidating the activity and interaction of other cell wall-active agents. In summary, these two cell wall-targeted antifungal agents, FK and NZ, showed marked time-dependent in vitro synergistic activity against A. fumigatus. PMID:11709302

Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: the role of GSK-3beta in the maintenance of steady-state levels of insulin receptor signaling molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells.

PubMed

Nemoto, Takayuki; Yanagita, Toshihiko; Kanai, Tasuku; Wada, Akihiko

2009-02-01

Glycogen synthase kinase-3 (GSK-3) is constitutively active in nonstimulated cells, where the majority of its substrates undergo inactivation/proteolysis by phosphorylation. Extracellular stimuli (e.g., insulin) catalyze inhibitory Ser(9)-phosphorylation of GSK-3beta, turning on signaling and causing other biological consequences otherwise constitutively suppressed by GSK-3beta. Regulated and dysregulated activities of GSK-3beta are pivotal to health, disease, and therapeutics (e.g., insulin resistance, neurodegeneration, tumorigenesis, inflammation); however, the underlying mechanisms of multifunctional GSK-3beta remain elusive. In cultured bovine adrenal chromaffin cells, 1) constitutive and negatively-regulated activities of GSK-3beta up- and down-regulated insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2, and Akt levels via controlling proteasomal degradation and protein synthesis; 2) nicotinic receptor/protein kinase C-alpha (PKC-alpha)/extracellular signal-regulated kinase (ERK) pathway up-regulated IRS-1 and IRS-2 levels, enhancing insulin-induced the phosphoinositide 3-kinase (PI3K)/Akt/GSK-3beta pathway; 3) inhibition of calcineurin by cyclosporin A or FK506 down-regulated IRS-2 level, attenuating insulin-like growth factor-I (IGF-I)-induced ERK and GSK-3beta pathways; and 4) insulin, IGF-I or therapeutics (e.g., lithium) up-regulated the voltage-dependent Na(v)1.7 sodium channel.

Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates.

PubMed

Denardi, Laura Bedin; Mario, Débora Alves Nunes; Loreto, Érico Silva; Santurio, Janio Morais; Alves, Sydney Hartz

2015-03-01

In vitro interaction between tacrolimus (FK506) and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole) against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%), followed by that of the combination with ketoconazole (37%), against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata , a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%), itraconazole (73%), voriconazole (63%) and fluconazole (60%). The synergisms that we observed in vitro , notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.

Improvement of FK506 Production in Streptomyces tsukubaensis by Genetic Enhancement of the Supply of Unusual Polyketide Extender Units via Utilization of Two Distinct Site-Specific Recombination Systems

PubMed Central

Chen, Dandan; Zhang, Qi; Zhang, Qinglin; Cen, Peilin

2012-01-01

FK506 is a potent immunosuppressant that has a wide range of clinical applications. Its 23-member macrocyclic scaffold, mainly with a polyketide origin, features two methoxy groups at C-13 and C-15 and one allyl side chain at C-21, due to the region-specific incorporation of two unusual extender units derived from methoxymalonyl-acyl carrier protein (ACP) and allylmalonyl-coenzyme A (CoA), respectively. Whether their intracellular formations can be a bottleneck for FK506 production remains elusive. In this study, we report the improvement of FK506 yield in the producing strain Streptomyces tsukubaensis by the duplication of two sets of pathway-specific genes individually encoding the biosyntheses of these two extender units, thereby providing a promising approach to generate high-FK506-producing strains via genetic manipulation. Taking advantage of the fact that S. tsukubaensis is amenable to two actinophage (ΦC31 and VWB) integrase-mediated recombination systems, we genetically enhanced the biosyntheses of methoxymalonyl-ACP and allylmalonyl-CoA, as indicated by transcriptional analysis. Together with the optimization of glucose supplementation, the maximal FK506 titer eventually increased by approximately 150% in comparison with that of the original strain. The strategy of engineering the biosynthesis of unusual extender units described here may be applicable to improving the production of other polyketide or nonribosomal peptide natural products that contain pathway-specific building blocks. PMID:22582065

vph6 mutants of Saccharomyces cerevisiae require calcineurin for growth and are defective in vacuolar H(+)-ATPase assembly.

PubMed

Hemenway, C S; Dolinski, K; Cardenas, M E; Hiller, M A; Jones, E W; Heitman, J

1995-11-01

We have characterized a Saccharomyces cerevisiae mutant strain that is hypersensitive to cyclosporin A (CsA) and FK506, immunosuppressants that inhibit calcineurin, a serine-threonine-specific phosphatase (PP2B). A single nuclear mutation, designated cev1 for calcineurin essential for viability, is responsible for the CsA-FK506-sensitive phenotype. The peptidyl-prolyl cis-trans isomerases cyclophilin A and FKBP12, respectively, mediate CsA and FK506 toxicity in the cev1 mutant strain. We demonstrate that cev1 is an allele of the VPH6 gene and that vph6 mutant strains fail to assemble the vacuolar H(+)-ATPase (V-ATPase). The VPH6 gene was mapped on chromosome VIII and is predicted to encode a 181-amino acid (21 kD) protein with no identity to other known proteins. We find that calcineurin is essential for viability in many mutant strains with defects in V-ATPase function or vacuolar acidification. In addition, we find that calcineurin modulates extracellular acidification in response to glucose, which we propose occurs via calcineurin regulation of the plasma membrane H(+)-ATPase PMA1. Taken together, our findings suggest calcineurin plays a general role in the regulation of cation transport and homeostasis.

Accuracy of estimating wolf summer territories by daytime locations

USGS Publications Warehouse

Demma, D.J.; Mech, L.D.

2011-01-01

We used locations of 6 wolves (Canis lupus) in Minnesota from Global Positioning System (GPS) collars to compare day-versus-night locations to estimate territory size and location during summer. We employed both minimum convex polygon (MCP) and fixed kernel (FK) methods. We used two methods to partition GPS locations for day-versus-night home-range comparisons: (1) daytime = 0800-2000 Ah; nighttime = 2000-0800 Ah; and (2) sunup versus sundown. Regardless of location-partitioning method, mean area of daytime MCPs did not differ significantly from nighttime MCPs. Similarly, mean area of daytime FKs (95% probability contour) were not significantly different from nightime FKs. FK core use areas (50% probability contour) did not differ between daytime and nighttime nor between sunup and sundown locations. We conclude that in areas similar to our study area day-only locations are adequate for describing the location, extent and core use areas of summer wolf territories by both MCP and FK methods. ?? 2011 American Midland Naturalist.

Accuracy of estimating wolf summer territories by daytime locations

USGS Publications Warehouse

Demma, Dominic J.; Mech, L. David

2011-01-01

We used locations of 6 wolves (Canis lupus) in Minnesota from Global Positioning System (GPS) collars to compare day-versus-night locations to estimate territory size and location during summer. We employed both minimum convex polygon (MCP) and fixed kernel (FK) methods. We used two methods to partition GPS locations for day-versus-night home-range comparisons: (1) daytime = 0800–2000 h; nighttime = 2000–0800 h; and (2) sunup versus sundown. Regardless of location-partitioning method, mean area of daytime MCPs did not differ significantly from nighttime MCPs. Similarly, mean area of daytime FKs (95% probability contour) were not significantly different from nightime FKs. FK core use areas (50% probability contour) did not differ between daytime and nighttime nor between sunup and sundown locations. We conclude that in areas similar to our study area day-only locations are adequate for describing the location, extent and core use areas of summer wolf territories by both MCP and FK methods.

Biological Treatment of Solvent-Based Paint

DTIC Science & Technology

2011-01-01

ESTCP Environmental Security Technology Certification Program FK-WTP Fort Kamehameha Wastewater Treatment Plant FTIR Fourier Transform Infrared...established by the Fort Kamehameha Wastewater Treatment Plant (FK-WTP) for the water; toxicity characteristic leaching procedure (TCLP) requirements for

Measurement of entanglement entropy in the two-dimensional Potts model using wavelet analysis.

PubMed

Tomita, Yusuke

2018-05-01

A method is introduced to measure the entanglement entropy using a wavelet analysis. Using this method, the two-dimensional Haar wavelet transform of a configuration of Fortuin-Kasteleyn (FK) clusters is performed. The configuration represents a direct snapshot of spin-spin correlations since spin degrees of freedom are traced out in FK representation. A snapshot of FK clusters loses image information at each coarse-graining process by the wavelet transform. It is shown that the loss of image information measures the entanglement entropy in the Potts model.

Complex Fuzzy Set-Valued Complex Fuzzy Measures and Their Properties

PubMed Central

Ma, Shengquan; Li, Shenggang

2014-01-01

Let F*(K) be the set of all fuzzy complex numbers. In this paper some classical and measure-theoretical notions are extended to the case of complex fuzzy sets. They are fuzzy complex number-valued distance on F*(K), fuzzy complex number-valued measure on F*(K), and some related notions, such as null-additivity, pseudo-null-additivity, null-subtraction, pseudo-null-subtraction, autocontionuous from above, autocontionuous from below, and autocontinuity of the defined fuzzy complex number-valued measures. Properties of fuzzy complex number-valued measures are studied in detail. PMID:25093202

RAPIDLY ROTATING, X-RAY BRIGHT STARS IN THE KEPLER FIELD

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

Howell, Steve B.; Mason, Elena; Boyd, Patricia

We present Kepler light curves and optical spectroscopy of twenty X-ray bright stars located in the Kepler field of view. The stars, spectral type F-K, show evidence for rapid rotation including chromospheric activity 100 times or more above the Sun at maximum and flaring behavior in their light curves. Eighteen of our objects appear to be (sub)giants and may belong to the class of FK Com variables, which are evolved rapidly spinning single stars with no excretion disk and high levels of chromospheric activity. Such stars are rare and are likely the result of W UMa binary mergers, a processmore » believed to produce the FK Com class of variable and their descendants. The FK Com stage, including the presence of an excretion disk, is short lived but leads to longer-lived stages consisting of single, rapidly rotating evolved (sub)giants with high levels of stellar activity.« less

Rapidly Rotating, X-Ray Bright Stars in the Kepler Field

NASA Technical Reports Server (NTRS)

Howell, Steve B.; Mason, Elena; Boyd, Patricia; Smith, Krista Lynne; Gelino, Dawn M.

2016-01-01

We present Kepler light curves and optical spectroscopy of twenty X-ray bright stars located in the Kepler field of view. The stars, spectral type F-K, show evidence for rapid rotation including chromospheric activity 100 times or more above the Sun at maximum and flaring behavior in their light curves. Eighteen of our objects appear to be (sub)giants and may belong to the class of FK Com variables, which are evolved rapidly spinning single stars with no excretion disk and high levels of chromospheric activity. Such stars are rare and are likely the result of W UMa binary mergers, a process believed to produce the FK Com class of variable and their descendants. The FK Com stage, including the presence of an excretion disk, is short lived but leads to longer-lived stages consisting of single, rapidly rotating evolved (sub)giants with high levels of stellar activity.

The immunosuppressives FK 506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer.

PubMed Central

Brabletz, T; Pietrowski, I; Serfling, E

1991-01-01

Like Cyclosporin A (CsA), the macrolide FK 506 is a potent immunosuppressive that inhibits early steps of T cell activation, including the synthesis of Interleukin 2 (II-2) and numerous other lymphokines. The block of II-2 synthesis occurs at the transcriptional level. At concentrations that block T cell activation, FK 506 and CsA inhibit the proto-enhancer activity of Purine boxes of the II-2 promoter and the generation of lymphocyte-specific factors binding to the Purine boxes. Under the same conditions, the DNA binding of other II-2 enhancer factors remains unaffected by both compounds. These results support the view that FK 506 and CsA, which both inhibit the activity of peptidylprolyl cis/trans isomerases, suppress T cell activation by a similar, if not identical mechanism. Images PMID:1707162

The immunosuppressives FK 506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer.

PubMed

Brabletz, T; Pietrowski, I; Serfling, E

1991-01-11

Like Cyclosporin A (CsA), the macrolide FK 506 is a potent immunosuppressive that inhibits early steps of T cell activation, including the synthesis of Interleukin 2 (II-2) and numerous other lymphokines. The block of II-2 synthesis occurs at the transcriptional level. At concentrations that block T cell activation, FK 506 and CsA inhibit the proto-enhancer activity of Purine boxes of the II-2 promoter and the generation of lymphocyte-specific factors binding to the Purine boxes. Under the same conditions, the DNA binding of other II-2 enhancer factors remains unaffected by both compounds. These results support the view that FK 506 and CsA, which both inhibit the activity of peptidylprolyl cis/trans isomerases, suppress T cell activation by a similar, if not identical mechanism.

Molecular mechanisms of neuroprotective action of immunosuppressants--facts and hypotheses.

PubMed

Kaminska, Bozena; Gaweda-Walerych, Katarzyna; Zawadzka, Malgorzata

2004-01-01

Cyclosporin A (CsA) and FK506 (Tacrolimus) are short polypeptides which block the activation of lymphocytes and other immune system cells. Immunosuppressants exert neuroprotective and neurotrophic action in traumatic brain injury, sciatic nerve injury, focal and global ischemia in animals. Their neuroprotective actions are not understood and many hypotheses have been formed to explain such effects. We discuss a role of drug target--calcineurin in neuroprotective action of immunosuppressants. Protein dephosphorylation by calcineurin plays an important role in neuronal signal transduction due to its ability to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In vitro FK506 protects cortex neurons from NMDA-induced death, augments NOS phosphorylation inhibiting its activity and NO synthesis. However, in vivo experiments demonstrated that FK506 in neuroprotective doses did not block excitotoxic cell death nor did it alter NO production during ischemia/reperfusion. Tissue damage in ischemia is the result of a complex pathophysiological cascade, which comprises a variety of distinct pathological events. Resident non-neuronal brain cells respond rapidly to neuronal cell death and may have both deleterious and useful role in neuronal damage. There is increasing evidence that reactive gliosis and post-ischemic inflammation involving microglia contribute to ischemic damage. We have demonstrated that FK506 modulates hypertrophic/proliferative responses and proinflammatory cytokine expression in astrocytes and microglia in vitro and in focal transient brain ischemia. Our findings suggest that astrocytes and microglia are direct targets of FK506 and modulation of glial response and inflammation is a possible mechanism of FK506-mediated neuroprotection in ischemia.

CD73 Protein as a Source of Extracellular Precursors for Sustained NAD+ Biosynthesis in FK866-treated Tumor Cells*

PubMed Central

Grozio, Alessia; Sociali, Giovanna; Sturla, Laura; Caffa, Irene; Soncini, Debora; Salis, Annalisa; Raffaelli, Nadia; De Flora, Antonio; Nencioni, Alessio; Bruzzone, Santina

2013-01-01

NAD+ is mainly synthesized in human cells via the “salvage” pathways starting from nicotinamide, nicotinic acid, or nicotinamide riboside (NR). The inhibition with FK866 of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), catalyzing the first reaction in the “salvage” pathway from nicotinamide, showed potent antitumor activity in several preclinical models of solid and hematologic cancers. In the clinical studies performed with FK866, however, no tumor remission was observed. Here we demonstrate that low micromolar concentrations of extracellular NAD+ or NAD+ precursors, nicotinamide mononucleotide (NMN) and NR, can reverse the FK866-induced cell death, this representing a plausible explanation for the failure of NAMPT inhibition as an anti-cancer therapy. NMN is a substrate of both ectoenzymes CD38 and CD73, with generation of NAM and NR, respectively. In this study, we investigated the roles of CD38 and CD73 in providing ectocellular NAD+ precursors for NAD+ biosynthesis and in modulating cell susceptibility to FK866. By specifically silencing or overexpressing CD38 and CD73, we demonstrated that endogenous CD73 enables, whereas CD38 impairs, the conversion of extracellular NMN to NR as a precursor for intracellular NAD+ biosynthesis in human cells. Moreover, cell viability in FK866-treated cells supplemented with extracellular NMN was strongly reduced in tumor cells, upon pharmacological inhibition or specific down-regulation of CD73. Thus, our study suggests that genetic or pharmacologic interventions interfering with CD73 activity may prove useful to increase cancer cell sensitivity to NAMPT inhibitors. PMID:23880765

Readability of Orthopaedic Oncology-related Patient Education Materials Available on the Internet.

PubMed

Shah, Akash K; Yi, Paul H; Stein, Andrew

2015-12-01

A person's health literacy is one of the most important indicators of a patient's health status. According to national recommendations, patient education materials should be written at no higher than the sixth- to eighth-grade reading level. The purpose of our study was to assess the readability of online patient education materials related to orthopaedic oncology on the websites of the American Academy of Orthopaedic Surgeons (AAOS), American Cancer Society (ACS), Bone and Cancer Foundation (BCF), and National Cancer Institute (NCI). We searched the online patient education libraries of the AAOS, ACS, BCF, and NCI for all articles related to orthopaedic oncology. The Flesch-Kincaid (FK) readability score was calculated for each article and compared between sources. A total of 227 articles were identified with an overall mean FK grade level of 9.8. Stratified by source, the mean FK grade levels were 10.1, 9.6, 11.1, and 9.5 for the AAOS, ACS, BCF, and NCI, respectively (P < 0.003). Only 31 articles (14%) and 1 article (0.4%) were at or below the recommended eighth- and sixth-grade levels, respectively. Online patient education materials related to orthopaedic oncology appear to be written at a level above the comprehension ability of the average patient. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Cosine problem in EPRL/FK spinfoam model

NASA Astrophysics Data System (ADS)

Vojinović, Marko

2014-01-01

We calculate the classical limit effective action of the EPRL/FK spinfoam model of quantum gravity coupled to matter fields. By employing the standard QFT background field method adapted to the spinfoam setting, we find that the model has many different classical effective actions. Most notably, these include the ordinary Einstein-Hilbert action coupled to matter, but also an action which describes antigravity. All those multiple classical limits appear as a consequence of the fact that the EPRL/FK vertex amplitude has cosine-like large spin asymptotics. We discuss some possible ways to eliminate the unwanted classical limits.

Screening of Cyanobacteria (Blue-Green algae) from Rice Paddy Soil for Antifungal Activity against Plant Pathogenic Fungi

PubMed Central

2006-01-01

Soil cyanobacteria isolated from the rice paddy fields of 10 different locations across Korea were evaluated by agar plate diffusion test for antifungal activity. Aqueous, petroleum ether, and methanol extracts from one hundred and forty two cyanobacterial strains belonging to the 14 genera were examined for antifungal properties against seven phytopathogenic fungi causing diseases in hot pepper (Capsicum annuum L). Of total cyanobacteria, nine cyanobacteria (6.34%) exhibited antifungal effects. The nine cyanobacteria selected with positive antifungal activities were two species of Oscillatoria, two of Anabaena, three of Nostoc, one of Nodularia, and one of Calothrix. Alternaria alternata and Botrytis cinerea were inhibited by nine and eight species of cyanobacteria, respectively. Rhizopus stolonifer was suppressed by only methanol extract of Nostoc commune FK-103. In particular, Nostoc commune FK-103 and Oscillatoria tenuis FK-109 showed strong antifungal activities against Phytophthora capsici. Their antifungal activity at the late exponential growth phase is related to the growth temperature and not associated with the growth parameters such as cell biomass and chlorophyll-α concentration. The high inhibition levels of antibiotics were 22.5 and 31.8 mm for N. commune FK-103 and O. tenuis FK-109, respectively. The optimal temperature for antibiotic productivity was 35℃. PMID:24039487

850nm light-emitting-diode phototherapy plus low-dose tacrolimus (FK-506) as combination therapy in the treatment of Dermatophagoides farinae-induced atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Kim, Chang-Hyun; Cheong, Kyung Ah; Lee, Ai-Young

2013-11-01

Light emitting diode (LED) phototherapy is an effective alternative for the treatment of inflammatory skin disorders. Tacrolimus (FK-506) is a potent immunomodulating agent, which has been used to treat AD. Combination therapy is often used in the treatment of AD to improve therapeutic efficacy or to reduce the dose of each drug. To investigate the therapeutic efficacy of monotherapy with either 850nm LED phototherapy or low-dose FK-506, and combination therapy in Dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice. The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with LED (10 and 25J/cm(2)) alone, low-dose FK-506 (1mg/kg) or in combination. The synergistic effects of combined therapy were evaluated by dermatitis scores, skin histology, skin barrier function, and immunological parameters, such as IgE, NO, Th2-mediated cytokines and chemokines. Combination therapy with 850nm (25J/cm(2)) LED and low-dose FK-506 showed a significant reduction in the severity of skin lesions. Combined therapy decreased in the serum level of IgE, NO, and in the splenic level of Th2-mediated cytokines and chemokines. Combination therapy significantly also reduced the inflammatory cellular infiltrate into the skin lesions. Moreover, combination therapy led to recovery of skin barrier function in the skin lesions. The use of combination of LED phototherapy and low-dose immunosuppressant improved Df-induced AD-like skin lesions in an NC/Nga mouse model by dominantly reducing IgE, NO, suppressing Th2-mediated immune responses, and inhibiting inflammatory cells, as well as improving skin barrier function. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Analysis of Solar Astrolabe Measurements during 20 Years

NASA Astrophysics Data System (ADS)

Poppe, P. C. R.; Leister, N. V.; Laclare, F.; Delmas, C.

1998-11-01

Recent observations of the Sun made between 1974 and 1995 at two observatories were examined to determine the constant and/or linear terms to the equinox and equator of the FK5 reference frame, the mean obliquity of the ecliptic, the mean longitude of the Sun, the mean eccentricity of the Earth's orbit, and the mean longitude of perihelion. The VSOP82 theory was used to reduce the data. The global solution of the weighted least-squares adjustment shows that the equinox of the FK5 requires a correction of +0.072" +/- 0.005" at the mean epoch 1987.24. The FK5 and dynamical equinox agree closely at J2000.0 (-0.040" +/- 0.020"), but an anomalous negative secular variation with respect to the dynamical equinox was detected: -0.881" +/- 0.116" century^-1. The FK5 equator requires a correction of +0.088" +/- 0.016", and there is no indication of a time rate of change. The corrections to the mean longitude of the Sun (-0.020" +/- 0.010") and to the mean obliquity of the ecliptic (-0.041" +/- 0.016") do appear to be statistically significant, although only marginally. The time rates of change for these quantities are not significant on the system to which the observations are referred. In spite of the short time span used in this analysis, the strong correlation between constant and linear terms was completely eliminated with the complete covering of the orbit by the data sets of both sites.

Photometric Observations of Main-belt Asteroids 1637 Swings 10498 Bobgent, and (25980) 2001 FK53

NASA Astrophysics Data System (ADS)

Brincat, Stephen M.; Galdies, Charles

2018-04-01

Photometric observations of asteroids 1637 Swings, 10498 Bobgent and (25980) 2001 FK 53 were acquired from Flarestar Observatory (MPC171) and Znith Observatory in 2017. The observations were made during a favourable apparition for each asteroid.

The neuroregenerative mechanism mediated by the Hsp90-binding immunophilin FKBP52 resembles the early steps of neuronal differentiation

PubMed Central

Quintá, HR; Galigniana, MD

2012-01-01

BACKGROUND AND PURPOSE The immunosuppressive macrolide FK506 (tacrolimus) shows neuroregenerative action by a mechanism that appears to involve the Hsp90-binding immunophilin FKBP52. This study analyses some aspects of the early steps of neuronal differentiation and neuroregeneration. EXPERIMENTAL APPROACH Undifferentiated murine neuroblastoma cells and hippocampal neurones isolated from embryonic day-17 rat embryos were induced to differentiate with FK506. Subcellular relocalization of FKBP52, Hsp90 and its co-chaperone p23 was analysed by indirect immunofluorescence confocal microscopy and by Western blots of axonal fractions isolated from cells grown on a porous transwell cell culture chamber. Neuroregeneration was evaluated using a scratch-wound assay. KEY RESULTS In undifferentiated cells, FKBP52, Hsp90 and p23 are located in the cell nucleus, forming an annular structure that disassembles when the differentiation process is triggered by FK506. This was observed in the N2a cell line and in hippocampal neurones. More importantly, the annular structure of chaperones is reassembled after damaging the neurones, whereas FK506 prompts their rapid regeneration, a process linked to the subcellular redistribution of the heterocomplex. CONCLUSIONS AND IMPLICATIONS There is a direct relationship between the disassembly of the chaperone complex and the progression of neuronal differentiation upon stimulation with the immunophilin ligand FK506. Both neuronal differentiation and neuroregeneration appear to be mechanistically linked, so the elucidation of one mechanism may lead to unravel the properties of the other. This study also implies that the discovery of FK506 derivatives, devoid of immunosuppressive action, would be therapeutically significant for neurotrophic use. PMID:22091865

Mechanistic studies of DepR in regulating FK228 biosynthesis in Chromobacterium violaceum no. 968

PubMed Central

Xue, Jiao; Lin, Wenjing; Deng, Zixin; Cheng, Yi-Qiang

2018-01-01

DepR, a LysR-type transcriptional regulator encoded by the last gene of the putative min operon (orf21-20-19-depR) located at the downstream region of the anticancer agent FK228 biosynthetic gene cluster in Chromobacterium violaceum No. 968, positively regulates the biosynthesis of FK228. In this work, the mechanism underlining this positive regulation was probed by multiple approaches. Electrophoretic mobility shift assay (EMSA) and DNase I footprinting assay (DIFA) identified a conserved 35-nt DNA segment in the orf21-orf22 intergenic region where the purified recombinant DepR binds to. Quantitative reverse transcription PCR (RT-qPCR) and green fluorescent protein (GFP) promoter probe assays established that transcription of phasin gene orf22 increases in the depR deletion mutant of C. violaceum (CvΔdepR) compared to the wild-type strain. FK228 production in the orf22-overexpressed strain C. violaceum was reduced compared with the wild-type strain. DepR has two conserved cysteine residues C199 and C208 presumed to form a disulfide bridge upon sensing oxidative stress. C199X point mutations that locked DepR in a reduced conformation decreased the DNA-binding affinity of DepR; T232A or R278A mutation also had a negative impact on DNA binding of DepR. Complementation of CvΔdepR with any of those versions of depR carrying a single codon mutation was not able to restore FK228 production to the level of wild-type strain. All evidences collectively suggested that DepR positively regulates the biosynthesis of FK228 through indirect metabolic networking. PMID:29672625

Mechanistic studies of DepR in regulating FK228 biosynthesis in Chromobacterium violaceum no. 968.

PubMed

Qiao, Yongjian; Tong, Tiantian; Xue, Jiao; Lin, Wenjing; Deng, Zixin; Cheng, Yi-Qiang; Zhu, Dongqing

2018-01-01

DepR, a LysR-type transcriptional regulator encoded by the last gene of the putative min operon (orf21-20-19-depR) located at the downstream region of the anticancer agent FK228 biosynthetic gene cluster in Chromobacterium violaceum No. 968, positively regulates the biosynthesis of FK228. In this work, the mechanism underlining this positive regulation was probed by multiple approaches. Electrophoretic mobility shift assay (EMSA) and DNase I footprinting assay (DIFA) identified a conserved 35-nt DNA segment in the orf21-orf22 intergenic region where the purified recombinant DepR binds to. Quantitative reverse transcription PCR (RT-qPCR) and green fluorescent protein (GFP) promoter probe assays established that transcription of phasin gene orf22 increases in the depR deletion mutant of C. violaceum (CvΔdepR) compared to the wild-type strain. FK228 production in the orf22-overexpressed strain C. violaceum was reduced compared with the wild-type strain. DepR has two conserved cysteine residues C199 and C208 presumed to form a disulfide bridge upon sensing oxidative stress. C199X point mutations that locked DepR in a reduced conformation decreased the DNA-binding affinity of DepR; T232A or R278A mutation also had a negative impact on DNA binding of DepR. Complementation of CvΔdepR with any of those versions of depR carrying a single codon mutation was not able to restore FK228 production to the level of wild-type strain. All evidences collectively suggested that DepR positively regulates the biosynthesis of FK228 through indirect metabolic networking.

Appropriate Statistics for Determining Chance-Removed Interpractitioner Agreement.

PubMed

Popplewell, Michael; Reizes, John; Zaslawski, Chris

2018-05-31

Fleiss' Kappa (FK) has been commonly, but incorrectly, employed as the "standard" for evaluating chance-removed inter-rater agreement with ordinal data. This practice may lead to misleading conclusions in inter-rater agreement research. An example is presented that demonstrates the conditions where FK produces inappropriate results, compared with Gwet's AC2, which is proposed as a more appropriate statistic. A novel format for recording a Chinese Medical (CM) diagnoses, called the Diagnostic System of Oriental Medicine (DSOM), was used to record and compare patient diagnostic data, which, unlike the contemporary CM diagnostic format, allows agreement by chance to be considered when evaluating patient data obtained with unrestricted diagnostic options available to diagnosticians. Five CM practitioners diagnosed 42 subjects drawn from an open population. Subjects' diagnoses were recorded using the DSOM format. All the available data were initially used to evaluate agreement. Then, the subjects were sorted into three groups to demonstrate the effects of differing data marginality on the calculated chance-removed agreement. Agreement between the practitioners for each subject was evaluated with linearly weighted simple agreement, FK and Gwet's AC2. In all cases, overall agreement was much lower with FK than Gwet's AC2. Larger differences occurred when the data were more free marginal. Inter-rater agreement determined with FK statistics is unlikely to be correct unless it can be shown that the data from which agreement is determined are, in fact, fixed marginal. It follows that results obtained on agreement between practitioners with FK are probably incorrect. It is shown that inter-rater agreement evaluated with AC2 statistic is an appropriate measure when fixed marginal data are neither expected nor guaranteed. The AC2 statistic should be used as the standard statistical approach for determining agreement between practitioners.

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

Moore, P.A.; Rosen, C.A.; Carter, K.C.

This report describes the localization of the human FKBP12-rapamycin-associated protein (FRAP) gene to human chromosome 1p36 using fluorescence in situ hybridization. This protein is the binding site for rapamycin and FK506, two potent immunosuppressive drugs. 12 refs., 1 fig.

Ventana{trade mark, serif} power train features and performance

NASA Astrophysics Data System (ADS)

Mohedano, R.; Benitez, P.; Zamora, P.; Miñano, J. C.; Mendes, J.; Cvetkovic, A.; Vilaplana, J.; Hernandez, M.; Chaves, J.; Biot, G.

2013-09-01

Most CPV systems are based on Fresnel lenses. Among these, LPI-patented Fresnel-Köhler (FK) concentrator outstands owing to performance and practical reasons. The Ventana{trade mark, serif} power train is the first off-the-shelf commercial product based on the FK and comprises both the primary (POE) lenses (a 36-units 1×1 m2 acrylic panel) and glass (or silica glass) secondary optics (SOE). This high concentration optical train (Cg=1,024×, ˜250mm optical depth) fits with 5×5 mm2 (at least) solar cells. The optical train is the fruit of a 1-year development that has included design, modeling, prototyping and characterization, and through the process we had the opportunity to find out how well the actual performance correlates with models, but also learned practical aspects of a CPV system of this kind, some of which have very positive impact on system performance and reliability.

Electro-optical properties of Cu2O for P excitons in the regime of Franz-Keldysh oscillations

NASA Astrophysics Data System (ADS)

Zielińska-Raczyńska, Sylwia; Ziemkiewicz, David; Czajkowski, Gerard

2018-04-01

We present the analytical method which enables one to compute the optical functions i.e., reflectivity, transmission, and absorption, including the excitonic effects, for a semiconductor crystal exposed to a uniform electric field for the energy region above the gap and for the external field suitable for the appearance of Franz-Keldysh (FK) oscillations. Our approach intrinsically takes into account the coherence between the carriers and the electromagnetic field. We quantitatively describe the amplitudes and periodicity of FK modulations as well as the influence of Rydberg excitons on the FK effect. Our analytical findings are illustrated numerically for P excitons in Cu2O crystal.

Regulator of calcineurin 1 controls growth plasticity of adult pancreas.

PubMed

Gurda, Grzegorz T; Crozier, Stephen J; Ji, Baoan; Ernst, Stephen A; Logsdon, Craig D; Rothermel, Beverly A; Williams, John A

2010-08-01

Growth of exocrine pancreas is regulated by gastrointestinal hormones, notably cholecystokinin (CCK). CCK-driven pancreatic growth requires calcineurin (CN), which activates Nuclear Factor of Activated T cells (NFATs), but the genetic underpinnings and feedback mechanisms that regulate this response are not known. Pancreatic growth was stimulated by protease inhibitor (PI)-containing chow, which induces secretion of endogenous CCK. Expression profiling of PI stimulation was performed on Affymetrix 430A chips, and CN was inhibited via FK506. Exocrine pancreas-specific overexpression of CN inhibitor Regulator of Calcineurin 1 (Rcan1) was achieved by breeding elastase-Cre(estrogen receptor [ER]) transgenics with "flox-on" Rcan1 mice. CN inhibitor FK506 blocked expression of 38 genes, as confirmed by quantitative polymerase chain reaction. The CN-dependent genes were linked to growth-related processes, whereas their promoters were enriched in NFAT and NFAT/AP1 sites. Multiple NFAT targets, including Rcan1, Rgs2, HB-EGF, Lif, and Gem, were validated by chromatin immunoprecipitation. One of these, a CN feedback inhibitor Rcan1, was induced >50 fold during 1-8 hours course of pancreatic growth and strongly inhibited (>99%) by FK506. To examine its role in pancreatic growth, we overexpressed Rcan1 in an inducible, acinar-specific fashion. Rcan1 overexpression inhibited CN-NFAT signaling, as shown using an NFAT-luciferase reporter and quantitative polymerase chain reaction. Most importantly, the increase in exocrine pancreas size, protein/DNA content, and acinar proliferation were all blocked in Rcan1 overexpressing mice. We profile adaptive pancreatic growth, identify Rcan1 as an important new feedback regulator, and firmly establish that CN-NFAT signaling is required for this response. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Statistical characterization of arsenic contamination in shallow tube wells of western Bangladesh

NASA Astrophysics Data System (ADS)

Hossain, Faisal; Bagtzoglou, Amvrossios C.; Nahar, Nurun; Delawer Hossain, M.

2006-04-01

A regional assessment of the arsenic (As) contamination scenario in shallow tube wells (depth < 150 m) of western Bangladesh is presented. Comparisons are made in light of bulk geological differences (Pleistocene versus Holocene deposits/northwest versus southwest) and As measurement protocols (field kit (FK) versus atomic absorption spectroscopy (AAS)). Our As database comprised the following: (1) the nationwide As survey completed in 1999 by the British Geological Survey in collaboration with the Department of Public Health Engineering (DPHE); and (2) a regional As survey conducted in southwest Bangladesh by the Japan International Cooperation Agency in collaboration with DPHE in 2002. First, we characterize the error structure of the semi-quantitative FK As measurements using collocated AAS As measurements as reference from a set of 307 wells located in southwest Bangladesh. The depth distribution of As is identified using a very dense cluster of 2963 wells over a 560 km2 domain. The probability of the FK method for successful detection of a well sample as unsafe (safe) was found to be 96.9% (34.1%) and 95.2% (80.3%) for the World Health Organization (WHO) and Bangladesh safe limits, respectively. Similarly, the probability of false alarms and false hopes for WHO (Bangladesh) safe limits were found to be 3.1% (4.8%) and 87.5% (19.7%), respectively. The depth at which the highest fraction of wells exceeding a given safe limit occurred could still be inferred correctly by FK measurements. A simple bias adjustment procedure on FK As data did not result in a more accurate characterization of depth distribution of As. This indicated that simple error statistics are inadequate for advancing the utility of FKs; rather, an understanding of the complex and multidimensional error structure is required. Regional anisotropy in the spatial dependence of As for the northwest was found to be stronger than the southwest. The correlation length for As concentration in the east-west direction of northwest Bangladesh (i.e. across major river floodplains) was found to be almost twice (158.80 km) that of the north-south direction (along the major axis of Pleistocene deposits) (78.21 km). For the southwest region, the ratio of east-west to north-south correlation lengths ranged from 1.40 to 1.51. For the northwest region, because it is well known to have the lowest concentrations of As countrywide, knowledge of this anisotropy appears to suggest the need for drilling twice as many remediation deep wells in the proximity of an unsafe shallow well in the north-south direction than in the east-west direction. Findings from this study are potentially useful in setting priority areas for emergency testing, distributing remediation resources equitably and formulating a regional water resources strategy for western Bangladesh.

Titanium surfaces immobilized with the major antimicrobial fragment FK-16 of human cathelicidin LL-37 are potent against multiple antibiotic-resistant bacteria.

PubMed

Mishra, Biswajit; Wang, Guangshun

2017-08-01

Infections on implanted medical devices are a challenging problem, especially when bacteria form difficult-to-treat biofilms. Antimicrobial peptides are considered to be a solution due to their potency against antibiotic-resistant superbugs. Previously, the authors' laboratory demonstrated the prevention of staphylococcal biofilm formation in an animal catheter model by injecting merecidin (formerly known as 17BIPHE2), a peptide engineered based on the only human cathelicidin. This study documents an alternative solution via covalent immobilization of FK-16, amino acid sequence FKRIVQRIKDFLRNLV-amide, which corresponds to the major antimicrobial region (residues 17-32) of LL-37. FK-16 is superior to the longer peptide LL-37 in terms of synthesis cost and the shorter peptide KR-12 in terms of activity spectrum. Indeed, the FK16-coated titanium surface showed a broad-spectrum activity against the ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. It also demonstrated anti-adhesion and biofilm inhibition capabilities against both S. aureus and E. coli.

Optical recognition of statistical patterns

NASA Astrophysics Data System (ADS)

Lee, S. H.

1981-12-01

Optical implementation of the Fukunaga-Koontz transform (FKT) and the Least-Squares Linear Mapping Technique (LSLMT) is described. The FKT is a linear transformation which performs image feature extraction for a two-class image classification problem. The LSLMT performs a transform from large dimensional feature space to small dimensional decision space for separating multiple image classes by maximizing the interclass differences while minimizing the intraclass variations. The FKT and the LSLMT were optically implemented by utilizing a coded phase optical processor. The transform was used for classifying birds and fish. After the F-K basis functions were calculated, those most useful for classification were incorporated into a computer generated hologram. The output of the optical processor, consisting of the squared magnitude of the F-K coefficients, was detected by a T.V. camera, digitized, and fed into a micro-computer for classification. A simple linear classifier based on only two F-K coefficients was able to separate the images into two classes, indicating that the F-K transform had chosen good features. Two advantages of optically implementing the FKT and LSLMT are parallel and real time processing.

Optical recognition of statistical patterns

NASA Technical Reports Server (NTRS)

Lee, S. H.

1981-01-01

Optical implementation of the Fukunaga-Koontz transform (FKT) and the Least-Squares Linear Mapping Technique (LSLMT) is described. The FKT is a linear transformation which performs image feature extraction for a two-class image classification problem. The LSLMT performs a transform from large dimensional feature space to small dimensional decision space for separating multiple image classes by maximizing the interclass differences while minimizing the intraclass variations. The FKT and the LSLMT were optically implemented by utilizing a coded phase optical processor. The transform was used for classifying birds and fish. After the F-K basis functions were calculated, those most useful for classification were incorporated into a computer generated hologram. The output of the optical processor, consisting of the squared magnitude of the F-K coefficients, was detected by a T.V. camera, digitized, and fed into a micro-computer for classification. A simple linear classifier based on only two F-K coefficients was able to separate the images into two classes, indicating that the F-K transform had chosen good features. Two advantages of optically implementing the FKT and LSLMT are parallel and real time processing.

Cyclosporin A and FK-506 both affect DNA binding of regulatory nuclear proteins to the human interleukin-2 promoter.

PubMed

Baumann, G; Geisse, S; Sullivan, M

1991-03-01

The structurally unrelated immunosuppressive drugs cyclosporin A (Sandimmun) and FK-506 both interfere with the process of T-cell proliferation by blocking the transcription of the T-cell growth factor interleukin-2 (IL-2). Here we demonstrate that the transcriptional activation of this gene requires the binding of regulatory nuclear proteins to a promoter element with sequence similarity to the consensus binding site for NF-kappa B-related transcription factors. We present evidence that the binding by regulatory nuclear proteins to the kappa B element of the IL-2 promoter is affected negatively by cyclosporin A and FK-506 at concentrations paralleling their immunosuppressive activity in vivo. The decrease in DNA-protein complex formation induced by the immunosuppressive drugs correlates with a decrease in IL-2 production. FK-506 is 10 to 100 times more potent than cyclosporin A in its ability to inhibit sequence-specific DNA binding and IL-2 production. Our findings suggest that the actions of both drugs converge at the level of DNA-protein interaction.

Transforming growth factor‐β enhances Rho‐kinase activity and contraction in airway smooth muscle via the nucleotide exchange factor ARHGEF1

PubMed Central

Shaifta, Yasin; MacKay, Charles E.; Irechukwu, Nneka; O'Brien, Katie A.; Wright, David B.; Ward, Jeremy P. T.

2017-01-01

Key points Transforming growth‐factor‐β (TGF‐β) and RhoA/Rho‐kinase are independently implicated in the airway hyper‐responsiveness associated with asthma, but how these proteins interact is not fully understood.We examined the effects of pre‐treatment with TGF‐β on expression and activity of RhoA, Rho‐kinase and ARHGEF1, an activator of RhoA, as well as on bradykinin‐induced contraction, in airway smooth muscle.TGF‐β enhanced bradykinin‐induced RhoA translocation, Rho‐kinase‐dependent phosphorylation and contraction, but partially suppressed bradykinin‐induced RhoA activity (RhoA‐GTP content).TGF‐β enhanced the expression of ARHGEF1, while a small interfering RNA against ARHGEF1 and a RhoGEF inhibitor prevented the effects of TGF‐β on RhoA and Rho‐kinase activity and contraction, respectively.ARHGEF1 expression was also enhanced in airway smooth muscle from asthmatic patients and ovalbumin‐sensitized mice.ARHGEF1 is a key TGF‐β target gene, an important regulator of Rho‐kinase activity and therefore a potential therapeutic target for the treatment of asthmatic airway hyper‐responsiveness. Abstract Transforming growth factor‐β (TGF‐β), RhoA/Rho‐kinase and Src‐family kinases (SrcFK) have independently been implicated in airway hyper‐responsiveness, but how they interact to regulate airway smooth muscle contractility is not fully understood. We found that TGF‐β pre‐treatment enhanced acute contractile responses to bradykinin (BK) in isolated rat bronchioles, and inhibitors of RhoGEFs (Y16) and Rho‐kinase (Y27632), but not the SrcFK inhibitor PP2, prevented this enhancement. In cultured human airway smooth muscle cells (hASMCs), TGF‐β pre‐treatment enhanced the protein expression of the Rho guanine nucleotide exchange factor ARHGEF1, MLC20, MYPT‐1 and the actin‐severing protein cofilin, but not of RhoA, ROCK2 or c‐Src. In hASMCs, acute treatment with BK triggered subcellular translocation of ARHGEF1 and RhoA and enhanced auto‐phosphorylation of SrcFK and phosphorylation of MYPT1 and MLC20, but induced de‐phosphorylation of cofilin. TGF‐β pre‐treatment amplified the effects of BK on RhoA translocation and MYPT1/MLC20 phosphorylation, but suppressed the effects of BK on RhoA‐GTP content, SrcFK auto‐phosphorylation and cofilin de‐phosphorylation. In hASMCs, an ARHGEF1 small interfering RNA suppressed the effects of BK and TGF‐β on RhoA‐GTP content, RhoA translocation and MYPT1 and MLC20 phosphorylation, but minimally influenced the effects of TGF‐β on cofilin expression and phosphorylation. ARHGEF1 expression was also enhanced in ASMCs of asthmatic patients and in lungs of ovalbumin‐sensitized mice. Our data indicate that TGF‐β enhances BK‐induced contraction, RhoA translocation and Rho‐kinase activity in airway smooth muscle largely via ARHGEF1, but independently of SrcFK and total RhoA‐GTP content. A role for smooth muscle ARHGEF1 in asthmatic airway hyper‐responsiveness is worthy of further investigation. PMID:29071730

Traumatic brain injury causes an FK506-sensitive loss and an overgrowth of dendritic spines in rat forebrain.

PubMed

Campbell, John N; Register, David; Churn, Severn B

2012-01-20

Traumatic brain injury (TBI) causes both an acute loss of tissue and a progressive injury through reactive processes such as excitotoxicity and inflammation. These processes may worsen neural dysfunction by altering neuronal circuitry beyond the focally-damaged tissue. One means of circuit alteration may involve dendritic spines, micron-sized protuberances of dendritic membrane that support most of the excitatory synapses in the brain. This study used a modified Golgi-Cox technique to track changes in spine density on the proximal dendrites of principal cells in rat forebrain regions. Spine density was assessed at 1 h, 24 h, and 1 week after a lateral fluid percussion TBI of moderate severity. At 1 h after TBI, no changes in spine density were observed in any of the brain regions examined. By 24 h after TBI, however, spine density had decreased in ipsilateral neocortex in layer II and III and dorsal dentate gyrus (dDG). This apparent loss of spines was prevented by a single, post-injury administration of the calcineurin inhibitor FK506. These results, together with those of a companion study, indicate an FK506-sensitive mechanism of dendritic spine loss in the TBI model. Furthermore, by 1 week after TBI, spine density had increased substantially above control levels, bilaterally in CA1 and CA3 and ipsilaterally in dDG. The apparent overgrowth of spines in CA1 is of particular interest, as it may explain previous reports of abnormal and potentially epileptogenic activity in this brain region.

Assessment of nerve regeneration across nerve allografts treated with tacrolimus.

PubMed

Haisheng, Han; Songjie, Zuo; Xin, Li

2008-01-01

Although regeneration of nerve allotransplant is a major concern in the clinic, there have been few papers quantitatively assessing functional recovery of animals' nerve allografts in the long term. In this study, functional recovery, histopathological study, and immunohistochemistry changes of rat nerve allograft with FK506 were investigated up to 12 weeks without slaughtering. C57 and SD rats were used for transplantation. The donor's nerve was sliced and transplanted into the recipient. The sciatic nerve was epineurally sutured with 10-0 nylon. In total, 30 models of transplantation were performed and divided into 3 groups that were either treated with FK506 or not. Functional recovery of the grafted nerve was serially assessed by the pin click test, walking track analysis and electrophysiological evaluations. A histopathological study and immunohistochemistry study were done in the all of the models. Nerve allografts treated with FK506 have no immune rejection through 12 weeks. Sensibility had similarly improved in both isografts and allografts. There has been no difference in each graft. Walk track analysis demonstrates significant recovery of motor function of the nerve graft. No histological results of difference were found up to 12 weeks in each graft. In the rodent nerve graft model, FK506 prevented nerve allograft rejection across a major histocompatibility barrier. Sensory recovery seems to be superior to motor function. Nerve isograft and allograft treated with FK506 have no significant difference in function recovery, histopathological result, and immunohistochemistry changes.

Reduction of FR900525 using an S-(2-aminoethyl) l-cysteine-resistant mutant.

PubMed

Shimizu, Shiho; Futase, Ayako; Yokoyama, Tatsuya; Ueda, Satoshi; Honda, Hiroyuki

2017-06-01

FK506 (tacrolimus), a macrolide compound with immunosuppressant activity, has been proven to have clinical importance and has been manufactured industrially since 1993 by using mutants with high FK506-production ability; these mutants have been developed from the wild strain Streptomyces tsukubaensis No. 9993. FR900525 is one of the by-products of FK506 production. However, there was no effective industrial method to separate FR900525 from FK506 due to the structural similarity between the two compounds. Therefore, reducing the level of FR900525 was a serious problem in the industrial strain A. In this study, we aimed to reduce the FR900525 production. We first determined that pipecolic acid level was a critical parameter for controlling FR900525 production in strain A. S-(2-Aminoethyl) l-cysteine (AEC)-resistant mutants has been reported to increase lysine productivity successfully in a variety of lysine-producing microorganisms. Therefore, next, we applied a selection of AEC-resistant mutants to enhance pipecolic acid biosynthesis. Finally, four AEC-resistant mutants were obtained from strain A using ultraviolet irradiation, and three of them showed less FR900525 productivity compared to the parental strain A. Our findings indicated that AEC resistance was effective phenotype marker for increasing pipecolic acid productivity and for reducing FR900525 production in S. tsukubaensis. Thus, our study provides an efficient method for reducing FR90025 level during FK506 biosynthesis. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

The role of optoelectronic feedback on Franz-Keldysh voltage modulation of transistor lasers

NASA Astrophysics Data System (ADS)

Chang, Chi-Hsiang; Chang, Shu-Wei; Wu, Chao-Hsin

2016-03-01

Possessing both the high-speed characteristics of heterojunction bipolar transistors (HBTs) and enhanced radiative recombination of quantum wells (QWs), the light-emitting transistor (LET) which operates in the regime of spontaneous emissions has achieved up to 4.3 GHz modulation bandwidth. A 40 Gbit/s transmission rate can be even achieved using transistor laser (TL). The transistor laser provides not only the current modulation but also direct voltage-controlled modulation scheme of optical signals via Franz-Keldysh (FK) photon-assisted tunneling effect. In this work, the effect of FK absorption on the voltage modulation of TLs is investigated. In order to analyze the dynamics and optical responses of voltage modulation in TLs, the conventional rate equations relevant to diode lasers (DLs) are first modified to include the FK effect intuitively. The theoretical results of direct-current (DC) and small-signal alternating-current (AC) characteristics of optical responses are both investigated. While the DC characteristics look physical, the intrinsic optical response of TLs under the FK voltage modulation shows an AC enhancement with a 20 dB peak, which however is not observed in experiment. A complete model composed of the intrinsic optical transfer function and an electrical transfer function fed back by optical responses is proposed to explain the behaviors of voltage modulation in TLs. The abnormal AC peak disappears through this optoelectronic feedback. With the electrical response along with FK-included photon-carrier rate equations taken into account, the complete voltage-controlled optical modulation response of TLs is demonstrated.

A key role for Pre-B cell colony-enhancing factor in experimental hepatitis.

PubMed

Moschen, Alexander R; Gerner, Romana; Schroll, Andrea; Fritz, Teresa; Kaser, Arthur; Tilg, Herbert

2011-08-01

Pre-B cell colony-enhancing factor (PBEF), also known as nicotinamide phosphoribosyltransferase or visfatin, plays an important role in metabolic, inflammatory, and malignant diseases. Recent evidence suggests that blocking its enzymatic activity using a specific small-molecule inhibitor (FK866) might be beneficial in acute experimental inflammation. We investigated the role of PBEF in human liver disease and experimental hepatitis. PBEF serum levels and hepatic expression were determined in patients with chronic liver diseases. These studies were followed by in vivo experiments using concanavalin A (ConA) and D-galactosamine/lipopolysaccharide (LPS) models of experimental hepatitis. PBEF was either overexpressed by hydrodynamic perfusion or inhibited by FK866. In vivo findings were corroborated studying inflammatory responses of lentivirally PBEF-silenced or control FL83B mouse hepatocytes. Here, we demonstrate that PBEF serum levels were increased in patients with chronic liver diseases irrespective of disease stage and etiology. In particular, we observed enhanced PBEF expression in hepatocytes. Liver-targeted overexpression of PBEF rendered mice more susceptible to ConA- and D-galactosamine/LPS-induced hepatitis compared with control animals. In contrast, inhibition of PBEF using FK866 protected mice from ConA-induced liver damage and apoptosis. Administration of FK866 resulted in depletion of liver nicotinamide adenine dinucleotide+ levels and reduced proinflammatory cytokine expression. Additionally, FK866 protected mice in the D-galactosamine/LPS model of acute hepatitis. In vitro, PBEF-silenced mouse hepatocytes showed decreased responses after stimulation with LPS, lipoteichoic acid, and tumor necrosis factor α. In primary murine Kupffer cells, FK866 suppressed LPS-induced interleukin (IL)-6 production, whereas incubation with recombinant PBEF resulted in increased IL-6 release. Our data suggest that PBEF is of key importance in experimental hepatitis. Its specific inhibition might be considered a novel treatment option for inflammatory liver diseases. Copyright © 2011 American Association for the Study of Liver Diseases.

Investigation of the FK5 system in the equatorial zone. Application to the instrumental system of the Second Quito astrolabe catalogue.

NASA Astrophysics Data System (ADS)

Kolesnik, Y. B.

1995-12-01

15 catalogues produced in the 1980s and 12 catalogues made from 1960 to 1978 have been used to assess the consistency of the FK5 system with observations in the declination zone from -30deg to 30deg. Classical δ-dependent and α-dependent systematic differences (Cat-FK5) have been formed for individual instrumental systems of the catalogues. The weighted mean instrumental systems for two subsets of catalogues centred at the epochs 1970 and 1987 have been constructed. External systematic and random accuracy of the catalogues under analysis and errors of the mean instrumental systems for both selections of catalogues have been estimated and presented in tables. The individual systematic differences of the catalogues and the mean instrumental systems are shown in figures. Numerical values of the total systematic deviations for both mean instrumental systems are given in tables. The results of intercomparison are discussed to assess the actual systematic deviations of the FK5 at the respective epochs and its actual random accuracy. It has been found that the mutual consistency of individual instrumental systems of catalogues of 1980s with respect to zonal systematic differences in both right ascension and declination is significantly better when comparing with the earlier catalogues. Consistency of both catalogue subsets is comparable with respect to α-dependent systematic differences. It is shown that the claimed random errors of the FK5 positions and proper motions are rather realistic, while deviations of the FK5 right ascension and declination system in the equatorial zone for both mean epochs exceed expected ones from the formal considerations. Quick degradation of the FK5 system with time is detected in right ascension. The results in declination are recognized to be less reliable, due to larger inconsistency of the individual instrumental systems. The system of the Second Quito Astrolabe Catalogue (QAC 2) has been investigated by comparison with two subsets of catalogues. It shows rather good consistency with both mean instrumental systems. Some conspicuous local deviations are outlined and discussed. We conclude that the QAC 2 might successfully be used in the compilation of the future second general catalogue of astrolabes as a link between northern and southern astrolabe catalogues.

Campath-1H + FK506 and Methylprednisolone for GVHD

ClinicalTrials.gov

2010-06-10

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

The cannabinoid receptor agonist WIN 55,212-2 inhibits antigen-induced plasma extravasation in guinea pig airways.

PubMed

Fukuda, Hironobu; Abe, Toshio; Yoshihara, Shigemi

2010-01-01

Although neurogenic inflammation of the airways via activation of C-fibers is thought to be important in the pathogenesis of asthma, the mechanisms regulating C-fiber activity remain uncertain. The influence of a cannabinoid receptor agonist, WIN 55,212-2, on C-fiber activation in guinea pig airways was investigated, as was the mechanism by which cannabinoids regulate antigen-induced airway inflammation. The inhibitory effect of WIN 55,212-2 on antigen-induced plasma extravasation was assessed in guinea pig tracheal tissues by photometric measurement of extravasated Evans blue dye after extraction with formamide. Pretreatment with WIN 55,212-2 (0.001, 0.01 or 0.1 mg/kg) significantly and dose-dependently reduced tracheal plasma extravasation induced by inhaling a 5% ovalbumin solution for 2 min after pretreatment with a neutral endopeptidedase inhibitor (phosphoramidon at 2.5 mg/kg i.v.). A cannabinoid CB2 receptor antagonist (SR144528) blunted the inhibitory effect of WIN 55,212-2, while a cannabinoid CB1 antagonist (SR141716A) did not. Pretreatment with a neurokinin-1 receptor antagonist (FK888) significantly reduced ovalbumin-induced extravasation of Evans blue dye. Pretreatment with the combination of WIN 55,212-2 and FK888 reduced antigen-induced plasma extravasation more markedly than FK888 alone. These findings suggest that WIN 55,212-2 inhibits C-fiber activation via the cannabinoid CB2 receptor and thus suppresses antigen-induced inflammation in guinea pig airways. 2010 S. Karger AG, Basel.

FK COMAE BERENICES, KING OF SPIN: THE COCOA-PUFS PROJECT

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

Ayres, Thomas R.; Kashyap, V.; Saar, S.

COCOA-PUFS is an energy-diverse, time-domain study of the ultra-fast spinning, heavily spotted, yellow giant FK Comae Berenices (FK Com: HD117555; G4 III). This single star is thought to be a recent binary merger, and is exceptionally active by measure of its intense ultraviolet (UV) and X-ray emissions, and proclivity to flare. COCOA-PUFS was carried out with the Hubble Space Telescope in the UV (1200–3000 Å), using mainly its high-performance Cosmic Origins Spectrograph, but also high precision Space Telescope Imaging Spectrograph; Chandra X-ray Observatory in the soft X-rays (0.5–10 keV), utilizing its High-Energy Transmission Grating Spectrometer; together with supporting photometry andmore » spectropolarimetry in the visible from the ground. This is an introductory report on the project. FK Com displayed variability on a wide range of timescales over all wavelengths during the week-long main campaign, including a large X-ray flare; “super-rotational broadening” of the far-ultraviolet “hot lines” (e.g., Si iv 1393 Å; 8 × 10{sup 4} K) together with chromospheric Mg ii 2800 Å and C ii 1335 Å (1–3 × 10{sup 4} K); large Doppler swings suggestive of bright regions alternately on advancing and retreating limbs of the star; and substantial redshifts of the epoch-average emission profiles. These behaviors paint a picture of a highly extended, dynamic, hot (∼10 MK) coronal magnetosphere around the star, threaded by cooler structures perhaps analogous to solar prominences and replenished continually by surface activity and flares. Suppression of angular momentum loss by the confining magnetosphere could temporarily postpone the inevitable stellar spindown, thereby lengthening this highly volatile stage of coronal evolution.« less

FK Comae Berenices, King of Spin: The COCOA-PUFS Project

NASA Astrophysics Data System (ADS)

Ayres, Thomas R.; Kashyap, V.; Saar, S.; Huenemoerder, D.; Korhonen, H.; Drake, J. J.; Testa, P.; Cohen, O.; Garraffo, C.; Granzer, T.; Strassmeier, K.

2016-03-01

COCOA-PUFS is an energy-diverse, time-domain study of the ultra-fast spinning, heavily spotted, yellow giant FK Comae Berenices (FK Com: HD117555; G4 III). This single star is thought to be a recent binary merger, and is exceptionally active by measure of its intense ultraviolet (UV) and X-ray emissions, and proclivity to flare. COCOA-PUFS was carried out with the Hubble Space Telescope in the UV (1200-3000 Å), using mainly its high-performance Cosmic Origins Spectrograph, but also high precision Space Telescope Imaging Spectrograph; Chandra X-ray Observatory in the soft X-rays (0.5-10 keV), utilizing its High-Energy Transmission Grating Spectrometer; together with supporting photometry and spectropolarimetry in the visible from the ground. This is an introductory report on the project. FK Com displayed variability on a wide range of timescales over all wavelengths during the week-long main campaign, including a large X-ray flare; “super-rotational broadening” of the far-ultraviolet “hot lines” (e.g., Si IV 1393 Å 8 × 104 K) together with chromospheric Mg II 2800 Å and C II 1335 Å (1-3 × 104 K); large Doppler swings suggestive of bright regions alternately on advancing and retreating limbs of the star; and substantial redshifts of the epoch-average emission profiles. These behaviors paint a picture of a highly extended, dynamic, hot (˜10 MK) coronal magnetosphere around the star, threaded by cooler structures perhaps analogous to solar prominences and replenished continually by surface activity and flares. Suppression of angular momentum loss by the confining magnetosphere could temporarily postpone the inevitable stellar spindown, thereby lengthening this highly volatile stage of coronal evolution. COordinated Campaign of Observations and Analysis, Photosphere to Upper Atmosphere, of a Fast-rotating Star.

Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

PubMed

Cui, Ju; Pang, Jing; Lin, Ya-Jun; Gong, Huan; Wang, Zhen-He; Li, Yun-Xuan; Li, Jin; Wang, Zai; Jiang, Ping; Dai, Da-Peng; Li, Jian; Cai, Jian-Ping; Huang, Jian-Dong; Zhang, Tie-Mei

2017-06-01

Recent studies have shown that KIF5B (conventional kinesin heavy chain) mediates glucose transporter type 4 translocation and adiponectin secretion in 3T3-L1 adipocytes, suggesting an involvement of KIF5B in the homeostasis of metabolism. However, the in vivo physiologic function of KIF5B in adipose tissue remains to be determined. In this study, adipose-specific Kif5b knockout (F-K5bKO) mice were generated using the Cre-LoxP strategy. F-K5bKO mice had similar body weights to controls fed on a standard chow diet. However, F-K5bKO mice had hyperlipidemia and significant glucose intolerance and insulin resistance. Deletion of Kif5b aggravated the deleterious impact of a high-fat diet (HFD) on body weight gain, hepatosteatosis, glucose tolerance, and systematic insulin sensitivity. These changes were accompanied by impaired insulin signaling, decreased secretion of adiponectin, and increased serum levels of leptin and proinflammatory adipokines. F-K5bKO mice fed on an HFD exhibited lower energy expenditure and thermogenic dysfunction as a result of whitening of brown adipose due to decreased mitochondria biogenesis and down-regulation of key thermogenic gene expression. In conclusion, selective deletion of Kif5b in adipose tissue exacerbates HFD-induced obesity and its associated metabolic disorders, partly through a decrease in energy expenditure, dysregulation of adipokine secretion, and insulin signaling.-Cui, J., Pang, J., Lin, Y.-J., Gong, H., Wang, Z.-H., Li, Y.-X., Li, J., Wang, Z., Jiang, P., Dai, D.-P., Li, J., Cai, J.-P., Huang, J.-D., Zhang, T.-M. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity. © FASEB.

Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew).

PubMed

Rudd, J A; Ngan, M P; Wai, M K

1999-02-05

The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.

Analytic representations of mK , FK, mη, and Fη in two loop S U (3 ) chiral perturbation theory

NASA Astrophysics Data System (ADS)

Ananthanarayan, B.; Bijnens, Johan; Friot, Samuel; Ghosh, Shayan

2018-06-01

In this work, we consider expressions for the masses and decay constants of the pseudoscalar mesons in S U (3 ) chiral perturbation theory. These involve sunset diagrams and their derivatives evaluated at p2=mP2 (P =π , K , η ). Recalling that there are three mass scales in this theory, mπ, mK and mη, there are instances when the finite part of the sunset diagrams do not admit an expression in terms of elementary functions, and have therefore been evaluated numerically in the past. In a recent publication, an expansion in the external momentum was performed to obtain approximate analytic expressions for mπ and Fπ, the pion mass and decay constant. We provide fully analytic exact expressions for mK and mη, the kaon and eta masses, and FK and Fη, the kaon and eta decay constants. These expressions, calculated using Mellin-Barnes methods, are in the form of double series in terms of two mass ratios. A numerical analysis of the results to evaluate the relative size of contributions coming from loops, chiral logarithms as well as phenomenological low-energy constants is presented. We also present a set of approximate analytic expressions for mK, FK, mη and Fη that facilitate comparisons with lattice results. Finally, we show how exact analytic expressions for mπ and Fπ may be obtained, the latter having been used in conjunction with the results for FK to produce a recently published analytic representation of FK/Fπ.

Dispersion, mode-mixing and the electron-phonon interaction in nanostructures

NASA Astrophysics Data System (ADS)

Dyson, A.; Ridley, B. K.

2018-03-01

The electron-phonon interaction with polar optical modes in nanostructures is re-examined in the light of phonon dispersion relations and the role of the Fuchs-Kliewer (FK) mode. At an interface between adjacent polar materials the frequencies of the FK mode are drawn from the dielectric constants of the adjacent materials and are significantly smaller than the corresponding frequencies of the longitudinal optic (LO) modes at the zone centre. The requirement that all polar modes satisfy mechanical and electrical boundary conditions forces the modes to become hybrids. For a hybrid to have both FK and LO components the LO mode must have the FK frequency, which can only come about through the reduction associated with phonon dispersion relations. We illustrate the effect of phonon dispersion relations on the Fröhlich interaction by considering a simple linear-chain model of the zincblende lattice. Optical and acoustic modes become mixed towards short wavelengths in both optical and acoustic branches. A study of GaAs, InP and cubic GaN and AlN shows that the polarity of the optical branch and the acousticity of the acoustic branch are reduced by dispersion in equal measures, but the effect is relatively weak. Coupling coefficients quantifying the strengths of the interaction with electrons for optical and acoustic components of mixed modes in the optical branch show that, in most cases, the polar interaction dominates the acoustic interaction, and it is reduced from the long-wavelength result towards the zone boundary by only a few percent. The effect on the lower-frequency FK mode can be large.

Antascomicins A, B, C, D and E. Novel FKBP12 binding compounds from a Micromonospora strain.

PubMed

Fehr, T; Sanglier, J J; Schuler, W; Gschwind, L; Ponelle, M; Schilling, W; Wioland, C

1996-03-01

5 novel ascomycin-like compounds, antascomicins A, B, C, D and E were isolated from a strain of Micromonospora. The antascomicins bind strongly to the FK506-binding protein FKBP12 and antagonize the immunosuppressive activity of FK506 and rapamycin. The strain description, fermentation, structure elucidation and biological activity of these compounds are described.

Experimental characterization of Fresnel-Köhler concentrators

NASA Astrophysics Data System (ADS)

Zamora, Pablo; Benítez, Pablo; Mohedano, Rubén; Cvetković, Aleksandra; Vilaplana, Juan; Li, Yang; Hernández, Maikel; Chaves, Julio; Miñano, Juan C.

2012-01-01

Most cost-effective concentrated photovoltaics (CPV) systems are based on an optical train comprising two stages, the first being a Fresnel lens. Among them, the Fresnel-Köhler (FK) concentrator stands out owing to both performance and practical reasons. We describe the experimental measurements procedure for FK concentrator modules. This procedure includes three main types of measurements: electrical efficiency, acceptance angle, and irradiance uniformity at the solar cell plane. We have collected here the performance features of two different FK prototypes (ranging different f-numbers, concentration ratios, and cell sizes). The electrical efficiencies measured in both prototypes are high and fit well with the models, achieving values up to 32.7% (temperature corrected, and with no antireflective coating on SOE or POE surfaces) in the best case. The measured angular transmission curves show large acceptance angles, again perfectly matching the expected values [measured concentration acceptance product (CAP) values over 0.56]. The irradiance pattern on the cell (obtained with a digital camera) shows an almost perfectly uniform distribution, as predicted by raytrace simulations. All these excellent on-sun results confirm the FK concentrator as a potentially cost-effective solution for the CPV market.

FK506-Binding Proteins and Their Diverse Functions.

PubMed

Tong, Mingming; Jiang, Yu

2015-01-01

FK506 binding proteins (FKBPs) are a family of highly conserved proteins in eukaryotes. The prototype of this protein family, FKBP12, is the binding partner for immunosuppressive drugs FK506 and rapamycin. FKBP12 functions as a cis/trans peptidyl prolyl isomerase (PPIase) that catalyzes interconversion between prolyl cis/trans conformations. Members of the FKBP family contain one or several PPIase domains, which do not always exhibit PPIase activity yet are all essential for their function. FKBPs are involved in diverse cellular functions including protein folding, cellular signaling, apoptosis and transcription. They elicit their function through direct binding and altering conformation of their target proteins, hence acting as molecular switches. In this review, we provide a general summary for the structures and diverse functions of FKBPs found in mammalian cells.

Progress In Fresnel-Köhler Concentrators

NASA Astrophysics Data System (ADS)

Mohedano, Rubén; Cvetković, Aleksandra; Benítez, Pablo; Chaves, Julio; Miñano, Juan C.; Zamora, Pablo; Hernandez, Maikel; Vilaplana, Juan

2011-12-01

The Fresnel Köhler (FK) concentrator was first presented in 2008. Since then, various CPV companies have adopted this technology as base for their future commercial product. The key for this rapid penetration is a mixture of simplicity (the FK is essentially a Fresnel lens concentrator, a technology that dominates the market) and excellent performance: high concentration without giving up large manufacturing/aiming tolerances, enabling high efficiency even at the array level. All these features together have a great potential to lower energy costs. This work shows recent results and progress regarding this device, covering new design features, measurements and tests along with first performance achievements at the array level (pilot 6.5 Kwp plant). The work also discusses the potential impact of the FK enhanced performance on the Levelized Cost Of Electricity (LCOE).

Detecting of transient vibration signatures using an improved fast spatial-spectral ensemble kurtosis kurtogram and its applications to mechanical signature analysis of short duration data from rotating machinery

NASA Astrophysics Data System (ADS)

Chen, BinQiang; Zhang, ZhouSuo; Zi, YanYang; He, ZhengJia; Sun, Chuang

2013-10-01

Detecting transient vibration signatures is of vital importance for vibration-based condition monitoring and fault detection of the rotating machinery. However, raw mechanical signals collected by vibration sensors are generally mixtures of physical vibrations of the multiple mechanical components installed in the examined machinery. Fault-generated incipient vibration signatures masked by interfering contents are difficult to be identified. The fast kurtogram (FK) is a concise and smart gadget for characterizing these vibration features. The multi-rate filter-bank (MRFB) and the spectral kurtosis (SK) indicator of the FK are less powerful when strong interfering vibration contents exist, especially when the FK are applied to vibration signals of short duration. It is encountered that the impulsive interfering contents not authentically induced by mechanical faults complicate the optimal analyzing process and lead to incorrect choosing of the optimal analysis subband, therefore the original FK may leave out the essential fault signatures. To enhance the analyzing performance of FK for industrial applications, an improved version of fast kurtogram, named as "fast spatial-spectral ensemble kurtosis kurtogram", is presented. In the proposed technique, discrete quasi-analytic wavelet tight frame (QAWTF) expansion methods are incorporated as the detection filters. The QAWTF, constructed based on dual tree complex wavelet transform, possesses better vibration transient signature extracting ability and enhanced time-frequency localizability compared with conventional wavelet packet transforms (WPTs). Moreover, in the constructed QAWTF, a non-dyadic ensemble wavelet subband generating strategy is put forward to produce extra wavelet subbands that are capable of identifying fault features located in transition-band of WPT. On the other hand, an enhanced signal impulsiveness evaluating indicator, named "spatial-spectral ensemble kurtosis" (SSEK), is put forward and utilized as the quantitative measure to select optimal analyzing parameters. The SSEK indicator is robuster in evaluating the impulsiveness intensity of vibration signals due to its better suppressing ability of Gaussian noise, harmonics and sporadic impulsive shocks. Numerical validations, an experimental test and two engineering applications were used to verify the effectiveness of the proposed technique. The analyzing results of the numerical validations, experimental tests and engineering applications demonstrate that the proposed technique possesses robuster transient vibration content detecting performance in comparison with the original FK and the WPT-based FK method, especially when they are applied to the processing of vibration signals of relative limited duration.

FK506 attenuates thymic output in patients with myasthenia gravis

PubMed Central

Kuroda, Yukiko; Ueno, Shu-ichi; Matsui, Naoko; Kaji, Ryuji

2013-01-01

Introduction Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4+ T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG. Material and methods We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants. Results T-cell receptor excision circle was not significantly different from those in age-matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4–CD8+ cells (p < 0.05), but total cell counts were not significantly changed. Conclusions These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also naïve T-cells. PMID:24482655

Fully developed turbulence and complex time singularities

NASA Astrophysics Data System (ADS)

Dombre, T.; Gagne, Y.; Hopfinger, E.

The hypothesis of Frisch and Morf (1981), relating intermittent bursts observed in high-pass-filtered turbulent-flow data to complex time singularities in the solution of the Navier-Stokes equations, is tested experimentally. Velocity signals filtered at high-pass frequency 1 kHz and low-pass frequency 6 kHz are recorded for 7 min at sampling frequency 20 kHz in a flow of mean velocity 6.1 m/s, with mesh length d = 7.5 cm, observation point x/d = 40, R sub lambda = 67, dissipation length eta = 0.5 mm, and Kolmogorov frequency fK = about 2 kHz. The results are presented in graphs, and it is shown that the exponential behavior of the energy spectrum settles well before fK, the spectra of individual bursts having exponential behavior and delta(asterisk) values consistent with the Frisch-Morf hypothesis, at least for high-amplitude events.

The "Horns" of FK Comae and the Complex Structure of its Outer Atmosphere

NASA Astrophysics Data System (ADS)

Saar, Steven H.; Ayres, T. R.; Kashyap, V.

2014-01-01

As part of a large multiwavelength campaign (COCOA-PUFS*) to explore magnetic activity in the unusual, single, rapidly rotating giant FK Comae, we have taken a time series of moderate resolution FUV spectra of the star with the COS spectrograph on HST. We find that the star has unusual, time-variable emission profiles in the chromosphere and transition region which show horn-like features. We use simple spatially inhomogeneous models to explain the variable line shapes. Modeling the lower chromospheric Cl I 1351 Å line, we find evidence for a very extended, spatial inhomogeneous outer atmosphere, likely composed of many huge "sling-shot" prominences of cooler material with embedded in a rotationally distended corona. We compare these results with hotter hotter transition region lines (Si IV) and optical spectra of the chromospheric He I D3 line. We also employ the model Cl I profiles, and data-derived empirical models, to fit the complex spectral region around the coronal Fe XXI 1354.1 Å line. We place limits on the flux of this line, and show these limits are consistent with expectations from the observed X-ray spectrum. *Campaign for Observation of the Corona and Outer Atmosphere of the Fast-rotating Star, FK Comae This work was supported by HST grant GO-12376.01-A.

Photovoltaic performance of the dome-shaped Fresnel-Köhler concentrator

NASA Astrophysics Data System (ADS)

Zamora, Pablo; Benítez, Pablo; Yang, Li; Miñano, Juan Carlos; Mendes-Lopes, Joao; Araki, Kenji

2012-10-01

In order to have a cost-effective CPV system, two key issues must be ensured: high concentration factor and high tolerance. The novel concentrator we are presenting, the dome-shaped Fresnel-Köhler, can widely fulfill these two and other essential issues in a CPV module. This concentrator is based on two previous successful CPV designs: the FK concentrator with a flat Fresnel lens and the dome-shaped Fresnel lens system developed by Daido Steel, resulting on a superior concentrator. The concentrator has shown outstanding simulation results, achieving an effective concentration-acceptance product (CAP) value of 0.72, and an optical efficiency of 85% on-axis (no anti-reflective coating has been used). Moreover, Köhler integration provides good irradiance uniformity on the cell surface and low spectral aberration of this irradiance. This ensures an optimal performance of the solar cell, maximizing its efficiency. Besides, the domeshaped FK shows optimal results for very compact designs, especially in the f/0.7-1.0 range. The dome-shaped Fresnel- Köhler concentrator, natural and enhanced evolution of the flat FK concentrator, is a cost-effective CPV optical design, mainly due to its high tolerances. Daido Steel advanced technique for demolding injected plastic pieces will allow for easy manufacture of the dome-shaped POE of DFK concentrator.

Readability of sports medicine-related patient education materials from the American Academy of Orthopaedic Surgeons and the American Orthopaedic Society for Sports Medicine.

PubMed

Ganta, Abhishek; Yi, Paul H; Hussein, Khalil; Frank, Rachel M

2014-04-01

Although studies have revealed high readability levels of orthopedic patient education materials, no study has evaluated sports medicine-related patient education materials. We conducted a study to assess the readability of sports medicine-related patient education materials from the American Academy of Orthopaedic Surgeons (AAOS) and the American Orthopaedic Society for Sports Medicine (AOSSM). All sports medicine patient education articles available online in 2012 from the AAOS and the AOSSM, including the Stop Sports Injuries Campaign (STOP), were identified, and their readability was assessed with the Flesch-Kinkaid (FK) readability test. Mean overall FK grade level of the 170 articles reviewed (104 from AAOS, 36 from AOSSM, 30 from STOP) was 10.2. Mean FK levels for the 3 sources were 9.5 (AAOS), 11.0 (AOSSM), and 11.5 (STOP) (P = .16). Fifteen (8.8%) of the 170 articles had a readability level at or below eighth grade (average reading level of US adults); only 2 (1.2%) of the 170 articles were at or below the recommended sixth-grade level. The majority of sports medicine-related patient education materials from AAOS and AOSSM had reading levels higher than recommended, indicating that the majority of the patient population may find it difficult to comprehend these articles.

Survival condition for low-frequency quasi-one-dimensional breathers in a two-dimensional strongly anisotropic crystal

NASA Astrophysics Data System (ADS)

Savin, A. V.; Zubova, E. A.; Manevitch, L. I.

2005-06-01

We investigate a two-dimensional (2D) strongly anisotropic crystal (2D SAC) on substrate: 2D system of coupled linear chains of particles with strong intrachain and weak interchain interactions, each chain being subjected to the sine background potential. Nonlinear dynamics of one of these chains when the rest of them are fixed is reduced to the well known Frenkel-Kontorova (FK) model. Depending on strengh of the substrate, the 2D SAC models a variety of physical systems: polymer crystals with identical chains having light side groups, an array of inductively coupled long Josephson junctions, anisotropic crystals having light and heavy sublattices. Continuum limit of the FK model, the sine-Gordon (sG) equation, allows two types of soliton solutions: topological solitons and breathers. It is known that the quasi-one-dimensional topological solitons can propagate also in a chain of 2D system of coupled chains and even in a helix chain in a three-dimensional model of polymer crystal. In contrast to this, numerical simulation shows that the long-living breathers inherent to the FK model do not exist in the 2D SAC with weak background potential. The effect changes scenario of kink-antikink collision with small relative velocity: at weak background potential the collision always results only in intensive phonon radiation while kink-antikink recombination in the FK model results in long-living low-frequency sG breather creation. We found the survival condition for breathers in the 2D SAC on substrate depending on breather frequency and strength of the background potential. The survival condition bears no relation to resonances between breather frequency and frequencies of phonon band—contrary to the case of the FK model.

The combination of FK506 and an anti-CD147 mAb exerts potential therapeutic effects on a mouse model of collagen-induced arthritis.

PubMed

Luan, Jing; Zhang, Kui; Yang, Peng; Zhang, Yang; Feng, Fei; Zhu, Yu-Meng; Zhu, Ping; Chen, Zhi-Nan

2018-05-25

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and excessive T lymphocyte activation plays a critical role in the development of inflammation. CD147 is an antigen related to T cell activation, CD147 blockade exerts beneficial effects on RA. FK506, also known as tacrolimus, exerts strong immunosuppressive effects by inhibiting T cell activation. In this study, RL73 (an anti-mouse CD147 functional-grade purified antibody) and FK506 were co-administered to mice with collagen-induced arthritis (CIA). As expected, the combination of these two drugs produced superior therapeutic effects than either drug alone and enabled the administration of each drug at a lower dose. Moreover, joint damage and destruction were significantly improved in mice injected with both FK506 and RL73 compared with mice injected with either agent alone. These effects might have been observed because the proportions of CD4 + T and CD8 + T cells in the mouse spleen of the combination regimen were clearly decreased compared with each monotherapy. In addition, the proportions of Th2 subsets in the mouse spleen and peripheral blood were clearly increased, and the serum levels of the cytokines interleukin 4 (IL-4) and IL-10 were markedly increased in mice treated with the combination therapy compared with the other groups of mice. The splenic total number of T lymphocytes also showed that the inhibition of T lymphocytes was the most obvious in the combined treatment group. Based on the results from the present study, combining FK506 and the anti-CD147 mAb might be a new practical therapeutic option for the treatment of RA. Copyright © 2018 Elsevier Ltd. All rights reserved.

Test characteristics of the SD FK80 Plasmodium falciparum/Plasmodium vivax malaria rapid diagnostic test in a non-endemic setting

PubMed Central

2009-01-01

Background The SD FK80 P.f/P.v Malaria Antigen Rapid Test (Standard Diagnostics, Korea) (FK80) is a three-band malaria rapid diagnostic test detecting Plasmodium falciparum histidine-rich protein-2 (HRP-2) and Plasmodium vivax-specific lactate dehydrogenase (Pv-pLDH). The present study assessed its performance in a non-endemic setting. Methods Stored blood samples (n = 416) from international travellers suspected of malaria were used, with microscopy corrected by PCR as the reference method. Samples infected by Plasmodium falciparum (n = 178), Plasmodium vivax (n = 99), Plasmodium ovale (n = 75) and Plasmodium malariae (n = 24) were included, as well as 40 malaria negative samples. Results Overall sensitivities for the diagnosis of P. falciparum and P. vivax were 91.6% (95% confidence interval (CI): 86.2% - 95.0%) and 75.8% (65.9% - 83.6%). For P. falciparum, sensitivity at parasite densities ≥ 100/μl was 94.6% (88.8% - 97.6%); for P. vivax, sensitivity at parasite densities ≥ 500/μl was 86.8% (75.4% - 93.4%). Four P. falciparum samples showed a Pv-pLDH line, three of them had parasite densities exceeding 50.000/μl. Two P. vivax samples, one P. ovale and one P. malariae sample showed a HRP-2 line. For the HRP-2 and Pv-pLDH lines, respectively 81.4% (136/167) and 55.8% (43/77) of the true positive results were read as medium or strong line intensities. The FK80 showed good reproducibility and reliability for test results and line intensities (kappa values for both exceeding 0.80). Conclusion The FK80 test performed satisfactorily in diagnosing P. falciparum and P. vivax infections in a non-endemic setting. PMID:19930609

Readability of Patient Education Materials From the Web Sites of Orthopedic Implant Manufacturers.

PubMed

Yi, Meghan M; Yi, Paul H; Hussein, Khalil I; Cross, Michael B; Della Valle, Craig J

2017-12-01

Prior studies indicate that orthopedic patient education materials are written at a level that is too high for the average patient. The purpose of this study was to assess the readability of online patient education materials provided by orthopedic implant manufacturers. All patient education articles available in 2013 from the web sites of the 5 largest orthopedic implant manufacturers were identified. Each article was evaluated with the Flesch-Kincaid (FK) readability test. The number of articles with readability ≤ the eighth-grade level (average reading ability of US adults) and the sixth-grade level (recommended level for patient education materials) was determined. Mean readability levels of each company's articles were compared using analysis of variance (significance set at P < .05). A total of 581 articles were reviewed from the 5 largest implant manufacturers. The mean overall FK grade level was 10.9 (range, 3.8-16.1). Only 58 articles (10%) were written ≤ the eighth-grade level, and only 13 (2.2%) were ≤ the sixth-grade level. The mean FK grade level was significantly different among groups (Smith & Nephew = 12.0, Stryker = 11.6, Biomet = 11.3, DePuy = 10.6, Zimmer = 10.1; P < .0001). The majority of patient education materials from implant manufacturers are written at a level too high to be comprehended by the average patient. Future efforts should be made to improve the readability of orthopedic patient education materials. Copyright © 2017 Elsevier Inc. All rights reserved.

Emodin alleviates severe acute pancreatitis-associated acute lung injury by decreasing pre-B-cell colony-enhancing factor expression and promoting polymorphonuclear neutrophil apoptosis.

PubMed

Cui, Hongzhang; Li, Shu; Xu, Caiming; Zhang, Jingwen; Sun, Zhongwei; Chen, Hailong

2017-10-01

The present study aimed to evaluate the protective effects of emodin on severe acute pancreatitis (SAP)‑associated acute lung injury (ALI), and investigated the possible mechanism involved. SAP was induced in Sprague‑Dawley rats by retrograde infusion of 5% sodium taurocholate (1 ml/kg), after which, rats were divided into various groups and were administered emodin, FK866 [a competitive inhibitor of pre‑B‑cell colony‑enhancing factor (PBEF)] or dexamethasone (DEX). DEX was used as a positive control. Subsequently, PBEF expression was detected in polymorphonuclear neutrophils (PMNs) isolated from rat peripheral blood by reverse transcription‑quantitative polymerase chain reaction and western blotting. In addition, histological alterations, apoptosis in lung/pancreatic tissues, apoptosis of peripheral blood PMNs and alterations in the expression of apoptosis‑associated proteins were examined by hematoxylin and eosin staining, terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assay, Annexin V/propidium iodide (PI) assay and western blotting, respectively. Serum amylase activity and wet/dry (W/D) weight ratios were also measured. An in vitro study was also conducted, in which PMNs were obtained from normal Sprague‑Dawley rats and were incubated with emodin, FK866 or DEX in the presence of lipopolysaccharide (LPS). Apoptosis of PMNs and the expression levels of apoptosis‑associated proteins were examined in cultured PMNs in vitro by Annexin V/PI assay and western blotting, respectively. The results demonstrated that emodin, FK866 and DEX significantly downregulated PBEF expression in peripheral blood PMNs. In addition, emodin, FK866 and DEX reduced serum amylase activity, decreased lung and pancreas W/D weight ratios, alleviated lung and pancreatic injuries, and promoted PMN apoptosis by regulating the expression of apoptosis‑associated proteins: Fas, Fas ligand, B‑cell lymphoma (Bcl)‑2‑associated X protein, cleaved caspase‑3 and Bcl‑extra‑large. In addition, the in vitro study demonstrated that emodin, FK866 and DEX significantly reversed the LPS‑induced decrease of apoptosis in PMNs by regulating the expression of apoptosis‑associated proteins. In conclusion, the present study demonstrated that emodin may protect against SAP‑associated ALI by decreasing PBEF expression, and promoting PMN apoptosis via the mitochondrial and death receptor apoptotic pathways.

Engineer Novel Anticancer Bioagents

DTIC Science & Technology

2010-10-01

selection (hence to create marker-free genetically modified organism – GMO as required by FDA regulations) have failed. The overall transformation...free genetically modified organism – GMO , as required by FDA regulations). Key Research Status 1. Reconstitution of a complete FK228 biosynthetic

Analytic representation of FK/Fπ in two loop chiral perturbation theory

NASA Astrophysics Data System (ADS)

Ananthanarayan, B.; Bijnens, Johan; Friot, Samuel; Ghosh, Shayan

2018-05-01

We present an analytic representation of FK/Fπ as calculated in three-flavor two-loop chiral perturbation theory, which involves expressing three mass scale sunsets in terms of Kampé de Fériet series. We demonstrate how approximations may be made to obtain relatively compact analytic representations. An illustrative set of fits using lattice data is also presented, which shows good agreement with existing fits.

The co-chaperones Fkbp4/5 control Argonaute2 expression and facilitate RISC assembly.

PubMed

Martinez, Natalia J; Chang, Hao-Ming; Borrajo, Jacob de Riba; Gregory, Richard I

2013-11-01

Argonaute2 (Ago2) protein and associated microRNAs (miRNAs) or small interfering RNAs (siRNAs) form the RNA-induced silencing complex (RISC) for target messenger RNA cleavage and post-transcriptional gene silencing. Although Ago2 is essential for RISC activity, the mechanism of RISC assembly is not well understood, and factors controlling Ago2 protein expression are largely unknown. A role for the Hsc70/Hsp90 chaperone complex in loading small RNA duplexes into the RISC has been demonstrated in cell extracts, and unloaded Ago2 is unstable and degraded by the lysosome in mammalian cells. Here we identify the co-chaperones Fkbp4 and Fkbp5 as Ago2-associated proteins in mouse embryonic stem cells. Pharmacological inhibition of this interaction using FK506 or siRNA-mediated Fkbp4/5 depletion leads to decreased Ago2 protein levels. We find FK506 treatment inhibits, whereas Fkbp4/5 overexpression promotes, miRNA-mediated stabilization of Ago2 expression. Simultaneous treatment with a lysosome inhibitor revealed the accumulation of unloaded Ago2 complexes in FK506-treated cells. We find that, consistent with unloaded miRNAs being unstable, FK506 treatment also affects miRNA abundance, particularly nascent miRNAs. Our results support a role for Fkbp4/5 in RISC assembly.

A novel class of dual-family immunophilins.

PubMed

Adams, Brian; Musiyenko, Alla; Kumar, Rajinder; Barik, Sailen

2005-07-01

Immunophilins are protein chaperones with peptidylprolyl isomerase activity that belong to one of two large families, the cyclosporin-binding cyclophilins (CyPs) and the FK506-binding proteins (FKBPs). Each family displays characteristic and conserved sequence features that differ between the two families. We report a novel group of dual-family immunophilins that contain both CyP and FKBP domains for which we propose the name FCBP (FK506- and cyclosporin-binding protein). The FCBP of Toxoplasma gondii, a protozoan parasite, contained N-terminal FKBP and C-terminal CyP domains joined by tetratricopeptide repeats. Structure-function analysis revealed that both domains were functional and exhibited family-specific drug sensitivity. The individual domains of FCBP inhibited calcineurin (protein phosphatase 2B) in the presence of the appropriate drugs. In binding studies, FCBP recruited calcineurin in the presence of FK506 and a putative target of rapamycin homolog in the presence of rapamycin. Two additional FCBP sequences in Flavobacterium and one in Treponema (spirochete) were also identified in which the CyP and FKBP domains were in the reverse order. T. gondii growth was inhibited by cyclosporin and FK506 in a moderately synergistic manner. The knockdown of FCBP by RNA interference revealed its essentiality for T. gondii growth. Clearly, the FCBPs are novel chaperones and potential targets of multiple immunosuppressant drugs.

Immunosuppressants: tools to investigate the physiological role of cytokines.

PubMed

Quesniaux, V F

1993-11-01

The cyclic peptide Cyclosporine A (CsA) is best known as the immunosuppressive drug which has revolutionized organ transplantation. It selectively suppresses T cell activation by blocking the transcription of cytokine genes such as IL-2 at the level of transcription factor modulation. The structurally unrelated immunosuppressant FK 506 acts on the same pathway and blocks cytokine gene expression. In contrast, rapamycin, a structural analogue of FK 506, interferes with the immune response at a different level, by blocking the response induced by cytokines such as IL-2. Although these drugs have been most studied for their immunosuppressive activities, it is clear that their effects on cytokine pathways extend far beyond the sole IL-2-mediated responses involved in the immune response. For instance, CsA and FK 506 inhibit the transcription of IL-3, IL-4, IFN gamma, TNF alpha or GM-CSF by activated T cells, and rapamycin has been shown to block the response to various growth factors such as IL-3, IL-4 or IL-6. Here, we recap what is known about the effects of CsA, FK 506 and rapamycin on hematopoiesis in vitro and in vivo and extrapolate on what these drugs can teach us about the physiological role of cytokines for hematopoiesis.

Rosat observations of FK comae berenices

NASA Technical Reports Server (NTRS)

Welty, Alan D.; Ramsey, Lawrence W.

1994-01-01

We obtained ROSAT PSPC observations of FK Com over a period of 24.4 h, or 0.42 rotation. During the observations the x-ray flux increased by a factor of at least 5 before declining toward its previous level. A single temperature Raymond-Smith model is adequate to model the low signal-to-noise ratio spectrum from each observation interval. Initially the spectrum was that of a 8.5 x 10(exp 6) K plasma, with L9sub x)=0.66 x 10(exp 31) erg s(exp -1). When the x-ray flux was greatest, the model plasma temperature rose to 2.5 x 10(exp 7) K, and L(sub x)=3.46 x 10(exp 31) ergs(exp -1). During the post-maximum decline in luminosity the plasma temperature was approximately 12 x 10(exp 6) K. We conclude that the increase of x-ray flux recorded by ROSAT was due to an x-ray flare with a 1.5 h decline time scale.

Deformation of biological cells in the acoustic field of an oscillating bubble.

PubMed

Zinin, Pavel V; Allen, John S

2009-02-01

In this work we develop a theoretical framework of the interaction of microbubbles with bacteria in the ultrasound field using a shell model of the bacteria, following an approach developed previously [P. V. Zinin, Phys. Rev. E 72, 61907 (2005)]. Within the shell model, the motion of the cell in an ultrasonic field is determined by the motion of three components: the internal viscous fluid, a thin elastic shell, and the surrounding viscous fluid. Several conclusions can be drawn from the modeling of sound interaction with a biological cell: (a) the characteristics of a cell's oscillations in an ultrasonic field are determined both by the elastic properties of the shell the viscosities of all components of the system, (b) for dipole quadrupole oscillations the cell's shell deforms due to a change in the shell area this oscillation depends on the surface area modulus K{A} , (c) the relative change in the area has a maximum at frequency f{K} approximately 1/2pi square root[K{A}(rhoa;{3})] , where a is the cell's radius and rho is its density. It was predicted that deformation of the cell wall at the frequency f{K} is high enough to rupture small bacteria such as E . coli in which the quality factor of natural vibrations is less than 1 (Q<1). For bacteria with high value quality factors (Q>1) , the area deformation has a strong peak near a resonance frequency f{K} however, the value of the deformation near the resonance frequency is not high enough to produce sufficient mechanical effect. The theoretical framework developed in this work can be extended for describing the deformation of a biological cell under any arbitrary, external periodic force including radiation forces unduced by acoustical (acoustical levitation) or optical waves (optical tweezers).

Isolation and identification of feline herpesvirus type 1 from a South China tiger in China.

PubMed

Sun, Heting; Li, Yuanguo; Jiao, Weiyi; Liu, Cunfa; Liu, Xiujuan; Wang, Haijun; Hua, Fuyou; Dong, Jianxiu; Fan, Shengtao; Yu, Zhijun; Gao, Yuwei; Xia, Xianzhu

2014-02-28

In 2012, an FHV-1-like virus was isolated from a tiger that presented with clinical signs of sialorrhea, sneezing and purulent rhinorrhea. Isolation was performed with the FK81 cell line, and the virus was identified by PCR, transmission electron microscopy (TEM), and the phylogenetic analysis of the partial thymidine kinase (TK) and glycoprotein B (gB) genes. A total of 253 bp of the TK gene and 566 bp of the gB gene were amplified from the trachea of the tiger by PCR/RT-PCR method. Phylogenetic analysis showed that the isolate belonged to the same cluster with other FHV-1 strains obtained from GenBank. Herpes-like viruses with an envelope and diameters of approximately 200 nm were observed in the culture supernatants of FK81 cells inoculated with samples from the tiger. The FHV-1 infection was confirmed by an animal challenge experiment in a cat model. Our finding extends the host range of FHV-1 and has implications for FHV-1 infection and South China tiger conservation.

Early Minocycline and Late FK506 Treatment Improves Survival and Alleviates Neuroinflammation, Neurodegeneration, and Behavioral Deficits in Prion-Infected Hamsters.

PubMed

Shah, Syed Zahid Ali; Zhao, Deming; Taglialatela, Giulio; Khan, Sher Hayat; Hussain, Tariq; Dong, Haodi; Lai, Mengyu; Zhou, Xiangmei; Yang, Lifeng

2017-04-01

Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosis followed by overt neuronal death. Gliosis is likely to be caused initially by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrP Sc ) of the normal cellular prion protein (PrP c ) in the brain. Proinflammatory cytokines and chemokines released by PrP Sc -activated glia and stressed neurons may also contribute directly or indirectly to the disease development by enhancing gliosis and inducing neurotoxicity. Recent studies have illustrated that early neuroinflammation activates nuclear factor of activated T cells (NFAT) in the calcineurin signaling cascade, resulting in nuclear translocation of nuclear factor kappa B (NF-κB) to promote apoptosis. Hence, useful therapeutic approaches to slow down the course of prion disease development should control early inflammatory responses to suppress NFAT signaling. Here we used a hamster model of prion diseases to test, for the first time, the neuroprotective and NFAT-suppressive effect of a second-generation semisynthetic tetracycline derivative, minocycline, versus a calcineurin inhibitor, FK506, with known NFAT suppressive activity. Our results indicate that prolonged treatment with minocycline, starting from the presymptomatic stage of prion disease was more effective than FK506 given either during the presymptomatic or symptomatic stage of prion disease. Specifically, minocycline treatment reduced the expression of the astrocyte activation marker glial fibrillary acidic protein and of the microglial activation marker ionized calcium-binding adapter molecule-1, subsequently reducing the level of proinflammatory cytokines interleukin 1β and tumor necrosis factor-α. We further found that minocycline and FK506 treatment inhibited mitogen-activated protein kinase p38 phosphorylation and NF-κB nuclear translocation in a caspase-dependent manner, and enhanced phosphorylated cyclic adenosine monophosphate response element-binding protein and phosphorylated Bcl2-associated death promoter levels to reduce cognitive impairment and apoptosis. Taken together, our results indicate that minocycline is a better choice for prolonged use in prion diseases and encourage its further clinical development as a possible treatment for this disease.

FK506-binding protein 1b/12.6: a key to aging-related hippocampal Ca2+ dysregulation?

PubMed Central

Gant, JC; Blalock, EM; K-C, Chen; Kadish, I; Porter, NM; Norris, CM; Thibault, O; Landfield, PW

2014-01-01

It has been recognized for some time that the Ca2+-dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies since have shown that other Ca2+-mediated electrophysiological responses are increased in hippocampus with aging, including Ca2+ transients, L-type voltage-gated Ca2+ channel activity, Ca2+ spike duration and action potential accommodation. Elevated Ca2+-induced Ca2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca2+ responses. Components of this Ca2+ dysregulation phenotype correlate with deficits in cognitive function and plasticity, indicating they may play critical roles in aging-related impairment of brain function. However, the molecular mechanisms underlying aging-related Ca2+ dysregulation are not well understood. FK506-binding proteins 1a and 1b (FKBP1a/1b, also known as FKBP12/12.6) are immunophilin proteins that bind the immunosuppressant drugs FK506 and rapamycin. In muscle cells, FKBP1a/1b also bind RyRs and inhibits Ca2+-induced Ca2+ release, but it is not clear whether FKBPs act similarly in brain cells. Recently, we found that selectively disrupting hippocampal FKBP1b function in young rats, either by microinjecting adeno-associated viral vectors containing siRNA, or by treatment with rapamycin, increases the sAHP and recapitulates much of the hippocampal Ca2+ dysregulation phenotype. Moreover, in microarray studies, we found FKBP1b gene expression was downregulated in hippocampus of aging rats and early-stage Alzheimer’s disease subjects. These results suggest the novel hypothesis that declining FKBP function is a key factor in aging-related Ca2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging. PMID:24291098

Study on the Feasibility of Mass Area Ordnance Decontamination

DTIC Science & Technology

1974-08-15

and Armor Plate Protection 11-50 11-20 Bucket Modifications 11-53 Appendices Figure Page III-1 The Relationship Between Rippability and Seismic...FK S. .. . ... L, i ! ,, ,,i , , W~AM0RPHIC ROK MINERALS 9 ORESm n, imI I’𔄃 1.. I 1. 1 .t’ I.* [ FIGURE III-l: The Relationship Between Rippability

Anti-Obesity Effects of Starter Fermented Kimchi on 3T3-L1 Adipocytes

PubMed Central

Lee, Kyung-Hee; Song, Jia-Le; Park, Eui-Seong; Ju, Jaehyun; Kim, Hee-Young; Park, Kun-Young

2015-01-01

The anti-obesity effects of starter (Leuconostoc mesenteroides+Lactobacillus plantarum) fermented kimchi on 3T3-L1 adipocyte were studied using naturally fermented kimchi (NK), a functional kimchi (FK, NK supplemented with green tea), and FK supplemented with added starters (FKS). Oil red O staining and cellular levels of triglyceride (TG) and glycerol were used to evaluate the in vitro anti-obesity effects of these kimchis in 3T3-L1 cells. The expressions of adipogenesis/lipogenesis-related genes of peroxisome proliferator-active receptor (PPAR)-γ, CCAAT/enhance-binding protein (C/EBP)-α, and fatty acid synthase (FAS) were determined by RT-PCR. Kimchis, especially FKS, markedly decreased TG levels and increased levels of intracellular glycerol and lipid lipolysis. In addition, FKS also reduced the mRNA levels of PPAR-γ, C/EBP-α, and FAS, which are related to adipogenesis/lipogenesis in 3T3-L1 cells. These results suggest the anti-obesity effects of FKS were to due to enhanced lipolysis and reduced adipogenesis/lipogenesis in 3T3-L1 adipocytes. PMID:26770918

Crystal structures of resorcin[4]arene and pyrogallol[4]arene complexes with DL-pipecolinic acid. Model compounds for the recognition of the pipecolinyl ring, a key fragment of FK506, through C-H⋯π interaction

NASA Astrophysics Data System (ADS)

Fujisawa, Ikuhide; Kitamura, Yuji; Kato, Ryo; Murayama, Kazutaka; Aoki, Katsuyuki

2014-01-01

Resorcin[4]arene (resorcinol cyclic tetramer, abbreviated as RCT) or pyrogallol[4]arene (pyrogallol cyclic tetramer, PCT) form host-guest 1:1 complexes with DL-pipecolinic acid (DL-pipeH), RCT·DL-pipeH·EtOH·8H2O (1), PCT DL-pipeH·EtOH·4H2O (2), and PCT·DL-pipeH·3H2O (3), whose crystal structures have been determined. In each complex, the pipeH ligand is incorporated into the bowl-shaped cavity of the RCT or PCT host molecules through C-H⋯π interactions between alkyl protons of the piperidine ring of pipeH and π-rings of RCT or PCT, forming an [(RCT/PCT)·pipeH] structural fragment. In 1 and 3, two [(RCT/PCT) pipeH] fragments self-associate across an inversion center to form a guest-mediated, obliquely declined dimeric structure [(RCT/PCT)·L-pipeH·D-pipeH (RCT/PCT)]. In 2, each PCT-capped pipeH ligand bridges to two adjacent PCT molecules to form guest-mediated, optically-discrete helical polymers [PCT·L-pipeH]n or [PCT·D-pipeH]n. An 1H NMR experiment shows that the complexation through C-H⋯π interaction between the piperidine ring of pipeH and π-rings of RCT or PCT occurs also in solution, with the binding constants of 9.7 ± 0.6 M-1 for RCT and 26.5 ± 1.5 M-1 for PCT. These complexes provide a synthetic model for the recognition of the pipecolinyl-ring moiety, a key constituent of immunosuppressant drugs such as FK506, FK520 or rapamycin, by their binding proteins through C-H⋯π interaction.

40 CFR 98.202 - GHGs to report.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., FK 5-1-12. (4) Carbon dioxide (CO2). (5) Any other GHGs (as defined in § 98.6). (b) You must report under subpart C of this part (General Stationary Fuel Combustion Sources) the CO2, N2O, and CH4...

40 CFR 98.202 - GHGs to report.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., FK 5-1-12. (4) Carbon dioxide (CO2). (5) Any other GHGs (as defined in § 98.6). (b) You must report under subpart C of this part (General Stationary Fuel Combustion Sources) the CO2, N2O, and CH4...

40 CFR 98.202 - GHGs to report.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., FK 5-1-12. (4) Carbon dioxide (CO2). (5) Any other GHGs (as defined in § 98.6). (b) You must report under subpart C of this part (General Stationary Fuel Combustion Sources) the CO2, N2O, and CH4...

40 CFR 98.202 - GHGs to report.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., FK 5-1-12. (4) Carbon dioxide (CO2). (5) Any other GHGs (as defined in § 98.6). (b) You must report under subpart C of this part (General Stationary Fuel Combustion Sources) the CO2, N2O, and CH4...

Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51.

PubMed

Kumar, Rajnish; Moche, Martin; Winblad, Bengt; Pavlov, Pavel F

2017-10-27

FK506 binding protein of 51 kDa (FKBP51) is a heat shock protein 90 (Hsp90) co-chaperone involved in the regulation of steroid hormone receptors activity. It is known for its role in various regulatory pathways implicated in mood and stress-related disorders, cancer, obesity, Alzheimer's disease and corticosteroid resistant asthma. It consists of two FKBP12 like active peptidyl prolyl isomerase (PPIase) domains (an active FK1 and inactive FK2 domain) and one tetratricopeptide repeat (TPR) domain that mediates interaction with Hsp90 via its C-terminal MEEVD peptide. Here, we report a combined x-ray crystallography and molecular dynamics study to reveal the binding mechanism of Hsp90 MEEVD peptide to the TPR domain of FKBP51. The results demonstrated that the Hsp90 C-terminal peptide binds to the TPR domain of FKBP51 with the help of di-carboxylate clamp involving Lys272, Glu273, Lys352, Asn322, and Lys329 which are conserved throughout several di-carboxylate clamp TPR proteins. Interestingly, the results from molecular dynamics study are also in agreement to the complex structure where all the contacts between these two partners were consistent throughout the simulation period. In a nutshell, our findings provide new opportunity to engage this important protein-protein interaction target by small molecules designed by structure based drug design strategy.

Additional boundary conditions and surface exciton dispersion relations

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

Rimbey, P.R.

1977-01-15

The surface-exciton dispersion curves in ZnO are derived from the surface impedances developed by Fuchs and Kliewer (FK) and Rimbey and Mahan (RM) including retardation. There exists a distinctive splitting between the two dispersions, the FK additional boundary conditions having longitudinal character, the RM additional boundary conditions being transverse. Surface-mode attenuation due to spatial dispersion is more pronouced in the RM formalism, although inclusion of a phenomenological damping parameter does not alter either dispersion curve. (AIP)

Manufacturing Science of Improved Molded Optics

DTIC Science & Technology

2013-12-05

Forrer, “Interaction of N-FK5 and L- BAL35 optical glass with various carbide and other precision glass mold tooling”, SPIE Optifab 2013 Conference...Richardson, S. Mourad, M. Huber, A. Kunz, M. Forrer. Interaction of N-FK5 and L-BAL35 optical glass with various carbide and other precision glass mold...stoichiometric compounds. As an example, if silicon and oxygen are present in a material, then it was assumed that they are present in the form of

Documentation for the machine-readable version of the Perth 75: A Catalogue of Positions of 2589 FK4 and FK4S Stars (Nikoloff and Hog 1982)

NASA Technical Reports Server (NTRS)

Warren, W. H., Jr.

1984-01-01

Detailed descriptions of the data and format of the machine-readable astronomical catalog are given. The machine version is identical in data content to the published edition, but minor modifications in the data format were made in order to effect uniformity with machine versions of other astronomical catalogs. Stellar motions and positions at epoch and equinox 1950.0 are reported.

Readability analysis of patient information on the American Academy of Otolaryngology-Head and Neck Surgery website.

PubMed

Greywoode, Jewel; Bluman, Eric; Spiegel, Joseph; Boon, Maurits

2009-11-01

To evaluate the readability of patient-oriented online health information (OHI) presented on the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) website. Review of the Flesch-Kincaid (FK) grade level for 104 articles on the AAO-HNS website. The FK grade level for 104 articles was determined using the readability calculator available within Microsoft Office Word 2003. The interobserver reliability for the FK grade level was determined by calculating the intraclass correlation coefficient (ICC) for 52 entries. The average FK grade reading level of the articles was 10.8 (range 6.3-16.7; 95% CI, 10.4-11.2). Eighty-one percent of the articles were written at a ninth grade level or higher. The intraclass correlation was good (r = 0.83) for the 52 articles that were independently reviewed. This analysis has shown that the average reading level for each article on the AAO-HNS site was higher than the recommended sixth grade reading level. Although the AAO-HNS site is written at a higher level than that suggested for the general public, it is important to realize that readability is just one consideration in the evaluation of OHI comprehension. Physicians need to be cognizant of their patients' ability to read and comprehend written information and tailor their educational material appropriately.

Lattice vibrations in the Frenkel-Kontorova model. I. Phonon dispersion, number density, and energy

NASA Astrophysics Data System (ADS)

Meng, Qingping; Wu, Lijun; Welch, David O.; Zhu, Yimei

2015-06-01

We studied the lattice vibrations of two interpenetrating atomic sublattices via the Frenkel-Kontorova (FK) model of a linear chain of harmonically interacting atoms subjected to an on-site potential using the technique of thermodynamic Green's functions based on quantum field-theoretical methods. General expressions were deduced for the phonon frequency-wave-vector dispersion relations, number density, and energy of the FK model system. As the application of the theory, we investigated in detail cases of linear chains with various periods of the on-site potential of the FK model. Some unusual but interesting features for different amplitudes of the on-site potential of the FK model are discussed. In the commensurate structure, the phonon spectrum always starts at a finite frequency, and the gaps of the spectrum are true ones with a zero density of modes. In the incommensurate structure, the phonon spectrum starts from zero frequency, but at a nonzero wave vector; there are some modes inside these gap regions, but their density is very low. In our approximation, the energy of a higher-order commensurate state of the one-dimensional system at a finite temperature may become indefinitely close to the energy of an incommensurate state. This finding implies that the higher-order incommensurate-commensurate transitions are continuous ones and that the phase transition may exhibit a "devil's staircase" behavior at a finite temperature.

Direct evidence that FK506 inhibition of FcepsilonRI-mediated exocytosis from RBL mast cells involves calcineurin.

PubMed

Hultsch, T; Brand, P; Lohmann, S; Saloga, J; Kincaid, R L; Knop, J

1998-05-01

FcepsilonRI-mediated exocytosis of preformed mediators from mast cells and basophils (e.g. histamine, serotonin, beta-hexosaminidase) is sensitive to the immunosuppressants cyclosporin A and FK506 (IC50 200 and 4 nM, respectively) but not rapamycin. The mechanism of inhibition does not appear to involve tyrosine phosphorylation, hydrolysis of inositol phosphates or calcium flux. Here we report experiments using a molecular approach to assess the role of calcineurin, a serine/threonine phosphatase thought to be the primary pharmacological target of these drugs. Calcineurin's activity requires association of its catalytic (A) subunit with an intrinsic regulatory (B) subunit. We hypothesized that calcineurin-sensitive signalling events should be affected by the depletion of calcineurin B subunits, thereby reducing the number of active A:B complexes. We therefore transfected rat basophilic leukemia (RBL) cells with an inhibitory (dominant negative) form of the calcineurin A subunit, which binds the calcineurin B subunit with high affinity but does not possess catalytic activity (B subunit knock-out, BKO). In these transfected cells, the dose-response curve for the inhibition of FcepsilonRI-mediated exocytosis by FK506 was shifted to the left, indicating an increased drug sensitivity of BKO-transfected cells. We conclude that FK506 inhibition of FcepsilonRI-mediated exocytosis in mast cells specifically targets calcineurin activity.

Frequency-Wavenumber (FK)-Based Data Selection in High-Frequency Passive Surface Wave Survey

NASA Astrophysics Data System (ADS)

Cheng, Feng; Xia, Jianghai; Xu, Zongbo; Hu, Yue; Mi, Binbin

2018-04-01

Passive surface wave methods have gained much attention from geophysical and civil engineering communities because of the limited application of traditional seismic surveys in highly populated urban areas. Considering that they can provide high-frequency phase velocity information up to several tens of Hz, the active surface wave survey would be omitted and the amount of field work could be dramatically reduced. However, the measured dispersion energy image in the passive surface wave survey would usually be polluted by a type of "crossed" artifacts at high frequencies. It is common in the bidirectional noise distribution case with a linear receiver array deployed along roads or railways. We review several frequently used passive surface wave methods and derive the underlying physics for the existence of the "crossed" artifacts. We prove that the "crossed" artifacts would cross the true surface wave energy at fixed points in the f-v domain and propose a FK-based data selection technique to attenuate the artifacts in order to retrieve the high-frequency information. Numerical tests further demonstrate the existence of the "crossed" artifacts and indicate that the well-known wave field separation method, FK filter, does not work for the selection of directional noise data. Real-world applications manifest the feasibility of the proposed FK-based technique to improve passive surface wave methods by a priori data selection. Finally, we discuss the applicability of our approach.

Frequency-Wavenumber (FK)-Based Data Selection in High-Frequency Passive Surface Wave Survey

NASA Astrophysics Data System (ADS)

Cheng, Feng; Xia, Jianghai; Xu, Zongbo; Hu, Yue; Mi, Binbin

2018-07-01

Passive surface wave methods have gained much attention from geophysical and civil engineering communities because of the limited application of traditional seismic surveys in highly populated urban areas. Considering that they can provide high-frequency phase velocity information up to several tens of Hz, the active surface wave survey would be omitted and the amount of field work could be dramatically reduced. However, the measured dispersion energy image in the passive surface wave survey would usually be polluted by a type of "crossed" artifacts at high frequencies. It is common in the bidirectional noise distribution case with a linear receiver array deployed along roads or railways. We review several frequently used passive surface wave methods and derive the underlying physics for the existence of the "crossed" artifacts. We prove that the "crossed" artifacts would cross the true surface wave energy at fixed points in the f- v domain and propose a FK-based data selection technique to attenuate the artifacts in order to retrieve the high-frequency information. Numerical tests further demonstrate the existence of the "crossed" artifacts and indicate that the well-known wave field separation method, FK filter, does not work for the selection of directional noise data. Real-world applications manifest the feasibility of the proposed FK-based technique to improve passive surface wave methods by a priori data selection. Finally, we discuss the applicability of our approach.

Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes

PubMed Central

Sinars, Cindy R.; Cheung-Flynn, Joyce; Rimerman, Ronald A.; Scammell, Jonathan G.; Smith, David F.; Clardy, Jon

2003-01-01

The ability to bind immunosuppressive drugs such as cyclosporin and FK506 defines the immunophilin family of proteins, and the FK506-binding proteins form the FKBP subfamily of immunophilins. Some FKBPs, notably FKBP12 (the 12-kDa FK506-binding protein), have defined roles in regulating ion channels or cell signaling, and well established structures. Other FKBPs, especially the larger ones, participate in important biological processes, but their exact roles and the structural bases for these roles are poorly defined. FKBP51 (the 51-kDa FKBP) associates with heat shock protein 90 (Hsp90) and appears in functionally mature steroid receptor complexes. In New World monkeys, FKBP51 has been implicated in cortisol resistance. We report here the x-ray structures of human FKBP51, to 2.7 Å, and squirrel monkey FKBP51, to 2.8 Å, by using multiwavelength anomalous dispersion phasing. FKBP51 is composed of three domains: two consecutive FKBP domains and a three-unit repeat of the TPR (tetratricopeptide repeat) domain. This structure of a multi-FKBP domain protein clarifies the arrangement of these domains and their possible interactions with other proteins. The two FKBP domains differ by an insertion in the second that affects the formation of the progesterone receptor complex. PMID:12538866

Frenkel-Kontorova model with a transversal degree of freedom: Static properties of kinks

NASA Astrophysics Data System (ADS)

Braun, Oleg M.; Chubykalo, Oksana A.; Kivshar, Yuri S.; Vázquez, Luis

1993-08-01

We consider a generalized Frenkel-Kontorova (FK) model with a transversal degree of freedom proposed by Braun and Kivshar [Phys. Rev. B 44, 7694 (1991)]. The model describes an atomic chain subjected to a two-dimensional (2D) substrate potential that is periodic in one direction and parabolic in the transversal direction, the interatomic interaction being exponentially repulsive. The ground state of the system undergoes a phase transition from the trivial one-dimensional (1D) to a quasi-2D state when the repulsion exceeds a certain critical value. The quasi-2D ground state admits two different types of kinks, ``massive,'' kinks which may be considered as a generalization of the kinks of the standard 1D FK chain, and ``nonmassive'' (phase) kinks, which appear to be due to dimerization of the ground state. We investigate the static characteristics of these two kinds of the kinks (the kink effective mass, the kink rest energy, and the height of the Peierls-Nabarro potential) analytically as well as by means of numerical simulations when the chain with the periodic boundary conditions contains a single kink. In particular, we show that the ``massive'' kinks may be described in the continuum approximation by a perturbed sine-Gordon equation while properties of the ``nonmassive'' kinks may be analyzed within the framework of an effective φ4 model derived for translational displacements. The role of the transversal degree of freedom in mass-transport properties of the generalized FK model applied to describe surface diffusion is also discussed.

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

Galat, Andrzej, E-mail: galat@dsvidf.cea.fr; Thai, Robert

Highlights: • The hFKBP25 interacts with diverse components of macromolecular entities. • We show that the endogenous human FKBP25 is bound to polyribosomes. • The endogenous hFKBP25 co-immunoprecipitated with nucleosomal proteins. • FKBP25 could induce conformational switch in macromolecular complexes. - Abstract: In this paper, we show some evidence that a member of the FK506-binding proteins, FKBP25 is associated to diverse components that are part of several different intracellular large-molecular mass entities. The FKBP25 is a high-affinity rapamycin-binding immunophilin, which has nuclear translocation signals present in its PPIase domain but it was detected both in the cytoplasm compartment and inmore » the nuclear proteome. Analyses of antiFKBP25-immunoprecipitated proteins have revealed that the endogenous FKBP25 is associated to the core histones of the nucleosome, and with several proteins forming spliceosomal complexes and ribosomal subunits. Using polyclonal antiFKBP25 we have detected FKBP25 associated with polyribosomes. Added RNAs or 0.5 M NaCl release FKBP25 that was associated with the polyribosomes indicating that the immunophilin has an intrinsic capacity to form complexes with polyribonucleotides via its charged surface patches. Rapamycin or FK506 treatments of the polyribosomes isolated from porcine brain, HeLa and K568 cells caused a residual release of the endogenous FKBP25, which suggests that the immunophilin also binds to some proteins via its PPIase cavity. Our proteomics study indicates that the nuclear pool of the FKBP25 targets various nuclear proteins that are crucial for packaging of DNA, chromatin remodeling and pre-mRNA splicing whereas the cytosolic pool of this immunophilin is bound to some components of the ribosome.« less

Effects of opiate-like peptides, morphine, and naloxone in the photosensitive baboon, Papio papio.

PubMed

Meldrum, B S; Menini, C; Stutzmann, J M; Naquet, R

1979-07-13

The effects of intracerebroventricular (i.c.v.) or systemic injections of Met- or Leu-enkephalin, beta-endorphin, FK 33.824 (D-Ala2, MePhe4, Met(O5)-ol-enkephalin) and of morphine and naloxone have been studied in baboons, Papio papio, which spontaneously show photically induced epileptic responses. Animals were chronically implanted with epidural or deep recording electrodes and a cannula in one lateral ventricle, and tested whilst seated in a primate chair. In some animals the natural syndrome was enhanced by the prior administration of DL-allylglycine, 100--200 mg/kg, i.v. Met- or Leu-enkephalin, 1--10 mg, i.c.v., did not lead to any manifest focal or generalized seizure discharges. Nor did it lead to any consistent enhancement or reduction of photically induced myoclonic responses (as tested 5--10 min after injection). beta-Endorphin, 0.1--0.5 mg, i.c.v., did not enhance or impair photically induced myoclonic responses. FK 33.824, 0.1--0.5 mg, i.c.v., depressed respiration and slowed EEG background rhythms for 9--15 h. This was associated with a loss of myoclonic responses to photic stimulation. These effects were reversed for 20--40 min following the injection of naloxone, 1 mg/kg i.m. A depression of respiration and a slowing of EEG rhythms was seen beginning 5--20 min after FK 33.824, 2 or 4 mg/kg, i.v. The higher dose also abolished photically induced myoclonic responses. Naloxone, 1 mg/kg, definitively reversed these effects. Morphine, 5--10 mg i.c.v., tended to increase the latency to onset of generalized myoclonus during photic stimulation. Myoclonic responses were delayed or diminished after morphine, 5 mg/kg, i.m. Naloxone, 1--2 mg/kg i.m., reversed this effect. Naloxone, 0.2--5.0 mg/kg i.m., alone, did not significantly modify photically induced myoclonus, either in animals of low or high initial responsiveness, or in those pretreated with allylglycine.

Analogues of the Frog-skin Antimicrobial Peptide Temporin 1Tb Exhibit a Wider Spectrum of Activity and a Stronger Antibiofilm Potential as Compared to the Parental Peptide

NASA Astrophysics Data System (ADS)

Grassi, Lucia; Maisetta, Giuseppantonio; Maccari, Giuseppe; Esin, Semih; Batoni, Giovanna

2017-04-01

The frog skin-derived peptide Temporin 1Tb (TB) has gained increasing attention as novel antimicrobial agent for the treatment of antibiotic-resistant and/or biofilm-mediated infections. Nevertheless, such a peptide possesses a preferential spectrum of action against Gram-positive bacteria. In order to improve the therapeutic potential of TB, the present study evaluated the antibacterial and antibiofilm activities of two TB analogues against medically relevant bacterial species. Of the two analogues, TB_KKG6A has been previously described in the literature, while TB_L1FK is a new analogue designed by us through statistical-based computational strategies. Both TB analogues displayed a faster and stronger bactericidal activity than the parental peptide, especially against Gram-negative bacteria in planktonic form. Differently from the parental peptide, TB_KKG6A and TB_L1FK were able to inhibit the formation of Staphylococcus aureus biofilms by more than 50% at 12 μM, while only TB_KKG6A prevented the formation of Pseudomonas aeruginosa biofilms at 24 μM. A marked antibiofilm activity against preformed biofilms of both bacterial species was observed for the two TB analogues when used in combination with EDTA. Analysis of synergism at the cellular level suggested that the antibiofilm activity exerted by the peptide-EDTA combinations against mature biofilms might be due mainly to a disaggregating effect on the extracellular matrix in the case of S. aureus, and to a direct activity on biofilm-embedded cells in the case of P. aeruginosa. Both analogues displayed a low hemolytic effect at the active concentrations and, overall, TB_L1FK resulted less cytotoxic towards mammalian cells. Collectively, the results obtained demonstrated that subtle changes in the primary sequence of TB may provide TB analogues that, used alone or in combination with adjuvant molecules such as EDTA, exhibit promising features against both planktonic and biofilm cells of medically relevant bacteria.

Cool covered sky-splitting spectrum-splitting FK

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

Mohedano, Rubén; Chaves, Julio; Falicoff, Waqidi

2014-09-26

Placing a plane mirror between the primary lens and the receiver in a Fresnel Köhler (FK) concentrator gives birth to a quite different CPV system where all the high-tech components sit on a common plane, that of the primary lens panels. The idea enables not only a thinner device (a half of the original) but also a low cost 1-step manufacturing process for the optics, automatic alignment of primary and secondary lenses, and cell/wiring protection. The concept is also compatible with two different techniques to increase the module efficiency: spectrum splitting between a 3J and a BPC Silicon cell formore » better usage of Direct Normal Irradiance DNI, and sky splitting to harvest the energy of the diffuse radiation and higher energy production throughout the year. Simple calculations forecast the module would convert 45% of the DNI into electricity.« less

Purification of FKBP-70, a novel immunophilin from Saccharomyces cerevisiae, and cloning of its structural gene, FPR3.

PubMed

Manning-Krieg, U C; Henríquez, R; Cammas, F; Graff, P; Gavériaux, S; Movva, N R

1994-09-19

A novel protein, belonging to the yeast family of FKBPs (FK-binding proteins), FKBP-70, was isolated from Saccharomyces cerevisiae by its interaction with the immunosuppressive agent FK-520. Its structural gene, FPR3, was cloned and the protein expressed and purified from Escherichia coli. This third member of the FKBP family in yeast is homologous to the other FKBPs at its carboxy terminus, showing conserved ligand binding and proline isomerase regions. It is, however, a longer acidic protein with several potential nuclear targeting sequences and a region of homology to nucleolins. Yeast strains deleted for FPR3, as well as a triple deletion mutant of this family of genes, FPR1, FPR2 and FPR3, are viable under normal conditions of growth, indicating that the FPR genes are not essential for life.

Trends in the biosynthesis and production of the immunosuppressant tacrolimus (FK506).

PubMed

Barreiro, Carlos; Martínez-Castro, Miriam

2014-01-01

The current off-patent state of tacrolimus (FK506) has opened the hunting season for new generic pharmaceutical formulations of this immunosuppressant. This fact has boosted the scientific and industrial research on tacrolimus for the last 5 years in order to improve its production. The fast discovery of tacrolimus producer strains has generated a huge number of producers, which presents the biosynthetic cluster of FK506 as a high promiscuous genetic region. For the first time, the current state-of-the-art on the tacrolimus biosynthesis, production improvements and drug purification is reviewed. On one hand, all the genes involved in the tacrolimus biosynthesis, in addition to the traditional PKS/NRPS, as well as their regulation are analysed. On the other hand, tacrolimus direct and indirect precursors are reviewed as a straight manner to improve the final yield, which is a current trend in the field. Twenty years of industrial and scientific improvements on tacrolimus production are summarised, whereas future trends are also drafted.

Structural studies of ROK fructokinase YdhR from Bacillus subtilis : insights into substrate binding and fructose specificity.

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

Nocek, B.; Stein, A.; Jedrzejczak, R.

2011-02-18

The main pathway of bacterial sugar phosphorylation utilizes specific phosphoenolpyruvate phosphotransferase system (PTS) enzymes. In addition to the classic PTS system, a PTS-independent secondary system has been described in which nucleotide-dependent sugar kinases are used for monosaccharide phosphorylation. Fructokinase (FK), which phosphorylates d-fructose with ATP as a cofactor, has been shown to be a member of this secondary system. Bioinformatic analysis has shown that FK is a member of the 'ROK' (bacterial Repressors, uncharacterized Open reading frames, and sugar Kinases) sequence family. In this study, we report the crystal structures of ROK FK from Bacillus subtilis (YdhR) (a) apo andmore » in the presence of (b) ADP and (c) ADP/d-fructose. All structures show that YdhR is a homodimer with a monomer composed of two similar {alpha}/{beta} domains forming a large cleft between domains that bind ADP and d-fructose. Enzymatic activity assays support YdhR function as an ATP-dependent fructose kinase.« less

Identification of Bacterial Plant Pathogens Using Multilocus Polymerase Chain Reaction/Electrospray Ionization-Mass Spectrometry

DTIC Science & Technology

2008-01-01

sandii FK-53; OLF#1 Oleander; USA 1 Xylophilus ampelinus FB-1178 Grape; S. Africa 1 Xylophilus ampelinus FJ-3; 60002 Grape; S. Africa 1 1160...campestris Xanthomonas campestris Xylella fastidiosa (6 strains) Xylella fastidiosa Xylophilus ampelinus (2 strains) Xylophilus ampelinus ...Rathayibacter iranicus Rathayibacter iranicus Xylophilus ampelinus Xylophilus ampelinus a Purified DNAs from multiple bacteria were mixed at equal

The effect of cyclosporin A, FK506 and rapamycin on the murine contact sensitivity reaction

PubMed Central

Salerno, A; Bonanno, C T; Caccamo, N; Cigna, D; Dominici, R; Ferro, C; Sireci, G; Dieli, F

1998-01-01

We have evaluated the effects of three potent immunosuppressive agents, cyclosporin A (CsA), FK506 and rapamycin, on the murine contact sensitivity (CS) reaction to the hapten trinitrochlorobenzene. Development of CS reaction requires participation of three distinct T cell subsets: αβ+, CD4+ T lymphocytes, which are the classical effector cell of the CS reaction, γδ+ T lymphocytes, and αβ+, double-negative (CD4− CD8−) T lymphocytes that express the B220 molecule and produce IL-4. We found that all three drugs inhibit the development of the CS reaction, but they affect different target cells. In fact, rapamycin and FK-506 block both αβ+, CD4+ and γδ+ T lymphocytes, while CsA inhibits only the αβ+, CD4+ T lymphocyte. None of the three drugs exerted any inhibitory activity on the αβ+, double-negative (CD4− CD8−) T lymphocytes. Hapten-immune lymph node cells from mice treated in vivo with CsA or FK506 failed to proliferate and to produce IL-2 when re-exposed to the specific antigen in vitro. In contrast, immune lymph node cells from mice that had been treated in vivo with rapamycin gave optimal antigen-specific proliferation and IL-2 production in vitro. The implications of these observations are discussed in relation to the use of these immunosuppressive agents for prevention of allograft rejection. PMID:9566798

Time-frequency analysis based on ensemble local mean decomposition and fast kurtogram for rotating machinery fault diagnosis

NASA Astrophysics Data System (ADS)

Wang, Lei; Liu, Zhiwen; Miao, Qiang; Zhang, Xin

2018-03-01

A time-frequency analysis method based on ensemble local mean decomposition (ELMD) and fast kurtogram (FK) is proposed for rotating machinery fault diagnosis. Local mean decomposition (LMD), as an adaptive non-stationary and nonlinear signal processing method, provides the capability to decompose multicomponent modulation signal into a series of demodulated mono-components. However, the occurring mode mixing is a serious drawback. To alleviate this, ELMD based on noise-assisted method was developed. Still, the existing environmental noise in the raw signal remains in corresponding PF with the component of interest. FK has good performance in impulse detection while strong environmental noise exists. But it is susceptible to non-Gaussian noise. The proposed method combines the merits of ELMD and FK to detect the fault for rotating machinery. Primarily, by applying ELMD the raw signal is decomposed into a set of product functions (PFs). Then, the PF which mostly characterizes fault information is selected according to kurtosis index. Finally, the selected PF signal is further filtered by an optimal band-pass filter based on FK to extract impulse signal. Fault identification can be deduced by the appearance of fault characteristic frequencies in the squared envelope spectrum of the filtered signal. The advantages of ELMD over LMD and EEMD are illustrated in the simulation analyses. Furthermore, the efficiency of the proposed method in fault diagnosis for rotating machinery is demonstrated on gearbox case and rolling bearing case analyses.

Lattice vibrations in the Frenkel-Kontorova model. I. Phonon dispersion, number density, and energy

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

Meng, Qingping; Wu, Lijun; Welch, David O.

2015-06-17

We studied the lattice vibrations of two inter-penetrating atomic sublattices via the Frenkel-Kontorova (FK) model of a linear chain of harmonically interacting atoms subjected to an on-site potential, using the technique of thermodynamic Green's functions based on quantum field-theoretical methods. General expressions were deduced for the phonon frequency-wave-vector dispersion relations, number density, and energy of the FK model system. In addition, as the application of the theory, we investigated in detail cases of linear chains with various periods of the on-site potential of the FK model. Some unusual but interesting features for different amplitudes of the on-site potential of themore » FK model are discussed. In the commensurate structure, the phonon spectrum always starts at a finite frequency, and the gaps of the spectrum are true ones with a zero density of modes. In the incommensurate structure, the phonon spectrum starts from zero frequency, but at a non-zero wave vector; there are some modes inside these gap regions, but their density is very low. In our approximation, the energy of a higher-order commensurate state of the one-dimensional system at a finite temperature may become indefinitely close to the energy of an incommensurate state. This finding implies that the higher-order incommensurate-commensurate transitions are continuous ones and that the phase transition may exhibit a “devil's staircase” behavior at a finite temperature.« less

Role of substance P in cough.

PubMed

Sekizawa, K; Jia, Y X; Ebihara, T; Hirose, Y; Hirayama, Y; Sasaki, H

1996-01-01

The sensory neuropeptide, substance P (SP), is present in human airway nerves, beneath and within the epithelium where the condensed localization of neutral endopeptidase (NEP), the major enzyme degrading SP, is observed. To test the hypothesis whether SP stimulates the cough reflex and NEP modifies the cough reflex, we studied the cough response to various stimuli in awake guinea-pigs. Inhibition of NEP with phosphoramidon caused cough, which was inhibited by systemic capsaicin treatment and by aerosols of a specific NK1 receptor antagonist FK 888. Aerosols of FK 888 also inhibited cough induced by bronchoconstricting agents such as acetylcholine and histamine in non-sensitized animals and by ovalbumin antigen in animals sensitized to ovalbumin. The number of coughs induced by histamine aerosols was inhibited by systemic capsaicin treatment and enhanced by pretreatment with a NEP inhibitor phosphoramidon. Likewise, FK 888 inhibited the augmented cough response to aerosolized capsaicin in female guinea-pigs treated with a long-term medication of an angiotensin-converting enzyme inhibitor, cilazapril. In humans, aerosols of SP did not cause cough in normal subjects, whereas it did in patients with common colds. The SP fragment a major metabolite of SP produced by NEP, was less effective compared with SP in these patients, suggesting that damaged epithelium may facilitate the penetration of SP. These findings suggest that SP released from sensory nerves in response to stimuli may mediate cough and NEP may have a role in modulating SP-induced effects.

The impact of biotic/abiotic interfaces in mineral nutrient cycling: A study of soils of the Santa Cruz chronosequence, California

USGS Publications Warehouse

White, Art F.; Schulz, Marjorie S.; Vivit, Davison V.; Bullen, Tomas D.; Fitzpatrick, John A.

2012-01-01

The fraction of a mineral nutrient annually cycled through the plants, compared to that lost from pore water discharge, is defined their respective fluxes Fj,plants = qj,plants/(qj,plants + qj,discharge) with average values for K and Ca (FK,plants = 0.99; FCa,plants = 0.93) much higher than for Mg and Na (FMg,plants 0.64; FNa,plants = 0.28). The discrimination against Rb and Sr by plants is described by fractionation factors (KSr/Ca = 0.86; KRb/K = 0.83) which are used in Rayleigh fractionation-mixing calculations to fit seasonal patterns in solute K and Ca cycling. KRb/K and K24Mg/22Mg values (derived from isotope data in the literature) fall within fractionation envelopes bounded by inputs from rainfall and mineral weathering. KSr/Ca and K44Ca/40Ca fractionation factors fall outside these envelopes indicating that Ca nutrient cycling is closed to these external inputs. Small net positive K and Ca fluxes (6–14 mol m-2 yr-1), based on annual mass balances, indicate that the soils are accumulating mineral nutrients, probably as a result of long-term environmental disequilibrium.

Calcineurin A beta deficiency ameliorates HFD-induced hypothalamic astrocytosis in mice.

PubMed

Pfuhlmann, Katrin; Schriever, Sonja C; Legutko, Beata; Baumann, Peter; Harrison, Luke; Kabra, Dhiraj G; Baumgart, Emily Violette; Tschöp, Matthias H; Garcia-Caceres, Cristina; Pfluger, Paul T

2018-02-08

ᅟ: Astrocytosis is a reactive process involving cellular, molecular, and functional changes to facilitate neuronal survival, myelin preservation, blood brain barrier function and protective glial scar formation upon brain insult. The overall pro- or anti-inflammatory impact of reactive astrocytes appears to be driven in a context- and disease-driven manner by modulation of astrocytic Ca 2+ homeostasis and activation of Ca 2+ /calmodulin-activated serine/threonine phosphatase calcineurin. Here, we aimed to assess whether calcineurin is dispensable for astrocytosis in the hypothalamus driven by prolonged high fat diet (HFD) feeding. Global deletion of calcineurin A beta (gene name: Ppp3cb) led to a decrease of glial fibrillary acidic protein (GFAP)-positive cells in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and arcuate nucleus (ARC) of mice exposed chronically to HFD. The concomitant decrease in Iba1-positive microglia in the VMH further suggests a modest impact of Ppp3cb deletion on microgliosis. Pharmacological inhibition of calcineurin activity by Fk506 had no impact on IBA1-positive microglia in hypothalami of mice acutely exposed to HFD for 1 week. However, Fk506-treated mice displayed a decrease in GFAP levels in the ARC. In vivo effects could not be replicated in cell culture, where calcineurin inhibition by Fk506 had no effect on astrocytic morphology, astrocytic cell death, GFAP, and vimentin protein levels or microglia numbers in primary hypothalamic astrocytes and microglia co-cultures. Further, adenoviral overexpression of calcineurin subunit Ppp3r1 in primary glia culture did not lead to an increase in GFAP fluorescence intensity. Overall, our results point to a prominent role of calcineurin in mediating hypothalamic astrocytosis as response to acute and chronic HFD exposure. Moreover, discrepant findings in vivo and in cell culture indicate the necessity of studying astrocytes in their "natural" environment, i.e., preserving an intact hypothalamic microenvironment with neurons and non-neuronal cells in close proximity.

Large Extremity Peripheral Nerve Repair

DTIC Science & Technology

2014-10-01

Shahani B. Peripheral-nerve allotransplantation in rats immunosuppressed with transient or long-term FK-506. Journal of reconstructive microsurgery ...multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions . Microsurgery . 2012 Jan;32(1):1-14. PubMed PMID: 22121093...PTB method can provide fixation strengths 6 approaching that of conventional microsurgery and that the PTB repair is unlikely to be disturbed in

Estimation of Velocity Structure Using Microtremor Recordings from Arrays: Comparison of Results from the SPAC and the F-K Analysis Methods

NASA Astrophysics Data System (ADS)

Flores-Estrella, H.; Aguirre, J.; Boore, D.; Yussim, S.

2001-12-01

Microtremor recordings have become a useful tool for microzonation studies in countries with low to moderate seismicity and also in countries where there are few seismographs or the recurrence time for an earthquake is quite long. Microtremor recordings can be made at almost any time and any place without needing to wait for an earthquake. The measurements can be made using one station or an array of stations. Microtremor recordings can be used to estimate site response directly (e.g. by using Nakamura's technique), or they can be used to estimate shear-wave velocities, from which site response can be calculated. A number of studies have found that the direct estimation of site response may be unreliable, except for identifying the fundamental resonant period of a site. Obtaining shear-wave velocities requires inverting measurements of Rayleigh wave phase velocities from microtremors, which are obtained by using the Spatial Autocorrelation (SPAC) (Aki, 1957) or the Frequency-Wave Number (F-K) (Horike, 1985) methods. Estimating shear-wave velocities from microtremor recordings is a cheaper alternative than direct methods, such as the logging of boreholes. In this work we use simultaneous microtremor recordings from triangular arrays located at two sites in Mexico City, Mexico, one ("Texcoco") with a lacustrine sediment layer of about 200 m depth, and the other one ("Ciudad Universitaria") underlain by 2,000 year old basaltic flows from Xitle volcano. The data are analyzed using both the SPAC method and by the standard F-K method. The results obtained from the SPAC method are more consistent with expectations from the geological conditions and an empirical transfer function (Montalvo et al., 2001) than those from F-K method. We also analyze data from the Hollister Municipal Airport in California. The triangular array at this site is located near a borehole from which seismic velocities have been obtained using a downhole logging method (Liu et al., 2000). We compare results from the microtremor recordings analyzed using both the SPAC and F-K methods with those obtained from the downhole logging.

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells*

PubMed Central

Tan, Bo; Dong, Sucai; Shepard, Robert L.; Kays, Lisa; Roth, Kenneth D.; Geeganage, Sandaruwan; Kuo, Ming-Shang; Zhao, Genshi

2015-01-01

Nicotinamide phosphoribosyltransferase (NAMPT) has been extensively studied due to its essential role in NAD+ biosynthesis in cancer cells and the prospect of developing novel therapeutics. To understand how NAMPT regulates cellular metabolism, we have shown that the treatment with FK866, a specific NAMPT inhibitor, leads to attenuation of glycolysis by blocking the glyceraldehyde 3-phosphate dehydrogenase step (Tan, B., Young, D. A., Lu, Z. H., Wang, T., Meier, T. I., Shepard, R. L., Roth, K., Zhai, Y., Huss, K., Kuo, M. S., Gillig, J., Parthasarathy, S., Burkholder, T. P., Smith, M. C., Geeganage, S., and Zhao, G. (2013) Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, in human cancer cells: metabolic basis and potential clinical implications. J. Biol. Chem. 288, 3500–3511). Due to technical limitations, we failed to separate isotopomers of phosphorylated sugars. In this study, we developed an enabling LC-MS methodology. Using this, we confirmed the previous findings and also showed that NAMPT inhibition led to accumulation of fructose 1-phosphate and sedoheptulose 1-phosphate but not glucose 6-phosphate, fructose 6-phosphate, and sedoheptulose 7-phosphate as previously thought. To investigate the metabolic basis of the metabolite formation, we carried out biochemical and cellular studies and established the following. First, glucose-labeling studies indicated that fructose 1-phosphate was derived from dihydroxyacetone phosphate and glyceraldehyde, and sedoheptulose 1-phosphate was derived from dihydroxyacetone phosphate and erythrose via an aldolase reaction. Second, biochemical studies showed that aldolase indeed catalyzed these reactions. Third, glyceraldehyde- and erythrose-labeling studies showed increased incorporation of corresponding labels into fructose 1-phosphate and sedoheptulose 1-phosphate in FK866-treated cells. Fourth, NAMPT inhibition led to increased glyceraldehyde and erythrose levels in the cell. Finally, glucose-labeling studies showed accumulated fructose 1,6-bisphosphate in FK866-treated cells mainly derived from dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Taken together, this study shows that NAMPT inhibition leads to attenuation of glycolysis, resulting in further perturbation of carbohydrate metabolism in cancer cells. The potential clinical implications of these findings are also discussed. PMID:25944913

Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-I activity

NASA Astrophysics Data System (ADS)

Fukuta, Tatsuya; Asai, Tomohiro; Ishii, Takayuki; Koide, Hiroyuki; Kiyokawa, Chiaki; Hashimoto, Masahiro; Kikuchi, Takashi; Shimizu, Kosuke; Harada, Norihiro; Tsukada, Hideo; Oku, Naoto

2016-07-01

The development of a diagnostic technology that can accurately determine the pathological progression of ischemic stroke and evaluate the therapeutic effects of cerebroprotective agents has been desired. We previously developed a novel PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-18F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) for detecting activity of mitochondrial complex I (MC-I). This probe was shown to visualize neuronal damage in the living brain of rodent and primate models of neurodegenerative diseases. In the present study, [18F]BCPP-EF was applied to evaluate the therapeutic effects of a neuroprotectant, liposomal FK506 (FK506-liposomes), on cerebral ischemia/reperfusion (I/R) injury in transient middle cerebral artery occlusion rats. The PET imaging using [18F]BCPP-EF showed a prominent reduction in the MC-I activity in the ischemic brain hemisphere. Treatment with FK506-liposomes remarkably increased the uptake of [18F]BCPP-EF in the ischemic side corresponding to the improvement of blood flow disorders and motor function deficits throughout the 7 days after I/R. Additionally, the PET scan could diagnose the extent of the brain damage accurately and showed the neuroprotective effect of FK506-liposomes at Day 7, at which 2, 3, 5-triphenyltetrazolium chloride staining couldn’t visualize them. Our study demonstrated that the PET technology using [18F]BCPP-EF has a potent capacity to evaluate the therapeutic effect of drug candidates in living brain.

Identification of BRCA1 and 2 Other Tumor Suppressor Genes on Chromosome 17 Through Positional Cloning.

DTIC Science & Technology

1998-07-01

F . . . .... . . . .. . . . .... . . . .... . . . .... . .- * * S 80 Homo sapiensý cvclin G1 mRNA...factor receptor substrate substrate 15 (~ homo sapiens) __!__5263151 15 T an fo mig ro thfa to , et rcforming0 80 ) .....g wth........fac or...........beta...nal-regulated kinase 3 270521 260 Homo sapiensERK3 protein kinase mRNA ____ ___________225681 .n FK 0 - id ngproteinl. (1ýkD

Improvement of coda phase detectability and reconstruction of global seismic data using frequency-wavenumber methods

NASA Astrophysics Data System (ADS)

Schneider, Simon; Thomas, Christine; Dokht, Ramin M. H.; Gu, Yu Jeffrey; Chen, Yunfeng

2018-02-01

Due to uneven earthquake source and receiver distributions, our abilities to isolate weak signals from interfering phases and reconstruct missing data are fundamental to improving the resolution of seismic imaging techniques. In this study, we introduce a modified frequency-wavenumber (fk) domain based approach using a `Projection Onto Convex Sets' (POCS) algorithm. POCS takes advantage of the sparsity of the dominating energies of phase arrivals in the fk domain, which enables an effective detection and reconstruction of the weak seismic signals. Moreover, our algorithm utilizes the 2-D Fourier transform to perform noise removal, interpolation and weak-phase extraction. To improve the directional resolution of the reconstructed data, we introduce a band-stop 2-D Fourier filter to remove the energy of unwanted, interfering phases in the fk domain, which significantly increases the robustness of the signal of interest. The effectiveness and benefits of this method are clearly demonstrated using both simulated and actual broadband recordings of PP precursors from an array located in Tanzania. When used properly, this method could significantly enhance the resolution of weak crust and mantle seismic phases.

Large Extremity Peripheral Nerve Repair

DTIC Science & Technology

2014-10-01

nerve allotransplantation in rats immunosuppressed with transient or long-term FK-506. Journal of reconstructive microsurgery . 1996 Oct;12(7):451-9...outcomes in sensory, mixed, and motor nerve reconstructions . Microsurgery . 2012 Jan;32(1):1-14. PubMed PMID: 22121093. Epub 2011/11/29. eng. 12...method can provide fixation strengths 5 approaching that of conventional microsurgery and that the PTB repair is unlikely to be disturbed in vivo

Synthetic activation of caspases: Artificial death switches

PubMed Central

MacCorkle, Rebecca A.; Freeman, Kevin W.; Spencer, David M.

1998-01-01

The development of safe vectors for gene therapy requires fail-safe mechanisms to terminate therapy or remove genetically altered cells. The ideal “suicide switch” would be nonimmunogenic and nontoxic when uninduced and able to trigger cell death independent of tissue type or cell cycle stage. By using chemically induced dimerization, we have developed powerful death switches based on the cysteine proteases, caspase-1 ICE (interleukin-1β converting enzyme) and caspase-3 YAMA. In both cases, aggregation of the target protein is achieved by a nontoxic lipid-permeable dimeric FK506 analog that binds to the attached FK506-binding proteins, FKBPs. We find that intracellular cross-linking of caspase-1 or caspase-3 is sufficient to trigger rapid apoptosis in a Bcl-xL-independent manner, suggesting that these conditional proapoptotic molecules can bypass intracellular checkpoint genes, such as Bcl-xL, that limit apoptosis. Because these chimeric molecules are derived from autologous proteins, they should be nonimmunogenic and thus ideal for long-lived gene therapy vectors. These properties should also make chemically induced apoptosis useful for developmental studies, for treating hyperproliferative disorders, and for developing animal models to a wide variety of diseases. PMID:9520421

FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action in Malassezia.

PubMed

Ianiri, Giuseppe; Applen Clancey, Shelly; Lee, Soo Chan; Heitman, Joseph

2017-10-24

The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506), ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1 Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2 Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats. IMPORTANCE Malassezia species are the most abundant fungal components of the mammalian and human skin microbiome. Although they belong to the natural skin commensal flora of humans, they are also associated with a variety of clinical skin disorders. The standard treatment for Malassezia -associated inflammatory skin infections is topical corticosteroids, although their use has adverse side effects and is not recommended for long treatment periods. Calcineurin inhibitors have been proposed as a suitable alternative to treat patients affected by skin lesions caused by Malassezia Although calcineurin inhibitors are well-known as immunosuppressive drugs, they are also characterized by potent antimicrobial activity. In the present study, we investigated the mechanism of action of FK506 (tacrolimus), ascomycin (FK520), and pimecrolimus in M. furfur and M. sympodialis and found that the conserved immunophilin FKBP12 is the target of these drugs with which it forms a complex that directly binds calcineurin and inhibits its signaling activity. We found that FKBP12 is also required for the additive activity of calcineurin inhibitors with fluconazole. Furthermore, the increasing natural occurrence in fungal pathogen populations of mutator strains poses a high risk for the rapid emergence of drug resistance and adaptation to host defense. This led us to generate an engineered hypermutator msh2 Δ mutant strain of M. sympodialis and genetically evaluate mutational events resulting in a substantially increased rate of resistance to FK506 compared to that of the wild type. Our study paves the way for the novel clinical use of calcineurin inhibitors with lower immunosuppressive activity that could be used clinically to treat a broad range of fungal infections, including skin disorders caused by Malassezia . Copyright © 2017 Ianiri et al.

FK Comae, King of Spin: the Movie

NASA Astrophysics Data System (ADS)

Ayres, Thomas

2010-09-01

FK Comae is an ultra-fast rotating, single yellow giant, product of a recent W UMa merger. Extraordinary levels of FUV and X-ray emission rate FK Comae a coronal powerhouse on par with the most extreme of the better known activity heavyweights: short-period RS CVn binaries. As a single star, FK Comae has clear advantages as a laboratory for exploring the outer limits of magnetospheric activity among the coronal cool stars. FK Comae has a long history of attention at optical and X-ray wavelengths, thanks to its generously spotted surface, and proclivity to flare regularly at high energies. FUSE discovered ultra-broad, redshifted profiles of O VI and C III, but unfortunately the singular observation could not be repeated, thanks to the satellite's flaky attitude system. The remarkable FUV spectrum was taken just a few months before STIS failed in 2004, so there was no opportunity to turn the more powerful gaze of Hubble to the task. Now, finally, the amazing sensitivity of Cosmic Origins Spectrograph can be brought to bear: a single orbit can capture an FUV spectrum of FK Comae with S/N at instrumental limits for bright lines, and digging down to faint Fe XXI 1354 {bridge to the coordinated Chandra HETGS pointing we also are proposing}.We will trace how the bright FUV regions relate spatially to the photospheric dark spots, to inform ideas of coronal structure and heating in these advanced objects. We will probe whether a global magnetosphere exists, and whether the field lines are loaded with hot coronal gas {>10 MK}, as well as the cooler 0.3 MK material already suggested by highly broadened FUSE O VI. Further, we will test whether the striking 100 km/s redshifts of the FUV lines, and similar shifts seen in Ne X by Chandra HETGS, are caused by a massive coronal outflow {perhaps implicated in magnetic braking}. Our method is to exploit, on the one hand, emission-line "Doppler imaging," whereby bright surface regions are mapped onto specific locations in the global profile, according to the line-of-sight rotational velocity. On the other hand, we compare features of different opacity and excitation {e.g., Si III 1206 and Si IV 1393} to deduce whether, say, a red asymmetry is caused by blueshifted absorption, or alternatively by infall of the entire feature. Multiple epochs spaced over two rotation periods break the degeneracy between profile distortions caused by disk passage of hot patches {Doppler imaging part}, and those caused by large-scale flows. Contemporaneous spot maps from the ground will provide a fundamental magnetic context for the coordinated FUV and X-ray "movies."

The Spinning Corona of FK Comae

NASA Astrophysics Data System (ADS)

Kashyap, Vinay

2010-09-01

FK Comae is an ultra-fast rotating, single yellow giant, product of a recent W UMa merger. Extraordinary levels of FUV and X-ray emission rate FK Comae a coronal powerhouse on par with the most extreme of the better known activity heavyweights: short-period RS CVn binaries. As a single star, FK Comae has clear advantages as a laboratory for exploring the outer limits of magnetospheric activity among the coronal cool stars. FK Comae has a long history of attention at optical and X-ray wavelengths, thanks to its generously spotted surface, and proclivity to flare regularly at high energies. FUSE discovered ultra-broad, redshifted profiles of OVI and CIII, but unfortunately the singular observation could not be repeated, thanks to the satellite's flaky attitude system. The remarkable FUV spectrum was taken just a few months before STIS failed in 2004, so there was no opportunity to turn the more powerful gaze of Hubble to the task. Now, finally, the amazing sensitivity of Cosmic Origins Spectrograph can be brought to bear: a single orbit can capture an FUV spectrum of FK Comae with S/N at instrumental limits for bright lines, and digging down to faint FeXXI 1354 {bridge to the coordinated Chandra HETGS pointing we are carrying out}.We will trace how the bright FUV regions relate spatially to the photospheric dark spots, to inform ideas of coronal structure and heating in these advanced objects. We will probe whether a global magnetosphere exists, and whether the field lines are loaded with hot coronal gas {>10 MK}, as well as the cooler 0.3 MK material already suggested by highly broadened FUSE OVI. Further, we will test whether the striking 100 km/s redshifts of the FUV lines, and similar shifts seen in NeX by Chandra HETGS, are caused by persistent coronal flows {outflows, perhaps implicated in magnetic braking; or inflows, like "coronal rain" on the Sun}. Our method is to exploit, on the one hand, emission-line "Doppler imaging," whereby bright surface regions are mapped onto specific locations in the global profile, according to the line-of-sight rotational velocity. On the other hand, we compare features of different opacity and excitation {e.g., SiIII 1206, SiIII 1892, and SiIV 1393} to deduce whether, say, a red asymmetry is caused by blueshifted absorption, or alternatively by infall of the entire feature. Multiple epochs spaced over two rotation periods break the degeneracy between profile distortions caused by disk passage of hot patches {Doppler imaging part}, and those caused by large-scale gas kinematics. Contemporaneous starspot maps from the ground will provide a fundamental magnetic context for the coordinated FUV and X-ray campaigns.

Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model

PubMed Central

Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

2016-01-01

Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5′-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors. PMID:26658104

Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.

PubMed

Sociali, Giovanna; Raffaghello, Lizzia; Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

2016-01-19

Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors.

FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action in Malassezia

PubMed Central

Ianiri, Giuseppe; Applen Clancey, Shelly; Lee, Soo Chan

2017-01-01

ABSTRACT The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis. In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506), ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats. PMID:29066552

Calcineurin Regulates Myocardial Function during Acute Endotoxemia

PubMed Central

Joshi, Mandar S.; Julian, Mark W.; Huff, Jennifer E.; Bauer, John A.; Xia, Yong; Crouser, Elliott D.

2006-01-01

Rationale: Cyclosporin A (CsA) is known to preserve cardiac contractile function during endotoxemia, but the mechanism is unclear. Increased nitric oxide (NO) production and altered mitochondrial function are implicated as mechanisms contributing to sepsis-induced cardiac dysfunction, and CsA has the capacity to reduce NO production and inhibit mitochondrial dysfunction relating to the mitochondrial permeability transition (MPT). Objectives: We hypothesized that CsA would protect against endotoxin-mediated cardiac contractile dysfunction by attenuating NO production and preserving mitochondrial function. Methods: Left ventricular function was measured continuously over 4 h in cats assigned as follows: control animals (n = 7); LPS alone (3 mg/kg, n = 8); and CsA (6 mg/kg, n = 7), a calcineurin inhibitor that blocks the MPT, or tacrolimus (FK506, 0.1 mg/kg, n = 7), a calcineurin inhibitor lacking MPT activity, followed in 30 min by LPS. Myocardial tissue was then analyzed for NO synthase-2 expression, tissue nitration, protein carbonylation, and mitochondrial morphology and function. Measurements and Main Results: LPS treatment resulted in impaired left ventricular contractility, altered mitochondrial morphology and function, and increased protein nitration. As hypothesized, CsA pretreatment normalized cardiac performance and mitochondrial respiration and reduced myocardial protein nitration. Unexpectedly, FK506 pretreatment had similar effects, normalizing both cardiac and mitochondrial parameters. However, CsA and FK506 pretreatments markedly increased protein carbonylation in the myocardium despite elevated manganese superoxide dismutase activity during endotoxemia. Conclusions: Our data indicate that calcineurin is a critical regulator of mitochondrial respiration, tissue nitration, protein carbonylation, and contractile function in the heart during acute endotoxemia. PMID:16424445

Comparative study of Gram stain, potassium hydroxide smear, culture and nested PCR in the diagnosis of fungal keratitis.

PubMed

Badiee, Parisa; Nejabat, Mahmood; Alborzi, Abdolvahab; Keshavarz, Fatemeh; Shakiba, Elaheh

2010-01-01

This study seeks to evaluate the efficacy and practicality of the molecular method, compared to the standard microbiological techniques for diagnosing fungal keratitis (FK). Patients with eye findings suspected of FK were enrolled for cornea sampling. Scrapings from the affected areas of the infected corneas were obtained and were divided into two parts: one for smears and cultures, and the other for nested PCR analysis. Of the 38 eyes, 28 were judged to have fungal infections based on clinical and positive findings in the culture, smear and responses to antifungal treatment. Potassium hydroxide, Gram staining, culture and nested PCR results (either positive or negative) matched in 76.3, 42.1, 68.4 and 81.6%, respectively. PCR is a sensitive method but due to the lack of sophisticated facilities in routine laboratory procedures, it can serve only complementarily and cannot replace conventional methods. Copyright © 2010 S. Karger AG, Basel.

Target engagement and drug residence time can be observed in living cells with BRET

PubMed Central

Robers, Matthew B.; Dart, Melanie L.; Woodroofe, Carolyn C.; Zimprich, Chad A.; Kirkland, Thomas A.; Machleidt, Thomas; Kupcho, Kevin R.; Levin, Sergiy; Hartnett, James R.; Zimmerman, Kristopher; Niles, Andrew L.; Ohana, Rachel Friedman; Daniels, Danette L.; Slater, Michael; Wood, Monika G.; Cong, Mei; Cheng, Yi-Qiang; Wood, Keith V.

2015-01-01

The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment. PMID:26631872

An Investigation into Current Construction Engineering and Management Programs and Curricula and Their Applicability to the U.S. Armed Forces

DTIC Science & Technology

1988-06-01

34Fioneer :. ConsruLtiCn EnIineeri Edcatio .’ JUrnalE 1WLC trutior, Enqineeri") anJ lar,-emert. AEt. c. 111. N1 :. 1. Mar.. 1985. 1-z.evis. A.C.. Fros and...34 Scciet y_fr Fronctg EnA Lneerinq Edution Civil EnoineerinQ Division Fk -1-1e t!in . ’J I . 7, ND. 1 . DEec .. I19i4 1 pp .6. Rainer, R.P., "Civil

K(3)TaF(8) from laboratory X-ray powder data.

PubMed

Smrcok, Lubomír; Cerný, Radovan; Boca, Miroslav; Macková, Iveta; Kubíková, Blanka

2010-02-01

The crystal structure of tripotassium octafluoridotantalate, K(3)TaF(8), determined from laboratory powder diffraction data by the simulated annealing method and refined by total energy minimization in the solid state, is built from discrete potassium cations, fluoride anions and monocapped trigonal-prismatic [TaF(7)](2-) ions. All six atoms in the asymmetric unit are in special positions of the P6(3)mc space group: the Ta and one F atom in the 2b (3m) sites, the K and two F atoms in the 6c (m) sites, and one F atom in the 2a (3m) site. The structure consists of face-sharing K(6) octahedra with a fluoride anion at the center of each octahedron, forming chains of composition [FK(3)](2+) running along [001] with isolated [TaF(7)](2-) trigonal prisms in between. The structure of the title compound is different from the reported structure of Na(3)TaF(8) and represents a new structure type.

Autoantibodies against cytochrome P450s in sera of children treated with immunosuppressive drugs

PubMed Central

LYTTON, S D; BERG, U; NEMETH, A; INGELMAN-SUNDBERG, M

2002-01-01

Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti-graft rejection and autoimmune disease therapy, is limited by their hepato-and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti-CYP reactivity in 16% of children on CyA for anti-graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8·5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti-cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection. PMID:11876753

Control of vascular smooth muscle function by Src-family kinases and reactive oxygen species in health and disease

PubMed Central

MacKay, Charles E; Knock, Greg A

2015-01-01

Abstract Reactive oxygen species (ROS) are now recognised as second messenger molecules that regulate cellular function by reversibly oxidising specific amino acid residues of key target proteins. Amongst these are the Src-family kinases (SrcFKs), a multi-functional group of non-receptor tyrosine kinases highly expressed in vascular smooth muscle (VSM). In this review we examine the evidence supporting a role for ROS-induced SrcFK activity in normal VSM contractile function and in vascular remodelling in cardiovascular disease. VSM contractile responses to G-protein-coupled receptor stimulation, as well as hypoxia in pulmonary artery, are shown to be dependent on both ROS and SrcFK activity. Specific phosphorylation targets are identified amongst those that alter intracellular Ca2+ concentration, including transient receptor potential channels, voltage-gated Ca2+ channels and various types of K+ channels, as well as amongst those that regulate actin cytoskeleton dynamics and myosin phosphatase activity, including focal adhesion kinase, protein tyrosine kinase-2, Janus kinase, other focal adhesion-associated proteins, and Rho guanine nucleotide exchange factors. We also examine a growing weight of evidence in favour of a key role for SrcFKs in multiple pro-proliferative and anti-apoptotic signalling pathways relating to oxidative stress and vascular remodelling, with a particular focus on pulmonary hypertension, including growth-factor receptor transactivation and downstream signalling, hypoxia-inducible factors, positive feedback between SrcFK and STAT3 signalling and positive feedback between SrcFK and NADPH oxidase dependent ROS production. We also discuss evidence for and against the potential therapeutic targeting of SrcFKs in the treatment of pulmonary hypertension. PMID:25384773

Autoantibodies against cytochrome P450s in sera of children treated with immunosuppressive drugs.

PubMed

Lytton, S D; Berg, U; Nemeth, A; Ingelman-Sundberg, M

2002-02-01

Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti-graft rejection and autoimmune disease therapy, is limited by their hepato- and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti-CYP reactivity in 16% of children on CyA for anti-graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8.5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti-cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.

Evaluation of online disaster and emergency preparedness resources.

PubMed

Friedman, Daniela B; Tanwar, Manju; Richter, Jane V E

2008-01-01

Increasingly, individuals are relying on the Internet as a major source of health information. When faced with sudden or pending disasters, people resort to the Internet in search of clear, current, and accurate instructions on how to prepare for and respond to such emergencies. Research about online health resources ascertained that information was written at the secondary education and college levels and extremely difficult for individuals with limited literacy to comprehend. This content analysis is the first to assess the reading difficulty level and format suitability of a large number of disaster and emergency preparedness Web pages intended for the general public. The aims of this study were to: (1) assess the readability and suitability of disaster and emergency preparedness information on the Web; and (2) determine whether the reading difficulty level and suitability of online resources differ by the type of disaster or emergency and/or Website domain. Fifty Websites containing information on disaster and/or emergency preparedness were retrieved using the Google search engine. Readability testing was conducted on the first Web page, suggested by Google, addressing preparedness for the general public. The reading level was assessed using Flesch-Kincaid (F-K) and Flesch Reading Ease (FRE) measures. The Suitability Assessment of Materials (SAM) instrument was used to evaluate additional factors such as graphics, layout, and cultural appropriateness. The mean F-K readability score of the 50 Websites was Grade 10.74 (95% CI = 9.93, 11.55). The mean FRE score was 45.74 (95% CI = 41.38, 50.10), a score considered "difficult."A Web page with content about both risk and preparedness supplies was the most difficult to read according to F-K (Grade level = 12.1). Web pages with general disaster and emergency information and preparedness supplies were considered most difficult according to the FRE (38.58, 95% CI = 30.09, 47.08). The average SAM score was 48% or 0.48 (95% CI = 0.45, 0.51), implying below average suitability of these Websites. Websites on pandemics and bioterrorism were the most difficult to read (F-K: p = 0.012; FRE: p = 0.014) and least suitable (SAM: p = 0.035) compared with other disasters and emergencies. The results suggest the need for readily accessible preparedness resources on the Web that are easy-to-read and visually appropriate. Interdisciplinary collaborations between public health educators, risk communication specialists, and Web page creators and writers are recommended to ensure the development and dissemination of disaster and emergency resources that consider literacy abilities of the general public.

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

Hoffman, D. Mark

Here, three polymers are routinely used as binders for plastic bonded explosives by Lawrence Livermore National Laboratory, FK-800, Viton A 100, and Oxy 461. Attenuated total reflectance Fourier transform infrared measurements were performed on 10 different lots of FK-800, 5 different lots of Oxy 461, and 3 different lots of Viton A-100, one sample of Viton VTR 5883 and 2 Fluorel polymers of hexafluoropropene and vinylidene fluoride. The characteristic IR bands were measured. If possible, their vibrational modes were assigned based on literature data. Simple Mopac calculations were used to validate these vibrational mode assignments. Somewhat more sophisticated calculations weremore » run using Gaussian on the same structures.« less

The second Quito astrolabe catalogue

NASA Astrophysics Data System (ADS)

Kolesnik, Y. B.; Davila, H.

1994-03-01

The paper contains 515 individual corrections {DELTA}α and 235 corrections {DELTA}δ to FK5 and FK5Supp. stars and 50 corrections to their proper motions computed from observations made with the classical Danjon astrolabe OPL-13 at Quito Astronomical Observatory of Ecuador National Polytechnical School during a period from 1964 to 1983. These corrections cover the declination zone from -30deg to +30deg. Mean probable errors of catalogue positions are 0.047" in αcosδ and 0.054" in δ. The systematic trends of the catalogue {DELTA}αalpha_cosδ, {DELTA}αdelta_cosδ, {DELTA}δalpha_, {DELTA}δdelta_ are presented for the observed zone.

Determinants of famous name processing speed: age of acquisition versus semantic connectedness.

PubMed

Smith-Spark, James H; Moore, Viv; Valentine, Tim

2013-02-01

The age of acquisition (AoA) and the amount of biographical information known about celebrities have been independently shown to influence the processing of famous people. In this experiment, we investigated the facilitative contribution of both factors to famous name processing. Twenty-four mature adults participated in a familiarity judgement task, in which the names of famous people were grouped orthogonally by AoA and by the number of bits of biographical information known about them (number of facts known; NoFK). Age of acquisition was found to have a significant effect on both reaction time (RT) and accuracy of response, but NoFK did not. The RT data also revealed a significant AoA×NoFK interaction. The amount of information known about a celebrity played a facilitative role in the processing of late-acquired, but not early-acquired, celebrities. Once AoA is controlled, it would appear that the semantic system ceases to have a significant overall influence on the processing of famous people. The pre-eminence of AoA over semantic connectedness is considered in the light of current theories of AoA and how their influence might interact. Copyright © 2012 Elsevier B.V. All rights reserved.

Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery

PubMed Central

Knock, Greg A.; Snetkov, Vladimir A.; Shaifta, Yasin; Drndarski, Svetlana; Ward, Jeremy P.T.; Aaronson, Philip I.

2008-01-01

Aims We investigated the role of src-family kinases (srcFKs) in hypoxic pulmonary vasoconstriction (HPV) and how this relates to Rho-kinase-mediated Ca2+ sensitization and changes in intracellular Ca2+ concentration ([Ca2+]i). Methods and results Intra-pulmonary arteries (IPAs) were obtained from male Wistar rats. HPV was induced in myograph-mounted IPAs. Auto-phosphorylation of srcFKs and phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and myosin light-chain (MLC20) in response to hypoxia were determined by western blotting. Translocation of Rho-kinase and effects of siRNA knockdown of src and fyn were examined in cultured pulmonary artery smooth muscle cells (PASMCs). [Ca2+]i was estimated in Fura-PE3-loaded IPA. HPV was inhibited by two blockers of srcFKs, SU6656 and PP2. Hypoxia enhanced phosphorylation of three srcFK proteins at Tyr-416 (60, 59, and 54 kDa, corresponding to src, fyn, and yes, respectively) and enhanced srcFK-dependent tyrosine phosphorylation of multiple target proteins. Hypoxia caused a complex, time-dependent enhancement of MYPT-1 and MLC20 phosphorylation, both in the absence and presence of pre-constriction. The sustained component of this enhancement was blocked by SU6656 and the Rho-kinase inhibitor Y27632. In PASMCs, hypoxia caused translocation of Rho-kinase from the nucleus to the cytoplasm, and this was prevented by anti-src siRNA and to a lesser extent by anti-fyn siRNA. The biphasic increases in [Ca2+]i that accompany HPV were also inhibited by PP2. Conclusion Hypoxia activates srcFKs and triggers protein tyrosine phosphorylation in IPA. Hypoxia-mediated Rho-kinase activation, Ca2+ sensitization, and [Ca2+]i responses are depressed by srcFK inhibitors and/or siRNA knockdown, suggesting a central role of srcFKs in HPV. PMID:18682436

Assessment of global ischemic/reperfusion and Tacrolimus administration on CA1 region of hippocampus: gene expression profiles of BAX and BCL2 genes.

PubMed

Badr, R; Hashemi, M; Javadi, G; Movafagh, A; Mahdian, R

2016-01-01

It is well known that hippocampus has a pivotal role in learning, formation and consolidation of memory. Global cerebral ischemia causes severe damage to pyramidal neurons of the CA1 region and usually results in residual neurological deficits following a recovery from ischemia. Scientists investigate to find the molecular mechanism of apoptosis and to use this cell death for clinical treatment. In this investigation, we evaluated the molecular mechanism of FK-506 in apoptosis using gene expression quantification of BAX and BCL-2 genes in hippocampus following global ischemic/reperfusion. In the present experimental study, adult male Wistar rats were obtained and housed under standard conditions. Each experimental group consisted of five rats and was equally distributed in the normal control, ischemia/reperfusion, ischemia/reperfusion followed by FK-506. Global ischemia was induced for animals in ischemia and drug groups. In the drug group, moreover, two doses of FK-506 were injected as IV injection and intra-peritoneal (IP) injection after 48 h. Then, hippocampus tissue was removed. Consequently, RNA isolated, cDNA was synthesized and Real-Time PCR was performed. Finally, the obtained data was analyzed statistically (p<0.05). The quantitative results showed the BAX expression ratio increased approximately 3-times in ischemia/reperfusion (3.11 ± 0.28) group compared to the untreated (NR) and the drug group (p<0.001). The statistical analysis showed a significant difference for BCL-2 expression between the experimental groups (p<0.001). The mRNA level of BCL-2 decreased in the ischemia/reperfusion group, while it was without alteration in the other groups. The results showed that global cerebral ischemia/reperfusion induced BAX as pro-apoptotic gene and tacrolimus a neuroprotective drug inhibited BAX gene expression and induced BCL-2 gene expression as anti-apoptotic gene (Tab. 2, Fig. 3, Ref. 21).

FK506 binding proteins: cellular regulators of intracellular Ca2+ signalling.

PubMed

MacMillan, Debbi

2013-01-30

In many cell types the intracellular Ca(2+) store performs a central role in the regulation of the cytosolic Ca(2+) concentration ([Ca(2+)](c)), the elevation of which triggers diverse and fundamental activities from reproduction to apoptosis, as well as being the major trigger for contraction. Two distinct classes of Ca(2+) release channels, which mobilize Ca(2+) from the store, exist; the inositol 1,4,5-trisphosphate (IP(3)) receptor and the ryanodine receptor. Considerable attention has been directed towards the importance of modulatory proteins that interact with these channels including, FK506 binding proteins (FKBPs), FKBP12 and its isoform, FKBP12.6. Although FKBP12 was first identified as the principal intracellular target for the immunosuppressive drugs, FK506 and rapamycin, new insights into the role of FKBPs have since emerged. These regulatory proteins are reportedly important modulators of intracellular Ca(2+) release. FKBPs may regulate ryanodine and IP(3) receptors either directly, by binding to the cytoplasmic aspect of the channel, or indirectly via modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR). Dissociation of FKBP12 or FKBP12.6 from either Ca(2+) release channel may increase, decrease or have no effect on ryanodine receptor- or IP(3) receptor-mediated Ca(2+) release. These important controversies may be attributed to FKBPs' ability to regulate the receptor indirectly via the kinase and phosphatase pathways modulated by the accessory proteins. This brief review discusses the regulation of intracellular ryanodine and IP(3) receptor Ca(2+) release channels by accessory FKBPs, with important implications for the role of FKBPs in the pathophysiology of a number of diseases. Copyright © 2012 Elsevier B.V. All rights reserved.

Inhibition of basolateral cAMP permeability in the toad urinary bladder.

PubMed

Boom, A; Golstein, P E; Frerotte, M; Sande, J V; Beauwens, R

2000-10-01

1. The effect of sulphonylurea drugs on hydrosmotic flow across toad urinary bladder epithelium was re-evaluated in the present study. Glibenclamide, added to the basolateral medium, significantly enhanced the osmotic flow induced by low doses of antidiuretic hormone (ADH) or forskolin (FK), while it inhibited the effect of exogenous cyclic adenosine monophosphate (cAMP) or its non-hydrolysable bromo derivative, 8-Br-cAMP, added to the basolateral medium. These opposite effects of glibenclamide on the transepithelial osmotic flow can be explained by a reduction of cAMP permeability across the basolateral membrane of the epithelium. The decrease in cAMP permeability leads, according to the direction of the cAMP gradient, to firstly an enhanced osmotic flow when cAMP is generated intracellularly by addition of ADH and FK, glibenclamide reducing cAMP exit from the cell, and secondly a decreased osmotic flow in response to cAMP (and 8-Br-cAMP) added to the basolateral medium, glibenclamide inhibiting, in this case, their entry into the cell. 2. The demonstration that glibenclamide actually inhibits the basolateral cAMP permeability rests on the fact that firstly it decreases the release of cAMP into the basolateral medium by about 40 %, at each concentration of ADH or forskolin tested, secondly it increases the cAMP content of paired hemibladders incubated in the presence of ADH or FK, when intracellular degradation was prevented by phosphodiesterase inhibition, and thirdly it decreases also the uptake of basolateral 8-Br-[3H]cAMP into paired toad hemibladders. 3. Taken together, the present data demonstrate that glibenclamide inhibits the toad urinary bladder basolateral membrane permeability to cAMP, most probably by a direct interaction with a membrane protein not yet indentified but distinct from the sulphonylurea receptor.

Beneficial Effects of Adding Ketamine to Intravenous Patient-Controlled Analgesia with Fentanyl after the Nuss Procedure in Pediatric Patients

PubMed Central

Cha, Moon Ho; Eom, Ji Hye; Lee, Yoon Sook; Kim, Woon Young; Park, Young Cheol; Min, Sam Hong

2012-01-01

Purpose The aim of this prospective, double-blind, randomized study was to investigate the analgesic effects of low-dose ketamine on intravenous patient-controlled analgesia (IV-PCA) with fentanyl for pain control in pediatric patients following the Nuss procedure for pectus excavatum. Materials and Methods Sixty pediatric patients undergoing the Nuss procedure were randomly assigned to receive fentanyl (Group F, n=30) or fentanyl plus ketamine (Group FK, n=30). Ten minutes before the end of surgery, following the loading dose of each solution, 0.5 µg/kg/hr of fentanyl or 0.5 µg/kg/hr of fentanyl plus 0.15 mg/kg/hr of ketamine was infused via an IV-PCA pump (basal rate, 1 mL/hr; bolus, 0.5 mL; lock out interval, 30 min). Fentanyl consumption, pain score, ketorolac use, nausea/vomiting, ondansetron use, pruritus, respiratory depression, hallucination, dreaming, and parent satisfaction with pain control were measured throughout the 48 hours following surgery. Results The pain scores, ketorolac use, and fentanyl consumption of Group FK were significantly lower than in Group F (p<0.05). The incidence of nausea/vomiting and ondansetron use in Group FK was significantly lower than in Group F (p<0.05). There were no reports of respiratory depression, hallucination or dreaming. Parent satisfaction with pain control was similar between the two groups. Conclusion We concluded that low-dose ketamine added to IV-PCA with fentanyl after the Nuss procedure in pediatric patients can reduce pain scores, consumption of fentanyl, and incidence of nausea/vomiting without increasing side effects. PMID:22318834

Ibuprofen reverts antifungal resistance on Candida albicans showing overexpression of CDR genes.

PubMed

Ricardo, Elisabete; Costa-de-Oliveira, Sofia; Dias, Ana Silva; Guerra, José; Rodrigues, Acácio Gonçalves; Pina-Vaz, Cidália

2009-06-01

Several mechanisms may be associated with Candida albicans resistance to azoles. Ibuprofen was described as being able to revert resistance related to efflux activity in Candida. The aim of this study was to uncover the molecular base of antifungal resistance in C. albicans clinical strains that could be reverted by ibuprofen. Sixty-two clinical isolates and five control strains of C. albicans were studied: the azole susceptibility phenotype was determined according to the Clinical Laboratory for Standards Institute, M27-A2 protocol and minimal inhibitory concentration values were recalculated with ibuprofen (100 microg mL(-1)); synergistic studies between fluconazole and FK506, a Cdr1p inhibitor, were performed using an agar disk diffusion assay and were compared with ibuprofen results. Gene expression was quantified by real-time PCR, with and without ibuprofen, regarding CDR1, CDR2, MDR1, encoding for efflux pumps, and ERG11, encoding for azole target protein. A correlation between susceptibility phenotype and resistance gene expression profiles was determined. Ibuprofen and FK506 showed a clear synergistic effect when combined with fluconazole. Resistant isolates reverting to susceptible after incubation with ibuprofen showed CDR1 and CDR2 overexpression especially of the latter. Conversely, strains that did not revert displayed a remarkable increase in ERG11 expression along with CDR genes. Ibuprofen did not alter resistance gene expression significantly (P>0.05), probably acting as a Cdrp blocker.

Methodology Investigation of AI(Artificial Intelligence) Test Officer Support Tool. Volume 2

DTIC Science & Technology

1989-03-01

a mathematical representation of a PE and its connections. This representation describes the " neurodynamics " of a PE. A sigmoid transfer function is...Element(i) Neurodynamics : Summation Function: Wo*XO + W,*X + W*X "X 0 0 1 1 2 W~fn Transfer Function: F(k) = (1 + e k) Output: x. - F(I) Figure 2-4...simplifies the description of the network operations. Thus, one or more PEs grouped together, with the same neurodynamics , is a layer [reference 5]. A

VizieR Online Data Catalog: Second Quito Astrolabe Catalogue (Kolesnik+ 1994)

NASA Astrophysics Data System (ADS)

Kolesnik, Y. B.; Davila, H.

1994-03-01

The paper contains 515 individual corrections {DELTA}α and 235 corrections {DELTA}δ to FK5 and FK5Supp. stars and 50 corrections to their proper motions computed from observations made with the classical Danjon astrolabe OPL-13 at Quito Astronomical Observatory of Ecuador National Polytechnical School during a period from 1964 to 1983. These corrections cover the declination zone from -30° to +30°. Mean probable errors of catalogue positions are 0.047" in αcosδ and 0.054" in δ. The systematic trends of the catalogue {DELTA}ααcosδ, {DELTA}αδcosδ, {DELTA}δα, {DELTA}δδ are presented for the observed zone. (2 data files).

Infrared properties of three plastic bonded explosive binders

DOE PAGES

Hoffman, D. Mark

2017-08-02

Here, three polymers are routinely used as binders for plastic bonded explosives by Lawrence Livermore National Laboratory, FK-800, Viton A 100, and Oxy 461. Attenuated total reflectance Fourier transform infrared measurements were performed on 10 different lots of FK-800, 5 different lots of Oxy 461, and 3 different lots of Viton A-100, one sample of Viton VTR 5883 and 2 Fluorel polymers of hexafluoropropene and vinylidene fluoride. The characteristic IR bands were measured. If possible, their vibrational modes were assigned based on literature data. Simple Mopac calculations were used to validate these vibrational mode assignments. Somewhat more sophisticated calculations weremore » run using Gaussian on the same structures.« less

Rapid isolation of novel FK506 binding proteins from multiple organisms using gDNA and cDNA T7 phage display.

PubMed

Piggott, Andrew M; Kriegel, Alison M; Willows, Robert D; Karuso, Peter

2009-10-01

Reverse chemical proteomics using T7 phage display is a powerful technique for identifying cellular receptors of biologically active small molecules. However, to date this method has generally been limited to cDNA libraries constructed from mRNA isolated from eukaryotes. In this paper, we describe the construction of the first prokaryotic T7 phage display libraries from randomly digested Pseudomonas stutzeri and Vibrio fischeri gDNA, as well as a plant cDNA library from Arabidopsis thaliana. We also describe the use of T7 phage display to identify novel proteins from environmental DNA samples using biotinylated FK506 as a model affinity probe.

Compressed Video Segmentation

DTIC Science & Technology

1996-09-01

Fk+gl1mGnCop![ qVa +HeU95.!:r%I>0&CFS+I,:Y45&C47%,:d&C$+&6%=( 1 (3`F-FS+/`+9597@s%8.1F:Q.18.1FS+I9V>AFG+He.: 45,(395`/=.R>t...Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per...penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 1 . REPORT DATE SEP 1996

76 FR 18587 - In the Matter of Corestream Energy, Inc. (f/k/a Zealous, Inc.); Order of Suspension of Trading

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-04

... SECURITIES AND EXCHANGE COMMISSION [File No. 500-1] In the Matter of Corestream Energy, Inc. (f/k... Corestream Energy, Inc. (``Corestream'') (f/k/a Zealous, Inc.) because it has failed to file certain periodic.... Therefore, it is ordered, pursuant to Section 12(k) of the Securities Exchange Act of 1934, that trading in...

Imp2, the PSTPIP homolog in fission yeast, affects sensitivity to the immunosuppressant FK506 and membrane trafficking in fission yeast

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

Kita, Ayako; Higa, Mari; Doi, Akira

Cytokinesis is a highly ordered process that divides one cell into two cells, which is functionally linked to the dynamic remodeling of the plasma membrane coordinately with various events such as membrane trafficking. Calcineurin is a highly conserved serine/threonine protein phosphatase, which regulates multiple biological functions, such as membrane trafficking and cytokinesis. Here, we isolated imp2-c3, a mutant allele of the imp2{sup +} gene, encoding a homolog of the mouse PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1), using a genetic screen for mutations that are synthetically lethal with calcineurin deletion in fission yeast. The imp2-c3 mutants showed a defect in cytokinesis withmore » multi-septated phenotypes, which was further enhanced upon treatment with the calcineurin inhibitor FK506. Notably, electron micrographs revealed that the imp2-c3 mutant cells accumulated aberrant multi-lamella Golgi structures and putative post-Golgi secretory vesicles, and exhibited fragmented vacuoles in addition to thickened septa. Consistently, imp2-c3 mutants showed a reduced secretion of acid phosphatase and defects in vacuole fusion. The imp2-c3 mutant cells exhibited a weakened cell wall, similar to the membrane trafficking mutants identified in the same genetic screen such as ypt3-i5. These findings implicate the PSTPIP1 homolog Imp2 in Golgi/vacuole function, thereby affecting various cellular processes, including cytokinesis and cell integrity. - Highlights: • We isolated imp2-c3, in a synthetic lethal screen with calcineurin in fission yeast. • The imp2{sup +} gene encodes a component of the actin contractile ring similar to Cdc15. • The imp2-c3 mutants showed defects in cytokinesis, which were exacerbated by FK506. • The imp2-c3 mutants were defective in membrane trafficking and cell wall integrity. • Our study revealed a novel role for Imp2 in the Golgi/vacuolar membrane trafficking.« less

Department of Defense In-House RDT&E Activities

DTIC Science & Technology

1979-10-30

OIVAI .. I-:JNLI’IONS/EQJIPMtN’r/CAPAt3ILIrflt.4 tNC’i4PAb-Eý, APPLO RUA INCL WRC DEV AND) SPT IN INTI:RLO got: ~ISI6 ANALYSIS. JAM,IJEtPSi(7 iNrt7L...LU*. CAPT. R. 4. tsROWN TECH1.L1R. MR. THOMAS RAMIREZ F. ~PROGRAM LJATA BY FISCAL YEAR (MILLION S PiKOtRAM 1979 IQ80fk~(ACTUJAL) (ACT + EsT) TUTAL

Assessment of conformational, spectral, antimicrobial activity, chemical reactivity and NLO application of Pyrrole-2,5-dicarboxaldehyde bis(oxaloyldihydrazone).

PubMed

Rawat, Poonam; Singh, R N

2015-04-05

An orange colored pyrrole dihydrazone: Pyrrole-2,5-dicarboxaldehyde bis(oxaloyldihydrazone) (PDBO) has been synthesized by reaction of oxalic acid dihydrazide with 2,5 diformyl-1H-pyrrole and has been characterized by spectroscopic analysis (1H, 13C NMR, UV-visible, FT-IR and DART Mass). The properties of the compound has been evaluated using B3LYP functional and 6-31G(d,p)/6-311+G(d,p) basis set. The symmetric (3319, 3320 cm(-1)) and asymmetric (3389, 3382 cm(-1)) stretching wave number confirm free NH2 groups in PDBO. NBO analysis shows, inter/intra molecular interactions within the molecule. Topological parameters have been analyzed by QTAIM theory and provide the existence of intramolecular hydrogen bonding (N-H⋯O). The local reactivity descriptors analyses determine the reactive sites within molecule. The calculated first hyperpolarizability value (β0=23.83×10(-30) esu) of pyrrole dihydrazone shows its suitability for non-linear optical (NLO) response. The preliminary bioassay suggested that the PDBO exhibits relatively good antibacterial and fungicidal activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pyogenes, Candida albicans, Aspergillus niger. The local reactivity descriptors--Fukui functions (fk+, fk-), local softnesses (sk+, sk-) and electrophilicity indices (ωk+, ωk-) analyses have been used to determine the reactive sites within molecule. Copyright © 2014 Elsevier B.V. All rights reserved.

Assessment of conformational, spectral, antimicrobial activity, chemical reactivity and NLO application of Pyrrole-2,5-dicarboxaldehyde bis(oxaloyldihydrazone)

NASA Astrophysics Data System (ADS)

Rawat, Poonam; Singh, R. N.

2015-04-01

An orange colored pyrrole dihydrazone: Pyrrole-2,5-dicarboxaldehyde bis(oxaloyldihydrazone) (PDBO) has been synthesized by reaction of oxalic acid dihydrazide with 2,5 diformyl-1H-pyrrole and has been characterized by spectroscopic analysis (1H, 13C NMR, UV-visible, FT-IR and DART Mass). The properties of the compound has been evaluated using B3LYP functional and 6-31G(d,p)/6-311+G(d,p) basis set. The symmetric (3319, 3320 cm-1) and asymmetric (3389, 3382 cm-1) stretching wave number confirm free NH2 groups in PDBO. NBO analysis shows, inter/intra molecular interactions within the molecule. Topological parameters have been analyzed by QTAIM theory and provide the existence of intramolecular hydrogen bonding (N-H⋯O). The local reactivity descriptors analyses determine the reactive sites within molecule. The calculated first hyperpolarizability value (β0 = 23.83 × 10-30 esu) of pyrrole dihydrazone shows its suitability for non-linear optical (NLO) response. The preliminary bioassay suggested that the PDBO exhibits relatively good antibacterial and fungicidal activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pyogenes, Candida albicans, Aspergillus niger. The local reactivity descriptors - Fukui functions (fk+, fk-), local softnesses (sk+, sk-) and electrophilicity indices (ωk+, ωk-) analyses have been used to determine the reactive sites within molecule.

The prolyl isomerase FKBP25 regulates microtubule polymerization impacting cell cycle progression and genomic stability

PubMed Central

Dilworth, David; Gudavicius, Geoff; Xu, Xiaoxue; Boyce, Andrew K J; O’Sullivan, Connor; Serpa, Jason J; Bilenky, Misha; Petrochenko, Evgeniy V; Borchers, Christoph H; Hirst, Martin; Swayne, Leigh Anne; Howard, Perry; Nelson, Christopher J

2018-01-01

Abstract FK506 binding proteins (FKBPs) catalyze the interconversion of cis-trans proline conformers in proteins. Importantly, FK506 drugs have anti-cancer and neuroprotective properties, but the effectors and mechanisms underpinning these properties are not well understood because the cellular function(s) of most FKBP proteins are unclear. FKBP25 is a nuclear prolyl isomerase that interacts directly with nucleic acids and is associated with several DNA/RNA binding proteins. Here, we show the catalytic FKBP domain binds microtubules (MTs) directly to promote their polymerization and stabilize the MT network. Furthermore, FKBP25 associates with the mitotic spindle and regulates entry into mitosis. This interaction is important for mitotic spindle dynamics, as we observe increased chromosome instability in FKBP25 knockdown cells. Finally, we provide evidence that FKBP25 association with chromatin is cell-cycle regulated by Protein Kinase C phosphorylation. This disrupts FKBP25–DNA contacts during mitosis while maintaining its interaction with the spindle apparatus. Collectively, these data support a model where FKBP25 association with chromatin and MTs is carefully choreographed to ensure faithful genome duplication. Additionally, they highlight that FKBP25 is a MT-associated FK506 receptor and potential therapeutic target in MT-associated diseases. PMID:29361176

Autoradiographic evidence for two classes of mu opioid binding sites in rat brain using (/sup 125/I)FK33824

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

Rothman, R.B.; Jacobson, A.E.; Rice, K.C.

1987-11-01

Previous studies demonstrated that pretreatment of brain membranes with the irreversible mu antagonist, beta-funaltrexamine (beta-FNA), partially eliminated mu binding sites (25,35), consistent with the existence of two mu binding sites distinguished by beta-FNA. This paper tests the hypothesis that the FNA-sensitive and FNA-insensitive mu binding sites have different anatomical distributions in rat brain. Prior to autoradiographic visualization of mu binding sites, (/sup 3/H)oxymorphone, (/sup 3/H)D-ala2-MePhe4, Gly-ol5-enkephalin (DAGO), and (/sup 125/I)D-ala2-Me-Phe4-met(o)-ol)enkephalin (FK33824) were shown to selectively label mu binding sites using slide mounted sections of molded minced rat brain. As found using membranes, beta-FNA eliminated only a portion of mu bindingmore » sites. Autoradiographic visualization of mu binding sites using the mu-selective ligand (/sup 125/I)FK33824 in control and FNA-treated sections of rat brain demonstrated that the proportion of mu binding sites sensitive to beta-FNA varied across regions of the brain, particularly the dorsal thalamus, ventrobasal complex and the hypothalamus, providing anatomical data supporting the existence of two classes of mu binding sites in rat brain.« less

Comparison Of Eigenvector-Based Statistical Pattern Recognition Algorithms For Hybrid Processing

NASA Astrophysics Data System (ADS)

Tian, Q.; Fainman, Y.; Lee, Sing H.

1989-02-01

The pattern recognition algorithms based on eigenvector analysis (group 2) are theoretically and experimentally compared in this part of the paper. Group 2 consists of Foley-Sammon (F-S) transform, Hotelling trace criterion (HTC), Fukunaga-Koontz (F-K) transform, linear discriminant function (LDF) and generalized matched filter (GMF). It is shown that all eigenvector-based algorithms can be represented in a generalized eigenvector form. However, the calculations of the discriminant vectors are different for different algorithms. Summaries on how to calculate the discriminant functions for the F-S, HTC and F-K transforms are provided. Especially for the more practical, underdetermined case, where the number of training images is less than the number of pixels in each image, the calculations usually require the inversion of a large, singular, pixel correlation (or covariance) matrix. We suggest solving this problem by finding its pseudo-inverse, which requires inverting only the smaller, non-singular image correlation (or covariance) matrix plus multiplying several non-singular matrices. We also compare theoretically the effectiveness for classification with the discriminant functions from F-S, HTC and F-K with LDF and GMF, and between the linear-mapping-based algorithms and the eigenvector-based algorithms. Experimentally, we compare the eigenvector-based algorithms using a set of image data bases each image consisting of 64 x 64 pixels.

Alternative Optical Architectures for Multichannel Adaptive Optical Processing

DTIC Science & Technology

1993-04-01

0j +,de 2; j__ -L12 izi j=#1 Pj F2VSIm YS F2 vdI ) N X exp[,2 x (,j + fF,)t]w.-- akx 2 f Fxxp(-j2Xskr W, (16)fsL 2Iu(-LJ:aherir F2VsIJX( 2 fk))r(6 ka...1:512) -off-we); Puss (offset) -1; Rl-Puls8. *31n(2*pi* ([1: 2048 )4phaisrr ./10.24); sukx1la±(221) ,plM (Rl) tit~le ( ’sen chanrnel niqual’) U~sin loop

Calcineurin plays key roles in the dimorphic transition and virulence of the human pathogenic zygomycete Mucor circinelloides.

PubMed

Lee, Soo Chan; Li, Alicia; Calo, Silvia; Heitman, Joseph

2013-01-01

Many pathogenic fungi are dimorphic and switch between yeast and filamentous states. This switch alters host-microbe interactions and is critical for pathogenicity. However, in zygomycetes, whether dimorphism contributes to virulence is a central unanswered question. The pathogenic zygomycete Mucor circinelloides exhibits hyphal growth in aerobic conditions but switches to multi-budded yeast growth under anaerobic/high CO₂ conditions. We found that in the presence of the calcineurin inhibitor FK506, Mucor exhibits exclusively multi-budded yeast growth. We also found that M. circinelloides encodes three calcineurin catalytic A subunits (CnaA, CnaB, and CnaC) and one calcineurin regulatory B subunit (CnbR). Mutations in the latch region of CnbR and in the FKBP12-FK506 binding domain of CnaA result in hyphal growth of Mucor in the presence of FK506. Disruption of the cnbR gene encoding the sole calcineurin B subunit necessary for calcineurin activity yielded mutants locked in permanent yeast phase growth. These findings reveal that the calcineurin pathway plays key roles in the dimorphic transition from yeast to hyphae. The cnbR yeast-locked mutants are less virulent than the wild-type strain in a heterologous host system, providing evidence that hyphae or the yeast-hyphal transition are linked to virulence. Protein kinase A activity (PKA) is elevated during yeast growth under anaerobic conditions, in the presence of FK506, or in the yeast-locked cnbR mutants, suggesting a novel connection between PKA and calcineurin. cnaA mutants lacking the CnaA catalytic subunit are hypersensitive to calcineurin inhibitors, display a hyphal polarity defect, and produce a mixture of yeast and hyphae in aerobic culture. The cnaA mutants also produce spores that are larger than wild-type, and spore size is correlated with virulence potential. Our results demonstrate that the calcineurin pathway orchestrates the yeast-hyphal and spore size dimorphic transitions that contribute to virulence of this common zygomycete fungal pathogen.

Multimodal determination of Rayleigh dispersion and attenuation curves using the circle fit method

NASA Astrophysics Data System (ADS)

Verachtert, R.; Lombaert, G.; Degrande, G.

2018-03-01

This paper introduces the circle fit method for the determination of multi-modal Rayleigh dispersion and attenuation curves as part of a Multichannel Analysis of Surface Waves (MASW) experiment. The wave field is transformed to the frequency-wavenumber (fk) domain using a discretized Hankel transform. In a Nyquist plot of the fk-spectrum, displaying the imaginary part against the real part, the Rayleigh wave modes correspond to circles. The experimental Rayleigh dispersion and attenuation curves are derived from the angular sweep of the central angle of these circles. The method can also be applied to the analytical fk-spectrum of the Green's function of a layered half-space in order to compute dispersion and attenuation curves, as an alternative to solving an eigenvalue problem. A MASW experiment is subsequently simulated for a site with a regular velocity profile and a site with a soft layer trapped between two stiffer layers. The performance of the circle fit method to determine the dispersion and attenuation curves is compared with the peak picking method and the half-power bandwidth method. The circle fit method is found to be the most accurate and robust method for the determination of the dispersion curves. When determining attenuation curves, the circle fit method and half-power bandwidth method are accurate if the mode exhibits a sharp peak in the fk-spectrum. Furthermore, simulated and theoretical attenuation curves determined with the circle fit method agree very well. A similar correspondence is not obtained when using the half-power bandwidth method. Finally, the circle fit method is applied to measurement data obtained for a MASW experiment at a site in Heverlee, Belgium. In order to validate the soil profile obtained from the inversion procedure, force-velocity transfer functions were computed and found in good correspondence with the experimental transfer functions, especially in the frequency range between 5 and 80 Hz.

Coarse graining flow of spin foam intertwiners

NASA Astrophysics Data System (ADS)

Dittrich, Bianca; Schnetter, Erik; Seth, Cameron J.; Steinhaus, Sebastian

2016-12-01

Simplicity constraints play a crucial role in the construction of spin foam models, yet their effective behavior on larger scales is scarcely explored. In this article we introduce intertwiner and spin net models for the quantum group SU (2 )k×SU (2 )k, which implement the simplicity constraints analogous to four-dimensional Euclidean spin foam models, namely the Barrett-Crane (BC) and the Engle-Pereira-Rovelli-Livine/Freidel-Krasnov (EPRL/FK) model. These models are numerically coarse grained via tensor network renormalization, allowing us to trace the flow of simplicity constraints to larger scales. In order to perform these simulations we have substantially adapted tensor network algorithms, which we discuss in detail as they can be of use in other contexts. The BC and the EPRL/FK model behave very differently under coarse graining: While the unique BC intertwiner model is a fixed point and therefore constitutes a two-dimensional topological phase, BC spin net models flow away from the initial simplicity constraints and converge to several different topological phases. Most of these phases correspond to decoupling spin foam vertices; however we find also a new phase in which this is not the case, and in which a nontrivial version of the simplicity constraints holds. The coarse graining flow of the BC spin net models indicates furthermore that the transitions between these phases are not of second order. The EPRL/FK model by contrast reveals a far more intricate and complex dynamics. We observe an immediate flow away from the original simplicity constraints; however, with the truncation employed here, the models generically do not converge to a fixed point. The results show that the imposition of simplicity constraints can indeed lead to interesting and also very complex dynamics. Thus we need to further develop coarse graining tools to efficiently study the large scale behavior of spin foam models, in particular for the EPRL/FK model.

Peridotite carbonation at the leading edge of the mantle wedge: OmDP Site BT1

NASA Astrophysics Data System (ADS)

Kelemen, P. B.; Godard, M.; Johnson, K. T. M.; Okazaki, K.; Manning, C. E.; Urai, J. L.; Michibayashi, K.; Harris, M.; Coggon, J. A.; Teagle, D. A. H.; Phase I Science Party, T. O. D. P.

2017-12-01

Hole BT1B sampled 3 layers of carbonated peridotite (listvenite, 0-80, 100-180, 185-197 m) separated by 2 layers of carbonate-bearing serpentinite (80-100, 180-185 m), underlain by 100 m metasediment and metabasalt. Listvenites (magnesite and/or dolomite + quartz + Fe-oxyhydroxides + chromian spinel ± fuchsite rocks) replacing mantle peridotite at and near the base of the Samail ophiolite (Stanger 85, Wilde ea 02, Nasir ea 07, Falk & Kelemen 15: FK15) reveal processes of carbon transfer into the mantle wedge (Kelemen & Manning 15) and suggest methods for CO2 capture and storage (Kelemen ea 11). Near BT1, 10 to 200 m thick tabular listvenites interlayered with partly serpentinized harzburgite have contacts parallel to the basal thrust. Imprecise Rb/Sr and 40Ar/39Ar ages indicate listvenite formed during obduction (FK15). Listvenite-peridotite contacts are gradational over 1-2 m. The listvenite matrix is microcrystalline quartz + magnesite. Quartz recrystallized from opal as in listvenites worldwide (Akbulut ea 06, Boschi ea 09, Jurkovic ea 12, Aftabi & Zarrinkoub 13, Posukhova ea 13, Ulrich ea 14) consistent with 80-120°C from clumped isotopes and phase equilibria (FK15). Thus listvenite formed - and deformed ductilely - at low T. Ubiquitous carbonate-rich veins locally comprise >10% of core sections; many have antitaxial textures consistent with expansion due to crystallization pressure. Carbonate-rich veins cut serpentinite and listvenite; veins formed a mesh, followed by replacement of mesh cores. Despite variability in and around veins, average Mg/Si, Fe/Si, Al/Si, Fe/Mg, and Cr/Al in listvenite (75 whole rocks, 7712 XRF scanner points) are indistinguishable from average Samail peridotite. CaO (average 5 wt%, range 0-40) and strongly correlated Sr were added to peridotite, most likely from subducting sediment. Rare core with >10 vol% dolomite has higher Fe/Mg than peridotite, but the same Mg/Si. Thus Mg, Si, Al and Cr, plus Fe in most rocks, were largely immobile on a 1-10 m scale during introduction of C, O, lesser Ca, minor Fe, and fluid mobile trace elements (Godard ea AGU 17) during transformation of Mg-silicates to carbonate + quartz. With prior and coeval serpentinization, this implies 80% solid volume expansion compared to unaltered peridotite, in a zone >200 m thick at the leading edge of the mantle wedge.

Linear indices of the "molecular pseudograph's atom adjacency matrix": definition, significance-interpretation, and application to QSAR analysis of flavone derivatives as HIV-1 integrase inhibitors.

PubMed

Marrero-Ponce, Yovani

2004-01-01

This report describes a new set of molecular descriptors of relevance to QSAR/QSPR studies and drug design, atom linear indices fk(xi). These atomic level chemical descriptors are based on the calculation of linear maps on Rn[fk(xi): Rn--> Rn] in canonical basis. In this context, the kth power of the molecular pseudograph's atom adjacency matrix [Mk(G)] denotes the matrix of fk(xi) with respect to the canonical basis. In addition, a local-fragment (atom-type) formalism was developed. The kth atom-type linear indices are calculated by summing the kth atom linear indices of all atoms of the same atom type in the molecules. Moreover, total (whole-molecule) linear indices are also proposed. This descriptor is a linear functional (linear form) on Rn. That is, the kth total linear indices is a linear map from Rn to the scalar R[ fk(x): Rn --> R]. Thus, the kth total linear indices are calculated by summing the atom linear indices of all atoms in the molecule. The features of the kth total and local linear indices are illustrated by examples of various types of molecular structures, including chain-lengthening, branching, heteroatoms-content, and multiple bonds. Additionally, the linear independence of the local linear indices to other 0D, 1D, 2D, and 3D molecular descriptors is demonstrated by using principal component analysis for 42 very heterogeneous molecules. Much redundancy and overlapping was found among total linear indices and most of the other structural indices presently in use in the QSPR/QSAR practice. On the contrary, the information carried by atom-type linear indices was strikingly different from that codified in most of the 229 0D-3D molecular descriptors used in this study. It is concluded that the local linear indices are an independent indices containing important structural information to be used in QSPR/QSAR and drug design studies. In this sense, atom, atom-type, and total linear indices were used for the prediction of pIC50 values for the cleavage process of a set of flavone derivatives inhibitors of HIV-1 integrase. Quantitative models found are significant from a statistical point of view (R of 0.965, 0.902, and 0.927, respectively) and permit a clear interpretation of the studied properties in terms of the structural features of molecules. A LOO cross-validation procedure revealed that the regression models had a fairly good predictability (q2 of 0.679, 0.543, and 0.721, respectively). The comparison with other approaches reveals good behavior of the method proposed. The approach described in this paper appears to be an excellent alternative or guides for discovery and optimization of new lead compounds.

Belching

MedlinePlus

... by the unconscious swallowing of air (aerophagia) Acid reflux disease (GERD) and heartburn ... 2016:chap 132. Richter JE, Friedenberg FK. Gastroesophageal reflux disease. In: Feldman M, Friedman LS, Brandt LJ, eds. ...

Cholecystokinin Activates Pancreatic Calcineurin-NFAT Signaling In Vitro and In Vivo

PubMed Central

Guo, LiLi; Lee, Sae-Hong; Molkentin, Jeffery D.; Williams, John A.

2008-01-01

Elevated endogenous cholecystokinin (CCK) release induced by protease inhibitors leads to pancreatic growth. This response has been shown to be mediated by the phosphatase calcineurin, but its downstream effectors are unknown. Here we examined activation of calcineurin-regulated nuclear factor of activated T-cells (NFATs) in isolated acinar cells, as well as in an in vivo model of pancreatic growth. Western blotting of endogenous NFATs and confocal imaging of NFATc1-GFP in pancreatic acini showed that CCK dose-dependently stimulated NFAT translocation from the cytoplasm to the nucleus within 0.5–1 h. This shift in localization correlated with CCK-induced activation of NFAT-driven luciferase reporter and was similar to that induced by a calcium ionophore and constitutively active calcineurin. The effect of CCK was dependent on calcineurin, as these changes were blocked by immunosuppressants FK506 and CsA and by overexpression of the endogenous protein inhibitor CAIN. Parallel NFAT activation took place in vivo. Pancreatic growth was accompanied by an increase in nuclear NFATs and subsequent elevation in expression of NFAT-luciferase in the pancreas, but not in organs unresponsive to CCK. The changes also required calcineurin, as they were blocked by FK506. We conclude that CCK activates NFATs in a calcineurin-dependent manner, both in vitro and in vivo. PMID:17978097

Mutagenicity studies of urine and faecal samples from rats treated orally with the food colourings Brown FK and Red 2G.

PubMed

Edwards, C N; Combes, R D

1984-08-01

Urine and faecal extracts from rats given Brown FK or Red 2G orally (800 mg/kg body weight) were investigated for mutagenicity. Extracts were subjected to liquid fluctuation and plate incorporation assays with Salmonella typhimurium strains TA98 and TA100 in the presence and absence of liver microsomes and/or a beta-glucuronidase-sulphatase preparation. Urine from Red 2G-treated rats only exhibited direct activity when coloured fractions from polyamide-column concentrates were tested with TA100. All other urines, as well as aqueous and ether faecal extracts from animals receiving either colouring, were no more mutagenic than the respective control extracts obtained from the same animals prior to dosing.

Stereoselective construction of the 5-hydroxy diazabicyclo[4.3.1]decane-2-one scaffold, a privileged motif for FK506-binding proteins.

PubMed

Bischoff, Matthias; Sippel, Claudia; Bracher, Andreas; Hausch, Felix

2014-10-17

A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp(3)-sp(2) Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode.

FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats

PubMed Central

Gant, John C.; Blalock, Eric M.; Chen, Kuey-Chu; Kadish, Inga; Thibault, Olivier; Porter, Nada M.

2018-01-01

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we tested the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls (YCs). Transcriptional profiling in the same animals identified 2342 genes with hippocampal expression that was upregulated/downregulated in aged controls (ACs) compared with YCs (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared with ACs, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in YCs. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency. Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b were associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial–neuroinflammatory, ribosomal, and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction and FKBP1b-mediated restoration of neuronal microtubular structure. Therefore, a previously unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression. SIGNIFICANCE STATEMENT Previously, we found that hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of intracellular Ca2+ responses, reverses both aging-related Ca2+ dysregulation and cognitive impairment. Here, we tested whether hippocampal FKBP1b overexpression also counteracts aging changes in gene transcriptional networks. In addition to reducing memory deficits in aged rats, FKBP1b selectively counteracted aging-induced expression changes in 37% of aging-dependent genes, with cytoskeletal and extracellular structure categories highly associated with the FKBP1b-rescued genes. Our results indicate that, in parallel with cognitive processes, a novel transcriptional network coordinating brain structural organization is dysregulated with aging and restored by FKBP1b. PMID:29255009

Approximating Matsubara dynamics using the planetary model: Tests on liquid water and ice

NASA Astrophysics Data System (ADS)

Willatt, Michael J.; Ceriotti, Michele; Althorpe, Stuart C.

2018-03-01

Matsubara dynamics is the quantum-Boltzmann-conserving classical dynamics which remains when real-time coherences are taken out of the exact quantum Liouvillian [T. J. H. Hele et al., J. Chem. Phys. 142, 134103 (2015)]; because of a phase-term, it cannot be used as a practical method without further approximation. Recently, Smith et al. [J. Chem. Phys. 142, 244112 (2015)] developed a "planetary" model dynamics which conserves the Feynman-Kleinert (FK) approximation to the quantum-Boltzmann distribution. Here, we show that for moderately anharmonic potentials, the planetary dynamics gives a good approximation to Matsubara trajectories on the FK potential surface by decoupling the centroid trajectory from the locally harmonic Matsubara fluctuations, which reduce to a single phase-less fluctuation particle (the "planet"). We also show that the FK effective frequency can be approximated by a direct integral over these fluctuations, obviating the need to solve iterative equations. This modification, together with use of thermostatted ring-polymer molecular dynamics, allows us to test the planetary model on water (gas-phase, liquid, and ice) using the q-TIP4P/F potential surface. The "planetary" fluctuations give a poor approximation to the rotational/librational bands in the infrared spectrum, but a good approximation to the bend and stretch bands, where the fluctuation lineshape is found to be motionally narrowed by the vibrations of the centroid.

Finger vein identification using fuzzy-based k-nearest centroid neighbor classifier

NASA Astrophysics Data System (ADS)

Rosdi, Bakhtiar Affendi; Jaafar, Haryati; Ramli, Dzati Athiar

2015-02-01

In this paper, a new approach for personal identification using finger vein image is presented. Finger vein is an emerging type of biometrics that attracts attention of researchers in biometrics area. As compared to other biometric traits such as face, fingerprint and iris, finger vein is more secured and hard to counterfeit since the features are inside the human body. So far, most of the researchers focus on how to extract robust features from the captured vein images. Not much research was conducted on the classification of the extracted features. In this paper, a new classifier called fuzzy-based k-nearest centroid neighbor (FkNCN) is applied to classify the finger vein image. The proposed FkNCN employs a surrounding rule to obtain the k-nearest centroid neighbors based on the spatial distributions of the training images and their distance to the test image. Then, the fuzzy membership function is utilized to assign the test image to the class which is frequently represented by the k-nearest centroid neighbors. Experimental evaluation using our own database which was collected from 492 fingers shows that the proposed FkNCN has better performance than the k-nearest neighbor, k-nearest-centroid neighbor and fuzzy-based-k-nearest neighbor classifiers. This shows that the proposed classifier is able to identify the finger vein image effectively.

Determination of Reference Catalogs for Meridian Observations Using Statistical Method

NASA Astrophysics Data System (ADS)

Li, Z. Y.

2014-09-01

The meridian observational data are useful for developing high-precision planetary ephemerides of the solar system. These historical data are provided by the jet propulsion laboratory (JPL) or the Institut De Mecanique Celeste Et De Calcul Des Ephemerides (IMCCE). However, we find that the reference systems (realized by the fundamental catalogs FK3 (Third Fundamental Catalogue), FK4 (Fourth Fundamental Catalogue), and FK5 (Fifth Fundamental Catalogue), or Hipparcos), to which the observations are referred, are not given explicitly for some sets of data. The incompleteness of information prevents us from eliminating the systematic effects due to the different fundamental catalogs. The purpose of this paper is to specify clearly the reference catalogs of these observations with the problems in their records by using the JPL DE421 ephemeris. The data for the corresponding planets in the geocentric celestial reference system (GCRS) obtained from the DE421 are transformed to the apparent places with different hypothesis regarding the reference catalogs. Then the validations of the hypothesis are tested by two kinds of statistical quantities which are used to indicate the significance of difference between the original and transformed data series. As a result, this method is proved to be effective for specifying the reference catalogs, and the missed information is determined unambiguously. Finally these meridian data are transformed to the GCRS for further applications in the development of planetary ephemerides.

Acoustic and Auditory Perception Effects of the Voice Therapy Technique Finger Kazoo in Adult Women.

PubMed

Christmann, Mara Keli; Cielo, Carla Aparecida

2017-05-01

This study aimed to verify and to correlate acoustic and auditory-perceptual measures of glottic source after the performance of finger kazoo (FK) technique. This is an experimental, cross-sectional, and qualitative study. We made an analysis of the vowel [a:] in 46 adult women with neither vocal complaints nor laryngeal alterations, through the Multi-Dimensional Voice Program Advanced and RASATI scale, before and immediately after performing three series of FK and 5 minutes after a period of silence. Kappa, Friedman, Wilcoxon, and Spearman tests were used. We found significant increase in fundamental frequency, reduction of amplitude variation, and degree of sub-harmonics immediately after performing FK. Positive correlations were measures of frequency and its perturbation, measures of amplitude, of soft phonation index, of degree and number of unvoiced segments with aspects of RASATI. Negative correlations were voice turbulence index, measures of frequency and its perturbation, and measures of soft phonation index with aspects of RASATI. There was fundamental frequency increase, within normal limits, and reduction of acoustic measures related to presence of noise and instability. In general, acoustic measures, suggestive of noise and instability, were reduced according to the decrease of perceptive-auditory aspects of vocal alteration. It shows that both instruments are complementary and that the acoustic vocal effect was positive. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Calcineurin mediates AKT dephosphorylation in the ischemic rat retina.

PubMed

Park, Chang Hwan; Kim, Yoon Sook; Kim, Young Hee; Choi, Mee Young; Yoo, Ji Myong; Kang, Sang Soo; Choi, Wan Sung; Cho, Gyeong Jae

2008-10-09

Calcineurin (CaN) is a calcium/calmodulin-dependent protein phosphatase that has an important role in ischemia-induced apoptosis. The serine/threonine kinase, Akt, which is also known as protein kinase B, has an important role in the cell death/survival pathways. Akt is activated by its phosphorylation, which is positively regulated by phosphatidylinositol 3-kinase (PI3K) and negatively regulated by a class of protein phosphatases (PPs) in tissue. However, the relationship between CaN and Akt after transient ischemia remains unclear. In the present study, we investigated whether CaN is involved in neuronal cell apoptosis and Akt dephosphorylation that occur during ischemic injury. We examined the interdependence between CaN and Akt/protein kinase B (PKB) in the rat retina after transient ischemia. After ischemic damage, we detected changes in levels of CaN, Akt and Bad in rats in the presence or absence FK506, CaN inhibitor. Our results show that CaN cleavage reduced Akt phosphorylation at Thr308 and Ser473, and led to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. After treatment with FK506, Akt and Bad dephosphorylation was greatly reduced. The total number of TUNEL-positive neurons was reduced by intravitreal injection of FK506 after transient ischemia. These results indicate that CaN cleavage negatively regulates Akt phosphorylation and is involved in retinal cell apoptosis after transient ischemia.

Approximating Matsubara dynamics using the planetary model: Tests on liquid water and ice.

PubMed

Willatt, Michael J; Ceriotti, Michele; Althorpe, Stuart C

2018-03-14

Matsubara dynamics is the quantum-Boltzmann-conserving classical dynamics which remains when real-time coherences are taken out of the exact quantum Liouvillian [T. J. H. Hele et al., J. Chem. Phys. 142, 134103 (2015)]; because of a phase-term, it cannot be used as a practical method without further approximation. Recently, Smith et al. [J. Chem. Phys. 142, 244112 (2015)] developed a "planetary" model dynamics which conserves the Feynman-Kleinert (FK) approximation to the quantum-Boltzmann distribution. Here, we show that for moderately anharmonic potentials, the planetary dynamics gives a good approximation to Matsubara trajectories on the FK potential surface by decoupling the centroid trajectory from the locally harmonic Matsubara fluctuations, which reduce to a single phase-less fluctuation particle (the "planet"). We also show that the FK effective frequency can be approximated by a direct integral over these fluctuations, obviating the need to solve iterative equations. This modification, together with use of thermostatted ring-polymer molecular dynamics, allows us to test the planetary model on water (gas-phase, liquid, and ice) using the q-TIP4P/F potential surface. The "planetary" fluctuations give a poor approximation to the rotational/librational bands in the infrared spectrum, but a good approximation to the bend and stretch bands, where the fluctuation lineshape is found to be motionally narrowed by the vibrations of the centroid.

Antipathogen genes and the replacement of disease-vectoring mosquito populations: a model-based evaluation

PubMed Central

Robert, Michael A; Okamoto, Kenichi W; Gould, Fred; Lloyd, Alun L

2014-01-01

Recently, genetic strategies aimed at controlling populations of disease-vectoring mosquitoes have received considerable attention as alternatives to traditional measures. Theoretical studies have shown that female-killing (FK), antipathogen (AP), and reduce and replace (R&R) strategies can each decrease the number competent vectors. In this study, we utilize a mathematical model to evaluate impacts on competent Aedes aegypti populations of FK, AP, and R&R releases as well as hybrid strategies that result from combinations of these three approaches. We show that while the ordering of efficacy of these strategies depends upon population life history parameters, sex ratio of releases, and switch time in combination strategies, AP-only and R&R/AP releases typically lead to the greatest long-term reduction in competent vectors. R&R-only releases are often less effective at long-term reduction of competent vectors than AP-only releases or R&R/AP releases. Furthermore, the reduction in competent vectors caused by AP-only releases is easier to maintain than that caused by FK-only or R&R-only releases even when the AP gene confers a fitness cost. We discuss the roles that density dependence and inclusion of females play in the order of efficacy of the strategies. We anticipate that our results will provide added impetus to continue developing AP strategies. PMID:25558284

Microarray Bactericidal Testing of Natural Products Against Yersinia intermedia and Bacillus anthracis

DTIC Science & Technology

2002-01-01

Based Preservation Systems and Probiotic Bacteria. In Food Microbiology: Fundamentals and Frontiers. M. P. Doyle, L.R. Beuchat and T.J. Montville...Microarray Bactericidal Testing of Natural Products Against Yersinia intermedia and Bacillus anthracis I.J. Fry1, F.K. Lee2, A. Turetsky2 and J.J...effective protection against biological warfare agents (BWA’s), natural products with a historical record of bactericidal efficacy such as

Installation Restoration Program. Phase 2. Confirmation/Quantification. Stage 1. Air Force Plant 4, Fort Worth, Texas. Volume 9. Appendices F-K.

DTIC Science & Technology

1987-12-01

mineralogy and igneous petrology . Consultant to Shield Energy. Inc.; performed mudlogging and well site geology duties on 4,670’ wildcat weil in...Taylor County, Texas. Evaluated prospects for hydrocarbon potential. Prepared geologic reports for drilling prospectus. Geologist, Wold Minerals...Exploration Company; conducted geologic and geophysi- cal mapping in Precambrian metamorphic terrain of West Texas for talc depos- its. Supervised the drilling

Strength functions, entropies, and duality in weakly to strongly interacting fermionic systems.

PubMed

Angom, D; Ghosh, S; Kota, V K B

2004-01-01

We revisit statistical wave function properties of finite systems of interacting fermions in the light of strength functions and their participation ratio and information entropy. For weakly interacting fermions in a mean-field with random two-body interactions of increasing strength lambda, the strength functions F(k) (E) are well known to change, in the regime where level fluctuations follow Wigner's surmise, from Breit-Wigner to Gaussian form. We propose an ansatz for the function describing this transition which we use to investigate the participation ratio xi(2) and the information entropy S(info) during this crossover, thereby extending the known behavior valid in the Gaussian domain into much of the Breit-Wigner domain. Our method also allows us to derive the scaling law lambda(d) approximately 1/sqrt[m] ( m is number of fermions) for the duality point lambda= lambda(d), where F(k) (E), xi(2), and S(info) in both the weak ( lambda=0 ) and strong mixing ( lambda= infinity ) basis coincide. As an application, the ansatz function for strength functions is used in describing the Breit-Wigner to Gaussian transition seen in neutral atoms CeI to SmI with valence electrons changing from 4 to 8.

Planar Perovskite Solar Cells with High Open-Circuit Voltage Containing a Supramolecular Iron Complex as Hole Transport Material Dopant.

PubMed

Saygili, Yasemin; Turren-Cruz, Silver-Hamill; Olthof, Selina; Saes, Bartholomeus Wilhelmus Henricus; Pehlivan, Ilknur Bayrak; Saliba, Michael; Meerholz, Klaus; Edvinsson, Tomas; Zakeeruddin, Shaik M; Grätzel, Michael; Correa-Baena, Juan-Pablo; Hagfeldt, Anders; Freitag, Marina; Tress, Wolfgang

2018-04-26

In perovskite solar cells (PSCs), the most commonly used hole transport material (HTM) is spiro-OMeTAD, which is typically doped by metalorganic complexes, for example, based on Co, to improve charge transport properties and thereby enhance the photovoltaic performance of the device. In this study, we report a new hemicage-structured iron complex, 1,3,5-tris(5'-methyl-2,2'-bipyridin-5-yl)ethylbenzene Fe(III)-tris(bis(trifluoromethylsulfonyl)imide), as a p-type dopant for spiro-OMeTAD. The formal redox potential of this compound was measured as 1.29 V vs. the standard hydrogen electrode, which is slightly (20 mV) more positive than that of the commercial cobalt dopant FK209. Photoelectron spectroscopy measurements confirm that the iron complex acts as an efficient p-dopant, as evidenced in an increase of the spiro-OMeTAD work function. When fabricating planar PSCs with the HTM spiro-OMeTAD doped by 5 mol % of the iron complex, a power conversion efficiency of 19.5 % (AM 1.5G, 100 mW cm -2 ) is achieved, compared to 19.3 % for reference devices with FK209. Open circuit voltages exceeding 1.2 V at 1 sun and reaching 1.27 V at 3 suns indicate that recombination at the perovskite/HTM interface is low when employing this iron complex. This work contributes to recent endeavors to reduce recombination losses in perovskite solar cells. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimum Multisensor, Multitarget Localization and Tracking.

DTIC Science & Technology

1983-06-07

parameter vector t is given by (see Equation (3.5.1-7)’ the simul- taneous solution of A(e) N B G --1 ae &j’ -4n-in (fk’ ijn k3jn ~ k )kjn kjn - knn =1 k...the coefficient of mutual dependence given by M = 12 -(K-2) 121M12 :(3l 11J12 ) (K-2 and Jij is given by (see Equation (6.4.1-2)) - - (_ I R knN kn K...Transactions on Acoustic, Speech and Signal Processing, Vol ASSP-29, No. 3, June 1981. 17. B. Friedlander, "An ARMA Modeling Approach to Multitarget Tracking

A booklet on participants' rights to improve consent for clinical research: a randomized trial.

PubMed

Benatar, Jocelyne R; Mortimer, John; Stretton, Matthew; Stewart, Ralph A H

2012-01-01

Information on the rights of subjects in clinical trials has become increasingly complex and difficult to understand. This study evaluates whether a simple booklet which is relevant to all research studies improves the understanding of rights needed for subjects to provide informed consent. 21 currently used informed consent forms (ICF) from international clinical trials were separated into information related to the specific research study, and general information on participants' rights. A booklet designed to provide information on participants' rights which used simple language was developed to replace this information in current ICF's Readability of each component of ICF's and the booklet was then assessed using the Flesch-Kincaid Reading ease score (FK). To further evaluate the booklet 282 hospital inpatients were randomised to one of three ways to present research information; a standard ICF, the booklet combined with a short ICF, or the booklet combined with a simplified ICF. Comprehension of information related to the research proposal and to participant's rights was assessed by questionnaire. Information related to participants' rights contributed an average of 44% of the words in standard ICFs, and was harder to read than information describing the clinical trial (FK 25 versus (vs.) 41 respectively, p = 0.0003). The booklet reduced the number of words and improved FK from 25 to 42. The simplified ICF had a slightly higher FK score than the standard ICF (50 vs. 42). Comprehension assessed in inpatients was better for the booklet and short ICF 62%, (95% confidence interval (CI) 56 to 67) correct, or simplified ICF 62% (CI 58 to 68) correct compared to 52%, (CI 47 to 57) correct for the standard ICF, p = 0.009. This was due to better understanding of questions on rights (62% vs. 49% correct, p = 0.0008). Comprehension of study related information was similar for the simplified and standard ICF (60% vs. 64% correct, p = 0.68). A booklet provides a simple consistent approach to providing information on participant rights which is relevant to all research studies, and improves comprehension of patients who typically participate in clinical trials.

A Booklet on Participants’ Rights to Improve Consent for Clinical Research: A Randomized Trial

PubMed Central

Benatar, Jocelyne R.; Mortimer, John; Stretton, Matthew; Stewart, Ralph A. H.

2012-01-01

Objective Information on the rights of subjects in clinical trials has become increasingly complex and difficult to understand. This study evaluates whether a simple booklet which is relevant to all research studies improves the understanding of rights needed for subjects to provide informed consent. Methods 21 currently used informed consent forms (ICF) from international clinical trials were separated into information related to the specific research study, and general information on participants’ rights. A booklet designed to provide information on participants’ rights which used simple language was developed to replace this information in current ICF’s Readability of each component of ICF’s and the booklet was then assessed using the Flesch-Kincaid Reading ease score (FK). To further evaluate the booklet 282 hospital inpatients were randomised to one of three ways to present research information; a standard ICF, the booklet combined with a short ICF, or the booklet combined with a simplified ICF. Comprehension of information related to the research proposal and to participant’s rights was assessed by questionnaire. Results Information related to participants’ rights contributed an average of 44% of the words in standard ICFs, and was harder to read than information describing the clinical trial (FK 25 versus (vs.) 41 respectively, p = 0.0003). The booklet reduced the number of words and improved FK from 25 to 42. The simplified ICF had a slightly higher FK score than the standard ICF (50 vs. 42). Comprehension assessed in inpatients was better for the booklet and short ICF 62%, (95% confidence interval (CI) 56 to 67) correct, or simplified ICF 62% (CI 58 to 68) correct compared to 52%, (CI 47 to 57) correct for the standard ICF, p = 0.009. This was due to better understanding of questions on rights (62% vs. 49% correct, p = 0.0008). Comprehension of study related information was similar for the simplified and standard ICF (60% vs. 64% correct, p = 0.68). Conclusions A booklet provides a simple consistent approach to providing information on participant rights which is relevant to all research studies, and improves comprehension of patients who typically participate in clinical trials. PMID:23094034

Variations in the S and P regions of the hepatitis B virus genome under immunosuppression in vitro and in vivo.

PubMed

Shen, Zhong-Yang; Zheng, Wei-Ping; Deng, Yong-Lin; Song, Hong-Li

2012-10-01

To provide a basis for improved prevention and treatment of hepatitis B virus (HBV) re-infection after liver transplantation, variations in the S and P genes of HBV under immunosuppression in vitro and their association with patient prognosis were investigated. For the in vitro study, HepG2.2.15 hepatocellular carcinoma cells stably producing HBV particles were treated with the immunosuppressants methylprednisolone (MP) and tacrolimus (FK506) at doses found to be non-toxic by the methylthiazolyl tetrazolium (MTT) cell viability assay. MP dose-dependently inhibited HBV DNA expression in HepG2.2.15 cells, while FK506 did not, as determined by quantitative real-time PCR (qRT-PCR). By gene sequencing, both MP and FK506 were found to cause variations in HBV S, P, and S/P overlapping regions. MP- but not FK506-induced mutations were common in the glucocorticoid response element of the P region, while both immunosuppressants caused mutations outside the nucleoside analogue resistance sites. For the in vivo study, 14 patients with HBV-related end-stage liver disease re-infected after liver transplantation, and 20 cases without HBV re-infection as controls, were studied. Seventy-five percent of re-infected recipients showed multi-loci amino acid mutations at different sites besides lamivudine (LAM)-resistant loci in the P region, including in the glucocorticoid response element. Fifty percent of re-infected recipients had mutations in the "a" determinant region and flanking sequences. Re-infection was associated with negative serum hepatitis B immunoglobulin (HBIG), as measured by a microparticle capture enzyme immunoassay. Nucleotide mutations in the S region caused missense or synonymous mutations, which caused synonymous mutations in the overlapping P region. These results showed that effects of immunosuppressants on HBV genes in vitro were different from those in clinical recipients. Positive HBV DNA and gene mutations pre-transplantation were factors affecting re-infection post-transplantation. Multiple mutations found in the P and S genes suggest that the formation of quasispecies contributes to HBV re-infection after liver transplantation.

Advice on drug safety in pregnancy: are there differences between commonly used sources of information?

PubMed

Frost Widnes, Sofia K; Schjøtt, Jan

2008-01-01

Safety regarding use in pregnancy is not established for many drugs. Inconsistencies between sources providing drug information can give rise to confusion with possible therapeutic consequences. Therefore, it is important to measure clinically important differences between drug information sources. The objective of this study was to compare two easily accessible Norwegian sources providing advice on drug safety in pregnancy - the product monographs in the Felleskatalog (FK), published by the pharmaceutical companies, and the five regional Drug Information Centres (DICs) in Norway - in addition to assessing the frequency of questions regarding drug safety in pregnancy made to the DICs according to the Anatomical Therapeutic Chemical (ATC) classification system. Advice on drug use in pregnancy provided by the DICs in 2003 and 2005 were compared with advice in the product monographs for the respective drugs in the FK. Comparison of advice was based on categorization to one of four categories: can be used, benefit-risk assessment, should not be used, or no available information. A total of 443 drug advice were categorized. Seven out of ten of drugs frequently enquired about, according to the ATC system, were drugs acting on the nervous system (group N). For 208 (47%) of the drugs, advice differed between the DICs and FK. Advice from the FK was significantly (p < 0.01) more restrictive than advice from the DICs. There were no differences in the level of consistency of advice between drugs that were newly introduced and those that had been on the market for a longer time, advice regarding use of drugs in the first trimester and advice regarding use of drugs in the second or third trimester, or between advice provided during 2003 and during 2005. The results of this study show considerable differences between two Norwegian sources providing advice on the use of drugs in pregnancy. Based on the knowledge that healthcare providers choose sources of information in a random manner, our results may be of clinical importance. We believe that the problem with heterogeneous drug information on this subject is not confined to Norway and that our results should be of international interest.

The 13-kD FK506 Binding Protein, FKBP13, Interacts with a Novel Homologue of the Erythrocyte Membrane Cytoskeletal Protein 4.1

PubMed Central

Walensky, Loren D.; Gascard, Philippe; Field, Michael E.; Blackshaw, Seth; Conboy, John G.; Mohandas, Narla; Snyder, Solomon H.

1998-01-01

We have identified a novel generally expressed homologue of the erythrocyte membrane cytoskeletal protein 4.1, named 4.1G, based on the interaction of its COOH-terminal domain (CTD) with the immunophilin FKBP13. The 129-amino acid peptide, designated 4.1G–CTD, is the first known physiologic binding target of FKBP13. FKBP13 is a 13-kD protein originally identified by its high affinity binding to the immunosuppressant drugs FK506 and rapamycin (Jin, Y., M.W. Albers, W.S. Lane, B.E. Bierer, and S.J. Burakoff. 1991. Proc. Natl. Acad. Sci. USA. 88:6677– 6681); it is a membrane-associated protein thought to function as an ER chaperone (Bush, K.T., B.A. Henrickson, and S.K. Nigam. 1994. Biochem. J. [Tokyo]. 303:705–708). We report the specific association of FKBP13 with 4.1G–CTD based on yeast two-hybrid, in vitro binding and coimmunoprecipitation experiments. The histidyl-proline moiety of 4.1G–CTD is required for FKBP13 binding, as indicated by yeast experiments with truncated and mutated 4.1G–CTD constructs. In situ hybridization studies reveal cellular colocalizations for FKBP13 and 4.1G–CTD throughout the body during development, supporting a physiologic role for the interaction. Interestingly, FKBP13 cofractionates with the red blood cell homologue of 4.1 (4.1R) in ghosts, inside-out vesicles, and Triton shell preparations. The identification of FKBP13 in erythrocytes, which lack ER, suggests that FKBP13 may additionally function as a component of membrane cytoskeletal scaffolds. PMID:9531554

Inhomogeneous galactic chemical evolution of r-process elements

NASA Astrophysics Data System (ADS)

Wehmeyer, Benjamin

2018-01-01

Stars provide a fundamental contribution to the cosmic life cycle. Gas clouds form and collapse to stars, experiencing different evolutionary stages according to their properties like mass and metal content. Small stars like our Sun end their life as planetary nebulae, while more massive stars end their evolution with violent explosions like supernovae or hypernovae, leaving behind either a neutron star or a black hole. These compact objects may also merge, leading to a new ejection of material. Today the origin of the heaviest elements is still matter of debate. The relative contributions of the proposed sources of r-process elements (e.g., Supernovae, Neutron Star Mergers) in the early galaxy as well as in the Sun is one of the main uncertainties. We use the inhomogeneous chemical evolution tool “ICE” [1, 2] to study the role of some of the main parameters of the cosmic life cycle. With ICE's high resolution (≥ 20parsec/cell) runs, we are able to get converged simulations of the inhomogeneities in the early Galactic evolution stages, and of the observed scatter of r-process elements in metal-poor stars [3].[1] B. Wehmeyer, M. Pignatari, F.-K. Thielemann, 2015 MNRAS 452, 1970–1981[2] B. Wehmeyer, M. Pignatari, F.-K. Thielemann, 2016 AIPC 1743, 040009[3] I. Roederer et al., 2010 ApJ 724:975–993

Niagara Falls IAP, New York. Revised Uniform Summary of Surface Weather Observations. Parts A-F.

DTIC Science & Technology

1987-09-30

TOTLS 1 21 . 32." 3 1. q 7 1 h .2 DO . 00 9.1 ..... .. . 30181 r, UPl’ OP O:’.rvI49A10.S: 33991? - A pPPPP,P~ppl A:. A RRRRR TY TIIII1 T0DD000D0...94.6 99.1 99.3 99.6 9’.q 99.9 530.0 10.0 130.0 100 .0 TO IAL hM "E" CF UnS[VATIONS: 9uU" .L K GLrObAL CLIPAIOLUGY BpAnFC P[.C[NfArE FkFELENCY OF

Fully-kinetic Ion Simulation of Global Electrostatic Turbulent Transport in C-2U

NASA Astrophysics Data System (ADS)

Fulton, Daniel; Lau, Calvin; Bao, Jian; Lin, Zhihong; Tajima, Toshiki; TAE Team

2017-10-01

Understanding the nature of particle and energy transport in field-reversed configuration (FRC) plasmas is a crucial step towards an FRC-based fusion reactor. The C-2U device at Tri Alpha Energy (TAE) achieved macroscopically stable plasmas and electron energy confinement time which scaled favorably with electron temperature. This success led to experimental and theoretical investigation of turbulence in C-2U, including gyrokinetic ion simulations with the Gyrokinetic Toroidal Code (GTC). A primary objective of TAE's new C-2W device is to explore transport scaling in an extended parameter regime. In concert with the C-2W experimental campaign, numerical efforts have also been extended in A New Code (ANC) to use fully-kinetic (FK) ions and a Vlasov-Poisson field solver. Global FK ion simulations are presented. Future code development is also discussed.

On the transition from the Ginzburg-Landau equation to the extended Fisher-Kolmogorov equation

NASA Astrophysics Data System (ADS)

Rottschäfer, Vivi; Doelman, Arjen

1998-07-01

The Ginzburg-Landau (GL) equation ‘generically’ describes the behaviour of small perturbations of a marginally unstable basic state in systems on unbounded domains. In this paper we consider the transition from this generic situation to a degenerate (co-dimension 2) case in which the GL approach is no longer valid. Instead of studying a general underlying model problem, we consider a two-dimensional system of coupled reaction-diffusion equations in one spatial dimension. We show that near the degeneration the behaviour of small perturbations is governed by the extended Fisher-Kolmogorov (eFK) equation (at leading order). The relation between the GL-equation and the eFK-equation is quite subtle, but can be analysed in detail. The main goal of this paper is to study this relation, which we do asymptotically. The asymptotic analysis is compared to numerical simulations of the full reaction-diffusion system. As one approaches the co-dimension 2 point, we observe that the stable stationary periodic patterns predicted by the GL-equation evolve towards various different families of stable, stationary (but not necessarily periodic) so-called ‘multi-bump’ solutions. In the literature, these multi-bump patterns are shown to exist as solutions of the eFK-equation, but there is no proof of the asymptotic stability of these solutions. Our results suggest that these multi-bump patterns can also be asymptotically stable in large classes of model problems.

Segundo Catálogo Estelar del Hemisferio Sur con Astrolabio Fotoeléctrico PAII

NASA Astrophysics Data System (ADS)

Manrique, W. T.; Podestá, R. C.; Alonso, E.; Actis, E. V.; Pacheco, A. M.; Bustos, G.; Lizhi, L.; Zezhi, W.; Fanmiao, Z.; Hongqi, W.; Perdomo, R.

Recordamos que entre el Observatorio Astronómico ``Félix Aguilar'', el Observatorio Astronómico de Beijing y el Observatorio Astronómico de La Plata, se ha convenido en desarrollar un Proyecto de Investigación conjunto, para la observación sistemática de estrellas en el Hemisferio Sur, con el objeto de la elaboración de un Catálogo Estelar Global utilizando un Astrolabio Fotoeléctrico PAII del Observatorio de Beijing, que ha sido usado con éxito en la República de China. En este trabajo se presenta el Segundo Catálogo Estelar del Hemisferio Sur, derivado de las observaciones realizadas con el PAII instalado en el OAFA, durante el períiodo Febrero de 1992 a Marzo de 1997. En este lapso se han observado mas de 400000 pasajes estelares, obteniéndose las correcciones Δ α y Δ δ de 5241 estrellas del FK4, FK5, FK5 Ext., SRS, CAMC y GC. Las precisiones medias son del orden de ± 3,2 ms en ascensión recta y ±0."057 en declinación. Rango de magnitudes : 2,0 a 11,5 Rango de declinaciones : -3o a -60o Epoca Media : 1994.9 Se analizan los residuos en función de la magnitud y tipo espectral, correcciones de grupo y frecuencia de distribución Δ α y Δ δ.

Characterization of tet(Y)-carrying LowGC plasmids exogenously captured from cow manure at a conventional dairy farm.

PubMed

Kyselková, Martina; Chrudimský, Tomáš; Husník, Filip; Chroňáková, Alica; Heuer, Holger; Smalla, Kornelia; Elhottová, Dana

2016-06-01

Manure from dairy farms has been shown to contain diverse tetracycline resistance genes that are transferable to soil. Here, we focus on conjugative plasmids that may spread tetracycline resistance at a conventional dairy farm. We performed exogenous plasmid isolation from cattle feces using chlortetracycline for transconjugant selection. The transconjugants obtained harbored LowGC-type plasmids and tet(Y). A representative plasmid (pFK2-7) was fully sequenced and this was compared with previously described LowGC plasmids from piggery manure-treated soil and a GenBank record from Acinetobacter nosocomialis that we also identified as a LowGC plasmid. The pFK2-7 plasmid had the conservative backbone typical of LowGC plasmids, though this region was interrupted with an insert containing the tet(Y)-tet(R) tetracycline resistance genes and the strA-strB streptomycin resistance genes. Despite Acinetobacter populations being considered natural hosts of LowGC plasmids, these plasmids were not found in three Acinetobacter isolates from the study farm. The isolates harbored tet(Y)-tet(R) genes in identical genetic surroundings as pFK2-7, however, suggesting genetic exchange between Acinetobacter and LowGC plasmids. Abundance of LowGC plasmids and tet(Y) was correlated in manure and soil samples from the farm, indicating that LowGC plasmids may be involved in the spread of tet(Y) in the environment. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

On the role, ecology, phylogeny, and structure of dual-family immunophilins.

PubMed

Barik, Sailen

2017-11-01

The novel class of dual-family immunophilins (henceforth abbreviated as DFI) represents naturally occurring chimera of classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker that may include a three-unit tetratricopeptide (TPR) repeat. Here, I report a comprehensive analysis of all current DFI sequences and their host organisms. DFIs are of two kinds: CFBP (cyclosporin- and FK506-binding protein) and FCBP (FK506- and cyclosporin-binding protein), found in eukaryotes. The CFBP type occurs in select bacteria that are mostly extremophiles, such as psychrophilic, thermophilic, halophilic, and sulfur-reducing. Essentially all DFI organisms are unicellular. I suggest that DFIs are specialized bifunctional chaperones that use their flexible interdomain linker to associate with large polypeptides or multisubunit megacomplexes to promote simultaneous folding or renaturation of two clients in proximity, essential in stressful and denaturing environments. Analysis of sequence homology and predicted 3D structures of the FKBP and CYN domains as well as the TPR linkers upheld the modular nature of the DFIs and revealed the uniqueness of their TPR domain. The CFBP and FCBP genes appear to have evolved in parallel pathways with no obvious single common ancestor. The occurrence of both types of DFI in multiple unrelated phylogenetic clades supported their selection in metabolic and environmental niche roles rather than a traditional taxonomic relationship. Nonetheless, organisms with these rare immunophilins may define an operational taxonomic unit (OTU) bound by the commonality of chaperone function.

Facilitation of apoptosis by cyclosporins A and H, but not FK506 in mouse bronchial eosinophils.

PubMed

Kitagaki, K; Nagai, H; Hayashi, S; Totsuka, T

1997-10-22

This study was undertaken to clarify whether or not binding to cyclophilin is a prerequisite for cyclosporin A-induced modulation of apoptotic cell death in eosinophils. Eosinophils were isolated from bronchoalveolar lavage fluid of mice challenged with inhaled allergen after sensitization. Apoptosis was determined by analysing the DNA content. At 72 h, 99% of the cells had died without addition of cytokines, whereas 55-60% of the cells survived in the presence of 10 U/ml recombinant murine interleukin 5 or recombinant murine granulocyte macrophage-colony stimulation factor (GM-CSF). Apoptotic cell death at 72 h in the presence of 10 U/ml interleukin 5 was increased by addition of cyclosporin H, an analogue of cyclosporin A without cyclophilin binding activity, in a concentration-dependent (0.3 to 3 microM) manner. The increase in apoptosis elicited by cyclosporin A and cyclosporin H took place also in the presence of 10 U/ml GM-CSF but to a lesser extent. There was a significant augmentation of apoptosis in eosinophils cultured in the presence of each cytokine for 72 h or longer. Tacrolimus (FK506) failed to augment apoptotic cell death. Thus, it is unlikely that binding of cyclosporin A to cyclophilin accounts for the increased apoptosis induced by cyclosporin A and its analogue in eosinophils. The increase in apoptosis induced by cyclosporin A, but not FK506, in activated eosinophils from the airways may be attributed to the anti-asthmatic effects of cyclosporin A.

Data Association Algorithms for Tracking Satellites

DTIC Science & Technology

2008-02-05

series of (I) about the current estimate: x{k — l|fc — 1) x-(fc) = f[k, x{k - l\\k - 1)] + fx {k - l)[x{k - 1) - x{k - l\\k - 1)] + l/2^el[x(fc - 1) - x(A...l|ik - 1)]’ i=l ■ fxx{k - l)[x{k - 1) - x{k - l\\k - 1)] + higher-order terms + v(k - 1) (5) where e; is the ith Cartesian basis vector and fx ...34x x{k\\k - 1) = fx {k - l)x(fc - l|fc - 1) + l/2^e!;[x /(fc - l|fc - l)/^{fc - l)x(fc - l|fc - 1) t=l - TvifUk - l)P{k - l\\k - I)

FK506-Binding Protein 22 from a Psychrophilic Bacterium, a Cold Shock-Inducible Peptidyl Prolyl Isomerase with the Ability to Assist in Protein Folding

PubMed Central

Budiman, Cahyo; Koga, Yuichi; Takano, Kazufumi; Kanaya, Shigenori

2011-01-01

Adaptation of microorganisms to low temperatures remains to be fully elucidated. It has been previously reported that peptidyl prolyl cis-trans isomerases (PPIases) are involved in cold adaptation of various microorganisms whether they are hyperthermophiles, mesophiles or phsycrophiles. The rate of cis-trans isomerization at low temperatures is much slower than that at higher temperatures and may cause problems in protein folding. However, the mechanisms by which PPIases are involved in cold adaptation remain unclear. Here we used FK506-binding protein 22, a cold shock protein from the psychrophilic bacterium Shewanella sp. SIB1 (SIB1 FKBP22) as a model protein to decipher the involvement of PPIases in cold adaptation. SIB1 FKBP22 is homodimer that assumes a V-shaped structure based on a tertiary model. Each monomer consists of an N-domain responsible for dimerization and a C-catalytic domain. SIB1 FKBP22 is a typical cold-adapted enzyme as indicated by the increase of catalytic efficiency at low temperatures, the downward shift in optimal temperature of activity and the reduction in the conformational stability. SIB1 FKBP22 is considered as foldase and chaperone based on its ability to catalyze refolding of a cis-proline containing protein and bind to a folding intermediate protein, respectively. The foldase and chaperone activites of SIB1 FKBP22 are thought to be important for cold adaptation of Shewanella sp. SIB1. These activities are also employed by other PPIases for being involved in cold adaptation of various microorganisms. Despite other biological roles of PPIases, we proposed that foldase and chaperone activities of PPIases are the main requirement for overcoming the cold-stress problem in microorganisms due to folding of proteins. PMID:21954357

Near-surface Imaging of a Maya Plaza Complex using Ground-Penetrating Radar

NASA Astrophysics Data System (ADS)

Aitken, J. A.; Stewart, R. R.

2005-05-01

The University of Calgary has conducted a number of ground-penetrating radar surveys at a Maya archaeological site. The purpose of the study is to discern the near-surface structure and stratigraphy of the plaza, and to assist the archaeologists in focusing their excavation efforts. The area of study is located in Belize, Central America at the ancient Maya site of Maax Na. Flanked by structures believed to be temples to the north and west, the archaeologists were interested in determining how many levels of plaza were built and if there was any discernable slope to the plaza. Over the last three years, both 2-D lines and 3-D grids were acquired at the plaza using a Sensors and Software Inc. Noggin Plus system at an antenna frequency of 250 MHz. The processing flow consisted of the application of gain, various filtering techniques and a diffraction stack migration using Reflexw. Interpolation of the gridded data was investigated using simple averaging, F-K migration, pre-stack migration and inversion techniques. As this study has evolved over different field seasons, measured velocities appear to change with the saturation level of the shallow section. Velocity measurements ranged from 0.058 - .106 m/ns during the wet conditions encountered in 2002 and 2004, while velocities of 1.22 - 1.40 m/ns were measured in the drought of 2003. The GPR images to date indicate continuous and interpretable images of the subsurface, showing evidence of structure, discontinuities and amplitude variations. A number of interesting anomalies have been identified, and prioritized for excavation.

Digitally Controlled Analog Signal Processing

DTIC Science & Technology

1988-04-01

each analog switch. The third is the parasiti - capacitance at the output (the capacitor side) of each analog switch. This last is of concern only when a...21) where fk (x) tf H(wk) -H(wk) for k = 1, 2,... n, and x denotes the vector containing n-+ I transfer function coefficients, a, a2 ,... am, and bl...b2, .... bt that are non-zero. We wish to solve this system of equations for x, the vector of unknown transfer function coefficients. The modified

Cardiopulmonary Effects of Acute Stressful Exercise at Altitude of Individuals with Sickle Cell Trait (SCT)

DTIC Science & Technology

1989-06-01

Annual Symposium on Blood. Stuttgart Germany: FK Schattauer Verlag, 1973; 91-94. Home M: Sickle cell anemia as a rheologic disease. Am J Med 1981; 70...AD___ AD-A222 948 CARDIOPULMONARY EFFECTS OF ACUTE STRESSFUL EXERCISE AT ALTITUDE OF INDIVIDUALS WITH SICKLE CELL TRAIT (SCT) FINAL REPORT Idelle M...Clawi’katiornj (U) Cardiopulmonlary Effects to Acute Stressful Exercise at Altitude of Individuals with - sickle Cell Trait (I1bAS) 12. PERSONAL. AUTHOR

Management and the Executive.

DTIC Science & Technology

1988-01-01

8217RDUCTION TO ORGANIZATIONAL BEHAVIOR. 2nd ed. New York, NY: fk; Graw -Hill, 1982. 590 p. HD 31 .M478 1982 (182) Mitroff, Ian I. STAKEHOIDERS OF THE...ROPES TO KNOW: STUDIES IN ORGANIZATIONAL BEHAVIOR. 2nd ed. Columbus, OH: Grid Pub., 1982. 290 p. HD 58.7 .R57 1982 (216) Robbins, Stephen ...34 Stephen J. Carroll and Dennis J. Gillen. W-ADEMY OF MANAGT REVIEN 12:38-51, January 1987 (290) 1 ( "Axe You Firing Talented nagers?" Richard Gould

Harmonic and anharmonic oscillations investigated by using a microcomputer-based Atwood's machine

NASA Astrophysics Data System (ADS)

Pecori, Barbara; Torzo, Giacomo; Sconza, Andrea

1999-03-01

We describe how the Atwood's machine, interfaced to a personal computer through a rotary encoder, is suited for investigating harmonic and anharmonic oscillations, exploiting the buoyancy force acting on a body immersed in water. We report experimental studies of oscillators produced by driving forces of the type F=-kxn with n=1,2,3, and F=-k sgn(x). Finally we suggest how this apparatus can be used for showing to the students a macroscopic model of interatomic forces.

Theory of Semiconducting Superlattices and Microstructures

DTIC Science & Technology

1992-03-01

the on-site energies a., range from - D12 to +D/2’. The calculations have been executed repeatedly W 2 for a single spin channel ’ and for finite...Spin can be neglected, because the occurs fo~r N =20 electrons. M = 40 lattice sites, recoil profiles 1(E) for each spin channel are indepen- and =100...values e, with rrobability I -x, and er, that one car e~aluate the Ijac s;-;;e-s fk, each of theie eB (with probability x). channels inuependentl. and

Postischemic changes in the immunophilin FKBP12 in the rat brain.

PubMed

Kato, H; Oikawa, T; Otsuka, K; Takahashi, A; Itoyama, Y

2000-12-08

An immunosuppressant tacrolimus (FK506) protects against neuronal damage following cerebral ischemia. On the other hand, the major physiological role of the immunophilin FK506-binding protein-12 (FKBP12) is a modulation of intracellular calcium flux. Since an increase in intracellular calcium concentration is a major mediator of ischemic neuronal death, we investigated the changes in FKBP12 following cerebral ischemia in the rat. We induced focal cerebral ischemia by intraluminal occlusion of the middle cerebral artery for 1 h, and global cerebral ischemia for 10 min by bilateral carotid artery occlusion combined with hypotension. The animals were killed at 4 h to 7 days after reperfusion. Immunohistochemistry was performed on paraffin sections using a monoclonal antibody raised against recombinant FKBP12. Immunoreactivity to FKBP12 in control brains was most pronounced in the CA1 subfield of the hippocampus and the striatum, the localization being primarily neuronal. Following focal ischemia, FKBP12 immunoreactivity decreased rapidly in the ischemic core by 4 h, but increased in surviving neurons in penumbra areas (4 h-7 days). Within an area of infarction, invading leukocytes and macrophages exhibited immunoreactivity to FKBP12 (3-7 days). Following global ischemia, FKBP12 immunoreactivity in CA1 neurons decreased after 1 day, and then it was lost between 2 and 7 days, although many CA1 neurons showed a transient increase in FKBP12 at 2 days. No FKBP12 immunoreactivity was observed in reactive glial cells. Thus, FKBP12 declined in dying neurons, whereas FKBP12 was upregulated in less severely injured neurons. The findings suggest that (1) FKBP12 plays an important role in the process of neuronal survival and death following cerebral ischemia, and (2) FKBP12 is involved in inflammatory reactions that occur within an area of infarction.

P38 mitogen-activated protein kinase (p38 MAPK) overexpression in clinical staging of nasopharyngeal carcinoma

NASA Astrophysics Data System (ADS)

Farhat; Asnir, R. A.; Yudhistira, A.; Daulay, E. R.; Muzakkir, M. M.; Yulius, S.

2018-03-01

Molecular biological research on nasopharyngeal carcinoma has been widely practiced, such as VEGF, EGFR, COX-2 expression and so on. MAPK plays a role in cell growth such as proliferation, differentiation, and apoptosis, primarily contributing to gene expression, where p38 MAPK pathway mostly associate with anti-apoptosis and cause cell transformation. The aim of this study is to determine the expression of p38 MAPK in clinical stage of nasopharyngeal carcinoma so that the result can be helpful in prognosis and adjunctive therapy in nasopharyngeal carcinoma. The research design is descriptive. It was done in THT- KL Department of FK USU/RSUP Haji Adam Malik, Medan and Pathology Anatomical Department of FK USU. The study was conducted from December 2011 to May 2012. The Samples are all patients who diagnosed with nasopharyngeal carcinoma in oncology division of Otorhinolaryngology Department. p38 MAPK overexpression was found in 21 samples (70%) from 30 nasopharyngeal carcinoma samples. The elevated of p38 MAPK expression most found on T4 by eight samples (38.1%), N3 lymph node group by nine samples (42.9%), stage IV of clinical staging is as many as 15 samples (71.4%). p38 MAPK most expressed in stage IV clinical staging of patients with nasopharyngeal carcinoma.

Anterior Chamber Angle Shape Analysis and Classification of Glaucoma in SS-OCT Images.

PubMed

Ni Ni, Soe; Tian, J; Marziliano, Pina; Wong, Hong-Tym

2014-01-01

Optical coherence tomography is a high resolution, rapid, and noninvasive diagnostic tool for angle closure glaucoma. In this paper, we present a new strategy for the classification of the angle closure glaucoma using morphological shape analysis of the iridocorneal angle. The angle structure configuration is quantified by the following six features: (1) mean of the continuous measurement of the angle opening distance; (2) area of the trapezoidal profile of the iridocorneal angle centered at Schwalbe's line; (3) mean of the iris curvature from the extracted iris image; (4) complex shape descriptor, fractal dimension, to quantify the complexity, or changes of iridocorneal angle; (5) ellipticity moment shape descriptor; and (6) triangularity moment shape descriptor. Then, the fuzzy k nearest neighbor (fkNN) classifier is utilized for classification of angle closure glaucoma. Two hundred and sixty-four swept source optical coherence tomography (SS-OCT) images from 148 patients were analyzed in this study. From the experimental results, the fkNN reveals the best classification accuracy (99.11 ± 0.76%) and AUC (0.98 ± 0.012) with the combination of fractal dimension and biometric parameters. It showed that the proposed approach has promising potential to become a computer aided diagnostic tool for angle closure glaucoma (ACG) disease.

Are English-language pedometer instructions readable?

PubMed

Wallace, Lorraine S; Bielak, Kenneth; Linn, Brian

2010-05-01

We evaluated readability and related features of English-language instructions accompanying pedometers, including reading grade level, layout/formatting characteristics, and emphasis of key points. We identified 15 pedometers currently available for purchase in the US. Reading grade level was calculated using Flesch-Kinkaid (FK) and SMOG formulas. Text point size was measured with a C-Thru Ruler. Page and illustration dimensions were measured to the nearest millimeter (mm) with a standard ruler. Layout features were evaluated using the criteria from the User-Friendliness Tool. FK scores ranged from 8th to 11th grade, while SMOG scores ranged from 8th to 12th grade. Text point size averaged 6.9 +/- 1.9 (range = 4-11). Instructions averaged 8.7 +/- 9.0 (range = 0-36) illustrations, most about the size of a US quarter. While many instructions avoided use of specialty fonts (n = 12; 80.0%), most used a minimal amount of white space. Just 4 (26.7%) sets of instructions highlighted the target goal of 10,000 steps-per-day. Pedometer instructions should be revised to meet the recommended 6th grade reading level. Paper size instructions are printed on should be enlarged, thereby allowing for larger text and illustrations, and additional white space. Recommended number of steps per day and proper pedometer positioning should also be predominantly highlighted.

The role of substance P release in the lung with esophageal acid.

PubMed

Kohrogi, H; Hamamoto, J; Kawano, O; Iwagoe, H; Fujii, K; Hirata, N; Ando, M

2001-12-03

To investigate whether tachykinins are released in the airways by stimulating the esophagus, airway plasma extravasation induced by intraesophageal hydrochloric acid (HCl) in the presence or absence of the neutral endopeptidase (NEP) inhibitor phosphoramidon and the neurokinin-1-receptor antagonist FK888 was studied in anesthetized guinea pigs. Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy. Propranolol and atropine were used in all animals to block adrenergic and cholinergic nerve effects. Airway plasma leakage was evaluated by measuring extravasated Evans blue dye. One normal HCl infusion into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation induced by HCl infusion into the esophagus in the trachea and main bronchi, and FK888 significantly inhibited extravasation in a dose-related manner. In capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilaterally vagotomized animals. These results suggest that locally acting substances are released by intraesophageal HCl stimulation that cause airway plasma extravasation. These substances are generated through activation of neural pathways, including some that traffic through the vagus nerves that link the esophagus or airways.

Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist

PubMed Central

Walpole, C S J; Brown, M C S; James, I F; Campbell, E A; McIntyre, P; Docherty, R; Ko, S; Hedley, L; Ewan, S; Buchheit, K-H; Urban, L A

1998-01-01

The in vitro and in vivo pharmacology of SDZ NKT 343 (2-nitrophenyl-carbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide), a novel tachykinin NK1 receptor antagonist was investigated.SDZ NKT 343 inhibited [3H]-substance P binding to the human NK1 receptor in transfected Cos-7 cell membranes (IC50=0.62±0.11 nM). In comparison, in the same assay Ki values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13±0.04 nM, 0.96±0.20 nM, 0.15±0.06 nM and 1.77±0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50=451±139 nM).SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]-substance P, suggesting a non-competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone-induced contraction of the guinea-pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible.SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfected Cos-7 cells (Ki of 0.52±0.04 μM and 3.4±1.2 μM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca2+ and Na+currents in guinea-pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)-SDZ NKT 343 was about 1000 times less active at human NK1 receptors expressed in Cos-7 cell membranes.Contractions of the guinea-pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration-dependent manner, with an IC50=1.60±0.94 nM, while the enantiomer (R,R)-SDZ NKT 343 was 100 times less active (IC50=162±26 nM). In comparison, in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90±07 nM, 0.14±0.02 nM, 11.4±2.9 nM and 2.4±0.83 nM, respectively.In anaesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar9]SP sulphone-evoked bronchoconstriction (70% reduction at 0.4 mg kg−1, i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected.In conclusion, SDZ NKT 343 is a highly selective NK1 receptor antagonist with high potency at the human and guinea-pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK1 receptor hyperfunction is involved. PMID:9630347

Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice.

PubMed

Hoenderop, Joost G J; Chon, Helena; Gkika, Dimitra; Bluyssen, Hans A R; Holstege, Frank C P; St-Arnaud, Rene; Braam, Branko; Bindels, Rene J M

2004-02-01

Pseudovitamin D deficiency rickets (PDDR) is an autosomal disease, characterized by undetectable levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), rickets and secondary hyperparathyroidism. Mice in which the 25-hydroxyvitamin D3-1 alpha-hydroxylase (1 alpha-OHase) gene was inactivated, presented the same clinical phenotype as patients with PDDR. cDNA Microarray technology was used on kidneys of 1 alpha-OHase knockout mice to study the expression profile of renal genes in this Ca2+-related disorder. Genome wide molecular events that occur during the rescue of these mice by high dietary Ca2+ intake were studied by the use of 15K cDNA microarray chips. 1 alpha-OHase knockout mice fed a normal Ca2+ diet developed severe hypocalcemia, rickets and died with an average life span of 12 +/- 2 weeks. Intriguingly, 1 alpha-OHase-/- mice supplemented with an enriched Ca2+ diet were normocalcemic and not significantly different from wild-type mice. Inactivation of the 1 alpha-OHase gene resulted in a significant regulation of +/- 1000 genes, whereas dietary Ca2+ supplementation of the 1 alpha-OHase-/- mice revealed +/- 2000 controlled genes. Interestingly, 557 transcripts were regulated in both situations implicating the involvement in the dietary Ca2+-mediated rescue mechanism of the 1 alpha-OHase-/- mice. Conspicuous regulated genes encoded for signaling molecules like the PDZ-domain containing protein channel interacting protein, FK binding protein type 4, kinases, and importantly Ca2+ transporting proteins including the Na+-Ca2+ exchanger, calbindin-D28K and the Ca2+ sensor calmodulin. Dietary Ca2+ intake normalized disturbances in the Ca2+ homeostasis due to vitamin D deficiency that were accompanied by the regulation of a subset of renal genes, including well-known renal Ca2+ transport protein genes, but also genes not previously identified as playing a role in renal Ca2+ handling.

Solar Radiative Flux Calculations from Standard Surface Meteorological Observations

DTIC Science & Technology

1982-03-01

the p round in T F3 "d = II3 0 2 and the sum of the terms transmitted through layer 2 𔃻 il, to te botton o0 layer 1 is RTI𔃺/ Ad G. (C; forms a pair o...no obstruc-k k tions to visibility are present. The next stige in; the jproccsts was to evaluate Fk and T’k for the var- 2 5•" k f3 q ious uniform...Boston, 9 bpp . 59. SOLMET, 1977: Hourly solai radiation - surface meteorological obser- vations. Vol. 1 - users Manual. Vol. 2, 1979, Final Report

Evaluation of the Quality, Accuracy, and Readability of Online Patient Resources for the Management of Articular Cartilage Defects.

PubMed

Wang, Dean; Jayakar, Rohit G; Leong, Natalie L; Leathers, Michael P; Williams, Riley J; Jones, Kristofer J

2017-04-01

Objective Patients commonly use the Internet to obtain their health-related information. The purpose of this study was to investigate the quality, accuracy, and readability of online patient resources for the management of articular cartilage defects. Design Three search terms ("cartilage defect," "cartilage damage," "cartilage injury") were entered into 3 Internet search engines (Google, Bing, Yahoo). The first 25 websites from each search were collected and reviewed. The quality and accuracy of online information were independently evaluated by 3 reviewers using predetermined scoring criteria. The readability was evaluated using the Flesch-Kincaid (FK) grade score. Results Fifty-three unique websites were evaluated. Quality ratings were significantly higher in websites with a FK score >11 compared to those with a score of ≤11 ( P = 0.021). Only 10 websites (19%) differentiated between focal cartilage defects and diffuse osteoarthritis. Of these, 7 (70%) were elicited using the search term "cartilage defect" ( P = 0.038). The average accuracy of the websites was high (11.7 out of maximum 12), and the average FK grade level (13.4) was several grades higher than the recommended level for readable patient education material (eighth grade level). Conclusions The quality and readability of online patient resources for articular cartilage defects favor those with a higher level of education. Additionally, the majority of these websites do not distinguish between focal chondral defects and diffuse osteoarthritis, which can fail to provide appropriate patient education and guidance for available treatment. Clinicians should help guide patients toward high-quality, accurate, and readable online patient education material.

Differences in Env and Gag protein expression patterns and epitope availability in feline immunodeficiency virus infected PBMC compared to infected and transfected feline model cell lines.

PubMed

Roukaerts, Inge D M; Grant, Chris K; Theuns, Sebastiaan; Christiaens, Isaura; Acar, Delphine D; Van Bockstael, Sebastiaan; Desmarets, Lowiese M B; Nauwynck, Hans J

2017-01-02

Env and Gag are key components of the FIV virion that are targeted to the plasma membrane for virion assembly. They are both important stimulators and targets of anti-FIV immunity. To investigate and compare the expression pattern and antigenic changes of Gag and Env in various research models, infected PBMC (the natural FIV host cells) and GFox, and transfected CrFK were stained over time with various Env and Gag specific MAbs. In FIV infected GFox and PBMC, Env showed changes in epitope availability for antibody binding during processing and trafficking, which was not seen in transfected CrFK. Interestingly, epitopes exposed on intracellular Env and Env present on the plasma membrane of CrFK and GFox seem to be hidden on plasma membrane expressed Env of FIV infected PBMC. A kinetic follow up of Gag and Env expression showed a polarization of both Gag and Env expression to specific sites at the plasma membrane of PBMC, but not in other cell lines. In conclusion, mature trimeric cell surface expressed Env might be antigenically distinct from intracellular monomeric Env in PBMC and might possibly be unrecognizable by feline humoral immunity. In addition, Env expression is restricted to a small area on the plasma membrane and co-localizes with a large moiety of Gag, which may represent a preferred FIV budding site, or initiation of virological synapses with direct cell-to-cell virus transmission. Copyright © 2016. Published by Elsevier B.V.

Metabolomics Analysis of Metabolic Effects of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibition on Human Cancer Cells

PubMed Central

Tolstikov, Vladimir; Nikolayev, Alexander; Dong, Sucai; Zhao, Genshi; Kuo, Ming-Shang

2014-01-01

Nicotinamide phosphoribosyltransferase (NAMPT) plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide–consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry–based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer) and HCT-116 (colorectal cancer) cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA), and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC)-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level. PMID:25486521

Calcineurin is required for pseudohyphal growth, virulence, and drug resistance in Candida lusitaniae.

PubMed

Zhang, Jing; Silao, Fitz Gerald S; Bigol, Ursela G; Bungay, Alice Alma C; Nicolas, Marilou G; Heitman, Joseph; Chen, Ying-Lien

2012-01-01

Candida lusitaniae is an emerging fungal pathogen that infects immunocompromised patients including HIV/AIDS, cancer, and neonatal pediatric patients. Though less prevalent than other Candida species, C. lusitaniae is unique in its ability to develop resistance to amphotericin B. We investigated the role of the calcium-activated protein phosphatase calcineurin in several virulence attributes of C. lusitaniae including pseudohyphal growth, serum survival, and growth at 37°C. We found that calcineurin and Crz1, a C. albicans Crz1 homolog acting as a downstream target of calcineurin, are required for C. lusitaniae pseudohyphal growth, a process for which the underlying mechanism remains largely unknown in C. lusitaniae but hyphal growth is fundamental to C. albicans virulence. We demonstrate that calcineurin is required for cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance in C. lusitaniae. To further examine the potential of targeting the calcineurin signaling cascade for antifungal drug development, we examined the activity of a calcineurin inhibitor FK506 in combination with caspofungin against echinocandin resistant C. lusitaniae clinical isolates. Broth microdilution and drug disk diffusion assays demonstrate that FK506 has synergistic fungicidal activity with caspofungin against echinocandin resistant isolates. Our findings reveal that pseudohyphal growth is controlled by the calcineurin signaling cascade, and highlight the potential use of calcineurin inhibitors and caspofungin for emerging drug-resistant C. lusitaniae infections.

Calcineurin Is Required for Pseudohyphal Growth, Virulence, and Drug Resistance in Candida lusitaniae

PubMed Central

Zhang, Jing; Silao, Fitz Gerald S.; Bigol, Ursela G.; Bungay, Alice Alma C.; Nicolas, Marilou G.; Heitman, Joseph; Chen, Ying-Lien

2012-01-01

Candida lusitaniae is an emerging fungal pathogen that infects immunocompromised patients including HIV/AIDS, cancer, and neonatal pediatric patients. Though less prevalent than other Candida species, C. lusitaniae is unique in its ability to develop resistance to amphotericin B. We investigated the role of the calcium-activated protein phosphatase calcineurin in several virulence attributes of C. lusitaniae including pseudohyphal growth, serum survival, and growth at 37°C. We found that calcineurin and Crz1, a C. albicans Crz1 homolog acting as a downstream target of calcineurin, are required for C. lusitaniae pseudohyphal growth, a process for which the underlying mechanism remains largely unknown in C. lusitaniae but hyphal growth is fundamental to C. albicans virulence. We demonstrate that calcineurin is required for cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance in C. lusitaniae. To further examine the potential of targeting the calcineurin signaling cascade for antifungal drug development, we examined the activity of a calcineurin inhibitor FK506 in combination with caspofungin against echinocandin resistant C. lusitaniae clinical isolates. Broth microdilution and drug disk diffusion assays demonstrate that FK506 has synergistic fungicidal activity with caspofungin against echinocandin resistant isolates. Our findings reveal that pseudohyphal growth is controlled by the calcineurin signaling cascade, and highlight the potential use of calcineurin inhibitors and caspofungin for emerging drug-resistant C. lusitaniae infections. PMID:22952924

Recent advances of mid-infrared compact, field deployable sensors: principles and applications

NASA Astrophysics Data System (ADS)

Tittel, Frank; Gluszek, Aleksander; Hudzikowski, Arkadiusz; Dong, Lei; Li, Chunguang; Patimisco, Pietro; Sampaolo, Angelo; Spagnolo, Vincenzo; Wojtas, Jacek

2016-04-01

The recent development of compact interband cascade lasers(ICLs) and quantum cascade lasers (QCLs) based trace gas sensors will permit the targeting of strong fundamental rotational-vibrational transitions in the mid-infrared which are one to two orders of magnitude more intense than transitions in the overtone and combination bands in the near-infrared. This has led to the design and fabrication of mid-infrared compact, field deployable sensors for use in the petrochemical industry, environmental monitoring and atmospheric chemistry. Specifically, the spectroscopic detection and monitoring of four molecular species, methane (CH4) [1], ethane (C2H6), formaldehyde (H2CO) [2] and hydrogen sulphide (H2S) [3] will be described. CH4, C2H6 and H2CO can be detected using two detection techniques: mid-infrared tunable laser absorption spectroscopy (TDLAS) using a compact multi-pass gas cell and quartz enhanced photoacoustic spectroscopy (QEPAS). Both techniques utilize state-of-the-art mid-IR, continuous wave (CW), distributed feedback (DFB) ICLs and QCLs. TDLAS was performed with an ultra-compact 54.6m effective optical path length innovative spherical multipass gas cell capable of 435 passes between two concave mirrors separated by 12.5 cm. QEPAS used a small robust absorption detection module (ADM) which consists of a quartz tuning fork (QTF), two optical windows, gas inlet/outlet ports and a low noise frequency pre-amplifier. Wavelength modulation and second harmonic detection were employed for spectral data processing. TDLAS and QEPAS can achieve minimum detectable absorption losses in the range from 10-8 to 10-11cm-1/Hz1/2. Several recent examples of real world applications of field deployable gas sensors will be described. For example, an ICL based TDLAS sensor system is capable of detecting CH4 and C2H6 concentration levels of 1 ppb in a 1 sec. sampling time, using an ultra-compact, robust sensor architecture. H2S detection was realized with a THz QEPAS sensor system using a custom quartz tuning fork (QTF) with a new geometry and a QCL emitting at 2.913 THz [4]. Furthermore, two new approaches aimed to achieve enhanced detection sensitivities with QEPAS based sensing can be realized. The first method will make use of a compact optical power buildup cavity, which achieves significantly lower minimum detectable trace gas concentration levels of < 10 pptv. The second approach will use custom fabricated QTFs capable of improved detection sensitivity. Acknowledgements F.K. Tittel acknowledges support by the National Science Foundation (NSF) ERC MIRTHE award, the Robert Welch Foundation (Grant C-0586) and DOE ARPA-E Monitor Proram. L. Dong acknowledges support by NSF-China (Grant #s. 61275213, 61108030), J. Wojtas acknowledges support by The National Centre for Research and Development, Poland (project ID: 179616). References [1] L. Dong, C. Li, N. P. Sanchez, A. K. Gluszek, R. Griffin and F. K. Tittel;" Compact CH4 sensor system based on a continuous-wave, low power consumption, room temperature interband cascade laser", Appl. Phys Lett. 108, 011106 (2016). [2] L. Dong, Y. Yu, C. Li, S. So, and F.K. Tittel, "Ppb-level formaldehyde detection using a CW room-temperature interband cascade laser and a miniature dense pattern multipass cell" Optics Express; 23, 19821-19830 (2015). [3] V. Spagnolo, P. Patimisco, R. Pennetta, A. Sampaolo, G. Scamarcio, M. Vitiello, and F.K. Tittel, "THz Quartz-enhanced photoacoustic sensor for H2S trace gas detection", Opt. Exp. 23, 7574-7582 (2015). [4] A. Sampaolo, P. Patimisco, L. Dong , A. Geras, S, G. Scamarcio' T. Starecki, F.K Tittel, V. Spagnolo; "Quartz-Enhanced Photoacoustic Spectroscopy exploiting tuning fork overtone modes", Appl. Phys Lett. 107, 231102 (2015).

Models of Acoustic Deception and ASW Support in a Task Group Operating Area

DTIC Science & Technology

1974-12-01

submarine case is: PK+FK + PK+E0 exp (- t(PK +SV - PK + E0 PK + Eo ep -T + h-p(1 -K) + h (Il-Eo) where K = I 6o = I - (1-6o)ao Ko = 1 -ao The equation...Table B-I (Concluded) Mode l Program Model Program Parameter Variable Parameter Variable ORI: Output: T TO T T0 p R1O A All 0 SO A AL 0 S K SKO 0 5DO K...O = (1.0--0 )’BB 01110 SK = RHO#(1.0-S),’BB 01120 EX = 1.0 - EXP(-T/TT: 01130 PS(I) = 1.0 - AH*EX 01140 PA(I) = AL.EX/PS(I) 01150 PKO(1) = . KO *EX/PS(I

Deformation of biological cells in the acoustic field of an oscillating bubble

NASA Astrophysics Data System (ADS)

Zinin, Pavel V.; Allen, John S., III

2009-02-01

In this work we develop a theoretical framework of the interaction of microbubbles with bacteria in the ultrasound field using a shell model of the bacteria, following an approach developed previously [P. V. Zinin , Phys. Rev. E 72, 61907 (2005)]. Within the shell model, the motion of the cell in an ultrasonic field is determined by the motion of three components: the internal viscous fluid, a thin elastic shell, and the surrounding viscous fluid. Several conclusions can be drawn from the modeling of sound interaction with a biological cell: (a) the characteristics of a cell’s oscillations in an ultrasonic field are determined both by the elastic properties of the shell the viscosities of all components of the system, (b) for dipole quadrupole oscillations the cell’s shell deforms due to a change in the shell area this oscillation depends on the surface area modulus KA , (c) the relative change in the area has a maximum at frequency fK˜(1)/(2π)KA/(ρa3) , where a is the cell’s radius and ρ is its density. It was predicted that deformation of the cell wall at the frequency fK is high enough to rupture small bacteria such as E . coli in which the quality factor of natural vibrations is less than 1 (Q<1) . For bacteria with high value quality factors (Q>1) , the area deformation has a strong peak near a resonance frequency fK ; however, the value of the deformation near the resonance frequency is not high enough to produce sufficient mechanical effect. The theoretical framework developed in this work can be extended for describing the deformation of a biological cell under any arbitrary, external periodic force including radiation forces unduced by acoustical (acoustical levitation) or optical waves (optical tweezers).

Web-Enabled Training-Development Tool for Pre-Deployment and Deployed Training

DTIC Science & Technology

2006-11-01

ACKNOWLEDGEMENT We gratefully acknowledge the 8upport of the US Army National Training Center Broncos Team, especially Lieutenant Colonel Rock Marcone...apply the ROE to this situation with the perso•mel in the area? El Am I still able to accomplish my original missioUo Model a Thinldng Enemy You got 50... El A d dress ri4)hl:f/-w~.La~ta.com/dbAO plip~aowldn1lthrspstact=previestnep=backgrou-rd US Ary Leder’rainig Assstan FeEdt V~eW FaltsTcrOE Fk~p__

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation.

PubMed

Yanagimachi, Masakatsu; Naruto, Takuya; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Hiroaki; Yagihashi, Tatsuhiko; Kosaki, Kenjiro; Yokota, Shumpei

2010-01-01

One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity. The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.   Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).   The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs. © 2009 John Wiley & Sons A/S.

Improved Fuzzy K-Nearest Neighbor Using Modified Particle Swarm Optimization

NASA Astrophysics Data System (ADS)

Jamaluddin; Siringoringo, Rimbun

2017-12-01

Fuzzy k-Nearest Neighbor (FkNN) is one of the most powerful classification methods. The presence of fuzzy concepts in this method successfully improves its performance on almost all classification issues. The main drawbackof FKNN is that it is difficult to determine the parameters. These parameters are the number of neighbors (k) and fuzzy strength (m). Both parameters are very sensitive. This makes it difficult to determine the values of ‘m’ and ‘k’, thus making FKNN difficult to control because no theories or guides can deduce how proper ‘m’ and ‘k’ should be. This study uses Modified Particle Swarm Optimization (MPSO) to determine the best value of ‘k’ and ‘m’. MPSO is focused on the Constriction Factor Method. Constriction Factor Method is an improvement of PSO in order to avoid local circumstances optima. The model proposed in this study was tested on the German Credit Dataset. The test of the data/The data test has been standardized by UCI Machine Learning Repository which is widely applied to classification problems. The application of MPSO to the determination of FKNN parameters is expected to increase the value of classification performance. Based on the experiments that have been done indicating that the model offered in this research results in a better classification performance compared to the Fk-NN model only. The model offered in this study has an accuracy rate of 81%, while. With using Fk-NN model, it has the accuracy of 70%. At the end is done comparison of research model superiority with 2 other classification models;such as Naive Bayes and Decision Tree. This research model has a better performance level, where Naive Bayes has accuracy 75%, and the decision tree model has 70%

Adaptive attenuation of aliased ground roll using the shearlet transform

NASA Astrophysics Data System (ADS)

Hosseini, Seyed Abolfazl; Javaherian, Abdolrahim; Hassani, Hossien; Torabi, Siyavash; Sadri, Maryam

2015-01-01

Attenuation of ground roll is an essential step in seismic data processing. Spatial aliasing of the ground roll may cause the overlap of the ground roll with reflections in the f-k domain. The shearlet transform is a directional and multidimensional transform that separates the events with different dips and generates subimages in different scales and directions. In this study, the shearlet transform was used adaptively to attenuate aliased and non-aliased ground roll. After defining a filtering zone, an input shot record is divided into segments. Each segment overlaps adjacent segments. To apply the shearlet transform on each segment, the subimages containing aliased and non-aliased ground roll, the locations of these events on each subimage are selected adaptively. Based on these locations, mute is applied on the selected subimages. The filtered segments are merged together, using the Hanning function, after applying the inverse shearlet transform. This adaptive process of ground roll attenuation was tested on synthetic data, and field shot records from west of Iran. Analysis of the results using the f-k spectra revealed that the non-aliased and most of the aliased ground roll were attenuated using the proposed adaptive attenuation procedure. Also, we applied this method on shot records of a 2D land survey, and the data sets before and after ground roll attenuation were stacked and compared. The stacked section after ground roll attenuation contained less linear ground roll noise and more continuous reflections in comparison with the stacked section before the ground roll attenuation. The proposed method has some drawbacks such as more run time in comparison with traditional methods such as f-k filtering and reduced performance when the dip and frequency content of aliased ground roll are the same as those of the reflections.

Involvement of Technical Reasoning More Than Functional Knowledge in Development of Tool Use in Childhood

PubMed Central

Remigereau, Chrystelle; Roy, Arnaud; Costini, Orianne; Osiurak, François; Jarry, Christophe; Le Gall, Didier

2016-01-01

It is well-known that even toddlers are able to manipulate tools in an appropriate manner according to their physical properties. The ability of children to make novel tools in order to solve problems is, however, surprisingly limited. In adults, mechanical problem solving (MPS) has been proposed to be supported by “technical reasoning skills,” which are thought to be involved in every situation requiring the use of a tool (whether conventional or unusual). The aim of this study was to investigate the typical development of real tool use (RTU) skills and its link with technical reasoning abilities in healthy children. Three experimental tasks were adapted from those used with adults: MPS (three different apparatus), RTU (10 familiar tool-object pairs), and functional knowledge (FK; 10 functional picture matching with familiar tools previously used). The tasks were administered to 85 healthy children divided into six age groups (from 6 to 14 years of age). The results revealed that RTU (p = 0.01) and MPS skills improve with age, even if this improvement differs according to the apparatus for the latter (p < 0.01 for the Hook task and p < 0.05 for the Sloping task). Results also showed that MPS is a better predictor of RTU than FK, with a significant and greater weight (importance weight: 0.65; Estimate ± Standard Error: 0.27 ± 0.08). Ours findings suggest that RTU and technical reasoning develop jointly in children, independently from development of FK. In addition, technical reasoning appears partially operative from the age of six onward, even though the outcome of these skills depends of the context in which they are applied (i.e., the type of apparatus). PMID:27877141

The Mannitol Utilization System of the Marine Bacterium Zobellia galactanivorans

PubMed Central

Groisillier, Agnès; Labourel, Aurore; Michel, Gurvan

2014-01-01

Mannitol is a polyol that occurs in a wide range of living organisms, where it fulfills different physiological roles. In particular, mannitol can account for as much as 20 to 30% of the dry weight of brown algae and is likely to be an important source of carbon for marine heterotrophic bacteria. Zobellia galactanivorans (Flavobacteriia) is a model for the study of pathways involved in the degradation of seaweed carbohydrates. Annotation of its genome revealed the presence of genes potentially involved in mannitol catabolism, and we describe here the biochemical characterization of a recombinant mannitol-2-dehydrogenase (M2DH) and a fructokinase (FK). Among the observations, the M2DH of Z. galactanivorans was active as a monomer, did not require metal ions for catalysis, and featured a narrow substrate specificity. The FK characterized was active on fructose and mannose in the presence of a monocation, preferentially K+. Furthermore, the genes coding for these two proteins were adjacent in the genome and were located directly downstream of three loci likely to encode an ATP binding cassette (ABC) transporter complex, suggesting organization into an operon. Gene expression analysis supported this hypothesis and showed the induction of these five genes after culture of Z. galactanivorans in the presence of mannitol as the sole source of carbon. This operon for mannitol catabolism was identified in only 6 genomes of Flavobacteriaceae among the 76 publicly available at the time of the analysis. It is not conserved in all Bacteroidetes; some species contain a predicted mannitol permease instead of a putative ABC transporter complex upstream of M2DH and FK ortholog genes. PMID:25548051

Online nutrition information for pregnant women: a content analysis.

PubMed

Storr, Tayla; Maher, Judith; Swanepoel, Elizabeth

2017-04-01

Pregnant women actively seek health information online, including nutrition and food-related topics. However, the accuracy and readability of this information have not been evaluated. The aim of this study was to describe and evaluate pregnancy-related food and nutrition information available online. Four search engines were used to search for pregnancy-related nutrition web pages. Content analysis of web pages was performed. Web pages were assessed against the 2013 Australian Dietary Guidelines to assess accuracy. Flesch-Kincaid (F-K), Simple Measure of Gobbledygook (SMOG), Gunning Fog Index (FOG) and Flesch reading ease (FRE) formulas were used to assess readability. Data was analysed descriptively. Spearman's correlation was used to assess the relationship between web page characteristics. Kruskal-Wallis test was used to check for differences among readability and other web page characteristics. A total of 693 web pages were included. Web page types included commercial (n = 340), not-for-profit (n = 113), blogs (n = 112), government (n = 89), personal (n = 36) and educational (n = 3). The accuracy of online nutrition information varied with 39.7% of web pages containing accurate information, 22.8% containing mixed information and 37.5% containing inaccurate information. The average reading grade of all pages analysed measured by F-K, SMOG and FOG was 11.8. The mean FRE was 51.6, a 'fairly difficult to read' score. Only 0.5% of web pages were written at or below grade 6 according to F-K, SMOG and FOG. The findings suggest that accuracy of pregnancy-related nutrition information is a problem on the internet. Web page readability is generally difficult and means that the information may not be accessible to those who cannot read at a sophisticated level. © 2016 John Wiley & Sons Ltd. © 2016 John Wiley & Sons Ltd.

Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway.

PubMed

Feng, Jun; Yan, Peng-Fei; Zhao, Hong-Yang; Zhang, Fang-Cheng; Zhao, Wo-Hua; Feng, Min

2016-01-01

Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100  μ M)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

Density of states, Potts zeros, and Fisher zeros of the Q

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

Kim, Seung-Yeon; Creswick, Richard J.

2001-06-01

The Q-state Potts model can be extended to noninteger and even complex Q by expressing the partition function in the Fortuin-Kasteleyn (F-K) representation. In the F-K representation the partition function Z(Q,a) is a polynomial in Q and v=a{minus}1 (a=e{sup {beta}J}) and the coefficients of this polynomial, {Phi}(b,c), are the number of graphs on the lattice consisting of b bonds and c connected clusters. We introduce the random-cluster transfer matrix to compute {Phi}(b,c) exactly on finite square lattices with several types of boundary conditions. Given the F-K representation of the partition function we begin by studying the critical Potts model Z{submore » CP}=Z(Q,a{sub c}(Q)), where a{sub c}(Q)=1+{radical}Q. We find a set of zeros in the complex w={radical}Q plane that map to (or close to) the Beraha numbers for real positive Q. We also identify {tilde Q}{sub c}(L), the value of Q for a lattice of width L above which the locus of zeros in the complex p=v/{radical}Q plane lies on the unit circle. By finite-size scaling we find that 1/{tilde Q}{sub c}(L){r_arrow}0 as L{r_arrow}{infinity}. We then study zeros of the antiferromagnetic (AF) Potts model in the complex Q plane and determine Q{sub c}(a), the largest value of Q for a fixed value of a below which there is AF order. We find excellent agreement with Baxter{close_quote}s conjecture Q{sub c}{sup AF}(a)=(1{minus}a)(a+3). We also investigate the locus of zeros of the ferromagnetic Potts model in the complex Q plane and confirm that Q{sub c}{sup FM}(a)=(a{minus}1){sup 2}. We show that the edge singularity in the complex Q plane approaches Q{sub c} as Q{sub c}(L){similar_to}Q{sub c}+AL{sup {minus}y{sub q}}, and determine the scaling exponent y{sub q} for several values of Q. Finally, by finite-size scaling of the Fisher zeros near the antiferromagnetic critical point we determine the thermal exponent y{sub t} as a function of Q in the range 2{le}Q{le}3. Using data for lattices of size 3{le}L{le}8 we find that y{sub t} is a smooth function of Q and is well fitted by y{sub t}=(1+Au+Bu{sup 2})/(C+Du) where u={minus}(2/{pi})cos{sup {minus}1}({radical}Q/2). For Q=3 we find y{sub t}{approx_equal}0.6; however if we include lattices up to L=12 we find y{sub t}{approx_equal}0.50(8) in rough agreement with a recent result of Ferreira and Sokal [J. Stat. Phys. >96, 461 (1999)].« less

Fort Simpson, Northwest Territories, Canada. Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts A-F.

DTIC Science & Technology

1972-01-25

CONDITIONS PART E DAILY MAX, M ,&MEAN TEMAP M ATMOSPHERIC PHENOMENA 0A16 N01 AVAILAbL~c EXTREME MAX & mIN TEMP j PART B PRECIPITATION pA Nor...FPREQJENCY riF UCCURRENUr OF RwEATHER CiliqUITIOtJS FROM 40LRLY UBSrkVATjoN5~ RAIN FREEZING SNO I OF SMOKE DUST % OF ORS TOTAL HOURS TOUR- M AND OR RHDG...262 - T S t,"PSOK NJ 1)T 5766PAR STATION STATION NAME YEARS M ONTH 1-FkCEP4TAGE PREQJ ENCY O’F UCCURRENCE OF WEATHER CUNUITIONS FRO HULALY

Expenditure Distribution Trends with Regard to the Availability of Funds in the DOA and DOAF Budgets.

DTIC Science & Technology

1987-06-01

TERMAS (Continu*on r evere of fleUdr’y and ident-loy by block number) GUp eGRU Budget, Outlays, DOAF, DOA, DOD, Expenditures, Increment alism This thesis...34ONE (Ilo de Arid Code) 22C ~fF(E SYo Prfso TervL McCafferv 408-646-2554 1Code 54Mm DO’ FORtM 1-473.5.4 MAR 83 APR ed-ton -ay be used wmu ntl " awsted ...SCHOOL June 1987 Author: Michael FkA.’ atto Approved by: MCC ! s~visor Dan Boer Seoand Reade ill A. treer ., r .. Chairman .zParr~to nstive Sciences

The anthraquinone emodin inhibits the non-exported FIKK kinase from Plasmodium falciparum.

PubMed

Lin, Benjamin C; Harris, Darcy R; Kirkman, Lucy M D; Perez, Astrid M; Qian, Yiwen; Schermerhorn, Janse T; Hong, Min Y; Winston, Dennis S; Xu, Lingyin; Lieber, Alexander M; Hamilton, Matthew; Brandt, Gabriel S

2017-12-01

The FIKK family of kinases is unique to parasites of the Apicomplexan order, which includes all malaria parasites. Plasmodium falciparum, the most virulent form of human malaria, has a family of 19 FIKK kinases, most of which are exported into the host red blood cell during malaria infection. Here, we confirm that FIKK 8 is a non-exported member of the FIKK kinase family. Through expression and purification of the recombinant kinase domain, we establish that emodin is a relatively high-affinity (IC 50 =2μM) inhibitor of PfFk8. Closely related anthraquinones do not inhibit PfFk8, suggesting that the particular substitution pattern of emodin is critical to the inhibitory pharmacophore. This first report of a P. falciparum FIKK kinase inhibitor lays the groundwork for developing specific inhibitors of the various members of the FIKK kinase family in order to probe their physiological function. Copyright © 2017 Elsevier Inc. All rights reserved.

Accelerators of Osteogenesis by Recombinant Human Bone Morphogenetic Protein-2

PubMed Central

Okubo, Yasunori; Kusumoto, Kenji; Bessho, Kazuhisa

2007-01-01

Bone morphogenetic protein (BMP) appears to be one of the most promising cytokine and for clinical use in reconstructive surgery for bony defects and augmentation. To evaluate the effect of basic fibroblast growth factor (bFGF), FK506, elcatonin, and hyperbaric oxygenation (HBO) on osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2), 2 or 5 μg of rhBMP-2 was implanted into intramuscular sites of rats. At 21 days after implantation, the osteoinductive activity in the treatment group and control group was compared radiographically, biochemically, and histologically. The amount of new bone in the treatment group was significantly greater than that in the control group. The alkaline phosphatase activity and calcium content in the treatment group were significantly higher than those in the control group. These results suggest that bFGF, FK506, elcatonin, and HBO accelerated the activity and rate of osteoinduction by rhBMP2. These results may be useful when BMP is applied clinically in near future. PMID:21901062

FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change.

PubMed

Rein, Theo

2016-09-01

This review portraits FK506 binding protein (FKBP) 51 as "reactivity protein" and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co-chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress. In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion. Also see the video abstract here. © 2016 WILEY Periodicals, Inc.

Bidirectional negative differential thermal resistance phenomenon and its physical mechanism in the Frenkel-Kontorova lattices

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

Jianqiang, Zhang; Linru, Nie, E-mail: lrnie@163.com; Chongyang, Chen

2016-07-15

Thermal conduction of the Frenkel-Kontorova (FK) lattices with interfacial coupling is investigated numerically. The results indicate that: (i) For appropriate lattice periods, as the system is symmetric, a bidirectional negative differential thermal resistance (NDTR) phenomenon will appear. If the system is asymmetric, the bidirectional NDTR is gradually converted into an unidirectional NDTR. (ii) The bidirectional NDTR phenomenon effect also depends on the period of the FK lattice as the other parameters remains unchanged. With the increment of the lattice period, the bidirectional NDTR will gradually disappear. (iii) From a stochastic dynamics point of view, thermal transport properties of the systemmore » are determined by the competition between the two types of thermal conduction: one comes from the collusion between atoms, the other is due to the elastic coupling between atoms. For the smaller lattice periods, the former type of thermal conduction occupies the dominating position and the NDTR effect will appear.« less

EPRL/FK asymptotics and the flatness problem

NASA Astrophysics Data System (ADS)

Oliveira, José Ricardo

2018-05-01

Spin foam models are an approach to quantum gravity based on the concept of sum over states, which aims to describe quantum spacetime dynamics in a way that its parent framework, loop quantum gravity, has not as of yet succeeded. Since these models’ relation to classical Einstein gravity is not explicit, an important test of their viabilitiy is the study of asymptotics—the classical theory should be obtained in a limit where quantum effects are negligible, taken to be the limit of large triangle areas in a triangulated manifold with boundary. In this paper we will briefly introduce the EPRL/FK spin foam model and known results about its asymptotics, proceeding then to describe a practical computation of spin foam and semiclassical geometric data for a simple triangulation with only one interior triangle. The results are used to comment on the ‘flatness problem’—a hypothesis raised by Bonzom (2009 Phys. Rev. D 80 064028) suggesting that EPRL/FK’s classical limit only describes flat geometries in vacuum.

FK506-binding protein 10 (FKBP10) regulates lung fibroblast migration via collagen VI synthesis.

PubMed

Knüppel, Larissa; Heinzelmann, Katharina; Lindner, Michael; Hatz, Rudolf; Behr, Jürgen; Eickelberg, Oliver; Staab-Weijnitz, Claudia A

2018-04-19

In idiopathic pulmonary fibrosis (IPF), fibroblasts gain a more migratory phenotype and excessively secrete extracellular matrix (ECM), ultimately leading to alveolar scarring and progressive dyspnea. Here, we analyzed the effects of deficiency of FK506-binding protein 10 (FKBP10), a potential IPF drug target, on primary human lung fibroblast (phLF) adhesion and migration. Using siRNA, FKBP10 expression was inhibited in phLF in absence or presence of 2ng/ml transforming growth factor-β1 (TGF-β1) and 0.1mM 2-phosphoascorbate. Effects on cell adhesion and migration were monitored by an immunofluorescence (IF)-based attachment assay, a conventional scratch assay, and single cell tracking by time-lapse microscopy. Effects on expression of key players in adhesion dynamics and migration were analyzed by qPCR and Western Blot. Colocalization was evaluated by IF microscopy and by proximity ligation assays. FKBP10 knockdown significantly attenuated adhesion and migration of phLF. Expression of collagen VI was decreased, while expression of key components of the focal adhesion complex was mostly upregulated. The effects on migration were 2-phosphoascorbate-dependent, suggesting collagen synthesis as the underlying mechanism. FKBP10 colocalized with collagen VI and coating culture dishes with collagen VI, and to a lesser extent with collagen I, abolished the effect of FKBP10 deficiency on migration. These findings show, to our knowledge for the first time, that FKBP10 interacts with collagen VI and that deficiency of FKBP10 reduces phLF migration mainly by downregulation of collagen VI synthesis. The results strengthen FKBP10 as an important intracellular regulator of ECM remodeling and support the concept of FKBP10 as drug target in IPF.

[Fractal dimension--a new EEG-based method of assessing the depth of anaesthesia].

PubMed

Willand, Monika; Rudner, Robert; Olejarczyk, Elzbieta; Wartak, Magdalena; Marciniak, Radosław; Stasiowski, Michał; Byrczek, Tomasz; Jałowiecki, Przemysław

2008-01-01

It has been suggested that analysis of the EEG signal using the fractal dimension method may be useful for assessment of depth of anaesthesia. Thirty ASA I and II patients, scheduled for elective surgery under general anaesthesia were induced with midazolam, fentanyl and propofol and paralyzed with rocuronium or cis-atracurium. Clinical signs of the depth of anaesthesia were classified to one of five OAA/S levels. Standard vital parameters were observed and brain electrical activity was measured using the bispectral index (BIS) and burst suppression ratio (BSR). The EEG signal was recorded and processed postoperatively to calculate Higuchi's fractal dimension (FD). The latter was presented as a derivative: (D(F)-1) x 100. Mean correlation coefficients between OAA/S scale levels, and BIS and (D(F)-1) x 100 values, were respectively: 0.749+/-0.172 and 0.753+/-0.220. In 28 (93.3%) patients, BIS correlated well with FD (r=0.63+/-0.33). In twenty cases, burst suppression occurred and the correlation coefficient between BIS and DF was much lower (r=0.5860+/-3650), when compared to the group of 10 patients in which no burst suppression was detected (r=0.711+/-0.251). Appropriate correction was made using the following formula: D(FK)=D(F)-(D(F) x BSR). The mean correlation coefficient between BIS values and D(FK) in the BS group was r=0.629+/-0.331. In all cases, the mean correlation coefficient between (D(F)-1) x 100 and BIS was r=0.661+/-0.307 (p<0.001). The fractal dimension method can be regarded as equal to BIS for assessment of depth of anaesthesia.

Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat: New Experimental Paradigms

PubMed Central

Valentine, Heather; Chen, Yi; Guo, Hongzhi; McCormick, Jocelyn; Wu, Yong; Sezen, Sena F.; Hoke, Ahmet; Burnett, Arthur L.; Steiner, Joseph P.

2009-01-01

Objectives We investigated the effects of the orally bioavailable non-immunosuppressive immunophilin ligand GPI 1046 (GPI) on erectile function and cavernous nerve (CN) histology following unilateral or bilateral crush injury (UCI, BCI, respectively) of the CNs. Methods Adult male Sprague-Dawley rats were administered GPI 15 mg/kg intraperitoneally (ip) or 30 mg/kg orally (po), FK506 1 mg/kg, ip, or vehicle controls for each route of administration just prior to UCI or BCI and daily up to 7 d following injury. At day 1 or 7 of treatment, erectile function induced by CN electrical stimulation was measured, and electron microscopic analysis of the injured CN was performed. Results Intraperitoneal administration of GPI to rats with injured CN protected erectile function, in a fashion similar to the prototypic immunophilin ligand FK506, compared with vehicle-treated animals (93% ± 9% vs. 70% ± 5% vs. 45% ± 1%, p < 0.01, respectively). Oral administration of GPI elicited the same level of significant protection from CN injury. GPI administered PO at 30 mg/kg/d, dosing either once daily or four times daily with 7.5 mg/kg, provided nearly complete protection of erectile function. In a more severe BCI model, PO administration of GPI maintained erectile function at 24 h after CN injury. Ultrastructural analysis of injured CNs indicated that GPI administered at the time of CN injury prevents degeneration of about 83% of the unmyelinated axons at 7 d after CN injury. Conclusions The orally administered immunophilin ligand GPI neuroprotects CNs and maintains erectile function in rats under various conditions of CN crush injury. PMID:17145129

Deformation of biological cells in the acoustic field of an oscillating bubble

PubMed Central

Zinin, Pavel V.; Allen, John S.

2009-01-01

In this work we develop a theoretical framework of the interaction of microbubbles with bacteria in the ultrasound field using a shell model of the bacteria, following an approach developed previously [P. V. Zinin et al., Phys. Rev. E 72, 61907 (2005)]. Within the shell model, the motion of the cell in an ultrasonic field is determined by the motion of three components: the internal viscous fluid, a thin elastic shell, and the surrounding viscous fluid. Several conclusions can be drawn from the modeling of sound interaction with a biological cell: (a) the characteristics of a cell’s oscillations in an ultrasonic field are determined both by the elastic properties of the shell the viscosities of all components of the system, (b) for dipole quadrupole oscillations the cell’s shell deforms due to a change in the shell area this oscillation depends on the surface area modulus KA, (c) the relative change in the area has a maximum at frequency fK∼12πKA/(ρa3), where a is the cell’s radius and ρ is its density. It was predicted that deformation of the cell wall at the frequency fK is high enough to rupture small bacteria such as E. coli in which the quality factor of natural vibrations is less than 1 (Q < 1). For bacteria with high value quality factors (Q > 1), the area deformation has a strong peak near a resonance frequency fK; however, the value of the deformation near the resonance frequency is not high enough to produce sufficient mechanical effect. The theoretical framework developed in this work can be extended for describing the deformation of a biological cell under any arbitrary, external periodic force including radiation forces unduced by acoustical (acoustical levitation) or optical waves (optical tweezers). PMID:19391781

An Elementary Proof of a Criterion for Linear Disjointness

ERIC Educational Resources Information Center

Dobbs, David E.

2013-01-01

An elementary proof using matrix theory is given for the following criterion: if "F"/"K" and "L"/"K" are field extensions, with "F" and "L" both contained in a common extension field, then "F" and "L" are linearly disjoint over "K" if (and only if) some…

The dynamics of histone H2A ubiquitination in HeLa cells exposed to rapamycin, ethanol, hydroxyurea, ER stress, heat shock and DNA damage.

PubMed

Nakata, Shiori; Watanabe, Tadashi; Nakagawa, Koji; Takeda, Hiroshi; Ito, Akihiro; Fujimuro, Masahiro

2016-03-25

Polyubiquitination plays key roles in proteasome-dependent and independent cellular events, whereas monoubiquitination is involved in gene expression, DNA repair, protein-protein interaction, and protein trafficking. We previously developed an FK2 antibody, which specifically recognizes poly-Ub moieties but not free Ub. To elucidate the role of Ub conjugation in response to cellular stress, we used FK2 to investigate whether chemical stress (rapamycin, ethanol, or hydroxyurea), ER stress (thapsigargin or tunicamycin), heat shock or DNA damage (H2O2 or methyl methanesulfonate) affect the formation of Ub conjugates including histone H2A (hH2A) ubiquitination. First, we found that all forms of stress tested increased poly-ubiquitinated proteins in HeLa cells. Furthermore, rapamycin and hydroxyurea treatment, and ER stress increased ubiquitination of hH2A, while methyl methanesulfonate (MMS) treatment induced deubiquitination of hH2A. The ethanol and H2O2 treatments, and heat shock transiently induced hH2A de-ubiquitination, although deubiquitinated hH2A were ubiquitinated again by subsequent cultivation. We also revealed that FK2 reacts with not only polyubiquitinated proteins but also mono-ubiquitinated hH2A. With the exception of MMS, all forms of stress tested increased the acetylation of K5-hH2A, K9-hH3 and K8-hH4 in addition to ubiquitination. K118 and K119 of hH2A were ubiquitinated in cells under normal conditions, and K119 was the major ubiquitination site. The MMS-treatment and heat shock induced the deubiquitination of both K118 and K119-histone H2A. Interestingly, MMS treatment did not affect cell HeLa cell viability expressing double-mutant hH2A (KK118,119AA-hH2A), while heat shock slightly but significantly decreased viability of double-mutant hH2A expressing cells, indicating that ubiquitination of both sites associates with recovery from heat shock but not MMS treatment. Thus, we characterized FK2 reactivity and demonstrated that various stresses alter the ubiquitination status, particularly ubiquitinated hH2A and with histone acetylation, and highlight the physiological importance of hH2A ubiquitination after exposure to stress stimuli. Copyright © 2016 Elsevier Inc. All rights reserved.

Development of an Interactive Computer Program to Produce Body Description Data

DTIC Science & Technology

1983-07-01

arbitrary and has varied over the time that the CVS Program and the ATB Model have been in existence. Program GOOD produces data describing an upper torso...N NN NfU NJ JANNJ NN N5~SA NJN N a~mn ain itn ft atK 0 ,0 9a fK C ca I n k0 rC 91 01 tol s 6, -Inb v v P w Dvf 4oa 0 0 0 IS t. faa 0 o In - v - allT...NAMES/ SUSTYP(4),-SEGLAB(1 5)*J.JTLA9C¶14),PLTSY4!(29), 014NIN(-1 :31 )PTTLEPUNlITS( 3,-1:1) REAL MEAN(C:lp2:3)p STDEVCO:lp2: 3) CHARACTER SU83TYP*20

The asymptotic behavior in a reversible random coagulation-fragmentation polymerization process with sub-exponential decay

NASA Astrophysics Data System (ADS)

Dong, Siqun; Zhao, Dianli

2018-01-01

This paper studies the subcritical, near-critical and supercritical asymptotic behavior of a reversible random coagulation-fragmentation polymerization process as N → ∞, with the number of distinct ways to form a k-clusters from k units satisfying f(k) =(1 + o (1)) cr-ke-kαk-β, where 0 < α < 1 and β > 0. When the cluster size is small, its distribution is proved to converge to the Gaussian distribution. For the medium clusters, its distribution will converge to Poisson distribution in supercritical stage, and no large clusters exist in this stage. Furthermore, the largest length of polymers of size N is of order ln N in the subcritical stage under α ⩽ 1 / 2.

The Design and Analysis of Efficient Learning Algorithms

DTIC Science & Technology

1991-01-01

will be c-close to the target concept with high probability. (Technically, their approach needs some minor modifications to handle, for instance, a...test in the sense that if cii = cik = cik then nothing can be concluded about the relative depth of 17, and Fk . However, our next lemnas give

Case-Based Policy and Goal Recognition

DTIC Science & Technology

2015-09-30

or noisy. Ontanón et al. [8] use case-based reasoning (CBR) to model human driving vehicle control behaviors and skill level to reduce teen crash...Snodgrass, S., Bonfiglio, D., Winston, F.K., McDonald, C., Gonzalez, A.J.: Case-based prediction of teen driver behavior and skill. In: Pro- ceedings

A Method to Compute the Force Signature of a Body Impacting on a Linear Elastic Structure Using Fourier Analysis

DTIC Science & Technology

1982-09-17

FK * 1PK (2) The convolution of two transforms in time domain is the inverse transform of the product in frequency domain. Thus Rp(s) - Fgc() Ipg(*) (3...its inverse transform by: R,(r)- R,(a.)e’’ do. (5)2w In order to nuke use f a very accurate numerical method to ompute Fourier "ke and coil...taorm. When the inverse transform it tken by using Eq. (15), the cosine transform, because it converges faster than the sine transform refu-ft the

Mountain Home AFB, Mountain Home, Idaho. Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts A-F

DTIC Science & Technology

1980-03-10

FEDERAL BUILDING i6W WOMENT M ~A BEEN APMRVED AHVLE .C FOR PUBLIC RELEASE AND SALE- ITS DI.SHEILEN.C -TR-IBUTION IS UNLIMTEW -7 WOI R~eview and A~proval...reduced visibility. -~~ -- 2 - _____ _____ _____ J" M ’LAL CL>v_*T-LCGY FkACil 7; T:4 Sr-~z~ VVJC;/:EATHER CONDITIONS 1 4~1 -GC"C AFi 79 65-77,7- 79 JA ’ S...01-0 5(OL-AuvlwaotoeloFw’omANoc AATro O~ m m -, imm.~-=--~ ~---=~- __41 4- Lc~.L CLIM4TOLOGY BR~ANCH UA T~.ATE C~ Cfl WEATHER CONDITIONS 2____-6

Secular changes in the lunar elements.

PubMed

Martin, C F; Van Flandern, T C

1970-04-10

Corrections to the adopted values for centennial rates of change of four elements of the lunar orbit, the location of the FK4 equinox, and the obliquity of the ecliptic are presented. They are derived from analyses of lunar occultations distributed over several centuries. Generally, these corrections help to resolve existing discrepancies between theory and observations.

Operation Brain Trauma Therapy

DTIC Science & Technology

2011-10-01

Nicotinamide Choline Atorvastatin FK 506 Minocycline Lithium Rolipram Aniracetam Pentostatin...possible effects on CBF and trophic factor production. They confer benefit in experimental TBI.24,25 Atorvastatin , simvastatin, and lovastatin all show...promise after TBI in rats. Impressive benefit was seen with atorvastatin therapy by Wang et al.24 where improved perfor- mance on rotarod and Morris

Seismic Waveform Modeling of Broadband Data From a Temporary High-Density Deployment in the Los Angeles Basin

NASA Astrophysics Data System (ADS)

Herrman, M.; Polet, J.

2016-12-01

A total of 73 broadband seismometers were deployed for a passive source seismic experiment called the Los Angeles Syncline Seismic Interferometry Experiment (LASSIE) from September to November of 2014. The purpose of this experiment was to collect high density seismic data for the Los Angeles Basin (LAB) to better understand basin structure and response. This research will use the data collected from LASSIE to assess and refine current velocity models of the LAB using a full waveform modeling approach. To this end we will compare seismograms recorded by LASSIE for a subset of the 53 earthquakes and quarry blasts located by the Southern California Seismic Network (SCSN) that occurred within or near the LAB during the deployment period to synthetic seismograms generated by the Frequency-Wavenumber (FK) code developed by Zhu and Rivera (2002). A first analysis of the data indicates that roughly 25 of the 53 events have waveforms with sufficiently high signal to noise ratio, providing approximately 500 seismograms that are of suitable quality for comparison. We observe significant changes in waveform characteristics between stations with a very small separation distance of approximately 1 km. Focal mechanisms for most of these events have been obtained from Dr. Egill Hauksson (personal communication). We will show comparisons between the broadband velocity waveforms recorded by stations across the LASSIE array and FK synthetics determined for a variety of 1D velocity models that have been developed for the LAB area (such as Hadley and Kanamori, 1977; Hauksson, 1989, 1995 and Magistrale, 1992). The results of these comparisons will be analyzed to provide additional constraints on the subsurface seismic velocity structure within the Los Angeles basin.

Preliminary data used to assess the accuracy of estimating female white-tailed deer diel birthing-season home ranges using only daytime locations

USGS Publications Warehouse

Barber-Meyer, Shannon M.; Mech, L. David

2014-01-01

Because many white-tailed deer (Odocoileus virginianus) home-range and habitat-use studies rely only on daytime radio-tracking data, we were interested in whether diurnal data sufficiently represented diel home ranges. We analyzed home-range and core-use size and overlap of 8 adult-female Global-Positioning-System-collared deer during May and June 2001 and 2002 in the Superior National Forest, Minnesota, USA. We used 2 traditional means of analysis: minimum-convex polygons (MCP) and fixed kernels (95% FK, home range and 50% FK, core use) and two methods to partition day and night location data: (1) daytime = 0800-2000 h versus nighttime = 2000-0800 h and (2) sunup versus sundown. We found no statistical difference in size of home-range and core-use areas across day and night comparisons; however, in terms of spatial overlap, approximately 30% of night-range areas on average were not accounted for using daytime locations, with even greater differences between core-use areas (on average approximately 50%). We conclude that diurnal data do not adequately describe diel adult-female-deer, May-June home-ranges due to differences in spatial overlap (location). We suggest research to determine (1) if our findings hold in other circumstances (e.g., exclusive of the parturition period, other age classes, etc.), (2) if our conclusions generalize under other conditions (e.g., across deer range, varying seasons, etc.), (3) if habitat-use conclusions are affected by the incomplete overlap between diurnal and diel data, (4) how many nocturnal locations must be included to generate sufficient overlap, and (5) the influence of using other kernel sizes (e.g., 75%, 90%).

Blending of phased array data

NASA Astrophysics Data System (ADS)

Duijster, Arno; van Groenestijn, Gert-Jan; van Neer, Paul; Blacquière, Gerrit; Volker, Arno

2018-04-01

The use of phased arrays is growing in the non-destructive testing industry and the trend is towards large 2D arrays, but due to limitations, it is currently not possible to record the signals from all elements, resulting in aliased data. In the past, we have presented a data interpolation scheme `beyond spatial aliasing' to overcome this aliasing. In this paper, we present a different approach: blending and deblending of data. On the hardware side, groups of receivers are blended (grouped) in only a few transmit/recording channels. This allows for transmission and recording with all elements, in a shorter acquisition time and with less channels. On the data processing side, this blended data is deblended (separated) by transforming it to a different domain and applying an iterative filtering and thresholding. Two different filtering methods are compared: f-k filtering and wavefield extrapolation filtering. The deblending and filtering methods are demonstrated on simulated experimental data. The wavefield extrapolation filtering proves to outperform f-k filtering. The wavefield extrapolation method can deal with groups of up to 24 receivers, in a phased array of 48 × 48 elements.

Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive.

PubMed

Miyata, Haruhiko; Satouh, Yuhkoh; Mashiko, Daisuke; Muto, Masanaga; Nozawa, Kaori; Shiba, Kogiku; Fujihara, Yoshitaka; Isotani, Ayako; Inaba, Kazuo; Ikawa, Masahito

2015-10-23

Calcineurin inhibitors, such as cyclosporine A and FK506, are used as immunosuppressant drugs, but their adverse effects on male reproductive function remain unclear. The testis expresses somatic calcineurin and a sperm-specific isoform that contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We demonstrate herein that male mice lacking Ppp3cc or Ppp3r2 genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 creates phenocopies of the sperm motility and morphological defects. These defects appear within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after we discontinued treatment. Because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis. Copyright © 2015, American Association for the Advancement of Science.

An Optimal Image-Based Method for Identification of Acoustic Emission (AE) Sources in Plate-Like Structures Using a Lead Zirconium Titanate (PZT) Sensor Array.

PubMed

Yan, Gang; Zhou, Li

2018-02-21

This paper proposes an innovative method for identifying the locations of multiple simultaneous acoustic emission (AE) events in plate-like structures from the view of image processing. By using a linear lead zirconium titanate (PZT) sensor array to record the AE wave signals, a reverse-time frequency-wavenumber (f-k) migration is employed to produce images displaying the locations of AE sources by back-propagating the AE waves. Lamb wave theory is included in the f-k migration to consider the dispersive property of the AE waves. Since the exact occurrence time of the AE events is usually unknown when recording the AE wave signals, a heuristic artificial bee colony (ABC) algorithm combined with an optimal criterion using minimum Shannon entropy is used to find the image with the identified AE source locations and occurrence time that mostly approximate the actual ones. Experimental studies on an aluminum plate with AE events simulated by PZT actuators are performed to validate the applicability and effectiveness of the proposed optimal image-based AE source identification method.

An Optimal Image-Based Method for Identification of Acoustic Emission (AE) Sources in Plate-Like Structures Using a Lead Zirconium Titanate (PZT) Sensor Array

PubMed Central

Zhou, Li

2018-01-01

This paper proposes an innovative method for identifying the locations of multiple simultaneous acoustic emission (AE) events in plate-like structures from the view of image processing. By using a linear lead zirconium titanate (PZT) sensor array to record the AE wave signals, a reverse-time frequency-wavenumber (f-k) migration is employed to produce images displaying the locations of AE sources by back-propagating the AE waves. Lamb wave theory is included in the f-k migration to consider the dispersive property of the AE waves. Since the exact occurrence time of the AE events is usually unknown when recording the AE wave signals, a heuristic artificial bee colony (ABC) algorithm combined with an optimal criterion using minimum Shannon entropy is used to find the image with the identified AE source locations and occurrence time that mostly approximate the actual ones. Experimental studies on an aluminum plate with AE events simulated by PZT actuators are performed to validate the applicability and effectiveness of the proposed optimal image-based AE source identification method. PMID:29466310

Light-front holographic distribution amplitudes of pseudoscalar mesons and their application to B -meson decays

DOE PAGES

Chang, Qin; Brodsky, Stanley J.; Li, Xin-Qiang

2017-05-30

In this article the dynamical spin effects of the light-front holographic wave functions for light pseudoscalar mesons are studied. These improved wave functions are then confronted with a number of hadronic observables: the decay constants of π and K mesons, their ξ -moments, the pion-to-photon transition form factor, and the pure annihilationmore » $$\\bar{B}_s$$ → π + π - and $$\\bar{B}_d$$ → K + K - decays. Taking f π , fK , and their ratio fK / f π as constraints, we perform a χ 2 analysis for the holographic parameters, including the mass scale parameter $$\\sqrtλ$$ and the effective quark masses, and find that the fitted results are quite consistent with the ones obtained from the light-quark hadronic Regge trajectories. In addition, we also show that the end point divergence appearing in the pure annihilation $$\\bar{B}_s$$ → π + π - and $$\\bar{B}_d$$ → K + K - decays can be controlled well by using these improved light-front holographic distribution amplitudes.« less

Comparison of bandage contact lens removal on the fourth versus seventh postoperative day after photorefractive keratectomy: A randomized clinical trial.

PubMed

Mohammadpour, Mehrdad; Shakoor, Delaram; Hashemi, Hassan; Aghaie Meybodi, Mohamad; Rajabi, Fateme; Hosseini, Pegah

2017-06-01

To compare the outcomes of bandage contact lens (BCL) removal on the fourth versus seventh post-operative day following photorefractive keratectomy (PRK). This study recruited eyes of patients who underwent PRK surgery. The patients were randomly assigned to 2 groups. In Group 1 BCL was removed on the 4th postoperative day, while in Group 2, BCL was removed on the 7th postoperative day. After BCL removal, patients were asked to express their pain score and eye discomfort. At one and three months follow-up examinations, visual acuity scale was assessed. Slit-lamp examination was performed in all visits to evaluate complications. 260 eyes of 130 patients underwent PRK. The age and sex ratio were not significantly different between the two groups. One month after the surgery, the logMAR uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were significantly lower in Group 2 (P value = 0.016, 0.001 respectively), however, the UDVA and CDVA were not significantly different after 3 months (P > 0.05). In Group 1, filamentary keratitis (FK) was observed in 10 (7.6%) eyes, 6 (4.61%) eyes were diagnosed with recurrent corneal erosion (RCE) and corneal haze was detected in 3 (2.3%) eyes. However, in Group 2, RCE was observed in 4 (2.3%) and FK was noted in 4 (3.07%) eyes. No haze was seen in Group 2. The difference in rate of complications was statistically significant (14.6% and 6.1% in Groups 1 and 2, respectively, P = 0.02). Pain and eye discomfort scores were not significantly different (P > 0.05). There was no major complications including infectious keratitis in either groups. Following PRK surgery, BCL removal on the seventh postoperative day yields faster visual rehabilitation and lower rate of postoperative complications with no increase in eye pain, discomfort or infection.

BIOMARKERS DISTINGUISH APOPTOTIC AND NECROTIC CELL DEATH DURING HEPATIC ISCHEMIA-REPERFUSION INJURY IN MICE

PubMed Central

Yang, Min; Antoine, Daniel J.; Weemhoff, James L.; Jenkins, Rosalind E.; Farhood, Anwar; Park, B. Kevin; Jaeschke, Hartmut

2014-01-01

Hepatic ischemia-reperfusion (IRP) injury is a significant clinical problem during tumor resection surgery (Pringle maneuver), and liver transplantation. However, the relative contribution of necrotic and apoptotic cell death to the overall liver injury is still controversial. In order to address this important issue in a standard murine model of hepatic IRP injury, plasma biomarkers of necrotic cell death such as micro-RNA-122, full-length cytokeratin-18 (FK18) and high mobility group box-1 (HMGB1) protein, and apoptosis including plasma caspase-3 activity and caspase-cleaved cytokeratin-18 (CK18), coupled with markers of inflammation (hyper-acetylated HMGB1) were compared with histological features in H&E- and TUNEL-stained liver sections. After 45 min of hepatic ischemia and 1–24h of reperfusion, all necrosis markers increased dramatically in plasma by 40-to->10,000-fold over baseline with a time course similar to ALT. These data correlated well with histological characteristics of necrosis. Within the area of necrosis, most cells were TUNEL-positive; initially (≤ 3h of RP) the staining was restricted to nuclei but later spread to the cytosol characteristic for karyorrhexis during necrotic cell death. In contrast, the lack of morphological evidence of apoptotic cell death and relevant caspase-3 activity in the postischemic liver correlated well with the absence of caspase-3 activity and CK18 (except a minor increase at 3h RP) in plasma. The quantitative comparison of FK18 (necrosis) and CK18 (apoptosis) release indicated the dominant cell death by necrosis during IRP and only a temporary and very minor degree of apoptosis. These data suggest that the focus of future research should be on the elucidation of necrotic signaling mechanisms to identify relevant targets, which may be used to attenuate hepatic IRP injury. PMID:25046819

Postinoculation PMPA Treatment, but Not Preinoculation Immunomodulatory Therapy, Protects against Development of Acute Disease Induced by the Unique Simian Immunodeficiency Virus SIVsmmPBj

PubMed Central

Hodge, Shekema; de Rosayro, Juliette; Glenn, Amanda; Ojukwu, Ifeoma C.; Dewhurst, Stephen; McClure, Harold M.; Bischofberger, Norbert; Anderson, Daniel C.; Klumpp, Sherry A.; Novembre, Francis J.

1999-01-01

The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. These biological characteristics include induction of peripheral blood mononuclear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the role of immune activation and viral replication on disease induction, animals infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a potent immunosuppressive agent, or PMPA, a potent antiretroviral agent. While PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal disease. However, these animals did show some evidence of modulation of immune activation, including reduced levels of CD25 antigen and FasL expression, as well as lower tissue viral loads. In contrast, macaques treated postinoculation with PMPA were completely protected from the development of acutely lethal disease. Treatment with PMPA beginning as late as 5 days postinfection was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated controls. Although PMPA-treated animals showed acute lymphopenia due to SIVsmmPBj14 infection, cell subset levels subsequently recovered and returned to normal. Based upon subsequent CD4+ cell counts, the results suggest that very early treatment following retroviral infection can have a significant effect on modifying the subsequent course of disease. These results also suggest that viral replication is an important factor involved in PBJ-induced disease. These studies reinforce the idea that the SIVsmmPBj model system is useful for therapy and vaccine testing. PMID:10482616

Co-existence of Fisheries and Marine Renewable Energy: The Spotlight on Fishers and Fishers' Knowledge (FK)

NASA Astrophysics Data System (ADS)

Campbell, M. S.; Ashley, M.; De Groot, J.; Rodwell, L.

2016-02-01

As an emerging industry, Marine Renewable Energy (MRE) is expected to play a major contributory role if the UK is to successfully reach it's desired target of renewable energy production by 2020. However, due to the competing objectives and priorities of MRE and other industries, for example fisheries, and in the delivering of conservation measures, the demand for space within our marine landscape is increasing, and interactions are inevitable. A semi structured interview was conducted with forty fishers across the UK to elicit further information on the challenges, barriers to progress and priority issues these fishers face in relation to MRE development. The questionnaire also included a fisher assessment of the mitigation agenda developed by de Groot et al. (2014) under the Natural Environment Research Council Marine Renewable Energy Knowledge Exchange Programme ( NERC MREKEP). Qualitative data were extracted and analysed using the text analysis software NVivo8. Fishers identified barriers to progress, and in order of the most important themes included; policy, consultation, trust, lack of knowledge, true representation of all fishers, science vs. fisher observation mismatch and timescales. Priority issues identified in order of importance were; displacement or loss of access, cable disturbance, timings of installation/repairs, effects on the seabed and specifically offshore windfarm (OWF) sitting. The consultation process caused discontent among all fishers interviewed. In relation to working towards a collaborative mitigation agenda, fishers highlighted issues of trust in relation to; trans-boundary management, data management and the consultation process. At all stages of the research, the response rate of the importance of gathering fishers' knowledge (FK) was high. Fishers underlined the importance of this data source in assessing the impacts of MRE on the sectors of the UK fleet. Thus, although at an early stage of development, an initial framework for the collection and application of FK is presented and further work on data needs highlighted.

Design, Synthesis, and Self-Assembly of Well-Defined Hybrid Materials Including Polymer Amphiphiles and Giant Tetrahedra Molecules Based on Poss Nanoparticles

NASA Astrophysics Data System (ADS)

Huang, Mingjun

"Bottom-up" techniques-based self-assembly are always attracting people's interests since this technology provides relatively low economic cost and fast route to construct organized structures at different scales. Considering unprecedented benefits from polymer materials, self-assemblies utilizing polymer building blocks have been extensively studied to achieve diverse hierarchical structures and various attractive properties. However, precise controls of chemical primary structures and compositions and exact constructions of hierarchal ordered structures in synthetic polymers are far from being fully appreciated. In this dissertation, a novel approach has been utilized to construct diverse well-defined nano-building blocks, giant molecules, via conjugating different, and functionalized molecular nanoparticles (MNPs) which are shape- and volume-persistent nano-objects with precise molecular structure and specific symmetry. The representative examples of the three basic categories of giant molecules, "giant polyhedra", "giant surfactants", and "giant shape amphiphiles" were discussed in details. First, a class of precisely defined, nanosized giant tetrahedra was constructed by placing different polyhedral oligomeric silsesquioxane (POSS) molecular nanoparticles at the vertices of a rigid tetrahedral framework. Designed symmetry breaking of these giant tetrahedra introduces accurate positional interactions and results in diverse selectively assembled, highly ordered supramolecular lattices including a Frank-Kasper (FK) A15 phase. The FK and quasicrystal phases are originally identified in metal alloys and only sporadically observed in soft matters. It remains unclear how to correlate their stability with the chemical composition and molecular topology in the self-assembling systems. We then for this purpose designed and studied the self-assembly phase transition sequences of four series of hybrid giant surfactants based on hydrophilic POSS cages tethered with one to four polystyrene (PS) tails. With increasing the number of tails, molecular topological variations not only affect phase boundaries in terms of the PS volume fraction, but also open a window to stabilize supramolecular FK and quasicrystal phases in the spherical phase region, demonstrating the critical role of molecular topology in dictating the formation of unconventional supramolecular lattices of "soft" spherical motifs. The FK A15 phase was even surprisingly observed in the giant shape amphiphile molecule, triphenylene-6BPOSS, which has a disk-like flat triphenylene core connected with six hydrophobic POSS cages by sides. Without conical molecular shape, triphenylene-6BPOSS self-assembled and stabilized into supramolecular sphere via pi-pi interactions through a completely different mechanism with precious two cases. These studies indicate that "bottom-up" self-assemble based on well-defined giant molecules approach can be rather powerful to fabricate usually complicated hierarchical structures and open up a wide field of supramolecular self-assembly with unexpected structure and properties.

Proposed Department of Defense Policy on Air Installations Compatible Use Zones

DTIC Science & Technology

1973-06-01

34 F-3 HIOHT MOW • 1! F-100 afterburner 2A B-52H military 2C-5 ! F-101 F-6 C/KC-135A... afterburner F-6 F-89 MONT MOW 10 F-8 F-94 F-ll T-38 B^7 military 2D A-5 B-58 military mONT MOW • HMNT MOUP * F-SO...imlitarv 2B-5 F S4F F MG F-104 military 2A-5 F-10« F-86E, F. H F-4B. C " F-86V \\ F-K HMNT MOW 4 B-67 F-3 afterburner

The hot corona of YY Mensae

NASA Technical Reports Server (NTRS)

Guedel, M.; Guinan, E. F.; Skinner, S. L.; Linsky, J. L.

1996-01-01

The results of a long time series of Rosat position sensitive proportional counter (PSPC) pointings are reported on together with the first Advanced Satellite for Cosmology and Astrophysics (ASCA) observation of the FK Comae-type star YY Mensae. This star reveals a hot dominant plasma of up to 3 keV, with less material at 0.7 keV.

Moderation of maltreatment effects on childhood borderline personality symptoms by gender and oxytocin receptor and FK506 binding protein 5 genes.

PubMed

Cicchetti, Dante; Rogosch, Fred A; Hecht, Kathryn F; Crick, Nicki R; Hetzel, Susan

2014-08-01

In this investigation, gene-environment-gender interaction effects in predicting child borderline personality disorder symptomatology among maltreated and nonmaltreated low-income children (N = 1,051) were examined. In the context of a summer research camp, adult-, peer-, and self-report assessments of borderline precursor indicators were obtained, as well as child self-report on the Borderline Personality Features Scale for Children. Genetic variants of the oxytocin receptor genotype and the FK506 binding protein 5 gene CATT haplotype were investigated. Children who self-reported high levels of borderline personality symptomatology were differentiated by adults, peers, and additional self-report on indicators of emotional instability, conflictual relationships with peers and adults, preoccupied attachment, and indicators of self-harm and suicidal ideation. Maltreated children also were more likely to evince many of these difficulties relative to nonmaltreated children. A series of analyses of covariance, controlling for age and ancestrally informative markers, indicated significant Maltreatment × Gene × Gender three-way interactions. Consideration of the maltreatment parameters of subtype, onset, and recency expanded understanding of variation among maltreated children. The three-way interaction effects demonstrated differential patterns among girls and boys. Among girls, the gene-environment interaction was more consistent with a diathesis-stress model, whereas among boys a differential-sensitivity interaction effect was indicated. Moreover, the genetic variants associated with greater risk for higher borderline symptomatology, dependent on maltreatment experiences, were opposite in girls compared to boys. The findings have important implications for understanding variability in early predictors of borderline personality pathology.

Site-directed mutagenesis studies on the uridine monophosphate binding sites of feedback inhibition in carbamoyl phosphate synthetase and effects on cytidine production by Bacillus amyloliquefaciens.

PubMed

Fang, Haitian; Liu, Huiyan; Chen, Ning; Zhang, Chenglin; Xie, Xixian; Xu, Qingyang

2013-06-01

A major problem when pyrimidine de novo biosynthesis is used for cytidine production is the existence of many negative regulatory factors. Cytidine biosynthesis in Bacillus amyloliquefaciens proceeds via a pathway that is controlled by uridine monophosphate (UMP) through feedback inhibition of carbamoyl phosphate synthetase (CPS), the enzyme that converts CO2, NH3, and glutamine to carbamoyl phosphate. In this study, the gene carB encoding the large subunit of CPS from B. amyloliquefaciens CYT1 was site directed, and the UMP binding sites of feedback inhibition in Bam-CPS are described. The residues Thr-941, Thr-970, and Lys-986 in CPS from B. amyloliquefaciens were subjected to site-directed mutagenesis to alter UMP's feedback inhibition of CPS. To find feedback-resistant B. amyloliquefaciens, the influence of the T941F, T970A, K986I, T941F/K986I, and T941F/T970A/K986I mutations on CPS enzymatic properties was studied. The recombinant B. amyloliquefaciens with mutated T941F/K986I and T941F/T970A/K986I CPS showed a 3.7- and 5.7-fold increase, respectively, in cytidine production in comparison with the control expressing wild-type CPS, which was more suitable for further application of the cytidine synthesis. To a certain extent, the 5 mutations were found to release the enzyme from UMP inhibition and to improve B. amyloliquefaciens cytidine-producing strains.

Publications | Argonne National Laboratory

Science.gov Websites

2011 2012 2013 2014 2015 2016 2017 2107 Author - Any - Abarzhi, S. I. Abate, J. Abdel-khalik, H. S . Abeysuriya, R. Abhishek, K. Abhyankar, S. Abhyankar, Shrirang Abla, G. Abou-Kandil, H. Abraham, J. A. Acharya , J. Adams, B. Adams, M. L. Addis, B. Adhikari, A. N. Adom, F.K. Adve, S. V. Afsahi, A. Agarwal, A.K

Structural Transformations in Chemically Modified Graphene

DTIC Science & Technology

2012-07-16

Mullen, Nano Lett. 8 (2007) 323–327. [7] J.T. Robinson, F.K. Perkins, E.S. Snow, Z. Wei, P.E. Sheehan, Nano Lett. 8 (2008) 3137–3140. [8] D.A. Dikin , S...97 (2006) 187401. [36] S. Stankovich, D.A. Dikin , R.D. Piner, K.A. Kohlhaas, A. Kleinhammes, Y. Jia, Y. Wu, S.T. Nguyen, R.S. Ruoff, Carbon 45 (2007

Dynamic Expression of FKBP5 in the Medial Prefrontal Cortex Regulates Resiliency to Conditioned Fear

ERIC Educational Resources Information Center

Criado-Marrero, Marangelie; Morales Silva, Roberto J.; Velazquez, Bethzaly; Hernández, Anixa; Colon, María; Cruz, Emmanuel; Soler-Cedeño, Omar; Porter, James T.

2017-01-01

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this…

Dynamic Fluid-Kinetic (DyFK) Simulations of Storm-Enhanced Density Supply of Cleft Ion Fountain Outflows

NASA Astrophysics Data System (ADS)

Horwitz, J. L.; Zeng, W.; Foster, J. C.; Strangeway, R. J.; Adrian, M. L.; Moore, T. E.

2008-12-01

Elevated ionospheric density regions frequently appear to be convected from the subauroral plasmaspheric region toward noon, in association with convection of plasmaspheric tails in the dayside magnetosphere, typically during large geomagnetic storms. In this presentation, we explore the possibility that these Storm Enhanced Density (SED) regions could provide ionospheric plasma source populations for cleft ion fountain outflows. We use our Dynamic Fluid Kinetic (DyFK) code to simulate the entry of a high-density "plasmasphere-like" flux tube entering the cleft region and subjected to an episode of wave-driven transverse ion heating. The results of including different proportions of SED and soft electron precipitation levels, together with transverse ion heating effects on the resulting outflows, will be presented, including the O+ and H+ ion density and related parameter profiles for the simulated SED involved events. We will also compare these modeling results with SED-outflow observations from GPS TEC, and the FAST and IMAGE spacecraft. Foster, J. C., P. J. Erickson, A. J. Coster, J. Goldstein, and F. J. Rich, Ionospheric signatures of plasmaspheric tails, Geophys. Res. Lett., 29(13), 1623, doi:10.1029/2002GL015067, 2002.

Evidence of In Vitro Preservation of Human Nephrogenesis at the Single-Cell Level.

PubMed

Pode-Shakked, Naomi; Gershon, Rotem; Tam, Gal; Omer, Dorit; Gnatek, Yehudit; Kanter, Itamar; Oriel, Sarit; Katz, Guy; Harari-Steinberg, Orit; Kalisky, Tomer; Dekel, Benjamin

2017-07-11

During nephrogenesis, stem/progenitor cells differentiate and give rise to early nephron structures that segment to proximal and distal nephron cell types. Previously, we prospectively isolated progenitors from human fetal kidney (hFK) utilizing a combination of surface markers. However, upon culture nephron progenitors differentiated and could not be robustly maintained in vitro. Here, by culturing hFK in a modified medium used for in vitro growth of mouse nephron progenitors, and by dissection of NCAM + /CD133 - progenitor cells according to EpCAM expression (NCAM + /CD133 - /EpCAM - , NCAM + /CD133 - /EpCAM dim , NCAM + /CD133 - /EpCAM bright ), we show at single-cell resolution a preservation of uninduced and induced cap mesenchyme as well as a transitioning mesenchymal-epithelial state. Concomitantly, differentiating and differentiated epithelial lineages are also maintained. In vitro expansion of discrete stages of early human nephrogenesis in nephron stem cell cultures may be used for drug screening on a full repertoire of developing kidney cells and for prospective isolation of mesenchymal or epithelial renal lineages for regenerative medicine. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Differential DNA methylation of the meiosis-specific gene FKBP6 in testes of yak and cattle-yak hybrids.

PubMed

Li, B; Luo, H; Weng, Q; Wang, S; Pan, Z; Xie, Z; Wu, W; Liu, H; Li, Q

2016-12-01

FK506-binding protein 6 (FKBP6) is essential for meiosis during mammalian spermatogenesis. However, the molecular regulation of FKBP6 during spermatogenesis remains unclear. In the present study, we performed molecular characterization of the meiosis-specific gene FKBP6 in yak testes. Yak FKBP6 encodes a polypeptide of 295 amino acid residues with an FK506-binding domain (FKBP_C) and three tetratricopeptide repeat domains. The methylation level of the FKBP6 promoter in testes was significantly higher in cattle-yak with male sterility than in yak, and the FKBP6 promoter was methylated in liver tissues in which FKBP6 is not expressed. FKBP6 promoter activity was significantly decreased after treatment with the M.SssI methyltransferase in vitro. Furthermore, the FKBP6 gene was remarkably activated in bovine mammary epithelial cells treated with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine. Taken together, our results demonstrate for the first time that the FKBP6 promoter is differentially methylated in testes; together with the functional promoter analysis, this suggests that methylation of this promoter may contribute to cattle-yak male infertility. © 2016 Blackwell Verlag GmbH.

Depinning and heterogeneous dynamics of colloidal crystal layers under shear flow

NASA Astrophysics Data System (ADS)

Gerloff, Sascha; Klapp, Sabine H. L.

2016-12-01

Using Brownian dynamics (BD) simulations and an analytical approach we investigate the shear-induced, nonequilibrium dynamics of dense colloidal suspensions confined to a narrow slit-pore. Focusing on situations where the colloids arrange in well-defined layers with solidlike in-plane structure, the confined films display complex, nonlinear behavior such as collective depinning and local transport via density excitations. These phenomena are reminiscent of colloidal monolayers driven over a periodic substrate potential. In order to deepen this connection, we present an effective model that maps the dynamics of the shear-driven colloidal layers to the motion of a single particle driven over an effective substrate potential. This model allows us to estimate the critical shear rate of the depinning transition based on the equilibrium configuration, revealing the impact of important parameters, such as the slit-pore width and the interaction strength. We then turn to heterogeneous systems where a layer of small colloids is sheared with respect to bottom layers of large particles. For these incommensurate systems we find that the particle transport is dominated by density excitations resembling the so-called "kink" solutions of the Frenkel-Kontorova (FK) model. In contrast to the FK model, however, the corresponding "antikinks" do not move.

Assessing the environmental impact of phenanthrene in different types of land use based on the binding characteristics with dissolved organic matter.

PubMed

Chen, Xiao-Meng; Zhao, Yue; Ma, Ying-Ying; Zhu, Long-Ji; Yang, Tian-Xue; Wei, Zi-Min; Dong, Ying-Li; Wei, Qing-Bin

2018-01-01

The binding characteristics of phenanthrene with dissolved organic matter (DOM) were studied by the excitation emission matrix fluorescence spectroscopy with parallel factor analysis in four types of land use which derived from forest (F), meadow (M), cropland (C), and greenhouse (G). The results showed that the humification degree and binding characteristics of phenanthrene with DOM were distinct differences in the four soils. The binding capacities of humic-like components with phenanthrene were stronger than those of protein-like components. The log K derived from the Stern-Volmer equation significantly correlated with the humification degree of DOM (p < 0.05) in different types of land use. Besides, correlation analysis demonstrated that the potential binding index (Fk) obtained from the modified Stern-Volmer model was a more accurate parameter to describe the combination degree of DOM with phenanthrene than log K, which presented a decrease order of C > F > M > G. Therefore, the environmental impact of phenanthrene in different types of land use could be assessed deeply based on the Fk and DOM concentration. Copyright © 2017 Elsevier Inc. All rights reserved.

FAST TRACK PAPER: Non-iterative multiple-attenuation methods: linear inverse solutions to non-linear inverse problems - II. BMG approximation

NASA Astrophysics Data System (ADS)

Ikelle, Luc T.; Osen, Are; Amundsen, Lasse; Shen, Yunqing

2004-12-01

The classical linear solutions to the problem of multiple attenuation, like predictive deconvolution, τ-p filtering, or F-K filtering, are generally fast, stable, and robust compared to non-linear solutions, which are generally either iterative or in the form of a series with an infinite number of terms. These qualities have made the linear solutions more attractive to seismic data-processing practitioners. However, most linear solutions, including predictive deconvolution or F-K filtering, contain severe assumptions about the model of the subsurface and the class of free-surface multiples they can attenuate. These assumptions limit their usefulness. In a recent paper, we described an exception to this assertion for OBS data. We showed in that paper that a linear and non-iterative solution to the problem of attenuating free-surface multiples which is as accurate as iterative non-linear solutions can be constructed for OBS data. We here present a similar linear and non-iterative solution for attenuating free-surface multiples in towed-streamer data. For most practical purposes, this linear solution is as accurate as the non-linear ones.

Processing and attenuation of noise in deep seismic-reflection data from the Gulf of Maine

USGS Publications Warehouse

Hutchinson, D.R.; Lee, M.W.

1989-01-01

The U.S. Geological Survey deep crustal studies reflection profile across the Gulf of Maine off southeastern New England was affected by three sources of noise: side-scattered noise, multiples, and 20-Hz whale sounds. The special processing most effective in minimizing this noise consisted of a combination of frequency-wavenumber (F-K) filtering, predictive deconvolution, and spectral whitening, each applied in the shot domain (prestack). Application of the F-K filter to remove side-scatter noise in the poststack domain resulted in a much poorer quality profile. The prestack noise suppression processing techniques resulted in a reflection profile with good signal-to-noise ratios and reliable strong reflections, especially at depths equivalent to the lower crust (24-34 km). Certain geologic features, such as a buried rift basin and a crustal fault are resolved much better within the upper crust after this processing. Finite difference migration of these data using realistic velocities produced excellent results. Migration was essential to distinguish between abundant dipping and subhorizontal reflections in the lower crust as well as to show an essentially transparent upper mantle. ?? 1989 Kluwer Academic Publishers.

Conditional fast expression and function of multimeric TRPV5 channels using Shield-1.

PubMed

Schoeber, Joost P H; van de Graaf, Stan F J; Lee, Kyu Pil; Wittgen, Hanneke G M; Hoenderop, Joost G J; Bindels, René J M

2009-01-01

A recently described novel controllable method to regulate protein expression is based on a mutated FK506-binding protein-12 (mtFKBP) that is unstable and rapidly degraded in mammalian cells. This instability can be conferred to other proteins directly fused to mtFKBP. Binding of a synthetic cell-permeant ligand (Shield-1) to mtFKBP reverses the instability, allowing conditional expression of mtFKBP-fused proteins. We adapted this strategy to study multimeric plasma membrane proteins using the ion channel TRPV5 as model protein. mtFKBP-TRPV5 forms functional ion channels and its expression can be controlled in a time- and dose-dependent fashion using Shield-1. Moreover, in the presence of Shield-1, mtFKBP-TRPV5 formed heteromultimeric channels with untagged TRPV5, which were codegraded upon washout of Shield-1, providing a strategy to study multimeric plasma membrane protein complexes without the need to destabilize all individual subunits.

Study of the semileptonic charm decays D(0)-->pi(-)l(+)nu and D(0)-->K(-)l(+)nu.

PubMed

Huang, G S; Miller, D H; Pavlunin, V; Sanghi, B; Shibata, E I; Shipsey, I P J; Adams, G S; Chasse, M; Cummings, J P; Danko, I; Napolitano, J; Cronin-Hennessy, D; Park, C S; Park, W; Thayer, J B; Thorndike, E H; Coan, T E; Gao, Y S; Liu, F; Stroynowski, R; Artuso, M; Boulahouache, C; Blusk, S; Butt, J; Dambasuren, E; Dorjkhaidav, O; Menaa, N; Mountain, R; Muramatsu, H; Nandakumar, R; Redjimi, R; Sia, R; Skwarnicki, T; Stone, S; Wang, J C; Zhang, K; Mahmood, A H; Csorna, S E; Bonvicini, G; Cinabro, D; Dubrovin, M; Bornheim, A; Lipeles, E; Pappas, S P; Weinstein, A J; Briere, R A; Chen, G P; Ferguson, T; Tatishvili, G; Vogel, H; Watkins, M E; Adam, N E; Alexander, J P; Berkelman, K; Cassel, D G; Duboscq, J E; Ecklund, K M; Ehrlich, R; Fields, L; Galik, R S; Gibbons, L; Gittelman, B; Gray, R; Gray, S W; Hartill, D L; Heltsley, B K; Hertz, D; Hsu, L; Jones, C D; Kandaswamy, J; Kreinick, D L; Kuznetsov, V E; Mahlke-Krüger, H; Meyer, T O; Onyisi, P U E; Patterson, J R; Pedlar, T K; Peterson, D; Pivarski, J; Riley, D; Rosner, J L; Ryd, A; Sadoff, A J; Schwarthoff, H; Shepherd, M R; Sun, W M; Thayer, J G; Urner, D; Wilksen, T; Weinberger, M; Athar, S B; Avery, P; Breva-Newell, L; Patel, R; Potlia, V; Stoeck, H; Yelton, J; Rubin, P; Cawlfield, C; Eisenstein, B I; Gollin, G D; Karliner, I; Kim, D; Lowrey, N; Naik, P; Sedlack, C; Selen, M; Thaler, J J; Williams, J; Wiss, J; Edwards, K W; Besson, D; Gao, K Y; Gong, D T; Kubota, Y; Li, S Z; Poling, R; Scott, A W; Smith, A; Stepaniak, C J; Urheim, J; Metreveli, Z; Seth, K K; Tomaradze, A; Zweber, P; Ernst, J; Arms, K; Gan, K K; Severini, H; Skubic, P; Asner, D M; Dytman, S A; Mehrabyan, S; Mueller, J A; Savinov, V; Li, Z; Lopez, A; Mendez, H; Ramirez, J

2005-01-14

We investigate the decays D(0)-->pi(-)l(+)nu and D(0)-->K(-)l(+)nu, where l is e or mu, using approximately 7 fb(-1) of data collected with the CLEO III detector. We find R(0) identical with B(D(0)-->pi(-)e(+)nu)/B(D(0)-->K(-)e(+)nu)=0.082+/-0.006+/-0.005. Fits to the kinematic distributions of the data provide parameters describing the form factor of each mode. Combining the form factor results and R(0) gives |f(pi)(+)(0)|(2)|V(cd)|(2)/|f(K)(+)(0)|(2)|V(cs)|(2)=0.038(+0.006+0.005)(-0.007-0.003).

FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action

PubMed Central

Gassen, Nils C; Hartmann, Jakob; Schmidt, Mathias V; Rein, Theo

2015-01-01

Levels of autophagy markers rise upon treatment of cells with antidepressants. However, it was not known whether this phenomenon might be linked to other antidepressant pathways or to any physiological effect. In this punctum, we summarize and discuss our recent findings that provide evidence for a role of the cochaperone FKBP5/FKBP51 (FK506 binding protein 5) in autophagy as a prerequisite for antidepressant action in cells, mice, and humans. FKBP5 associates with BECN1, changes its phosphorylation and protein levels and enhances markers of autophagy and autophagic flux. The effects of antidepressants on autophagy as well as their physiological effects in mice and human depend on FKBP5. PMID:25714272

Engineer Novel Anticancer Bioagents

DTIC Science & Technology

2009-10-01

Nonribosomally by Bacteria Gene depH is depicted as one of the three post- nonribosomal peptide synthetase (NRPS; dark red)/ polyketide synthase (PKS... polyketide synthase -NRPS pathway for FK228 biosynthesis in C. violaceum no. 968 (Cheng et al., 2007). This pathway would lead to the production of an imme...biosynthesis revealing unprecedented architectural complexity for a hybrid polyketide synthase and nonribosomal peptide synthetase. Chem. Biol. 11, 33–45

Optical Processing of Microwave Signals - Part B

DTIC Science & Technology

2003-04-01

Gay Lussac ,78851 Elancourt Cedex Daniel Dolfi, Sylvie Tonda-Goldstein, Jean-Pierre Huignard, Thales Research & Technology 91401 Orsay Cedex, France...each microwave frequency component fk (phase and amplitude) by the control of the transmission law of the SLMs’. When attributing one frequency to a...a high speed photodiode. Considering the capability offered by 2D SLMs to provide reconfigurable complex phase law , sophisticated programmable

Shearlet transform in aliased ground roll attenuation and its comparison with f-k filtering and curvelet transform

NASA Astrophysics Data System (ADS)

Abolfazl Hosseini, Seyed; Javaherian, Abdolrahim; Hassani, Hossien; Torabi, Siyavash; Sadri, Maryam

2015-06-01

Ground roll, which is a Rayleigh surface wave that exists in land seismic data, may mask reflections. Sometimes ground roll is spatially aliased. Attenuation of aliased ground roll is of importance in seismic data processing. Different methods have been developed to attenuate ground roll. The shearlet transform is a directional and multidimensional transform that generates subimages of an input image in different directions and scales. Events with different dips are separated in these subimages. In this study, the shearlet transform is used to attenuate the aliased ground roll. To do this, a shot record is divided into several segments, and the appropriate mute zone is defined for all segments. The shearlet transform is applied to each segment. The subimages related to the non-aliased and aliased ground roll are identified by plotting the energy distributions of subimages with visual checking. Then, muting filters are used on selected subimages. The inverse shearlet transform is applied to the filtered segment. This procedure is repeated for all segments. Finally, all filtered segments are merged using the Hanning window. This method of aliased ground roll attenuation was tested on a synthetic dataset and a field shot record from the west of Iran. The synthetic shot record included strong aliased ground roll, whereas the field shot record did not. To produce the strong aliased ground roll on the field shot record, the data were resampled in the offset direction from 30 to 60 m. To show the performance of the shearlet transform in attenuating the aliased ground roll, we compared the shearlet transform with the f-k filtering and curvelet transform. We showed that the performance of the shearlet transform in the aliased ground roll attenuation is better than that of the f-k filtering and curvelet transform in both the synthetic and field shot records. However, when the dip and frequency content of the aliased ground roll are the same as the reflections, ability of the shearlet transform is limited in attenuating the aliased ground roll.

Deficiency of FK506-binding protein (FKBP) 51 alters sleep architecture and recovery sleep responses to stress in mice.

PubMed

Albu, Stefana; Romanowski, Christoph P N; Letizia Curzi, M; Jakubcakova, Vladimira; Flachskamm, Cornelia; Gassen, Nils C; Hartmann, Jakob; Schmidt, Mathias V; Schmidt, Ulrike; Rein, Theo; Holsboer, Florian; Hausch, Felix; Paez-Pereda, Marcelo; Kimura, Mayumi

2014-04-01

FK506-binding protein 51 (FKBP51) is a co-chaperone of the glucocorticoid receptor, functionally linked to its activity via an ultra-short negative feedback loop. Thus, FKBP51 plays an important regulatory role in the hypothalamic-pituitary-adrenocortical (HPA) axis necessary for stress adaptation and recovery. Previous investigations illustrated that HPA functionality is influenced by polymorphisms in the gene encoding FKBP51, which are associated with both increased protein levels and depressive episodes. Because FKBP51 is a key molecule in stress responses, we hypothesized that its deletion impacts sleep. To study FKBP51-involved changes in sleep, polysomnograms of FKBP51 knockout (KO) mice and wild-type (WT) littermates were compared at baseline and in the recovery phase after 6-h sleep deprivation (SD) and 1-h restraint stress (RS). Using another set of animals, the 24-h profiles of hippocampal free corticosterone levels were also determined. The most dominant effect of FKBP51 deletion appeared as increased nocturnal wake, where the bout length was significantly extended while non-rapid eye movement sleep (NREMS) and rapid eye movement sleep were rather suppressed. After both SD and RS, FKBP51KO mice exhibited less recovery or rebound sleep than WTs, although slow-wave activity during NREMS was higher in KOs, particularly after SD. Sleep compositions of KOs were nearly opposite to sleep profiles observed in human depression. This might result from lower levels of free corticosterone in FKBP51KO mice, confirming reduced HPA reactivity. The results indicate that an FKBP51 deletion yields a pro-resilience sleep phenotype. FKBP51 could therefore be a therapeutic target for stress-induced mood and sleep disorders. © 2013 European Sleep Research Society.

Heat shock protein 47 and 65-kDa FK506-binding protein weakly but synergistically interact during collagen folding in the endoplasmic reticulum.

PubMed

Ishikawa, Yoshihiro; Holden, Paul; Bächinger, Hans Peter

2017-10-20

Collagen is the most abundant protein in the extracellular matrix in humans and is critical to the integrity and function of many musculoskeletal tissues. A molecular ensemble comprising more than 20 molecules is involved in collagen biosynthesis in the rough endoplasmic reticulum. Two proteins, heat shock protein 47 (Hsp47/ SERPINH1 ) and 65-kDa FK506-binding protein (FKBP65/ FKBP10 ), have been shown to play important roles in this ensemble. In humans, autosomal recessive mutations in both genes cause similar osteogenesis imperfecta phenotypes. Whereas it has been proposed that Hsp47 and FKBP65 interact in the rough endoplasmic reticulum, there is neither clear evidence for this interaction nor any data regarding their binding affinities for each other. In this study using purified endogenous proteins, we examined the interaction between Hsp47, FKBP65, and collagen and also determined their binding affinities and functions in vitro Hsp47 and FKBP65 show a direct but weak interaction, and FKBP65 prefers to interact with Hsp47 rather than type I collagen. Our results suggest that a weak interaction between Hsp47 and FKBP65 confers mutual molecular stability and also allows for a synergistic effect during collagen folding. We also propose that Hsp47 likely acts as a hub molecule during collagen folding and secretion by directing other molecules to reach their target sites on collagens. Our findings may explain why osteogenesis imperfecta-causing mutations in both genes result in similar phenotypes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Substance P induced preprotachykinin-a mRNA, neutral endopeptidase mRNA and substance P in cultured normal fibroblasts.

PubMed

Bae, Sang-Jae; Matsunaga, Yoshitaka; Takenaka, Motoi; Tanaka, Yoichi; Hamazaki, Yoichiro; Shimizu, Kazuhiro; Katayama, Ichiro

2002-04-01

In certain skin diseases, stress can modulate the induction and/or progression of cutaneous manifestations. However, little is known about the circuit in neuroendocrine and in the immune systems of the skin. To address this question, we have analyzed the regulatory mechanisms of autocrine induction of substance P (SP) by cultured normal human fibroblasts that compose the major population of the skin and might augment stress-induced skin inflammatory responses. In nonstimulated conditions, normal fibroblasts express a moderate amount of preprotachykinin-A (PPT-A), a precursor of SP mRNA, and exogenous SP significantly upregulated PPT-A mRNA expression. Maximum response of SP peptide and SP mRNA in fibroblasts was observed 1-3 h after stimulation with SP. In contrast, the expression of neutral endopeptidase (NEP), a cell surface peptide with hydrolyzing activity of SP, was increased in fibroblasts stimulated with SP after 24 h. The administration of NEP inhibitor (phosphoramidon) to the fibroblasts induced higher SP production. In addition, the neurokinin (NK) receptor antagonists (spantide, FK224 and FK888) and protein synthesis inhibitor (cycloheximide) inhibited SP production by 30-40% of control response. In immunostaining study, specific cytoplasmic staining of SP was observed in fibroblasts stimulated with SP. Finally, we confirmed that the nucleotide sequence of the PPT-A expressed in fibroblasts perfectly corresponded to the gene bank human PPT-A cDNA. This is the first report that SP mRNA, NEP mRNA and SP peptide can be induced by normal human skin fibroblasts in response to exogenous SP, and that fibroblast-derived SP might play an important role in the induction and acceleration of certain cutaneous diseases. Copyright 2002 S. Karger AG, Basel

Recombinant Protein Truncation Strategy for Inducing Bactericidal Antibodies to the Macrophage Infectivity Potentiator Protein of Neisseria meningitidis and Circumventing Potential Cross-Reactivity with Human FK506-Binding Proteins

PubMed Central

Bielecka, Magdalena K.; Devos, Nathalie; Gilbert, Mélanie; Hung, Miao-Chiu; Weynants, Vincent; Heckels, John E.

2014-01-01

A recombinant macrophage infectivity potentiator (rMIP) protein of Neisseria meningitidis induces significant serum bactericidal antibody production in mice and is a candidate meningococcal vaccine antigen. However, bioinformatics analysis of MIP showed some amino acid sequence similarity to human FK506-binding proteins (FKBPs) in residues 166 to 252 located in the globular domain of the protein. To circumvent the potential concern over generating antibodies that could recognize human proteins, we immunized mice with recombinant truncated type I rMIP proteins that lacked the globular domain and the signal leader peptide (LP) signal sequence (amino acids 1 to 22) and contained the His purification tag at either the N or C terminus (C-term). The immunogenicity of truncated rMIP proteins was compared to that of full (i.e., full-length) rMIP proteins (containing the globular domain) with either an N- or C-terminal His tag and with or without the LP sequence. By comparing the functional murine antibody responses to these various constructs, we determined that C-term His truncated rMIP (−LP) delivered in liposomes induced high levels of antibodies that bound to the surface of wild-type but not Δmip mutant meningococci and showed bactericidal activity against homologous type I MIP (median titers of 128 to 256) and heterologous type II and III (median titers of 256 to 512) strains, thereby providing at least 82% serogroup B strain coverage. In contrast, in constructs lacking the LP, placement of the His tag at the N terminus appeared to abrogate bactericidal activity. The strategy used in this study would obviate any potential concerns regarding the use of MIP antigens for inclusion in bacterial vaccines. PMID:25452551

Real-time feedback to improve gait in children with cerebral palsy.

PubMed

van Gelder, Linda; Booth, Adam T C; van de Port, Ingrid; Buizer, Annemieke I; Harlaar, Jaap; van der Krogt, Marjolein M

2017-02-01

Real-time feedback may be useful for enhancing information gained from clinical gait analysis of children with cerebral palsy (CP). It may also be effective in functional gait training, however, it is not known if children with CP can adapt gait in response to real-time feedback of kinematic parameters. Sixteen children with cerebral palsy (age 6-16; GMFCS I-III), walking with a flexed-knee gait pattern, walked on an instrumented treadmill with virtual reality in three conditions: regular walking without feedback (NF), feedback on hip angle (FH) and feedback on knee angle (FK). Clinically relevant gait parameters were calculated and the gait profile score (GPS) was used as a measure of overall gait changes between conditions. All children, except one, were able to improve hip and/or knee extension during gait in response to feedback, with nine achieving a clinically relevant improvement. Peak hip extension improved significantly by 5.1±5.9° (NF: 8.9±12.8°, FH: 3.8±10.4°, p=0.01). Peak knee extension improved significantly by 7.7±7.1° (NF: 22.2±12.0°, FK: 14.5±12.7°, p<0.01). GPS did not change between conditions due to increased deviations in other gait parameters. Responders to feedback were shown to have worse initial gait as measured by GPS (p=0.005) and functional selectivity score (p=0.049). In conclusion, ambulatory children with CP show adaptability in gait and are able to respond to real-time feedback, resulting in significant and clinically relevant improvements in peak hip and knee extension. These findings show the potential of real-time feedback as a tool for functional gait training and advanced gait analysis in CP. Copyright © 2016 Elsevier B.V. All rights reserved.

Genetic and Genomic Architecture of the Evolution of Resistance to Antifungal Drug Combinations

PubMed Central

Hill, Jessica A.; Ammar, Ron; Torti, Dax; Nislow, Corey; Cowen, Leah E.

2013-01-01

The evolution of drug resistance in fungal pathogens compromises the efficacy of the limited number of antifungal drugs. Drug combinations have emerged as a powerful strategy to enhance antifungal efficacy and abrogate drug resistance, but the impact on the evolution of drug resistance remains largely unexplored. Targeting the molecular chaperone Hsp90 or its downstream effector, the protein phosphatase calcineurin, abrogates resistance to the most widely deployed antifungals, the azoles, which inhibit ergosterol biosynthesis. Here, we evolved experimental populations of the model yeast Saccharomyces cerevisiae and the leading human fungal pathogen Candida albicans with azole and an inhibitor of Hsp90, geldanamycin, or calcineurin, FK506. To recapitulate a clinical context where Hsp90 or calcineurin inhibitors could be utilized in combination with azoles to render resistant pathogens responsive to treatment, the evolution experiment was initiated with strains that are resistant to azoles in a manner that depends on Hsp90 and calcineurin. Of the 290 lineages initiated, most went extinct, yet 14 evolved resistance to the drug combination. Drug target mutations that conferred resistance to geldanamycin or FK506 were identified and validated in five evolved lineages. Whole-genome sequencing identified mutations in a gene encoding a transcriptional activator of drug efflux pumps, PDR1, and a gene encoding a transcriptional repressor of ergosterol biosynthesis genes, MOT3, that transformed azole resistance of two lineages from dependent on calcineurin to independent of this regulator. Resistance also arose by mutation that truncated the catalytic subunit of calcineurin, and by mutation in LCB1, encoding a sphingolipid biosynthetic enzyme. Genome analysis revealed extensive aneuploidy in four of the C. albicans lineages. Thus, we identify molecular determinants of the transition of azole resistance from calcineurin dependence to independence and establish multiple mechanisms by which resistance to drug combinations evolves, providing a foundation for predicting and preventing the evolution of drug resistance. PMID:23593013

Photoluminescence characteristics of Eu2O3 doped calcium fluoroborate glasses

NASA Astrophysics Data System (ADS)

Krishnapuram, Pavani; Jakka, Suresh Kumar; Thummala, Chengaiah; Lalapeta, Rama Moorthy

2012-11-01

The present work reports the preparation and characterization of calcium fluoroborate (CFB) glasses doped with different concentrations of Eu2O3. The spectroscopic free-ion parameters are evaluated from the experimentally observed energy levels of Eu3+ ions in CFB glasses by using the free-ion Hamiltonian model (HFI). The phenomenological Judd-Ofelt (J-O) parameters, Ω2, Ω4 and Ω6, are evaluated from the intensities of Eu3+ ion absorption bands by various constraints. From these J-O parameters (Ωλ), the radiative parameters such as transition probabilities (AR), branching ratios (βR), stimulated emission cross sections (σe) and radiative lifetimes (τR) are evaluated for 5D→7(4fASO+αL(L+1)+βG(G2)+γG(R7)+∑j=0,2,4 Mjmj+∑k=2,4,6 PKpK where Eavg includes the kinetic energy of the electrons and their interaction with the nucleus. It shifts only the barycentre of the whole 4fN configuration. Fk (k = 2, 4, 6) are free electron repulsion parameters, ξ4f is the spin-orbit coupling constant, α, β and γ are the three interaction parameters, Mj (j = 0, 2, 4) and Pk (k = 2, 4, 6) are magnetic interaction parameters. Among all the interactions, Fk and ξ4f are the main ones which give rise to the 2LJ levels. The rest only make corrections in the energies of these levels without removing their degeneracy. The parametric fits have been carried out as has been done in our earlier work [16]. The quality of the parametric fit is generally described in terms of the root mean square (rms) deviation, σrms between the experimental and calculated energies by the relation σrms=√{{∑}/{i=1N(Eiexp-Eical)2N}} where Eiexp and Eical are the experimental and calculated energies, respectively, for level 'i' and N denotes the total number of levels included in the energy level fit.

Nuclear Explosion and Infrasound Event Resources of the SMDC Monitoring Research Program

DTIC Science & Technology

2008-09-01

2008 Monitoring Research Review: Ground-Based Nuclear Explosion Monitoring Technologies 928 Figure 7. Dozens of detected infrasound signals from...investigate alternative detection schemes at the two infrasound arrays based on frequency-wavenumber (fk) processing and the F-statistic. The results of... infrasound signal - detection processing schemes. REFERENCES Bahavar, M., B. Barker, J. Bennett, R. Bowman, H. Israelsson, B. Kohl, Y-L. Kung, J. Murphy

Interaction between Water Borne Waves and Seismic Waves in the Ocean Bottom: The Forward- and Inverse Problem,

DTIC Science & Technology

1986-04-15

Petroleum Directorate for supplying- and giving consent to publish the shot data. The financial travel support given by the Royal Norwegian Council for...9i 4CY - 30 o 0 0 0 0 0 0 A 0 0 0 0 140R. 4AVENUMERC i/Mi Figure 3. 17: F-k diagram for shot number 100. A: surfi.sc ,nt linear salp

Health literacy and the Internet: a study on the readability of Australian online health information.

PubMed

Cheng, Christina; Dunn, Matthew

2015-08-01

Almost 80% of Australian Internet users seek out health information online so the readability of this information is important. This study aimed to evaluate the readability of Australian online health information and determine if it matches the average reading level of Australians. Two hundred and fifty-one web pages with information on 12 common health conditions were identified across sectors. Readability was assessed by the Flesch-Kincaid (F-K), Simple Measure of Gobbledygook (SMOG) and Flesch Reading Ease (FRE) formulas, with grade 8 adopted as the average Australian reading level. The average reading grade measured by F-K and SMOG was 10.54 and 12.12 respectively. The mean FRE was 47.54, a 'difficult-to-read' score. Only 0.4% of web pages were written at or below grade 8 according to SMOG. Information on dementia was the most difficult to read overall, while obesity was the most difficult among government websites. The findings suggest that the readability of Australian health websites is above the average Australian levels of reading. A quantifiable guideline is needed to ensure online health information accommodates the reading needs of the general public to effectively use the Internet as an enabler of health literacy. © 2015 Public Health Association of Australia.

Central pontine myelinolysis (CPM) associated with tacrolimus (FK506) after liver transplantation.

PubMed

Fukazawa, Kyota; Nishida, Seigo; Aguina, Luz; Pretto, Ernesto

2011-01-01

Central pontine myelinolysis (CPM) is the most detrimental neurologic complication after liver transplantation. The incidence of CPM after liver transplantation ascends to 17%. Although the precise etiology and pathogenesis of CPM is largely unknown, a growing literature implicates a possible role of immunosuppressive agents, such as Cyclosporine (incidence 30%) on its development. Other immunosuppressive agents also can cause CPM but the frequency of these cases is less compared to Cyclosporine. There is only one case report for Tacrolimus (FK506)-associated speech disorder, which might be an atypical presentation of CPM, and no case reports for Rapamycin. We present a case of Tacrolimus induced CPM. A 62-year-old woman who underwent liver transplantation developed clinical symptoms with radiologic evidence consistent with CPM 7 days after liver transplant. Since the electrolytes in this patient remained normal from her admission, the hypothesis of inmunossupressor neurotoxicity was established and the therapy was switched, resulting in an evident clinical and radiological improvement of her condition in the following days. Five months later, the patient's only neurological deficit was slight dysarthria and a follow-up MRI showed no abnormalities. This case provides evidence of Tacrolimus-associated CPM after transplantation, which presented with a classic "lock-in syndrome" with radiographic confirmation.

Structure and Activity of the Peptidyl-Prolyl Isomerase Domain from the Histone Chaperone Fpr4 toward Histone H3 Proline Isomerization*

PubMed Central

Monneau, Yoan R.; Soufari, Heddy; Nelson, Christopher J.; Mackereth, Cameron D.

2013-01-01

The FK506-binding protein (FKBP) family of peptidyl-prolyl isomerases (PPIases) is characterized by a common catalytic domain that binds to the inhibitors FK506 and rapamycin. As one of four FKBPs within the yeast Saccharomyces cerevisiae, Fpr4 has been described as a histone chaperone, and is in addition implicated in epigenetic function in part due to its mediation of cis-trans conversion of proline residues within histone tails. To better understand the molecular details of this activity, we have determined the solution structure of the Fpr4 C-terminal PPIase domain by using NMR spectroscopy. This canonical FKBP domain actively increases the rate of isomerization of three decapeptides derived from the N terminus of yeast histone H3, whereas maintaining intrinsic cis and trans populations. Observation of the uncatalyzed and Fpr4-catalyzed isomerization rates at equilibrium demonstrate Pro16 and Pro30 of histone H3 as the major proline targets of Fpr4, with little activity shown against Pro38. This alternate ranking of the three target prolines, as compared with affinity determination or the classical chymotrypsin-based fluorescent assay, reveals the mechanistic importance of substrate residues C-terminal to the peptidyl-prolyl bond. PMID:23888048

Calcineurin inhibition enhances motor neuron survival following injury

PubMed Central

Hui, Kelvin KW; Liadis, Nicole; Robertson, Jennifer; Kanungo, Anish; Henderson, Jeffrey T

2010-01-01

Abstract The immunosuppressive agents cyclosporin A (CsA) and FK-506 have previously been shown to exhibit neurotrophic and neuroprotective properties in vivo. Given that significant clinical expertise exists for both drugs, they represent an attractive starting point for treatment of acute neural injuries. One putative mechanism for neuroprotection by these drugs relates to inhibition of calcineurin activity. However each drug–immunophilin complex can potentially influence additional signal transduction pathways. Furthermore, several non-immunosuppressive immunophilin ligands have been described as possessing neuroprotective properties, suggesting that neuroprotection may be separable from calcineurin inhibition. In the present study, we examined the mechanism of this neuroprotection in facial motor neurons following axotomy-induced injury. Similar to previous studies in rats, CsA and FK-506 enhanced motor neuron survival in mice following acute injury. To examine the mechanism responsible for neuroprotection by these agents, pharmacologic inhibitors of several potential alternate signalling pathways (17-(allylamino)-17-demethoxygeldanamycin, rapamycin, cypermethrin) were evaluated with respect to neuroprotection. Of these, only cypermethrin, a direct calcineurin inhibitor not previously associated with neuronal survival properties, was observed to significantly enhance motor neuron survival following injury. The results demonstrate for the first time that direct inhibition of calcineurin is neuroprotective in vivo. These data support a model in which calcineurin inhibition promotes neuronal survival, distinct from effects upon neurite outgrowth. PMID:19243469

A long-term study of H(alpha) line variations in FK Comae Berenices

NASA Technical Reports Server (NTRS)

Welty, Alan D.; Ramsey, Lawrence W.; Iyengar, Mrinal; Nations, Harold L.; Buzasi, Derek L.

1993-01-01

We present observations of H(alpha) V/R ratio variations in FK Comae Berencies obtained during several observing seasons from 1981 to 1992. The raw H(alpha) emission profile is always observed to be double peaked due to the stellar-absorption component. During the most years the V/R ratio varies regularly with the period of the photometric light curve. The V/R periodicity is most obvious when time spans no longer than several stellar rotations are considered. We propose that the bulk of the emission component of the H(alpha) line arises in corotating circumstellar material that may be similar to that of a quiescent solar prominence. The lifetime of these structures appears to be on the order of weeks. A weak contribution from a circumstellar disk is evident and chromospheric emission may also be present. The appearance or disappearance of circumstellar structures over periods longer than a few weeks, or the total absence of such structures, blurs the more regular variations in H(alpha) seen over short time scales. Other more stochastic activity, such as flares, also clearly occurs. Phase shifts of the V/R ratio from year to year rule out the hypothesis that mass tranfer in a close binary system is responsible for the V/R variations.

40 CFR Table I-4 to Subpart I of... - Default Emission Factors (1-Uij) for Gas Utilization Rates (Uij) and By-Product Formation Rates...

Code of Federal Regulations, 2013 CFR

2013-07-01

... C5F8 C4F8O Plasma Etching 1-Ui 0.80 0.80 0.48 0.14 NA 0.29 0.32 0.37 0.09 NA NA BCF4 NA NA 0.0018 0... NA NA NA NA NA Chamber Cleaning In situ plasma cleaning: 1-Ui NA NA NA NA NA NA 0.23 NA NA NA NA BCF4... NA NA NA NA NA Remote Plasma Cleaning: 1-Ui NA NA NA NA 0.063 NA 0.018 NA NA NA NA BCF4 NA NA NA NA...

40 CFR Table I-4 to Subpart I - Table I-4 to Subpart I of Part 98-Default Emission Factors (1-Uij) for Gas Utilization Rates (Uij...

Code of Federal Regulations, 2012 CFR

2012-07-01

... NA NA NA NA NA NA NA NA NA NA Chamber Cleaning In situ plasma cleaning: 1-Ui NA NA NA NA NA NA 0.23... NA NA NA NA NA In Situ Thermal Cleaning: 1-Ui NA NA NA NA NA NA 0.28 NA NA NA NA BCF4 NA NA NA NA NA...

Oleate ameliorates palmitate-induced reduction of NAMPT activity and NAD levels in primary human hepatocytes and hepatocarcinoma cells.

PubMed

Penke, Melanie; Schuster, Susanne; Gorski, Theresa; Gebhardt, Rolf; Kiess, Wieland; Garten, Antje

2017-10-03

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide adenine dinucleotide (NAD) levels are crucial for liver function. The saturated fatty acid palmitate and the unsaturated fatty acid oleate are the main free fatty acids in adipose tissue and human diet. We asked how these fatty acids affect cell survival, NAMPT and NAD levels in HepG2 cells and primary human hepatocytes. HepG2 cells were stimulated with palmitate (0.5mM), oleate (1mM) or a combination of both (0.5mM/1mM) as well as nicotinamide mononucleotide (NMN) (0.5 mM) or the specific NAMPT inhibitor FK866 (10nM). Cell survival was measured by WST-1 assay and Annexin V/propidium iodide staining. NAD levels were determined by NAD/NADH Assay or HPLC. Protein and mRNA levels were analysed by Western blot analyses and qPCR, respectively. NAMPT enzyme activity was measured using radiolabelled 14 C-nicotinamide. Lipids were stained by Oil red O staining. Palmitate significantly reduced cell survival and induced apoptosis at physiological doses. NAMPT activity and NAD levels significantly declined after 48h of palmitate. In addition, NAMPT mRNA expression was enhanced which was associated with increased NAMPT release into the supernatant, while intracellular NAMPT protein levels remained stable. Oleate alone did not influence cell viability and NAMPT activity but ameliorated the negative impact of palmitate on cell survival, NAMPT activity and NAD levels, as well as the increased NAMPT mRNA expression and secretion. NMN was able to normalize intracellular NAD levels but did not ameliorate cell viability after co-stimulation with palmitate. FK866, a specific NAMPT inhibitor did not influence lipid accumulation after oleate-treatment. Palmitate targets NAMPT activity with a consequent cellular depletion of NAD. Oleate protects from palmitate-induced apoptosis and variation of NAMPT and NAD levels. Palmitate-induced cell stress leads to an increase of NAMPT mRNA and accumulation in the supernatant. However, the proapoptotic action of palmitate seems not to be mediated by decreased NAD levels.

The Assessment of Quality, Accuracy, and Readability of Online Educational Resources for Platelet-Rich Plasma.

PubMed

Ghodasra, Jason H; Wang, Dean; Jayakar, Rohit G; Jensen, Andrew R; Yamaguchi, Kent T; Hegde, Vishal V; Jones, Kristofer J

2018-01-01

To critically evaluate the quality, accuracy, and readability of readily available Internet patient resources for platelet-rich plasma (PRP) as a treatment modality for musculoskeletal injuries. Using the 3 most commonly used Internet search engines (Google, Bing, Yahoo), the search term "platelet rich plasma" was entered, and the first 50 websites from each search were reviewed. The website's affiliation was identified. Quality was evaluated using 25-point criteria based on guidelines published by the American Academy of Orthopaedic Surgeons, and accuracy was assessed with a previously described 12-point grading system by 3 reviewers independently. Readability was evaluated using the Flesch-Kincaid (FK) grade score. A total of 46 unique websites were identified and evaluated. The average quality and accuracy was 9.4 ± 3.4 (maximum 25) and 7.9 ± 2.3 (maximum 12), respectively. The average FK grade level was 12.6 ± 2.4, which is several grades higher than the recommended eighth-grade level for patient education material. Ninety-one percent (42/46) of websites were authored by physicians, and 9% (4/46) contained commercial bias. Mean quality was significantly greater in websites authored by health care providers (9.8 ± 3.1 vs 5.9 ± 4.7, P = .029) and in websites without commercial bias (9.9 ± 3.1 vs 4.5 ± 3.2, P = .002). Mean accuracy was significantly lower in websites authored by health care providers (7.6 ± 2.2 vs 11.0 ± 1.2, P = .004). Only 24% (11/46) reported that PRP remains an investigational treatment. The accuracy and quality of online patient resources for PRP are poor, and the information overestimates the reading ability of the general population. Websites authored by health care providers had higher quality but lower accuracy. Additionally, the majority of websites do not identify PRP as an experimental treatment, which may fail to provide appropriate patient understanding and expectations. Physicians should educate patients that many online patient resources have poor quality and accuracy and can be difficult to read. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

A photocleavable rapamycin conjugate for spatiotemporal control of small GTPase activity.

PubMed

Umeda, Nobuhiro; Ueno, Tasuku; Pohlmeyer, Christopher; Nagano, Tetsuo; Inoue, Takanari

2011-01-12

We developed a novel method to spatiotemporally control the activity of signaling molecules. A newly synthesized photocaged rapamycin derivative induced rapid dimerization of FKBP (FK-506 binding protein) and FRB (FKBP-rapamycin binding protein) upon UV irradiation. With this system and the spatially confined UV irradiation, we achieved subcellularly localized activation of Rac, a member of small GTPases. Our technique offers a powerful approach to studies of dynamic intracellular signaling events.

A Matched Field Processing Framework for Coherent Detection Over Local and Regional Networks

DTIC Science & Technology

2011-06-01

Northern Finland Seismological Network, FN) and to the University of Helsinki for data from the VRF and HEF stations (part of the Finnish seismograph ...shows the results of classification with the FK measurement . Most of the events are incorrectly assigned to one particular mine (K2 – Rasvumchorr...generalization of the single-phase matched field processing method that encodes the full structure of the entire wavefield? What would this

40 CFR Table I-3 to Subpart I of... - Default Emission Factors (1-Uij) for Gas Utilization Rates (Uij) and By-Product Formation Rates...

Code of Federal Regulations, 2012 CFR

2012-07-01

... C4F6 C5F8 C4F8O Plasma Etching 1-Ui 0.69 0.56 0.38 0.093 NA 0.25 0.038 0.20 0.14 NA NA BCF4 NA 0.23 0... NA NA NA NA NA NA NA Chamber Cleaning In situ plasma cleaning: 1-Ui 0.92 0.55 NA NA 0.40 0.10 0.18 NA... BC3F8 NA NA NA NA NA NA NA NA NA NA NA Remote plasma cleaning: 1-Ui NA NA NA NA NA NA 0.018 NA NA NA NA...

40 CFR Table I-3 to Subpart I of... - Default Emission Factors (1-Uij) for Gas Utilization Rates (Uij) and By-Product Formation Rates...

Code of Federal Regulations, 2013 CFR

2013-07-01

... C4F6 C5F8 C4F8O Plasma Etching 1-Ui 0.69 0.56 0.38 0.093 NA 0.25 0.038 0.20 0.14 NA NA BCF4 NA 0.23 0... NA NA NA NA NA NA NA Chamber Cleaning In situ plasma cleaning: 1-Ui 0.92 0.55 NA NA 0.40 0.10 0.18 NA... BC3F8 NA NA NA NA NA NA NA NA NA NA NA Remote plasma cleaning: 1-Ui NA NA NA NA NA NA 0.018 NA NA NA NA...

T-phase and tsunami signals recorded by IMS hydrophone triplets during the 2011 Tohoku earthquake

NASA Astrophysics Data System (ADS)

Matsumoto, H.; Haralabus, G.; Zampolli, M.; Ozel, N. M.; Yamada, T.; Mark, P. K.

2016-12-01

A hydrophone station of the International Monitoring System (IMS) of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) is used to estimate the back-azimuth of T-phase signals generated by the 2011 Tohoku earthquake. Among the 6 IMS hydrophone stations required by the Treaty, 5 stations consist of two triplets, with the exception of HA1 (Australia), which has only one. The hydrophones of each triplet are suspended in the SOFAR channel and arranged to form an equilateral triangle with each side being approximately two kilometers long. The waveforms from the Tohoku earthquake were received at HA11, located on Wake Island, which is located approximately 3100 km south-east of the earthquake epicenter. The frequency range used in the array analysis was chosen to be less than 0.375 Hz, which assumed the target phase velocity to be 1.5 km/s for T-phases. The T-phase signals that originated from the seismic source however show peaks in the frequency band above one Hz. As a result of the inter-element distances of 2 km, spatial aliasing is observed in the frequency-wavenumber analysis (F-K analysis) if the entire 100 Hz bandwidth of the hydrophones is used. This spatial aliasing is significant because the distance between hydrophones in the triplet is large in comparison to the ratio between the phase velocity of T-phase signals and the frequency. To circumvent this spatial aliasing problem, a three-step processing technique used in seismic array analysis is applied: (1) high-pass filtering above 1 Hz to retrieve the T-phase, followed by (2) extraction of the envelope of this signal to highlight the T-phase contribution, and finally (3) low-pass filtering of the envelope below 0.375 Hz. The F-K analysis provides accurate back-azimuth and slowness estimations without spatial aliasing. Deconvolved waveforms are also processed to retrieve tsunami components by using a three-pole model of the frequency-amplitude-phase (FAP) response below 0.1 Hz and the measured sensor response for higher frequencies. It is also shown that short-period pressure fluctuations recorded by the IMS hydrophones correspond to theoretical dispersion curves of tsunamis. Thus, short-period dispersive tsunami signals can be identified by the IMS hydrophone triplets.

Genotypic and phenotypic diversity in tropical strains of Aspergillus spp. (section Circumdati) isolated from insects.

PubMed

Moraes, Aurea; Holanda, Veronica; Zahner, Viviane

2006-04-01

The morphology, multilocus enzyme electrophoresis (MLEE), and RAPD-PCR profiles of a panel of 63 strains of Aspergilus section Circumdati, all isoloated from Brazilian insects, were examined. When compared to the descriptions reported in the literature, differences were observed in terms of colony diameter for the representatives studies. Numerical taxonomy based on data generated by MLEE identified two distinct subgroups among the A. ochraceus isolates. In addition, phosphoglucose isomerase (GPI-1) was detected only in A. sclerotiorum, while phosphofructokinase (FK-1) and acid phosphatase (ACP-2) were present only in strains of A. sulphureus, suggesting that these alleles (bands) could be used for species-specific detection. Using RAPD-PCR, species-specific molecular markers were identified for both A. petrakii and A. sulphureus. These results are important from the taxonomic viewpoint and may also be used in the design of screening programs for the isoloation of new strains.

Theoretical and Computational Studies of Stability, Transition and Flow Control in High-Speed Flows

DTIC Science & Technology

2008-02-14

subsonic perturbations, there is an overlapping of four modes. This case has not been considered yet elsewhere. Similarly to the other cases , one can derive...weights for the vorticity and entropy modes. Similarly to the incompressible case [Tum03], one can see that there is a discrepancy between the...turbulence’ [FK01]. In conventional computational studies , one could observe the generation of the instability mode only in the far field, where the

Applications of Molecular Modeling to Transition State Energies and Conformations

DTIC Science & Technology

1992-05-08

reactivity trends for similar systems are known. Illuminati and Mandolini have done research on the lactone formation from w-bromoalkane-carboxylate...strikingly similar to that determined for Illuminati and Mandolini’s similar lactonization system (see Figure 20). The AE, for the 4- 69 membered ring...Brown, F.K.; Spellmeyer, D.C.; Metz, J.T.; Li, Y.; Loncharich, R.L. Science. 1986, 231, 1108-17. Illuminati , G.; Mandolini, L. Accts. of Chem. Res. 1981

ARGOS Testbed: Study of Multidisciplinary Challenges of Future Spaceborne Interferometric Arrays

DTIC Science & Technology

2004-09-01

optimized ex- tensively by ZEMAX . One drawback of the cemented dou- blet is that it has bonded glasses, therefore if there is a change of temperature, the...residual aberrations @root mean square ~rms! wavefront errors predicted by ZEMAX #. The final FK51- BaK2 design achieves 271.6 mm chromatic focal shift...of ZEMAX , a complete ARGOS optics layout is constructed based on the optical specifications of a subaperture, pyramidal mirror, and the beam combining

Aspect: A Formal Specification Language for Detecting Bugs

DTIC Science & Technology

1992-06-01

the Aspect state from Chapter 6 and, below it, the definition of the approximating state used by the checker. The additional component Multilocs marks...stages. First, each collection object in Multilocs is expanded into a set of objects whose dependency and value sets are subsets of those of the... Multilocs x Prelocs Env = Var ý7 PLoc x PSource Store = Loc x Aspect F-k Val x PSource Vat = Unknown + PLoc Aspect = PlainAspect + Pointer + Collection

Polynomials with Restricted Coefficients and Their Applications

DTIC Science & Technology

1987-01-01

sums of exponentials of quadratics, he reduced such ýzums to exponentials of linears (geometric sums!) by simplg multiplying by their conjugates...n, the same algebraic manipulations as before lead to rn V`-~ v ie ? --8-- el4V’ .fk ts with 𔄃 = a+(2r+l)t, A = a+(2r+2m+l)t. To estimate the right...coefficients. These random polynomials represent the deviation in frequency response of a linear , equispaced antenna array cauised by coefficient

Broadband ground motion simulation using a paralleled hybrid approach of Frequency Wavenumber and Finite Difference method

NASA Astrophysics Data System (ADS)

Chen, M.; Wei, S.

2016-12-01

The serious damage of Mexico City caused by the 1985 Michoacan earthquake 400 km away indicates that urban areas may be affected by remote earthquakes. To asses earthquake risk of urban areas imposed by distant earthquakes, we developed a hybrid Frequency Wavenumber (FK) and Finite Difference (FD) code implemented with MPI, since the computation of seismic wave propagation from a distant earthquake using a single numerical method (e.g. Finite Difference, Finite Element or Spectral Element) is very expensive. In our approach, we compute the incident wave field (ud) at the boundaries of the excitation box, which surrounding the local structure, using a paralleled FK method (Zhu and Rivera, 2002), and compute the total wave field (u) within the excitation box using a parallelled 2D FD method. We apply perfectly matched layer (PML) absorbing condition to the diffracted wave field (u-ud). Compared to previous Generalized Ray Theory and Finite Difference (Wen and Helmberger, 1998), Frequency Wavenumber and Spectral Element (Tong et al., 2014), and Direct Solution Method and Spectral Element hybrid method (Monteiller et al., 2013), our absorbing boundary condition dramatically suppress the numerical noise. The MPI implementation of our method can greatly speed up the calculation. Besides, our hybrid method also has a potential use in high resolution array imaging similar to Tong et al. (2014).

Geometry induced sequence of nanoscale Frank–Kasper and quasicrystal mesophases in giant surfactants

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

Yue, Kan; Huang, Mingjun; Marson, Ryan L.

Frank–Kasper (F-K) and quasicrystal phases were originally identified in metal alloys and only sporadically reported in soft materials. These unconventional sphere-packing schemes open up possibilities to design materials with different properties. The challenge in soft materials is how to correlate complex phases built from spheres with the tunable parameters of chemical composition and molecular architecture. Here, we report a complete sequence of various highly ordered mesophases by the self-assembly of specifically designed and synthesized giant surfactants, which are conjugates of hydrophilic polyhedral oligomeric silsesquioxane cages tethered with hydrophobic polystyrene tails. We show that the occurrence of these mesophases results frommore » nanophase separation between the heads and tails and thus is critically dependent on molecular geometry. Variations in molecular geometry achieved by changing the number of tails from one to four not only shift compositional phase boundaries but also stabilize F-K and quasicrystal phases in regions where simple phases of spheroidal micelles are typically observed. These complex self-assembled nanostructures have been identified by combining X-ray scattering techniques and real-space electron microscopy images. Brownian dynamics simulations based on a simplified molecular model confirm the architecture-induced sequence of phases. Our results demonstrate the critical role of molecular architecture in dictating the formation of supramolecular crystals with “soft” spheroidal motifs and provide guidelines to the design of unconventional self-assembled nanostructures.« less

Geometry induced sequence of nanoscale Frank–Kasper and quasicrystal mesophases in giant surfactants

PubMed Central

Yue, Kan; Huang, Mingjun; Marson, Ryan L.; He, Jinlin; Huang, Jiahao; Zhou, Zhe; Wang, Jing; Liu, Chang; Yan, Xuesheng; Wu, Kan; Guo, Zaihong; Liu, Hao; Ni, Peihong; Wesdemiotis, Chrys; Zhang, Wen-Bin; Glotzer, Sharon C.; Cheng, Stephen Z. D.

2016-01-01

Frank–Kasper (F-K) and quasicrystal phases were originally identified in metal alloys and only sporadically reported in soft materials. These unconventional sphere-packing schemes open up possibilities to design materials with different properties. The challenge in soft materials is how to correlate complex phases built from spheres with the tunable parameters of chemical composition and molecular architecture. Here, we report a complete sequence of various highly ordered mesophases by the self-assembly of specifically designed and synthesized giant surfactants, which are conjugates of hydrophilic polyhedral oligomeric silsesquioxane cages tethered with hydrophobic polystyrene tails. We show that the occurrence of these mesophases results from nanophase separation between the heads and tails and thus is critically dependent on molecular geometry. Variations in molecular geometry achieved by changing the number of tails from one to four not only shift compositional phase boundaries but also stabilize F-K and quasicrystal phases in regions where simple phases of spheroidal micelles are typically observed. These complex self-assembled nanostructures have been identified by combining X-ray scattering techniques and real-space electron microscopy images. Brownian dynamics simulations based on a simplified molecular model confirm the architecture-induced sequence of phases. Our results demonstrate the critical role of molecular architecture in dictating the formation of supramolecular crystals with “soft” spheroidal motifs and provide guidelines to the design of unconventional self-assembled nanostructures. PMID:27911786

Developmental pathways from child maltreatment to adolescent marijuana dependence: Examining moderation by FK506 binding protein 5 gene (FKBP5).

PubMed

Handley, Elizabeth D; Rogosch, Fred A; Cicchetti, Dante

2015-11-01

The current study examined the prospective association between child maltreatment and the development of substance use disorder in adolescence with the aim of investigating pathways underlying this relation, as well as genetic moderation of these developmental mechanisms. Specifically, we tested whether youth who experienced maltreatment prior to age 8 were at risk for the development of marijuana dependence in adolescence by way of a childhood externalizing pathway and a childhood internalizing pathway. Moreover, we tested whether variation in FK506 binding protein 5 gene (FKBP5) CATT haplotype moderated these pathways. The participants were 326 children (n =179 maltreated; n = 147 nonmaltreated) assessed across two waves of data collection (childhood: ages 7-9 and adolescence: ages 15-18). Results indicated that higher levels of child externalizing symptoms significantly mediated the effect of child maltreatment on adolescent marijuana dependence symptoms for individuals with one or two copies of the FKBP5 CATT haplotype only. We did not find support for an internalizing pathway from child maltreatment to adolescent marijuana dependence, nor did we find evidence of moderation of the internalizing pathway by FKBP5 haplotype variation. Findings extend previous research by demonstrating that whether a maltreated child will traverse an externalizing pathway toward substance use disorder in adolescence is dependent on FKBP5 genetic variation.

The interactive effects of child maltreatment and the FK506 binding protein 5 gene (FKBP5) on dissociative symptoms in adolescence.

PubMed

Yaylaci, Fatima Tuba; Cicchetti, Dante; Rogosch, Fred A; Bulut, Okan; Hetzel, Susan R

2017-08-01

The FK506 binding protein 5 gene (FKBP5) has been associated with susceptibility to pathogenic effects of childhood trauma including dissociative symptoms. This study examines the impact of maltreatment on dissociative tendencies in adolescence as moderated by the FKBP5 gene. Dissociative symptoms and variation within FKBP5 were assessed in a high-risk, low socioeconomic status community sample of 279 maltreated and 171 nonmaltreated adolescents. Following the assignment of haplotypes across four single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080), individuals with one or more copies of the CATT haplotype (N = 230) were grouped together and compared to individuals with zero copies of this haplotype (N = 185). Analyses of covariance were conducted to test hypotheses regarding the effects of developmental timing and the chronicity of maltreatment and the CATT haplotype. We found a significant interactive effect of timing/chronicity of maltreatment and the CATT haplotype on dissociative symptoms. Among adolescents who had no copies of the CATT haplotype, dissociative symptoms were higher for chronically maltreated adolescents who had an infancy onset compared to those who were not maltreated or whose maltreatment experience was either relatively less chronic or not started in infancy. The groups did not differ significantly among subjects who carry one or more copies of the CATT haplotype.

Nucleoplasmin-like domain of FKBP39 from Drosophila melanogaster forms a tetramer with partly disordered tentacle-like C-terminal segments

PubMed Central

Kozłowska, Małgorzata; Tarczewska, Aneta; Jakób, Michał; Bystranowska, Dominika; Taube, Michał; Kozak, Maciej; Czarnocki-Cieciura, Mariusz; Dziembowski, Andrzej; Orłowski, Marek; Tkocz, Katarzyna; Ożyhar, Andrzej

2017-01-01

Nucleoplasmins are a nuclear chaperone family defined by the presence of a highly conserved N-terminal core domain. X-ray crystallographic studies of isolated nucleoplasmin core domains revealed a β-propeller structure consisting of a set of five monomers that together form a stable pentamer. Recent studies on isolated N-terminal domains from Drosophila 39-kDa FK506-binding protein (FKBP39) and from other chromatin-associated proteins showed analogous, nucleoplasmin-like (NPL) pentameric structures. Here, we report that the NPL domain of the full-length FKBP39 does not form pentameric complexes. Multi-angle light scattering (MALS) and sedimentation equilibrium ultracentrifugation (SE AUC) analyses of the molecular mass of the full-length protein indicated that FKBP39 forms homotetrameric complexes. Molecular models reconstructed from small-angle X-ray scattering (SAXS) revealed that the NPL domain forms a stable, tetrameric core and that FK506-binding domains are linked to it by intrinsically disordered, flexible chains that form tentacle-like segments. Analyses of full-length FKBP39 and its isolated NPL domain suggested that the distal regions of the polypeptide chain influence and determine the quaternary conformation of the nucleoplasmin-like protein. These results provide new insights regarding the conserved structure of nucleoplasmin core domains and provide a potential explanation for the importance of the tetrameric structural organization of full-length nucleoplasmins. PMID:28074868

High diffraction efficiency of three-layer diffractive optics designed for wide temperature range and large incident angle.

PubMed

Mao, Shan; Cui, Qingfeng; Piao, Mingxu; Zhao, Lidong

2016-05-01

A mathematical model of diffraction efficiency and polychromatic integral diffraction efficiency affected by environment temperature change and incident angle for three-layer diffractive optics with different dispersion materials is put forward, and its effects are analyzed. Taking optical materials N-FK5 and N-SF1 as the substrates of multilayer diffractive optics, the effect on diffraction efficiency and polychromatic integral diffraction efficiency with intermediate materials POLYCARB is analyzed with environment temperature change as well as incident angle. Therefore, three-layer diffractive optics can be applied in more wide environmental temperature ranges and larger incident angles for refractive-diffractive hybrid optical systems, which can obtain better image quality. Analysis results can be used to guide the hybrid imaging optical system design for optical engineers.

FKBP51 and FKBP52 in Signaling and Disease

PubMed Central

Storer, Cheryl L.; Dickey, Chad A.; Galigniana, Mario D.; Rein, Theo; Cox, Marc B.

2011-01-01

FKBP51 and FKBP52 are diverse regulators of steroid hormone receptor signaling including regulation of receptor maturation, hormone binding, and nuclear translocation. Although structurally similar, they are functionally divergent, which is largely attributed to differences in the FK1 domain and the proline-rich loop. FKBP51 and FKBP52 have emerged as likely contributors to a variety of hormone-dependent diseases including stress-related diseases, immune function, reproductive functions and a variety of cancers. In addition, recent studies have implicated FKBP51 and FKBP52 in Alzheimer’s disease and other protein aggregation disorders. This review summarizes our current understanding of FKBP51 and FKBP52 interactions within the receptor-chaperone complex, their contributions to health and disease, and their potential as therapeutic targets for the treatment of these diseases. PMID:21889356

Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant

NASA Astrophysics Data System (ADS)

Yuchi, Zhiguang; Yuen, Siobhan M. Wong King; Lau, Kelvin; Underhill, Ainsley Q.; Cornea, Razvan L.; Fessenden, James D.; van Petegem, Filip

2015-08-01

Ryanodine receptors (RyRs) form calcium release channels located in the membranes of the sarcoplasmic and endoplasmic reticulum. RyRs play a major role in excitation-contraction coupling and other Ca2+-dependent signalling events, and consist of several globular domains that together form a large assembly. Here we describe the crystal structures of the SPRY1 and tandem-repeat domains at 1.2-1.5 Å resolution, which reveal several structural elements not detected in recent cryo-EM reconstructions of RyRs. The cryo-EM studies disagree on the position of SPRY domains, which had been proposed based on homology modelling. Computational docking of the crystal structures, combined with FRET studies, show that the SPRY1 domain is located next to FK506-binding protein (FKBP). Molecular dynamics flexible fitting and mutagenesis experiments suggest a hydrophobic cluster within SPRY1 that is crucial for FKBP binding. A RyR1 disease mutation, N760D, appears to directly impact FKBP binding through interfering with SPRY1 folding.

Malaria, Leishmaniasis and Shistosomiasis Vector Ecology, Transmission, Immunology and Prophylaxis in Kenya

DTIC Science & Technology

1994-01-27

medium supplemented with 20% fetal bovine serum, 250 ug/ml streptomycin, 250 U/ml penicillin , and 500 KEMRI Final Report DAMD17-87-G-7016 & DAMD17-89-Z...Leishmania major in a Kenyan Patient: Clinical Description and Parasite Characterization Larry Hendricks , Y.B. Mebrahtu, P.G. Lawyer, R. Muigai, C. Oster, P...Adungo, F.K. Owaga, P.V. Perkins, L.D. Hendricks , and R.E. Whitmire. Attack Rates of Malaria in School Children in The Siaya and Kisumu Districts, Nyanza

Safety and Efficacy of Oral Transmucosal Fentanyl Citrate for Prehospital Pain Control on the Battlefield

DTIC Science & Technology

2012-01-01

Butler FK, Blackbourne LH. We don’t know what we don’t know: combat casualty care pre-hospital data. US Army Med Dep J. 2011;11 14. 50. Kotwal RS... used for prehospital analgesia on the battlefield during the past century has been morphine. Intramuscular morphine has a delayed onset of pain relief...to March 31, 2010, were analyzed. Patients were US Army Special Operations Command casualties. Patients receiving OTFC for acute pain were evaluated

Acoustic Observation of the Time Dependence of the Roughness of Sandy Seafloors

DTIC Science & Technology

2009-11-25

relations between acoustic and roughness temporal correlations are developed and applied. Manuscript received April 23, 2007; revised June 04. 2008 and...Fourier transform of the relief function as follows: (F(K2, t2)F*(Klt h)) = W(KU tu t2)6{Ki - K2) . (6) The presence of the Dirac delta function is only...appropriate if /(R, t) is stationary with infinite extent in the spatial coordi- nates. As a result of the windowing assumed here, the delta func

An elementary proof of a criterion for linear disjointness

NASA Astrophysics Data System (ADS)

Dobbs, David E.

2013-06-01

An elementary proof using matrix theory is given for the following criterion: if F/K and L/K are field extensions, with F and L both contained in a common extension field, then F and L are linearly disjoint over K if (and only if) some K-vector space basis of F is linearly independent over L. The material in this note could serve as enrichment material for the unit on fields in a first course on abstract algebra.

Evaluation of the Perforation Capability of a Rod Projectile as a Function of Impact Velocity

DTIC Science & Technology

1974-10-01

target. Thia analysis permits conclusions to be drawn regarding the terminal ballistics advantages obtained by increased impact velocity. 4 ýj Fk ii... advantages , if any, to be derived from rod pro- jectile impact velocities above conventional values of 2000 to 3000 ft/sec. In particular this section is...continues beyond those points but i* the additional benefit becomes marginal. Figures 17 and 18 show alternative presentations of the same date T!nI

Tacrolimus Optic Neuropathy.

PubMed

Rasool, Nailyn; Boudreault, Katherine; Lessell, Simmons; Prasad, Sashank; Cestari, Dean M

2018-06-01

Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. Case series and review of the literature. We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.

Bio-inspired voltage-dependent calcium channel blockers.

PubMed

Yang, Tingting; He, Lin-Ling; Chen, Ming; Fang, Kun; Colecraft, Henry M

2013-01-01

Ca(2+) influx via voltage-dependent CaV1/CaV2 channels couples electrical signals to biological responses in excitable cells. CaV1/CaV2 channel blockers have broad biotechnological and therapeutic applications. Here we report a general method for developing novel genetically encoded calcium channel blockers inspired by Rem, a small G-protein that constitutively inhibits CaV1/CaV2 channels. We show that diverse cytosolic proteins (CaVβ, 14-3-3, calmodulin and CaMKII) that bind pore-forming α1-subunits can be converted into calcium channel blockers with tunable selectivity, kinetics and potency, simply by anchoring them to the plasma membrane. We term this method 'channel inactivation induced by membrane-tethering of an associated protein' (ChIMP). ChIMP is potentially extendable to small-molecule drug discovery, as engineering FK506-binding protein into intracellular sites within CaV1.2-α1C permits heterodimerization-initiated channel inhibition with rapamycin. The results reveal a universal method for developing novel calcium channel blockers that may be extended to develop probes for a broad cohort of unrelated ion channels.

Interactions between the Tetrasodium Salts of EDTA and 1-Hydroxyethane 1,1-Diphosphonic Acid with Sodium Hypochlorite Irrigants.

PubMed

Biel, Philippe; Mohn, Dirk; Attin, Thomas; Zehnder, Matthias

2017-04-01

A clinically useful all-in-one endodontic irrigant with combined proteolytic and decalcifying properties is still elusive. In this study, the chemical effects of dissolving the tetrasodium salts of 1-hydroxyethane 1,1-diphosphonic acid (Na 4 HEDP) or Na 4 EDTA directly in sodium hypochlorite (NaOCl) irrigants in polypropylene syringes were assessed during the course of 1 hour. The solubility of the salts in water was determined. Their compatibility with 1% and 5% NaOCl was measured by iodometric titration and in a calcium complexation experiment by using a Ca 2+ -selective electrode. The salts dissolved within 1 minute. The dissolution maximum of Na 4 HEDP in water (wt/total wt) was 44.6% ± 1.6%. The corresponding dissolution maximum of Na 4 EDTA was 38.2% ± 0.8%. Na 4 HEDP at 18% in 5% NaOCl caused a mere loss of 16% of the initially available chlorine during 1 hour. In contrast, a corresponding mixture between NaOCl and the Na 4 EDTA salt caused 95% reduction in available chlorine after 1 minute. Mixtures of 3% Na 4 EDTA with 1% NaOCl were more stable, but only for 30 minutes. Na 4 HEDP lost 24% of its calcium complexation capacity after 60 minutes. The corresponding loss for Na 4 EDTA was 34%. The compatibility and solubility of particulate Na 4 HEDP with/in NaOCl solutions are such that these components can be mixed and used for up to 1 hour. In contrast, short-term compatibility of the Na 4 EDTA salt with NaOCl solutions was considerably lower, decreasing at higher concentrations of either compound. Especially for Na 4 HEDP but also for Na 4 EDTA, the NaOCl had little effect on calcium complexation. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Condition of Si crystal formation by vaporizing Na from NaSi

NASA Astrophysics Data System (ADS)

Morito, Haruhiko; Karahashi, Taiki; Yamane, Hisanori

2012-09-01

NaSi was heated at various Na vapor pressures (pNa 0.1-1.2 atm) and temperatures (973-1173 K) to investigate the condition of Si crystal formation from NaSi by Na evaporation. Silicon single crystals 1-3 mm in diameter were grown by evaporation of Na from Na-Si melt at 1173 K and pNa=0.74 atm.

Catálogo de Radio-Fuentes Opticas con Astrolabio Fotoeléctrico PAII

NASA Astrophysics Data System (ADS)

Manrique, W. T.; Podestá, R. C.; Alonso, E.; Actis, E. V.; Pacheco, A. M.; Bustos, G.; Lizhi, L.; Zezhi, W.; Fanmiao, Z.; Hongqi, W.; Perdomo, R.

Usando los datos observados en San Juan con el Astrolabio Fotoeléctrico PAII desde Febrero de 1992 hasta Marzo de 1997, se ha realizado el Catálogo de Radio-Fuentes Opticas de San Juan conteniendo 69 estrellas. Las observaciones de las posiciones de las radio-fuentes están realizadas para la época y equinoccio J2000,0 y en un sistema cercano al del FK5. Las precisiones medias son ± 2,2 ms y ± 0,"035 en ascensión recta y declinación respectivamente. Las magnitudes de las estrellas son desde 0,9 a 10,7 . Las declinaciones son desde --2,5 grados a --60 grados. La época media es 1995,1. Se muestran también los resultados comparados con el Catálogo Hiparcos.

Rapamycin Exerts Antifungal Activity In Vitro and In Vivo against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor

PubMed Central

Bastidas, Robert J.; Shertz, Cecelia A.; Lee, Soo Chan; Heitman, Joseph

2012-01-01

The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis. PMID:22210828

Quality of online pediatric orthopaedic education materials.

PubMed

Feghhi, Daniel P; Komlos, Daniel; Agarwal, Nitin; Sabharwal, Sanjeev

2014-12-03

Increased availability of medical information on the Internet empowers patients to look up answers to questions about their medical conditions. However, the quality of medical information available on the Internet is highly variable. Various tools for the assessment of online medical information have been developed and used to assess the quality and accuracy of medical web sites. In this study we used the LIDA tool (Minervation) to assess the quality of pediatric patient information on the AAOS (American Academy of Orthopaedic Surgeons) and POSNA (Pediatric Orthopaedic Society of North America) web sites. The accessibility, usability, and reliability of online medical information in the "Children" section of the AAOS web site and on the POSNA web site were assessed with use of the LIDA tool. Flesch-Kincaid (FK) and Flesch Reading Ease (FRE) values were also calculated to assess the readability of the pediatric education material. Patient education materials on each web site scored in the moderate range in assessments of accessibility, usability, and reliability. FK and FRE values indicated that the readability of each web site remained at a somewhat higher (more difficult) level than the recommended benchmark. The quality and readability of online information for children on the AAOS and POSNA web sites are acceptable but can be improved further. The quality of online pediatric orthopaedic patient education materials may affect communication with patients and their caregivers, and further investigation and modification of quality are needed. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.

NAMPT-Mediated Salvage Synthesis of NAD+ Controls Morphofunctional Changes of Macrophages

PubMed Central

Venter, Gerda; Oerlemans, Frank T. J. J.; Willemse, Marieke; Wijers, Mietske; Fransen, Jack A. M.; Wieringa, Bé

2014-01-01

Functional morphodynamic behavior of differentiated macrophages is strongly controlled by actin cytoskeleton rearrangements, a process in which also metabolic cofactors ATP and NAD(H) (i.e. NAD+ and NADH) and NADP(H) (i.e. NADP+ and NADPH) play an essential role. Whereas the link to intracellular ATP availability has been studied extensively, much less is known about the relationship between actin cytoskeleton dynamics and intracellular redox state and NAD+-supply. Here, we focus on the role of nicotinamide phosphoribosyltransferase (NAMPT), found in extracellular form as a cytokine and growth factor, and in intracellular form as one of the key enzymes for the production of NAD+ in macrophages. Inhibition of NAD+ salvage synthesis by the NAMPT-specific drug FK866 caused a decrease in cytosolic NAD+ levels in RAW 264.7 and Maf-DKO macrophages and led to significant downregulation of the glycolytic flux without directly affecting cell viability, proliferation, ATP production capacity or mitochondrial respiratory activity. Concomitant with these differential metabolic changes, the capacity for phagocytic ingestion of particles and also substrate adhesion of macrophages were altered. Depletion of cytoplasmic NAD+ induced cell-morphological changes and impaired early adhesion in phagocytosis of zymosan particles as well as spreading performance. Restoration of NAD+ levels by NAD+, NMN, or NADP+ supplementation reversed the inhibitory effects of FK866. We conclude that direct coupling to local, actin-based, cytoskeletal dynamics is an important aspect of NAD+’s cytosolic role in the regulation of morphofunctional characteristics of macrophages. PMID:24824795

Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor.

PubMed

Bastidas, Robert J; Shertz, Cecelia A; Lee, Soo Chan; Heitman, Joseph; Cardenas, Maria E

2012-03-01

The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.

An Improvement To The k-Nearest Neighbor Classifier For ECG Database

NASA Astrophysics Data System (ADS)

Jaafar, Haryati; Hidayah Ramli, Nur; Nasir, Aimi Salihah Abdul

2018-03-01

The k nearest neighbor (kNN) is a non-parametric classifier and has been widely used for pattern classification. However, in practice, the performance of kNN often tends to fail due to the lack of information on how the samples are distributed among them. Moreover, kNN is no longer optimal when the training samples are limited. Another problem observed in kNN is regarding the weighting issues in assigning the class label before classification. Thus, to solve these limitations, a new classifier called Mahalanobis fuzzy k-nearest centroid neighbor (MFkNCN) is proposed in this study. Here, a Mahalanobis distance is applied to avoid the imbalance of samples distribition. Then, a surrounding rule is employed to obtain the nearest centroid neighbor based on the distributions of training samples and its distance to the query point. Consequently, the fuzzy membership function is employed to assign the query point to the class label which is frequently represented by the nearest centroid neighbor Experimental studies from electrocardiogram (ECG) signal is applied in this study. The classification performances are evaluated in two experimental steps i.e. different values of k and different sizes of feature dimensions. Subsequently, a comparative study of kNN, kNCN, FkNN and MFkCNN classifier is conducted to evaluate the performances of the proposed classifier. The results show that the performance of MFkNCN consistently exceeds the kNN, kNCN and FkNN with the best classification rates of 96.5%.

Efficient one-cycle affinity selection of binding proteins or peptides specific for a small-molecule using a T7 phage display pool.

PubMed

Takakusagi, Yoichi; Kuramochi, Kouji; Takagi, Manami; Kusayanagi, Tomoe; Manita, Daisuke; Ozawa, Hiroko; Iwakiri, Kanako; Takakusagi, Kaori; Miyano, Yuka; Nakazaki, Atsuo; Kobayashi, Susumu; Sugawara, Fumio; Sakaguchi, Kengo

2008-11-15

Here, we report an efficient one-cycle affinity selection using a natural-protein or random-peptide T7 phage pool for identification of binding proteins or peptides specific for small-molecules. The screening procedure involved a cuvette type 27-MHz quartz-crystal microbalance (QCM) apparatus with introduction of self-assembled monolayer (SAM) for a specific small-molecule immobilization on the gold electrode surface of a sensor chip. Using this apparatus, we attempted an affinity selection of proteins or peptides against synthetic ligand for FK506-binding protein (SLF) or irinotecan (Iri, CPT-11). An affinity selection using SLF-SAM and a natural-protein T7 phage pool successfully detected FK506-binding protein 12 (FKBP12)-displaying T7 phage after an interaction time of only 10 min. Extensive exploration of time-consuming wash and/or elution conditions together with several rounds of selection was not required. Furthermore, in the selection using a 15-mer random-peptide T7 phage pool and subsequent analysis utilizing receptor ligand contact (RELIC) software, a subset of SLF-selected peptides clearly pinpointed several amino-acid residues within the binding site of FKBP12. Likewise, a subset of Iri-selected peptides pinpointed part of the positive amino-acid region of residues from the Iri-binding site of the well-known direct targets, acetylcholinesterase (AChE) and carboxylesterase (CE). Our findings demonstrate the effectiveness of this method and general applicability for a wide range of small-molecules.

IR and Raman spectra of nitroanthracene isomers: substitional effects based on density functional theory study.

PubMed

Alparone, Andrea; Librando, Vito

2012-04-01

Structure, IR and Raman spectra of 1-, 2- and 9-nitroanthracene isomers (1-NA, 2-NA and 9-NA) were calculated and analyzed through density functional theory computations using the B3LYP functional with the 6-311+G** basis set. Steric and π-conjugative effects determine the characteristic ONCC dihedral angles, which vary from 0° (2-NA) to 28-29° (1-NA) and 59° (9-NA), influencing the relative order of stability along the series 9-NA<1-NA<2-NA. The spectral regions at wavenumber values>3000 cm(-1) and <1000 cm(-1) little depend on the substituent position. The Raman and IR intensity values of the characteristic symmetric nitro group stretching transition, appearing between 1310 and 1345 cm(-1), are rather sensitive to the position of the substituent, decreasing regularly on passing from the planar to the NO2-rotated isomers (9-NA<1-NA<2-NA). In the medium-energy spectral region (1000-1700 cm(-1)), the number and the relative position of the strongest Raman bands are of potential utility to discriminate the NA isomers. Structural and spectroscopic results suggest that the unknown mutagenic activity of 1-NA is expected to be between that of 9-NA and 2-NA. Copyright © 2011 Elsevier B.V. All rights reserved.

Oxaliplatin regulates chemotherapy induced peripheral neuropathic pain in the dorsal horn and dorsal root ganglion via the Calcineurin/NFAT pathway.

PubMed

Huang, Wan; Huang, Jingxiu; Jiang, Yu; Huang, Xuanwei; Xing, Wei; He, Yaoxuan; Ouyang, Handong

2018-05-24

The aim of this study was to investigate the mechanism of oxaliplatin in the induction of neuropathic pain as a symptom of chemotherapy-induced peripheral neuropathy (CIPN). The CIPN rat model was induced with a one-time injection of oxaliplatin, and the paw withdrawal response was determined using von Frey filaments. The paw withdrawal threshold (PWT) value was recorded and the dorsal horn (DH) and dorsal root ganglion (DRG) tissues were collected. The mRNA and protein levels of calcineurin (CaN), nuclear factor of activated T cells (NFAT), and other relevant cytokines were determined. CaN and NFAT inhibition reagents, FK506 and 11R-VIVIT, were applied in order to investigate the functions of the CaN/NFAT pathway in the neuropathic pain processes. The levels of the downstream inflammatory cytokines, TNF-α and IL-1β, were assessed by ELISA. The application of oxaliplatin reduced the value of PWT by 4 times on days 7（4±1.33）and 14（5.13±3.07）compared with the control group(14±0.91; 13.67±0.76). After treatment, the CaN mRNA level decreased and that of NFAT increased in DH and DRG tissues (P<0.05). However, treatment with FK506 and 11R-VIVIT decreased the value of PWT that had increased after oxaliplatin treatment. The expression of downstream cytokines related to the CaN/NFAT pathway increased, including CCR2, COX2, p-ERK, and p-P38 (all p<0.05). In addition, when the CaN/NFAT pathway was activated, the concentration of TNFα increased to 40pg/mg in DH tissues and 60pg/mg in DRG tissues compared with the control group, while the concentration of IL-1β increased to over 60pg/mg in DH and DRG tissues. It was the first time to prove that oxaliplatin-induced neuropathic pain was correlated to the activation of the CaN/NFAT pathway in our rat model. This finding can provide a new direction for explore the mechanism of oxaliplatin-induced neuropathic pain. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Response of saliva Na/K ratio to changing Na supply of lactating cows under tropical conditions.

PubMed

Thiangtum, Wandee; Schonewille, J Thomas; Verstegen, Martin Wa; Arsawakulsudhi, Supot; Rukkwamsuk, Theera; Hendriks, Wouter H

2017-06-01

Factorial determination of the sodium (Na) requirement of heat-stressed lactating cows is hindered by accurate estimates of the Na losses through sweat. Direct studies, therefore, may be needed requiring information on the time course of healthy animals to become Na depleted and the subsequent rate of repletion. The rate of Na depletion and subsequent rate of Na repletion with two levels of dietary Na to lactating dairy cows housed under tropical conditions were investigated using the salivary Na/K. The 12 lactating cows (salivary Na/K ratio 14.6) rapidly developed clinical signs of Na deficiency, including pica, polyuria and polydipsia, reduced body weight and reduced milk yield when fed a low-Na ration (0.33 g kg -1 dry matter (DM)) for 3 weeks. Deficiency symptoms were associated with a rapid decrease in salivary Na/K ratio to <4.3 from 7 to 21 days. Subsequent repletion of the cows with NaCl to a ration concentration of 1.1 or 1.6 g Na kg -1 DM for 5 weeks did not restore salivary Na/K ratio to values of >6. A daily Na intake of heat-stressed lactating cows to a ration intake of 1.6 g Na kg -1 DM was insufficient to restore Na deficiency. One week was sufficient to deplete heat-stressed lactating cows of Na, allowing for rapid dose-response studies utilizing the salivary Na/K ratio as a parameter for Na status of cows under tropical conditions. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Flip-flops of FK Comae Berenices

NASA Astrophysics Data System (ADS)

Hackman, T.; Pelt, J.; Mantere, M. J.; Jetsu, L.; Korhonen, H.; Granzer, T.; Kajatkari, P.; Lehtinen, J.; Strassmeier, K. G.

2013-05-01

Context.FK Comae Berenices is a rapidly rotating magnetically active star, the light curve of which is modulated by cool spots on its surface. It was the first star where the "flip-flop" phenomenon was discovered. Since then, flip-flops in the spot activity have been reported in many other stars. Follow-up studies with increasing length have shown, however, that the phenomenon is more complex than was thought right after its discovery. Aims: Therefore, it is of interest to perform a more thorough study of the evolution of the spot activity in FK Com. In this study, we analyse 15 years of photometric observations with two different time series analysis methods, with a special emphasis on detecting flip-flop type events from the data. Methods: We apply the continuous period search and carrier fit methods on long-term standard Johnson-Cousins V-observations from the years 1995-2010. The observations were carried out with two automated photometric telescopes, Phoenix-10 and Amadeus T7 located in Arizona. Results: We identify complex phase behaviour in 6 of the 15 analysed data segments. We identify five flip-flop events and two cases of phase jumps, where the phase shift is Δφ < 0.4. In addition we see two mergers of spot regions and two cases where the apparent phase shifts are caused by spot regions drifting with respect to each other. Furthermore we detect variations in the rotation period corresponding to a differential rotation coefficient of |k| > 0.031. Conclusions: The flip-flop cannot be interpreted as a single phenomenon, where the main activity jumps from one active longitude to another. In some of our cases the phase shifts can be explained by differential rotation: two spot regions move with different angular velocity and even pass each other. Comparison between the methods show that the carrier fit utility is better in retrieving slow evolution especially from a low amplitude light curve, while the continuous period search is more sensitive in case of rapid changes. Based on data obtained with the Amadeus T7 Automatic Photoelectric Telescope (APT) at Fairborn Observatory, jointly operated by the University of Vienna and AIP, the Phoenix-10 APT at Mt. Hopkins, Arizona, and the Nordic Optical Telescope, Observatorio Roque de los Muchachos, La Palma, Canary Islands.The photometric observations are only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/553/A40

Evolutionary diversification of Mesobuthus α-scorpion toxins affecting sodium channels.

PubMed

Zhu, Shunyi; Peigneur, Steve; Gao, Bin; Lu, Xiuxiu; Cao, Chunyang; Tytgat, Jan

2012-01-01

α-Scorpion toxins constitute a family of peptide modulators that induce a prolongation of the action potential of excitable cells by inhibiting voltage-gated sodium channel inactivation. Although they all adopt a conserved structural scaffold, the potency and phylogentic preference of these toxins largely vary, which render them an intriguing model for studying evolutionary diversification among family members. Here, we report molecular characterization of a new multigene family of α-toxins comprising 13 members (named MeuNaTxα-1 to MeuNaTxα-13) from the scorpion Mesobuthus eupeus. Of them, five native toxins (MeuNaTxα-1 to -5) were purified to homogeneity from the venom and the solution structure of MeuNaTxα-5 was solved by nuclear magnetic resonance. A systematic functional evaluation of MeuNaTxα-1, -2, -4, and -5 was conducted by two-electrode voltage-clamp recordings on seven cloned mammalian voltage-gated sodium channels (Na(v)1.2 to Na(v)1.8) and the insect counterpart DmNa(v)1 expressed in Xenopus oocytes. Results show that all these four peptides slow inactivation of DmNa(v)1 and are inactive on Na(v)1.8 at micromolar concentrations. However, they exhibit differential specificity for the other six channel isoforms (Na(v)1.2 to Na(v)1.7), in which MeuNaTxα-4 shows no activity on these isoforms and thus represents the first Mesobuthus-derived insect-selective α-toxin identified so far with a half maximal effective concentration of 130 ± 2 nm on DmNa(v)1 and a half maximal lethal dose of about 200 pmol g(-1) on the insect Musca domestica; MeuNaTxα-2 only affects Na(v)1.4; MeuNaTxα-1 and MeuNaTxα-5 have a wider range of channel spectrum, the former active on Na(v)1.2, Na(v)1.3, Na(v)1.6, and Na(v)1.7, whereas the latter acting on Na(v)1.3-Na(v)1.7. Remarkably, MeuNaTxα-4 and MeuNaTxα-5 are two nearly identical peptides differing by only one point mutation at site 50 (A50V) but exhibit rather different channel subtype selectivity, highlighting a switch role of this site in altering the target specificity. By the maximum likelihood models of codon substitution, we detected nine positively selected sites (PSSs) that could be involved in functional diversification of Mesobuthus α-toxins. The PSSs include site 50 and other seven sites located in functional surfaces of α-toxins. This work represents the first thorough investigation of evolutionary diversification of α-toxins derived from a specific scorpion lineage from the perspectives of sequence, structure, function, and evolution.

Acidosis Differentially Modulates Inactivation in NaV1.2, NaV1.4, and NaV1.5 Channels

PubMed Central

Vilin, Yury Y.; Peters, Colin H.; Ruben, Peter C.

2012-01-01

NaV channels play a crucial role in neuronal and muscle excitability. Using whole-cell recordings we studied effects of low extracellular pH on the biophysical properties of NaV1.2, NaV1.4, and NaV1.5, expressed in cultured mammalian cells. Low pH produced different effects on different channel subtypes. Whereas NaV1.4 exhibited very low sensitivity to acidosis, primarily limited to partial block of macroscopic currents, the effects of low pH on gating in NaV1.2 and NaV1.5 were profound. In NaV1.2 low pH reduced apparent valence of steady-state fast inactivation, shifted the τ(V) to depolarizing potentials and decreased channels availability during onset to slow and use-dependent inactivation (UDI). In contrast, low pH delayed open-state inactivation in NaV1.5, right-shifted the voltage-dependence of window current, and increased channel availability during onset to slow and UDI. These results suggest that protons affect channel availability in an isoform-specific manner. A computer model incorporating these results demonstrates their effects on membrane excitability. PMID:22701426

Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart.

PubMed

Facer, Paul; Punjabi, Prakash P; Abrari, Andleeb; Kaba, Riyaz A; Severs, Nicholas J; Chambers, John; Kooner, Jaspal S; Anand, Praveen

2011-01-01

We have shown that the gene SCN10A encoding the sodium channel Na(v)1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na(v)1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na(v)1.8 and other key nociceptive ion channels, including Na(v)1.7, Na(v)1.9, capsaicin receptor TRPV1, and purinergic receptor P2X(3), have not been reported in human heart. The aim of this study was to determine the distribution of Na(v)1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na(v)1.8 and other markers. Na(v)1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na(v)1.8 nerve fibres per mm(2) correlated significantly with vascular markers. Na(v)1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na(v)1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na(v)1.7, Na(v)1.9, TRPV1, P2X(3)/P2X(2), and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na(v)1.8 is present in sensory nerves and cardiomyocytes of human heart. Na(v)1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia.

Functional identification and characterization of sodium binding sites in Na symporters

PubMed Central

Loo, Donald D. F.; Jiang, Xuan; Gorraitz, Edurne; Hirayama, Bruce A.; Wright, Ernest M.

2013-01-01

Sodium cotransporters from several different gene families belong to the leucine transporter (LeuT) structural family. Although the identification of Na+ in binding sites is beyond the resolution of the structures, two Na+ binding sites (Na1 and Na2) have been proposed in LeuT. Na2 is conserved in the LeuT family but Na1 is not. A biophysical method has been used to measure sodium dissociation constants (Kd) of wild-type and mutant human sodium glucose cotransport (hSGLT1) proteins to identify the Na+ binding sites in hSGLT1. The Na1 site is formed by residues in the sugar binding pocket, and their mutation influences sodium binding to Na1 but not to Na2. For the canonical Na2 site formed by two –OH side chains, S392 and S393, and three backbone carbonyls, mutation of S392 to cysteine increased the sodium Kd by sixfold. This was accompanied by a dramatic reduction in the apparent sugar and phlorizin affinities. We suggest that mutation of S392 in the Na2 site produces a structural rearrangement of the sugar binding pocket to disrupt both the binding of the second Na+ and the binding of sugar. In contrast, the S393 mutations produce no significant changes in sodium, sugar, and phlorizin affinities. We conclude that the Na2 site is conserved in hSGLT1, the side chain of S392 and the backbone carbonyl of S393 are important in the first Na+ binding, and that Na+ binding to Na2 promotes binding to Na1 and also sugar binding. PMID:24191006

Surface Wave Effects on High-Frequency Currents Over a Shelf Edge Bank

DTIC Science & Technology

2013-08-01

as part of projects sponsored by the Naval Research Laboratory (NRL) [Mixing Over Rough Topography (MORT)] and by the Bureau of Ocean Energy Management ...random wave fieldUS(z) is calculated as an ensemble average of wave components (Kenyon 1969), where US(z)5 4p ðf c f min ð2p 0 fkE(f , u)G(f , z) du df...Energy Management (BOEM; formerly Min- erals Management Service) in the project referred to as ‘‘Currents Over Banks (COB)’’ through the Interagency

Isolation and Growth of Prostate Stem Cells and Establishing Cancer Cell Lines from Human Prostate Tumors

DTIC Science & Technology

2008-05-01

cells. J Mol Med, 2008. 20. Collins, A. T., Habib , F. K., Maitland, N. J., and Neal, D. E. Identification and isolation of human prostate...The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med 2008;86:1025–32. 20. Collins AT, Habib FK...cells. J Cell Sci 2004;117: 3539–45. 23. Litvinov IV, Vander Griend DJ, Xu Y, Antony L, Dalrymple SL , Isaacs JT. Low-calcium serum-free defined

Terahertz Oscillations of Hot Electrons in Graphene

DTIC Science & Technology

2015-01-01

half the frequency ?F = 2?eF/~?OP , where 2?/?F is the time taken for carriers to accelerate ballistically to the optic phonon...resonance. Such resonance occurs at about half the frequency ωF = 2πeF/~ωOP , where 2π/ωF is the time taken for carriers to accelerate ballistically to the ... The current density on the plane is given by, Jx(t) = −4evF ∑ ~k f(~k, t) cos(φ), (2.16) where φ is the angle between ~k and the kx axis. Figure

Orientation of the JPL Ephemerides, DE 200/LE 200, to the dynamical equinox of J 2000

NASA Technical Reports Server (NTRS)

Standish, E. M., Jr.

1982-01-01

The lunar and planetary ephemerides, DE 200/LE 200 have been recently produced at JPL. They will form the basis of the ephemerides in the 'Astronomical Almanac' starting in the year 1984. The origin has been referenced to the J 2000 dynamical equinox of the ephemerides themselves. The procedure for this orientation is described here in detail. Analyses of the ephemerides also provide comparisons with the equinox of the FK 4 and with presently adopted values for the earth's obliquity.

Combining Symbolic Computation and Theorem Proving: Some Problems of Ramanujan

DTIC Science & Technology

1994-01-01

1994 CMU-CS--94- 103 ¶ DTIC MAY 0e o99 c -rnepe Combining symbolic computation and theorem proving: some problems of Ramanujan Edmund Clarke Xudong Zhao...Research and Development Center, Aeronautical Systems Division (AFSC), U.S. Air Force, Wright-Patterson AFB, Ohio 45433-6543 under Contract F33615-90- C ...Availability Codes n n = f Avail and Ior7. k= f(k) = _L k~of(nk Dist Special 8. =I f (k + c ) =_k=,+ I f (k) A .[ 3. List of problems The list of challenge

Proceedings of the Colloquium of the International Astronomical Union (127th). Reference Systems Held in Virginia Beach, Virginia on October 14-20, 1990

DTIC Science & Technology

1991-09-06

R.L. Duncombe, O.G. Franz, capabilities of the Hubble Space L.W. Fredrick, T. Gerard, Telescope fine guidance sensors P.D. Hemenway, B. McArthur, J...frame: Counterproposal to the Circular Letter no. 4 of Kovalevsky - I - .) 10. H. Eichhorn The organization of space : frames, systems and 97 standards...Heifets of REGATTA-ASTRO space astrometry program 48. W. Jin, T. Xu, Influence of systematic differences of FK4 on 280 P. Lu, and D. Liao determining

The dome-shaped Fresnel-Köhler concentrator

NASA Astrophysics Data System (ADS)

Zamora, P.; Benitez, P.; Li, Y.; Miñano, J. C.; Mendes-Lopes, J.; Araki, K.

2012-10-01

Manufacturing tolerances, along with a high concentration ratio, are key issues in order to obtain cheap CPV systems for mass production. Consequently, this manuscript presents a novel tolerant and cost effective concentrator optic: the domed-shaped Fresnel-Köhler, presenting a curved Fresnel lens as Primary Optical Element (POE). This concentrator is based on two previous successful CPV designs: the FK concentrator, based on a flat Fresnel lens, and the dome-shaped Fresnel lens system developed by Daido Steel, resulting on a superior concentrator. The manuscript shows outstanding simulation results for geometrical concentration factor of Cg = 1,230x: high tolerance and high optical efficiency, achieving acceptance angles of 1.18° (dealing to a CAP*=0.72) and efficiencies over 85% (without any anti-reflective coating). Moreover, Köhler integration provides good irradiance uniformity on the cell surface without increasing system complexity by means of any extra element. Daido Steel advanced technique for demolding injected plastic pieces will allow for easy manufacture of the dome-shaped POE of DFK concentrator.

Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation.

PubMed

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

2012-08-01

Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Towards practical cadmium phytoextraction with Noccaea caerulescens.

PubMed

Simmons, R W; Chaney, R L; Angle, J S; Kruatrachue, M; Klinphoklap, S; Reeves, R D; Bellamy, P

2015-01-01

A series of field trials were conducted to investigate the potential of Noccaea caerulescens F.K. Mey [syn. Thlaspi caerulescens J &C Presl. (see Koch and Al-Shehbaz 2004)] populations (genotypes) derived from southern France to phytoextract localized Cd/Zn contamination in Thailand. Soil treatments included pH variation and fertilization level and application of fungicide. N. caerulescens populations were transplanted to the field plots three months after germination and harvested in May, prior to the onset of seasonal rains. During this period growth was rapid with shoot biomass ranging from 0.93-2.2 g plant(-1) (280-650 kg ha(-1)) DW. Shoot Cd and Zn concentrations for the four populations evaluated ranged from 460-600 and 2600-2900 mg kg(-1) DW respectively. Cadmium and Zn Translocation Factors (shoot/root) for the populations tested ranged from 0.91-1.0 and 1.7-2.1 and Bioaccumulation Factors ranged from 12-15 and 1.2-1.3. We conclude that optimizing the use of fungicidal sprays, acidic soil pH, planting density and increasing the effective cropping period will increase rates of Cd and Zn removal enough to facilitate practical Cd phytoextraction from rice paddy soils in Thailand.

Role of Na+ conductance, Na+-H+ exchange, and Na+-K+-2Cl− symport in the regulatory volume increase of rat hepatocytes

PubMed Central

Wehner, Frank; Tinel, Hanna

1998-01-01

In rat hepatocytes under hypertonic stress, the entry of Na+ (which is thereafter exchanged for K+ via Na+-K+-ATPase) plays the key role in regulatory volume increase (RVI).In the present study, the contributions of Na+ conductance, Na+-H+ exchange and Na+-K+-2Cl− symport to this process were quantified in confluent primary cultures by means of intracellular microelectrodes and cable analysis, microfluorometric determinations of cell pH and buffer capacity, and measurements of frusemide (furosemide)/bumetanide-sensitive 86Rb+ uptake, respectively. Osmolarity was increased from 300 to 400 mosmol l−1 by addition of sucrose.The experiments indicate a relative contribution of approximately 4:1:1 to hypertonicity-induced Na+ entry for the above-mentioned transporters and the overall Na+ yield equalled 51 mmol l−1 (10 min)−1.This Na+ gain is in good agreement with the stimulation of Na+ extrusion via Na+-K+-ATPase plus the actual increase in cell Na+, namely 55 mmol l−1 (10 min)−1, as was determined on the basis of ouabain-sensitive 86Rb+ uptake and by means of Na+-sensitive microelectrodes, respectively.The overall increase in Na+ and K+ activity plus the expected concomitant increase in cell Cl− equalled 68 mmol l−1, which fits well with the increase in osmotic activity expected to occur from an initial cell shrinkage to 87.5 % and a RVI to 92.6 % of control, namely 53 mosmol l−1.The prominent role of Na+ conductance in the RVI of rat hepatocytes could be confirmed on the basis of the pharmacological profile of this process, which was characterized by means of confocal laser-scanning microscopy. PMID:9481677

Thermal decomposition of sodium amide, NaNH2, and sodium amide hydroxide composites, NaNH2-NaOH.

PubMed

Jepsen, Lars H; Wang, Peikun; Wu, Guotao; Xiong, Zhitao; Besenbacher, Flemming; Chen, Ping; Jensen, Torben R

2016-09-14

Sodium amide, NaNH 2 , has recently been shown to be a useful catalyst to decompose NH 3 into H 2 and N 2 , however, sodium hydroxide is omnipresent and commercially available NaNH 2 usually contains impurities of NaOH (<2%). The thermal decomposition of NaNH 2 and NaNH 2 -NaOH composites is systematically investigated and discussed. NaNH 2 is partially dissolved in NaOH at T > 100 °C, forming a non-stoichiometric solid solution of Na(OH) 1-x (NH 2 ) x (0 < x < ∼0.30), which crystallizes in an orthorhombic unit cell with the space group P2 1 2 1 2 1 determined by synchrotron powder X-ray diffraction. The composite xNaNH 2 -(1 - x)NaOH (∼0.70 < x < 0.72) shows a lowered melting point, ∼160 °C, compared to 200 and 318 °C for neat NaNH 2 and NaOH, respectively. We report that 0.36 mol of NH 3 per mol of NaNH 2 is released below 400 °C during heating in an argon atmosphere, initiated at its melting point, T = 200 °C, possibly due to the formation of the mixed sodium amide imide solid solution. Furthermore, NaOH reacts with NaNH 2 at elevated temperatures and provides the release of additional NH 3 .

Insight into Ca-Substitution Effects on O3-Type NaNi1/3 Fe1/3 Mn1/3 O2 Cathode Materials for Sodium-Ion Batteries Application.

PubMed

Sun, Liqi; Xie, Yingying; Liao, Xiao-Zhen; Wang, Hong; Tan, Guoqiang; Chen, Zonghai; Ren, Yang; Gim, Jihyeon; Tang, Wan; He, Yu-Shi; Amine, Khalil; Ma, Zi-Feng

2018-04-18

O3-type NaNi 1/3 Fe 1/3 Mn 1/3 O 2 (NaNFM) is well investigated as a promising cathode material for sodium-ion batteries (SIBs), but the cycling stability of NaNFM still needs to be improved by using novel electrolytes or optimizing their structure with the substitution of different elements sites. To enlarge the alkali-layer distance inside the layer structure of NaNFM may benefit Na + diffusion. Herein, the effect of Ca-substitution is reported in Na sites on the structural and electrochemical properties of Na 1- x Ca x /2 NFM (x = 0, 0.05, 0.1). X-ray diffraction (XRD) patterns of the prepared Na 1- x Ca x /2 NFM samples show single α-NaFeO 2 type phase with slightly increased alkali-layer distance as Ca content increases. The cycling stabilities of Ca-substituted samples are remarkably improved. The Na 0.9 Ca 0.05 Ni 1/3 Fe 1/3 Mn 1/3 O 2 (Na 0.9 Ca 0.05 NFM) cathode delivers a capacity of 116.3 mAh g -1 with capacity retention of 92% after 200 cycles at 1C rate. In operando XRD indicates a reversible structural evolution through an O3-P3-P3-O3 sequence of Na 0.9 Ca 0.05 NFM cathode during cycling. Compared to NaNMF, the Na 0.9 Ca 0.05 NFM cathode shows a wider voltage range in pure P3 phase state during the charge/discharge process and exhibits better structure recoverability after cycling. The superior cycling stability of Na 0.9 Ca 0.05 NFM makes it a promising material for practical applications in sodium-ion batteries. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of alkali carbonate and salt in topochemical synthesis of K1/2Na1/2NbO3 and NaNbO3 templates

NASA Astrophysics Data System (ADS)

Lee, Jae-Seok; Jeon, Jae-Ho; Choi, Si-Young

2013-11-01

Since the properties of lead-free piezoelectric materials have thus far failed to meet those of lead-based materials, either chemical doping or morphological texturing should be employed to improve the piezoelectric properties of lead-free piezoelectric ceramics. The goal of this study was to synthesize plate-like K1/2Na1/2NbO3 and NaNbO3 particles, which are the most favorable templates for morphological texturing of K1/2Na1/2NbO3 ceramics. To achieve this goal, Bi2.5Na3.5Nb5O18 precursors in a plate-like shape were first synthesized and subsequently converted into K1/2Na1/2NbO3 or NaNbO3 particles that retain the morphology of Bi2.5Na3.5Nb5O18. In this study, we found that sodium or potassium carbonate does not play a major role in converting the Bi2.5Na3.5Nb5O18 precursor to K1/2Na1/2NbO3 or NaNbO3, on the contrary to previous reports; however, the salt contributes to the conversion reaction. All synthesis processes have been performed via a molten salt method, and scanning electron microscopy, scanning probe microscopy, and inductively coupled plasma mass spectroscopy were used to characterize the synthesized K1/2Na1/2NbO3 or NaNbO3 templates.

Shoot Na+ exclusion and increased salinity tolerance engineered by cell type-specific alteration of Na+ transport in Arabidopsis.

PubMed

Møller, Inge S; Gilliham, Matthew; Jha, Deepa; Mayo, Gwenda M; Roy, Stuart J; Coates, Juliet C; Haseloff, Jim; Tester, Mark

2009-07-01

Soil salinity affects large areas of cultivated land, causing significant reductions in crop yield globally. The Na+ toxicity of many crop plants is correlated with overaccumulation of Na+ in the shoot. We have previously suggested that the engineering of Na+ exclusion from the shoot could be achieved through an alteration of plasma membrane Na+ transport processes in the root, if these alterations were cell type specific. Here, it is shown that expression of the Na+ transporter HKT1;1 in the mature root stele of Arabidopsis thaliana decreases Na+ accumulation in the shoot by 37 to 64%. The expression of HKT1;1 specifically in the mature root stele is achieved using an enhancer trap expression system for specific and strong overexpression. The effect in the shoot is caused by the increased influx, mediated by HKT1;1, of Na+ into stelar root cells, which is demonstrated in planta and leads to a reduction of root-to-shoot transfer of Na+. Plants with reduced shoot Na+ also have increased salinity tolerance. By contrast, plants constitutively expressing HKT1;1 driven by the cauliflower mosaic virus 35S promoter accumulated high shoot Na+ and grew poorly. Our results demonstrate that the modification of a specific Na+ transport process in specific cell types can reduce shoot Na+ accumulation, an important component of salinity tolerance of many higher plants.

Reduced expression of Na(v)1.6 sodium channels and compensation by Na(v)1.2 channels in mice heterozygous for a null mutation in Scn8a.

PubMed

Vega, Ana V; Henry, Diane L; Matthews, Gary

2008-09-05

The voltage-gated sodium channel alpha subunit Na(v)1.6, encoded by the Scn8a gene, accumulates at high density at mature nodes of Ranvier of myelinated axons, replacing the Na(v)1.2 channels found at nodes earlier in development. To investigate this preferential expression of Na(v)1.6 at adult nodes, we examined isoform-specific expression of sodium channels in mice heterozygous for a null mutation in Scn8a. Immunoblots from these +/- mice had 50% of the wild-type level of Na(v)1.6 protein, and their optic-nerve nodes of Ranvier had correspondingly less anti-Na(v)1.6 immunofluorescence. Protein level and nodal immunofluorescence of the Na(v)1.2 alpha subunit increased in Scn8a(+/-) mice, keeping total sodium channel expression approximately constant despite partial loss of Na(v)1.6 channels. The results are consistent with a model in which Na(v)1.6 and Na(v)1.2 compete for binding partners at sites of high channel density, such as nodes of Ranvier. We suggest that Na(v)1.6 channels normally occupy most of the molecular machinery responsible for channel clustering because they have higher binding affinity, and not because they are exclusively recognized by mechanisms for transport and insertion of sodium channels in myelinated axons. The reduced amount of Na(v)1.6 protein in Scn8a(+/-) mice is apparently insufficient to saturate the nodal binding sites, allowing Na(v)1.2 channels to compete more successfully.

NHash: Randomized N-Gram Hashing for Distributed Generation of Validatable Unique Study Identifiers in Multicenter Research.

PubMed

Zhang, Guo-Qiang; Tao, Shiqiang; Xing, Guangming; Mozes, Jeno; Zonjy, Bilal; Lhatoo, Samden D; Cui, Licong

2015-11-10

A unique study identifier serves as a key for linking research data about a study subject without revealing protected health information in the identifier. While sufficient for single-site and limited-scale studies, the use of common unique study identifiers has several drawbacks for large multicenter studies, where thousands of research participants may be recruited from multiple sites. An important property of study identifiers is error tolerance (or validatable), in that inadvertent editing mistakes during their transmission and use will most likely result in invalid study identifiers. This paper introduces a novel method called "Randomized N-gram Hashing (NHash)," for generating unique study identifiers in a distributed and validatable fashion, in multicenter research. NHash has a unique set of properties: (1) it is a pseudonym serving the purpose of linking research data about a study participant for research purposes; (2) it can be generated automatically in a completely distributed fashion with virtually no risk for identifier collision; (3) it incorporates a set of cryptographic hash functions based on N-grams, with a combination of additional encryption techniques such as a shift cipher; (d) it is validatable (error tolerant) in the sense that inadvertent edit errors will mostly result in invalid identifiers. NHash consists of 2 phases. First, an intermediate string using randomized N-gram hashing is generated. This string consists of a collection of N-gram hashes f1, f2, ..., fk. The input for each function fi has 3 components: a random number r, an integer n, and input data m. The result, fi(r, n, m), is an n-gram of m with a starting position s, which is computed as (r mod |m|), where |m| represents the length of m. The output for Step 1 is the concatenation of the sequence f1(r1, n1, m1), f2(r2, n2, m2), ..., fk(rk, nk, mk). In the second phase, the intermediate string generated in Phase 1 is encrypted using techniques such as shift cipher. The result of the encryption, concatenated with the random number r, is the final NHash study identifier. We performed experiments using a large synthesized dataset comparing NHash with random strings, and demonstrated neglegible probability for collision. We implemented NHash for the Center for SUDEP Research (CSR), a National Institute for Neurological Disorders and Stroke-funded Center Without Walls for Collaborative Research in the Epilepsies. This multicenter collaboration involves 14 institutions across the United States and Europe, bringing together extensive and diverse expertise to understand sudden unexpected death in epilepsy patients (SUDEP). The CSR Data Repository has successfully used NHash to link deidentified multimodal clinical data collected in participating CSR institutions, meeting all desired objectives of NHash.

Indigenous Advanced Fighter Aircraft in Israel: Considerations for Decision-Making.

DTIC Science & Technology

1981-12-01

13 ISO 11,i 30 2 0.2 3.3 1975 924 1029 555 6219 3036 25 255 16.6 33 9 0.4 4.1 1976 969 1022 6311 6676 3164 34 405 IS3 32.3 0.5 6.1 1971 1047... Iso 49 NA 47.1 14 4 NA 30.6 NA 4138 1179 1975 3.5 190 54 NA 54.3 15.4 NA 23.4 NA 4127 1308 1976 3 5 190 57 NA 54.3 16.3 NA 30.0 NA 4087 1337 1977 3.6...357 17400 28266 15200 24692 0. I 1 4 1970 10 15 200 308 19100 29503 18100 27958 0.0 1.1 197 t0 14 ISO 220 21300 31305 20800 30570 0 0 0.7 1972 20

Structure and properties of α-NaFeO{sub 2}-type ternary sodium iridates

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

Baroudi, Kristen, E-mail: kbaroudi@princeton.edu; Yim, Cindi; Wu, Hui

2014-02-15

The synthesis, structure, and elementary magnetic and electronic properties are reported for layered compounds of the type Na{sub 3−x}MIr{sub 2}O{sub 6} and Na{sub 3−x}M{sub 2}IrO{sub 6}, where M is a transition metal from the 3d series (M=Zn, Cu, Ni, Co, Fe and Mn). The rhombohedral structures, in space group R−3m, were determined by refinement of neutron and synchrotron powder diffraction data. No clear evidence for long range 2:1 or 1:2 honeycomb-like M/Ir ordering was found in the neutron powder diffraction patterns except in the case of M=Zn, and thus in general the compounds are best designated as sodium deficient α-NaFeO{submore » 2}-type phases with formulas Na{sub 1−x}M{sub 1/3}Ir{sub 2/3}O{sub 2} or Na{sub 1−x}M{sub 2/3}Ir{sub 1/3}O{sub 2}. Synchrotron powder diffraction patterns indicate that several of the compounds likely have honeycomb in-plane metal–iridium ordering with disordered stacking of the layers. All the compounds are sodium deficient under our synthetic conditions and are black and insulating. Weiss constants derived from magnetic susceptibility measurements indicate that Na{sub 0.62}Mn{sub 0.61}Ir{sub 0.39}O{sub 2}, Na{sub 0.80}Fe{sub 2/3}Ir{sub 1/3}O{sub 2}, Na{sub 0.92}Ni{sub 1/3}Ir{sub 2/3}O{sub 2}, Na{sub 0.86}Cu{sub 1/3}Ir{sub 2/3}O{sub 2}, and Na{sub 0.89}Zn{sub 1/3}Ir{sub 2/3}O{sub 2} display dominant antiferromagnetic interactions. For Na{sub 0.90}Co{sub 1/3}Ir{sub 2/3}O{sub 2} the dominant magnetic interactions at low temperature are ferromagnetic while at high temperatures they are antiferromagnetic; there is also a change in the effective moment. Low temperature specific heat measurements (to 2 K) on Na{sub 0.92}Ni{sub 1/3}Ir{sub 2/3}O{sub 2} indicate the presence of a broad magnetic ordering transition. X-ray absorption spectroscopy shows that iridium is at or close to the 4+ oxidation state in all compounds. {sup 23}Na nuclear magnetic resonance measurements comparing Na{sub 2}IrO{sub 3} to Na{sub 0.92}Ni{sub 1/3}Ir{sub 2/3}O{sub 2} and Na{sub 0.89}Zn{sub 1/3}Ir{sub 2/3}O{sub 2} provide strong indications that the electron spins are short-range ordered in the latter two materials. Na{sub 0.62}Mn{sub 0.61}Ir{sub 0.39}O{sub 2}, Na{sub 0.80}Fe{sub 2/3}Ir{sub 1/3}O{sub 2}, Na{sub 0.90}Co{sub 1/3}Ir{sub 2/3}O{sub 2}, Na{sub 0.92}Ni{sub 1/3}Ir{sub 2/3}O{sub 2}, Na{sub 0.86}Cu{sub 1/3}Ir{sub 2/3}O{sub 2} and Na{sub 0.89}Zn{sub 1/3}Ir{sub 2/3}O{sub 2} are spin glasses. (CSD-numbers: Na{sub 0.62}Mn{sub 0.61}Ir{sub 0.39}O{sub 2}: 426657, Na{sub 0.80}Fe{sub 2/3}Ir{sub 1/3}O{sub 2}: 426659, Na{sub 0.90}Co{sub 1/3}Ir{sub 2/3}O{sub 2}: 426658, Na{sub 0.92}Ni{sub 1/3}Ir{sub 2/3}O{sub 2}: 426656, Na{sub 0.86}Cu{sub 1/3}Ir{sub 2/3}O{sub 2}: 426655, and Na{sub 2.8}ZnIr{sub 2}O{sub 6}: 426660.) - Graphical abstract: Diffraction patterns of Na{sub 0.92}Ni{sub 1/3}Ir{sub 2/3}O{sub 2}, Na{sub 0.86}Cu{sub 1/3}Ir{sub 2/3}O{sub 2} and Na{sub 0.89}Zn{sub 1/3}Ir{sub 2/3}O{sub 2}: neutron diffraction patterns in the main panel and synchrotron diffraction in the insets. The patterns show a small amount of ordering in the transition metal iridium layer. Display Omitted - Highlights: • We report six ternary sodium iridates with the α-NaFeO{sub 2} structure. • Compounds Na{sub 1−x}M{sub 1/3}Ir{sub 2/3}O{sub 2}, M=Co, Ni, Cu, Zn and Na{sub 1−x}M{sub 2/3}Ir{sub 1/3}O{sub 2}, M=Mn, Fe. • Rietveld refinement of powder neutron diffraction data. • All compounds are spin glasses. • NMR comparison to Na{sub 2}IrO{sub 3}.« less

Biphasic voltage-dependent inactivation of human NaV 1.3, 1.6 and 1.7 Na+ channels expressed in rodent insulin-secreting cells.

PubMed

Godazgar, Mahdieh; Zhang, Quan; Chibalina, Margarita V; Rorsman, Patrik

2018-05-01

Na + current inactivation is biphasic in insulin-secreting cells, proceeding with two voltage dependences that are half-maximal at ∼-100 mV and -60 mV. Inactivation of voltage-gated Na + (Na V ) channels occurs at ∼30 mV more negative voltages in insulin-secreting Ins1 and primary β-cells than in HEK, CHO or glucagon-secreting αTC1-6 cells. The difference in inactivation between Ins1 and non-β-cells persists in the inside-out patch configuration, discounting an involvement of a diffusible factor. In Ins1 cells and primary β-cells, but not in HEK cells, inactivation of a single Na V subtype is biphasic and follows two voltage dependences separated by 30-40 mV. We propose that Na V channels adopt different inactivation behaviours depending on the local membrane environment. Pancreatic β-cells are equipped with voltage-gated Na + channels that undergo biphasic voltage-dependent steady-state inactivation. A small Na + current component (10-15%) inactivates over physiological membrane potentials and contributes to action potential firing. However, the major Na + channel component is completely inactivated at -90 to -80 mV and is therefore inactive in the β-cell. It has been proposed that the biphasic inactivation reflects the contribution of different Na V α-subunits. We tested this possibility by expression of TTX-resistant variants of the Na V subunits found in β-cells (Na V 1.3, Na V 1.6 and Na V 1.7) in insulin-secreting Ins1 cells and in non-β-cells (including HEK and CHO cells). We found that all Na V subunits inactivated at 20-30 mV more negative membrane potentials in Ins1 cells than in HEK or CHO cells. The more negative inactivation in Ins1 cells does not involve a diffusible intracellular factor because the difference between Ins1 and CHO persisted after excision of the membrane. Na V 1.7 inactivated at 15--20 mV more negative membrane potentials than Na V 1.3 and Na V 1.6 in Ins1 cells but this small difference is insufficient to solely explain the biphasic inactivation in Ins1 cells. In Ins1 cells, but never in the other cell types, widely different components of Na V inactivation (separated by 30 mV) were also observed following expression of a single type of Na V α-subunit. The more positive component exhibited a voltage dependence of inactivation similar to that found in HEK and CHO cells. We propose that biphasic Na V inactivation in insulin-secreting cells reflects insertion of channels in membrane domains that differ with regard to lipid and/or membrane protein composition. © 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Precision measurements of the timelike electromagnetic form factors of pion, kaon, and proton.

PubMed

Pedlar, T K; Cronin-Hennessy, D; Gao, K Y; Gong, D T; Hietala, J; Kubota, Y; Klein, T; Lang, B W; Li, S Z; Poling, R; Scott, A W; Smith, A; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Zweber, P; Ernst, J; Arms, K; Severini, H; Dytman, S A; Love, W; Mehrabyan, S; Mueller, J A; Savinov, V; Li, Z; Lopez, A; Mendez, H; Ramirez, J; Huang, G S; Miller, D H; Pavlunin, V; Sanghi, B; Shipsey, I P J; Adams, G S; Anderson, M; Cummings, J P; Danko, I; Napolitano, J; He, Q; Muramatsu, H; Park, C S; Thorndike, E H; Coan, T E; Gao, Y S; Liu, F; Artuso, M; Boulahouache, C; Blusk, S; Butt, J; Dorjkhaidav, O; Li, J; Menaa, N; Mountain, R; Randrianarivony, K; Redjimi, R; Sia, R; Skwarnicki, T; Stone, S; Wang, J C; Zhang, K; Csorna, S E; Bonvicini, G; Cinabro, D; Dubrovin, M; Lincoln, A; Bornheim, A; Pappas, S P; Weinstein, A J; Briere, R A; Chen, G P; Chen, J; Ferguson, T; Tatishvili, G; Vogel, H; Watkins, M E; Rosner, J L; Adam, N E; Alexander, J P; Berkelman, K; Cassel, D G; Duboscq, J E; Ecklund, K M; Ehrlich, R; Fields, L; Galik, R S; Gibbons, L; Gray, R; Gray, S W; Hartill, D L; Heltsley, B K; Hertz, D; Jones, C D; Kandaswamy, J; Kreinick, D L; Kuznetsov, V E; Mahlke-Krüger, H; Meyer, T O; Onyisi, P U E; Patterson, J R; Peterson, D; Phillips, E A; Pivarski, J; Riley, D; Ryd, A; Sadoff, A J; Schwarthoff, H; Shi, X; Shepherd, M R; Stroiney, S; Sun, W M; Wilksen, T; Weaver, K M; Weinberger, M; Athar, S B; Avery, P; Breva-Newell, L; Patel, R; Potlia, V; Stoeck, H; Yelton, J; Rubin, P; Cawlfield, C; Eisenstein, B I; Karliner, I; Kim, D; Lowrey, N; Naik, P; Sedlack, C; Selen, M; White, E J; Williams, J; Wiss, J; Asner, D M; Edwards, K W; Besson, D

2005-12-31

Using 20.7 pb(-1) of e(+)e(-) annihilation data taken at sq.rt(r) = 3.671 GeV with the CLEO-c detector, precision measurements of the electromagnetic form factors of the charged pion, charged kaon, and proton have been made for timelike momentum transfer of |Q(2)| = 13.48 GeV(2) by the reaction e(+)e(-) --> h(+)h(-). The measurements are the first ever with identified pions and kaons of |Q(2)| > 4 GeV(2), with the results F(13.48 GeV(2)) = 0.075 +/- 0.008(stat) +/- 0.005(syst) and F(K)(13.48 GeV(2)) = 0.063 +/- 0.004(stat) +/- 0.001(syst). The result for the proton, assuming G(p)(E) = G(p)(M), is G(p)(M)(13.48 GeV(2)) = 0.014 +/- 0.002(stat) +/- 0.001(syst), which is in agreement with earlier results.

Childhood Adversity and Epigenetic Regulation of Glucocorticoid Signaling Genes: Associations in Children and Adults

PubMed Central

Tyrka, Audrey R.; Ridout, Kathryn K.; Parade, Stephanie H.

2017-01-01

Early childhood experiences have lasting effects on development, including the risk for psychiatric disorders. Research examining the biologic underpinnings of these associations has revealed the impact of childhood maltreatment on the physiologic stress response and activity of the hypothalamic pituitary adrenal (HPA) axis. A growing body of literature supports the hypothesis that environmental exposures mediate their biological effects via epigenetic mechanisms. Methylation, which is thought to be the most stable form of epigenetic change, is a likely mechanism by which early life exposures has lasting effects. In this review, we present recent evidence related to epigenetic regulation of genes involved in HPA axis regulation, namely the glucocorticoid receptor gene (NR3C1) and FK506 binding protein 51 (FKBP5), after childhood adversity and associations with risk for psychiatric disorders. Implications for the development of interventions and future research are discussed. PMID:27691985

Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii.

PubMed

Billmyre, R Blake; Clancey, Shelly Applen; Heitman, Joseph

2017-09-26

Pathogenic microbes confront an evolutionary conflict between the pressure to maintain genome stability and the need to adapt to mounting external stresses. Bacteria often respond with elevated mutation rates, but little evidence exists of stable eukaryotic hypermutators in nature. Whole genome resequencing of the human fungal pathogen Cryptococcus deuterogattii identified an outbreak lineage characterized by a nonsense mutation in the mismatch repair component MSH2. This defect results in a moderate mutation rate increase in typical genes, and a larger increase in genes containing homopolymer runs. This allows facile inactivation of genes with coding homopolymer runs including FRR1 , which encodes the target of the immunosuppresive antifungal drugs FK506 and rapamycin. Our study identifies a eukaryotic hypermutator lineage spread over two continents and suggests that pathogenic eukaryotic microbes may experience similar selection pressures on mutation rate as bacterial pathogens, particularly during long periods of clonal growth or while expanding into new environments.

Microwave emission from the coronae of late-type dwarf stars

NASA Technical Reports Server (NTRS)

Linsky, J. L.; Gary, D. E.

1983-01-01

VLA microwave observations of 14 late-type dwarf and subgiant stars and binary systems are examined. In this extensive set of observations, four sources at 6 cm (Chi-1 Ori, UV Cet, YY Gem, and Wolf 630AB) were detected and low upper limits for the remaining stars were found. The microwave luminosities of the nondetected F-K dwarfs are as small as 0.01 those of the dMe stars. The detected emission is slowly variable in all cases and is consistent with gyroresonant emission from thermal electrons spiraling in magnetic fields of about 300 gauss if the source sizes are as large as R/R(asterisk) = 3-4. This would correspond to magnetic fields that are probably in the range 0.001-0.0001 gauss at the photospheric level. An alternative mechanism is gyrosynchrotron emission from a relatively small number of electrons with effective temperature.

23Na and 35/37Cl as NMR probes of growth and shape of sodium taurodeoxycholate micellar aggregates in the presence of NaCl.

PubMed

Asaro, Fioretta; Feruglio, Luigi; Galantini, Luciano; Nardelli, Alessia

2013-02-15

The growth of the aggregates of the dihydroxylated bile salt sodium taurodeoxycholate (NaTDC) upon NaCl addition and the involvement of the counterion were investigated by NMR spectroscopy of monoatomic ionic species. (23)Na T(1) values from 0.015, 0.100, and 0.200 mol kg(-1) NaTDC solutions in D(2)O, at variable NaCl content, proved to be sensitive to the transition from primary to secondary aggregates, which occurs in the former sample, and to intermicellar interaction. Some (79)Br NMR measurements were performed on a 0.100 mol kg(-1) NaTDC sample added by NaBr in place of NaCl for comparison purposes. The (23)Na, (35)Cl, and (37)Cl double quantum filtered (DQF) patterns, from the 0.100 mol kg(-1) NaTDC sample, and (23)Na ones also from the 0.200 mol kg(-1) NaTDC one, in the presence of 0.750 mol kg(-1) NaCl, are a clear manifestation of motional anisotropy. Moreover, the DQF spectra of (23)Na and (37)Cl, which possess close quadrupole moments, display a striking similarity. The DQF lineshapes were simulated exploiting the Scilab environment to obtain an estimate of the residual quadrupole splitting magnitude. These results support the description of NaTDC micelles as cylindrical aggregates, strongly interacting at high ionic strengths, and capable of association with added electrolytes. Copyright © 2012 Elsevier Inc. All rights reserved.

Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters*

PubMed Central

Giral, Hector; Lanzano, Luca; Caldas, Yupanqui; Blaine, Judith; Verlander, Jill W.; Lei, Tim; Gratton, Enrico; Levi, Moshe

2011-01-01

The sodium-dependent phosphate (Na/Pi) transporters NaPi-2a and NaPi-2c play a major role in the renal reabsorption of Pi. The functional need for several transporters accomplishing the same role is still not clear. However, the fact that these transporters show differential regulation under dietary and hormonal stimuli suggests different roles in Pi reabsorption. The pathways controlling this differential regulation are still unknown, but one of the candidates involved is the NHERF family of scaffolding PDZ proteins. We propose that differences in the molecular interaction with PDZ proteins are related with the differential adaptation of Na/Pi transporters. Pdzk1−/− mice adapted to chronic low Pi diets showed an increased expression of NaPi-2a protein in the apical membrane of proximal tubules but impaired up-regulation of NaPi-2c. These results suggest an important role for PDZK1 in the stabilization of NaPi-2c in the apical membrane. We studied the specific protein-protein interactions of Na/Pi transporters with NHERF-1 and PDZK1 by FRET. FRET measurements showed a much stronger interaction of NHERF-1 with NaPi-2a than with NaPi-2c. However, both Na/Pi transporters showed similar FRET efficiencies with PDZK1. Interestingly, in cells adapted to low Pi concentrations, there were increases in NaPi-2c/PDZK1 and NaPi-2a/NHERF-1 interactions. The differential affinity of the Na/Pi transporters for NHERF-1 and PDZK1 proteins could partially explain their differential regulation and/or stability in the apical membrane. In this regard, direct interaction between NaPi-2c and PDZK1 seems to play an important role in the physiological regulation of NaPi-2c. PMID:21388960

Mechanism and molecular basis for the sodium channel subtype specificity of µ-conopeptide CnIIIC

PubMed Central

Markgraf, René; Leipold, Enrico; Schirmeyer, Jana; Paolini-Bertrand, Marianne; Hartley, Oliver; Heinemann, Stefan H

2012-01-01

BACKGROUND AND PURPOSE Voltage-gated sodium channels (NaV channels) are key players in the generation and propagation of action potentials, and selective blockade of these channels is a promising strategy for clinically useful suppression of electrical activity. The conotoxin µ-CnIIIC from the cone snail Conus consors exhibits myorelaxing activity in rodents through specific blockade of skeletal muscle (NaV1.4) NaV channels. EXPERIMENTAL APPROACH We investigated the activity of µ-CnIIIC on human NaV channels and characterized its inhibitory mechanism, as well as the molecular basis, for its channel specificity. KEY RESULTS Similar to rat paralogs, human NaV1.4 and NaV1.2 were potently blocked by µ-CnIIIC, the sensitivity of NaV1.7 was intermediate, and NaV1.5 and NaV1.8 were insensitive. Half-channel chimeras revealed that determinants for the insensitivity of NaV1.8 must reside in both the first and second halves of the channel, while those for NaV1.5 are restricted to domains I and II. Furthermore, domain I pore loop affected the total block and therefore harbours the major determinants for the subtype specificity. Domain II pore loop only affected the kinetics of toxin binding and dissociation. Blockade by µ-CnIIIC of NaV1.4 was virtually irreversible but left a residual current of about 5%, reflecting a ‘leaky’ block; therefore, Na+ ions still passed through µ-CnIIIC-occupied NaV1.4 to some extent. TTX was excluded from this binding site but was trapped inside the pore by µ-CnIIIC. CONCLUSION AND IMPLICATIONS Of clinical significance, µ-CnIIIC is a potent and persistent blocker of human skeletal muscle NaV1.4 that does not affect activity of cardiac NaV1.5. PMID:22537004

Visceral and somatic pain modalities reveal NaV1.7‐independent visceral nociceptive pathways

PubMed Central

Hockley, James R. F.; González‐Cano, Rafael; McMurray, Sheridan; Tejada‐Giraldez, Miguel A.; McGuire, Cian; Torres, Antonio; Wilbrey, Anna L.; Cibert‐Goton, Vincent; Nieto, Francisco R.; Pitcher, Thomas; Knowles, Charles H.; Baeyens, José Manuel; Wood, John N.; Winchester, Wendy J.; Bulmer, David C.; Cendán, Cruz Miguel

2017-01-01

Key points Voltage‐gated sodium channels play a fundamental role in determining neuronal excitability.Specifically, voltage‐gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown.Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling.These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality‐specific manner and help to direct drug discovery efforts towards novel visceral analgesics. Abstract Voltage‐gated sodium channel NaV1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor‐specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small‐molecule NaV1.7 antagonist PF‐5198007. NaV1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve–gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage‐gated sodium channel α subunits revealed NaV1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV1.7 (in NaV1.8‐expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV1.7 antagonist PF‐5198007. Our data demonstrate that NaV1.7 (in NaV1.8‐expressing neurons) contributes to defined pain pathways in a modality‐dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. PMID:28105664

Veterans Attitude Tracking Study -- 1983, Wave I. Data Tables. Supplement 1,

DTIC Science & Technology

1984-05-01

5.6 9.9 6.8 8.2 Admini strative 18.5 20.4 13.U 17.2 Medical 3.6 0.7 0.7 1.3 Other 0.4 0.7 0.0 0.9 Dont know .b 4.6 4.1 3.4 1) Asked only of respondents...toward Guard/ Reserve participation, -- Talked with their co-workers about enlisting in the Guard/Reserve, or -- Seen notices, posters , or other...A N/A 72.9 9 17 Total N/A N/A N/A N/A 100% (11.6%) (23.5%) Seen any notices, posters , or other literature at workplace(’Q R-35b) Yes N/A N/A N/A N/A

Shoot Na+ Exclusion and Increased Salinity Tolerance Engineered by Cell Type–Specific Alteration of Na+ Transport in Arabidopsis[W][OA

PubMed Central

Møller, Inge S.; Gilliham, Matthew; Jha, Deepa; Mayo, Gwenda M.; Roy, Stuart J.; Coates, Juliet C.; Haseloff, Jim; Tester, Mark

2009-01-01

Soil salinity affects large areas of cultivated land, causing significant reductions in crop yield globally. The Na+ toxicity of many crop plants is correlated with overaccumulation of Na+ in the shoot. We have previously suggested that the engineering of Na+ exclusion from the shoot could be achieved through an alteration of plasma membrane Na+ transport processes in the root, if these alterations were cell type specific. Here, it is shown that expression of the Na+ transporter HKT1;1 in the mature root stele of Arabidopsis thaliana decreases Na+ accumulation in the shoot by 37 to 64%. The expression of HKT1;1 specifically in the mature root stele is achieved using an enhancer trap expression system for specific and strong overexpression. The effect in the shoot is caused by the increased influx, mediated by HKT1;1, of Na+ into stelar root cells, which is demonstrated in planta and leads to a reduction of root-to-shoot transfer of Na+. Plants with reduced shoot Na+ also have increased salinity tolerance. By contrast, plants constitutively expressing HKT1;1 driven by the cauliflower mosaic virus 35S promoter accumulated high shoot Na+ and grew poorly. Our results demonstrate that the modification of a specific Na+ transport process in specific cell types can reduce shoot Na+ accumulation, an important component of salinity tolerance of many higher plants. PMID:19584143

Diverse variation of reproductive barriers in three intraspecific rice crosses.

PubMed Central

Harushima, Yoshiaki; Nakagahra, Masahiro; Yano, Masahiro; Sasaki, Takuji; Kurata, Nori

2002-01-01

Reproductive barriers are thought to play an important role in the processes of speciation and differentiation. Asian rice cultivars, Oryza sativa, can be classified into two main types, Japonica and Indica, on the basis of several characteristics. The fertility of Japonica-Indica hybrids differs from one cross to another. Many genes involved in reproductive barriers (hybrid sterility, hybrid weakness, and gametophytic competition genes) have been reported in different Japonica-Indica crosses. To clarify the state of Japonica-Indica differentiation, all reproductive barriers causing deviation from Mendelian segregation ratios in F(2) populations were mapped and compared among three different Japonica-Indica crosses: Nipponbare/Kasalath (NK), Fl1084/Dao Ren Qiao (FD), and Fl1007/Kinandang puti (FK). Mapping of reproductive barriers was performed by regression analysis of allele frequencies of DNA markers covering the entire genome. Allele frequencies were explained by 33 reproductive barriers (15 gametophytic and 18 zygotic) in NK, 32 barriers (15 gametophytic and 17 zygotic) in FD, and 37 barriers (19 gametophytic and 18 zygotic) in FK. The number of reproductive barriers in the three crosses was similar; however, most of the barriers were mapped at different loci. Therefore, these reproductive barriers formed after Japonica-Indica differentiation. Considering the high genetic similarity within Japonica and Indica cultivars, the differences in the reproductive barriers of each cross were unexpectedly numerous. The reproductive barriers of Japonica-Indica hybrids likely evolved more rapidly than other genetic elements. One possible force responsible for such rapid evolution of the barriers may have been the domestication of rice. PMID:11805066

Design and force analysis of end-effector for plug seedling transplanter.

PubMed

Jiang, Zhuohua; Hu, Yang; Jiang, Huanyu; Tong, Junhua

2017-01-01

Automatic transplanters have been very important in greenhouses since the popularization of seedling nurseries. End-effector development is a key technology for transplanting plug seedlings. Most existing end-effectors have problems with holding root plugs or releasing plugs. An efficient end-effector driven by a linear pneumatic cylinder was designed in this study, which could hold root plugs firmly and release plugs easily. This end-effector with four needles could clamp the plug simultaneously while the needles penetrate into the substrate. The depth and verticality of the needles could be adjusted conveniently for different seedling trays. The effectiveness of this end-effector was tested by a combinational trial examining three seedling nursery factors (the moisture content of the substrate, substrate bulk density and the volume proportion of substrate ingredients). Results showed that the total transplanting success rate for the end-effector was 100%, and the root plug harm rate was below 17%. A force measure system with tension and pressure transducers was installed on the designed end-effector. The adhesive force FL between the root plug and the cell of seedling trays and the extrusion force FK on the root plug were measured and analyzed. The results showed that all three variable factors and their interactions had significant effects on the extrusion force. Each factor had a significant effect on adhesive force. Additionally, it was found that the end-effector did not perform very well when the value of FK/FL was beyond the range of 5.99~8.67. This could provide a scientific basis for end-effector application in transplanting.

Design and force analysis of end-effector for plug seedling transplanter

PubMed Central

Hu, Yang; Jiang, Huanyu; Tong, Junhua

2017-01-01

Automatic transplanters have been very important in greenhouses since the popularization of seedling nurseries. End-effector development is a key technology for transplanting plug seedlings. Most existing end-effectors have problems with holding root plugs or releasing plugs. An efficient end-effector driven by a linear pneumatic cylinder was designed in this study, which could hold root plugs firmly and release plugs easily. This end-effector with four needles could clamp the plug simultaneously while the needles penetrate into the substrate. The depth and verticality of the needles could be adjusted conveniently for different seedling trays. The effectiveness of this end-effector was tested by a combinational trial examining three seedling nursery factors (the moisture content of the substrate, substrate bulk density and the volume proportion of substrate ingredients). Results showed that the total transplanting success rate for the end-effector was 100%, and the root plug harm rate was below 17%. A force measure system with tension and pressure transducers was installed on the designed end-effector. The adhesive force FL between the root plug and the cell of seedling trays and the extrusion force FK on the root plug were measured and analyzed. The results showed that all three variable factors and their interactions had significant effects on the extrusion force. Each factor had a significant effect on adhesive force. Additionally, it was found that the end-effector did not perform very well when the value of FK/FL was beyond the range of 5.99~8.67. This could provide a scientific basis for end-effector application in transplanting. PMID:28678858

Ground roll attenuation using polarization analysis in the t-f-k domain

NASA Astrophysics Data System (ADS)

Wang, C.; Wang, Y.

2017-07-01

S waves travel slower than P waves and have a lower dominant frequency. Therefore, applying common techniques such as time-frequency filtering and f-k filtering to separate S waves from ground roll is difficult because ground roll is also characterized by slow velocity and low frequency. In this study, we present a method for attenuating ground roll using a polarization filtering method based on the t-f-k transform. We describe the particle motion of the waves by complex vector signals. Each pair of frequency components, whose frequencies have the same absolute value but different signs, of the complex signal indicate an elliptical or linear motion. The polarization parameters of the elliptical or linear motion are explicitly related to the two Fourier coefficients. We then extend these concepts to the t-f-k domain and propose a polarization filtering method for ground roll attenuation based on the t-f-k transform. The proposed approach can define automatically the time-varying reject zones on the f-k panel at different times as a function of the reciprocal ellipticity. Four attributes, time, frequency, apparent velocity and polarization are used to identify and extract the ground roll simultaneously. Thus, the ground roll and body waves can be separated as long as they are dissimilar in one of these attributes. We compare our method with commonly used filtering techniques by applying the methods to synthetic and real seismic data. The results indicate that our method can attenuate ground roll while preserving body waves more effectively than the other methods.

Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5).

PubMed

Tyrka, Audrey R; Ridout, Kathryn K; Parade, Stephanie H; Paquette, Alison; Marsit, Carmen J; Seifer, Ronald

2015-11-01

A growing body of evidence suggests that alterations of the stress response system may be a mechanism by which childhood maltreatment alters risk for psychopathology. FK506 binding protein 51 (FKBP5) binds to the glucocorticoid receptor and alters its ability to respond to stress signaling. The aim of the present study was to examine methylation of the FKBP5 gene (FKBP5), and the role of an FKBP5 genetic variant, in relation to childhood maltreatment in a sample of impoverished preschool-aged children. One hundred seventy-four families participated in this study, including 69 with child welfare documentation of moderate to severe maltreatment in the past 6 months. The children, who ranged in age from 3 to 5 years, were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors; and a composite variable assessed the number exposures to these adversities. Methylation of two sites in intron 7 of FKBP5 was measured via sodium bisulfite pyrosequencing. Maltreated children had significantly lower levels of methylation at both CpG sites (p < .05). Lifetime contextual stress exposure showed a trend for lower levels of methylation at one of the sites, and a trend for an interaction with the FKBP5 polymorphism. A composite adversity variable was associated with lower levels of methylation at one of the sites as well (p < .05). FKBP5 alters glucocorticoid receptor responsiveness, and FKBP5 gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.

Impact of novel histone deacetylase inhibitors, CHAP31 and FR901228 (FK228), on adenovirus-mediated transgene expression.

PubMed

Taura, Kojiro; Yamamoto, Yuzo; Nakajima, Akio; Hata, Koichiro; Uchinami, Hiroshi; Yonezawa, Kei; Hatano, Etsuro; Nishino, Norikazu; Yamaoka, Yoshio

2004-05-01

Histone deacetylase inhibitors (HDIs) are known to enhance adenovirus (Ad)-mediated transgene expression. Recently, novel HDIs, including cyclic hydroxamic-acid-containing peptide 31 (CHAP31) and FR901228 (FK228), have been developed. The effects of these two novel HDIs on Ad-transduced or endogenous gene expression were investigated. Acetylation of core histones and the expression of the coxsackie and adenovirus receptor (CAR) in HDI-treated cells were examined using Western blot and a quantitative reverse transcription polymerase chain reaction (TaqMan RT-PCR), respectively. Their in vivo effect on adenoviral gene expression was investigated in BALB/c mice. Both compounds enhanced and prolonged Ad-mediated beta-galactosidase expression more effectively than did trichostatin A, a classic HDI. The same effect was observed in Ad-transduced heat shock protein 72 (HSP72), but not in hyperthermia-induced endogenous expression of HSP72, suggesting that the effect is specific for transduced gene expression. Hyperacetylation of core histones induced by HDIs was considered responsible for the augmentative effects of gene expression. Intravenous administration of either CHAP31 or FR901228 enhanced beta-galactosidase expression in mice infected with AdLacZ. CHAP31 and FR901228 amplified Ad-mediated transgene expression. The enhancement of transgene expression by HDIs may result in fewer vector doses for necessary gene expression, helping to alleviate disadvantages caused by Ad vectors. This could be a useful tool in overcoming current limitations of gene therapy using adenovirus vectors. Copyright 2004 John Wiley & Sons, Ltd.

Sparsity-optimized separation of body waves and ground-roll by constructing dictionaries using tunable Q-factor wavelet transforms with different Q-factors

NASA Astrophysics Data System (ADS)

Chen, Xin; Chen, Wenchao; Wang, Xiaokai; Wang, Wei

2017-10-01

Low-frequency oscillatory ground-roll is regarded as one of the main regular interference waves, which obscures primary reflections in land seismic data. Suppressing the ground-roll can reasonably improve the signal-to-noise ratio of seismic data. Conventional suppression methods, such as high-pass and various f-k filtering, usually cause waveform distortions and loss of body wave information because of their simple cut-off operation. In this study, a sparsity-optimized separation of body waves and ground-roll, which is based on morphological component analysis theory, is realized by constructing dictionaries using tunable Q-factor wavelet transforms with different Q-factors. Our separation model is grounded on the fact that the input seismic data are composed of low-oscillatory body waves and high-oscillatory ground-roll. Two different waveform dictionaries using a low Q-factor and a high Q-factor, respectively, are confirmed as able to sparsely represent each component based on their diverse morphologies. Thus, seismic data including body waves and ground-roll can be nonlinearly decomposed into low-oscillatory and high-oscillatory components. This is a new noise attenuation approach according to the oscillatory behaviour of the signal rather than the scale or frequency. We illustrate the method using both synthetic and field shot data. Compared with results from conventional high-pass and f-k filtering, the results of the proposed method prove this method to be effective and advantageous in preserving the waveform and bandwidth of reflections.

Conditionally controlling nuclear trafficking in yeast by chemical-induced protein dimerization

PubMed Central

Xu, Tao; Johnson, Cole A; Gestwicki, Jason E; Kumar, Anuj

2016-01-01

We present here a protocol to conditionally control the nuclear trafficking of target proteins in yeast. In this system, rapamycin is used to heterodimerize two chimeric proteins. one chimera consists of a FK506-binding protein (FKBp12) fused to a cellular ‘address’ (nuclear localization signal or nuclear export sequence). the second chimera consists of a target protein fused to a fluorescent protein and the FKBp12-rapamycin-binding (FrB) domain from FKBp-12-rapamycin associated protein 1 (Frap1, also known as mtor). rapamycin induces dimerization of the FKBp12- and FrB-containing chimeras; these interactions selectively place the target protein under control of the cell address, thereby directing the protein into or out of the nucleus. By chemical-induced dimerization, protein mislocalization is reversible and enables the identification of conditional loss-of-function and gain-of-function phenotypes, in contrast to other systems that require permanent modification of the targeted protein. Yeast strains for this analysis can be constructed in 1 week, and the technique allows protein mislocalization within 15 min after drug treatment. PMID:21030958

Conditionally controlling nuclear trafficking in yeast by chemical-induced protein dimerization.

PubMed

Xu, Tao; Johnson, Cole A; Gestwicki, Jason E; Kumar, Anuj

2010-11-01

We present here a protocol to conditionally control the nuclear trafficking of target proteins in yeast. In this system, rapamycin is used to heterodimerize two chimeric proteins. One chimera consists of a FK506-binding protein (FKBP12) fused to a cellular 'address' (nuclear localization signal or nuclear export sequence). The second chimera consists of a target protein fused to a fluorescent protein and the FKBP12-rapamycin-binding (FRB) domain from FKBP-12-rapamycin associated protein 1 (FRAP1, also known as mTor). Rapamycin induces dimerization of the FKBP12- and FRB-containing chimeras; these interactions selectively place the target protein under control of the cell address, thereby directing the protein into or out of the nucleus. By chemical-induced dimerization, protein mislocalization is reversible and enables the identification of conditional loss-of-function and gain-of-function phenotypes, in contrast to other systems that require permanent modification of the targeted protein. Yeast strains for this analysis can be constructed in 1 week, and the technique allows protein mislocalization within 15 min after drug treatment.

Concentration dependence of Li+/Na+ diffusion in manganese hexacyanoferrates

NASA Astrophysics Data System (ADS)

Takachi, Masamitsu; Fukuzumi, Yuya; Moritomo, Yutaka

2016-06-01

Manganese hexacyanoferrates (Mn-HCFs) with a jungle-gym-type structure are promising cathode materials for Li+/Na+ secondary batteries (LIBs/SIBs). Here, we investigated the diffusion constants D Li/D Na of Li+/Na+ against the Li+/Na+ concentration x Na/x Li and temperature (T) of A 1.32Mn[Fe(CN)6]0.833.6H2O (A = Li and Na). We evaluated the activation energy E\\text{a}\\text{Li}/E\\text{a}\\text{Na} of D Li/D Na against x Na/x Li. We found that E\\text{a}\\text{Na} steeply increases with x Na from 0.41 eV at x Na = 0.69 to 0.7 eV at 1.1. The increase in E\\text{a}\\text{Na} is ascribed to the occupancy effect of the Na+ site. The increase in E\\text{a}\\text{Li} is suppressed, probably because the number of Li+ sites is three times that of Na+ sites.

14 CFR Section 22 - General Reporting Instructions

Code of Federal Regulations, 2014 CFR

2014-01-01

... aircraft engines A X X X P-1.1 Statement of operations SA (2) NA NA P-1.2 Statement of operations Q (1) X X P-1(a) Interim operations report M X X X P-2 Notes to RSPA Form 41 report Q (1) X X P-5.1 Aircraft operating expenses Q(1), SA(2) X NA NA P-5.2 Aircraft operating expenses Q NA X X P-6 Operating expenses by...

14 CFR Section 22 - General Reporting Instructions

Code of Federal Regulations, 2011 CFR

2011-01-01

... aircraft engines A X X X P-1.1 Statement of operations SA (2) NA NA P-1.2 Statement of operations Q (1) X X P-1(a) Interim operations report M X X X P-2 Notes to RSPA Form 41 report Q (1) X X P-5.1 Aircraft operating expenses Q(1), SA(2) X NA NA P-5.2 Aircraft operating expenses Q NA X X P-6 Operating expenses by...