Time-shifted synchronization of chaotic oscillator chains without explicit coupling delays.

PubMed

Blakely, Jonathan N; Stahl, Mark T; Corron, Ned J

2009-12-01

We examine chains of unidirectionally coupled oscillators in which time-shifted synchronization occurs without explicit delays in the coupling. In numerical simulations and in an experimental system of electronic oscillators, we examine the time shift and the degree of distortion (primarily in the form of attenuation) of the waveforms of the oscillators located far from the drive oscillator. Surprisingly, under weak coupling we observe minimal attenuation in spite of a significant total time shift. In contrast, at higher coupling strengths the observed attenuation increases dramatically and approaches the value predicted by an analytically derived estimate. In this regime, we verify directly that generalized synchronization is maintained over the entire chain length despite severe attenuation. These results suggest that weak coupling generally may produce higher quality synchronization in systems for which truly identical synchronization is not possible.

Assessment of attenuated Salmonella vaccine strains in controlling experimental Salmonella Typhimurium infection in chickens

PubMed Central

Pei, Yanlong; Parreira, Valeria R.; Roland, Kenneth L.; Curtiss, Roy; Prescott, John F.

2014-01-01

Salmonella hold considerable promise as vaccine delivery vectors for heterologous antigens in chickens. Such vaccines have the potential additional benefit of also controlling Salmonella infection in immunized birds. As a way of selecting attenuated strains with optimal immunogenic potential as antigen delivery vectors, this study screened 20 novel Salmonella Typhimurium vaccine strains, differing in mutations associated with delayed antigen synthesis and delayed attenuation, for their efficacy in controlling colonization by virulent Salmonella Typhimurium, as well as for their persistence in the intestine and the spleen. Marked differences were observed between strains in these characteristics, which provide the basis for selection for further study as vaccine vectors. PMID:24396177

Assessment of attenuated Salmonella vaccine strains in controlling experimental Salmonella Typhimurium infection in chickens.

PubMed

Pei, Yanlong; Parreira, Valeria R; Roland, Kenneth L; Curtiss, Roy; Prescott, John F

2014-01-01

Salmonella hold considerable promise as vaccine delivery vectors for heterologous antigens in chickens. Such vaccines have the potential additional benefit of also controlling Salmonella infection in immunized birds. As a way of selecting attenuated strains with optimal immunogenic potential as antigen delivery vectors, this study screened 20 novel Salmonella Typhimurium vaccine strains, differing in mutations associated with delayed antigen synthesis and delayed attenuation, for their efficacy in controlling colonization by virulent Salmonella Typhimurium, as well as for their persistence in the intestine and the spleen. Marked differences were observed between strains in these characteristics, which provide the basis for selection for further study as vaccine vectors.

Mathematical Modeling and Analysis of a Wide Bandwidth Bipolar Power Supply for the Fast Correctors in the APS Upgrade

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

Song, Byeong M.; Wang, Ju

This paper presents the mathematical modeling and analysis of a wide bandwidth bipolar power supply for the fast correctors in the APS Upgrade. A wide bandwidth current regulator with a combined PI and phase-lead compensator has been newly proposed, analyzed, and simulated through both a mathematical model and a physical electronic circuit model using MATLAB and PLECS. The proposed regulator achieves a bandwidth with a -1.23dB attenuation and a 32.40° phase-delay at 10 kHz for a small signal less than 1% of the DC scale. The mathematical modeling and design, simulation results of a fast corrector power supply control systemmore » are presented in this paper.« less

Improved disturbance rejection for predictor-based control of MIMO linear systems with input delay

NASA Astrophysics Data System (ADS)

Shi, Shang; Liu, Wenhui; Lu, Junwei; Chu, Yuming

2018-02-01

In this paper, we are concerned with the predictor-based control of multi-input multi-output (MIMO) linear systems with input delay and disturbances. By taking the future values of disturbances into consideration, a new improved predictive scheme is proposed. Compared with the existing predictive schemes, our proposed predictive scheme can achieve a finite-time exact state prediction for some smooth disturbances including the constant disturbances, and a better disturbance attenuation can also be achieved for a large class of other time-varying disturbances. The attenuation of mismatched disturbances for second-order linear systems with input delay is also investigated by using our proposed predictor-based controller.

MIIP, a cytoskeleton regulator that blocks cell migration and invasion, delays mitosis, and suppresses tumorogenesis.

PubMed

Wang, Yingmei; Wen, Jing; Zhang, Wei

2011-02-01

The migration and invasion inhibitory protein (MIIP) was initially discovered in a yeast two-hybrid screen for proteins that interact and inhibit the migration and invasion-promoting protein insulin-like growth factor binding protein 2 (IGFBP2). Recent studies have shown that MIIP not only modulates IGFBP2 but also regulates microtubule by binding to and inhibiting HDAC6, a class 2 histone deacetylase that deacetylates α-tubulin, heat-shock protein 90 (HSP90), and cortactin. In addition, MIIP also regulates the mitosis checkpoint, another microtubule-associated process. The location of the MIIP gene in chromosomal region 1p36, a commonly deleted region in a broad spectrum of human cancers, and the observation that MIIP attenuates tumorigenesis in a mouse model suggest that it functions as a tumor-suppressor gene. This review summarizes the recent progress in characterizing this novel protein, which regulates cell migration and mitosis, two processes that rely on the highly coordinated dynamics of the microtubule and cytoskeleton systems.

Parecoxib suppresses CHOP and Foxo1 nuclear translocation, but increases GRP78 levels in a rat model of focal ischemia.

PubMed

Ye, Zhi; Wang, Na; Xia, Pingping; Wang, E; Liao, Juan; Guo, Qulian

2013-04-01

Parecoxib, a novel COX-2 inhibitor, functions as a neuroprotective agent and rescues neurons from cerebral ischemic reperfusion injury-induced apoptosis. However, the molecular mechanisms underlying parecoxib neuroprotection remain to be elucidated. There is growing evidence that endoplasmic reticulum (ER) stress plays an important role in neuronal death caused by brain ischemia. However, very little is known about the role of parecoxib in mediating pathophysiological reactions to ER stress induced by ischemic reperfusion injury. Therefore, in the present study, we investigated whether delayed administration of parecoxib attenuates brain damage via suppressing ER stress-induced cell death. Adult male Sprague-Dawley rats were administered parecoxib (10 or 30 mg kg(-1), IP) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion (MCAO) for three consecutive days. The expressions of glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150) and C/EBP-homologous protein (CHOP) and forkhead box protein O 1 (Foxo1) in cytoplasmic and nuclear fraction were determined by Western blotting. The levels of caspase-12 expression were checked by immunohistochemistry analysis, served as a marker for ER stress-induced apoptosis. Parecoxib significantly suppressed cerebral ischemic injury-induced nuclear translocation of CHOP and Foxo1 and attenuated the immunoreactivity of caspase-12 in ischemic penumbra. Furthermore, the protective effect of delayed administration of parecoxib was accompanied by an increased GRP78 and ORP150 expression. Therefore, our study suggested that elevation of GRP78 and ORP150, and suppression of CHOP and Foxo1 nuclear translocation may contribute to parecoxib-mediated neuroprotection during ER stress responses.

Inducible and Conditional Deletion of Extracellular Signal-regulated Kinase 5 Disrupts Adult Hippocampal Neurogenesis*

PubMed Central

Pan, Yung-Wei; Zou, Junhui; Wang, Wenbin; Sakagami, Hiroyuki; Garelick, Michael G.; Abel, Glen; Kuo, Chay T.; Storm, Daniel R.; Xia, Zhengui

2012-01-01

Recent studies have led to the exciting idea that adult-born neurons in the dentate gyrus of the hippocampus may play a role in hippocampus-dependent memory formation. However, signaling mechanisms that regulate adult hippocampal neurogenesis are not well defined. Here we report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, is selectively expressed in the neurogenic regions of the adult mouse brain. We present evidence that shRNA suppression of ERK5 in adult hippocampal neural stem/progenitor cells (aNPCs) reduces the number of neurons while increasing the number of cells expressing markers for stem/progenitor cells or proliferation. Furthermore, shERK5 attenuates both transcription and neuronal differentiation mediated by Neurogenin 2, a transcription factor expressed in adult hippocampal neural progenitor cells. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, promotes neurogenesis in cultured aNPCs and in the dentate gyrus of the mouse brain. Moreover, neurotrophins including NT3 activate ERK5 and stimulate neuronal differentiation in aNPCs in an ERK5-dependent manner. Finally, inducible and conditional deletion of ERK5 specifically in the neurogenic regions of the adult mouse brain delays the normal progression of neuronal differentiation and attenuates adult neurogenesis in vivo. These data suggest ERK5 signaling as a critical regulator of adult hippocampal neurogenesis. PMID:22645146

Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.

PubMed

Lee, Tsung-Ming; Chang, Nen-Chung; Lin, Shinn-Zong

2017-03-01

During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling. Copyright © 2017 Elsevier Inc. All rights reserved.

ATM-dependent DNA damage checkpoint functions regulate gene expression in human fibroblasts

PubMed Central

Zhou, Tong; Chou, Jeff; Zhou, Yingchun; Simpson, Dennis A.; Cao, Feng; Bushel, Pierre R.; Paules, Richard S.; Kaufmann, William K.

2013-01-01

The relationships between profiles of global gene expression and DNA damage checkpoint functions were studied in cells from patients with ataxia telangiectasia (AT). Three telomerase-expressing AT fibroblast lines displayed the expected hypersensitivity to ionizing radiation (IR) and defects in DNA damage checkpoints. Profiles of global gene expression in AT cells were determined at 2, 6 and 24 h after treatment with 1.5 Gy IR or sham-treatment, and were compared to those previously recognized in normal human fibroblasts. Under basal conditions 160 genes or ESTs were differentially expressed in AT and normal fibroblasts, and these were associated by gene ontology with insulin-like growth factor binding and regulation of cell growth. Upon DNA damage, 1091 gene mRNAs were changed in at least two of the three AT cell lines. When compared with the 1811 genes changed in normal human fibroblasts after the same treatment, 715 were found in both AT and normal fibroblasts, including most genes categorized by gene ontology into cell cycle, cell growth and DNA damage response pathways. However, the IR-induced changes in these 715 genes in AT cells usually were delayed or attenuated in comparison to normal cells. The reduced change in DNA-damage-response genes and the attenuated repression of cell-cycle-regulated genes may account for the defects in cell cycle checkpoint function in AT cells. PMID:17699107

FHF2 isoforms differentially regulate Nav1.6 mediated resurgent sodium currents in dorsal root ganglion neurons

PubMed Central

Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J.; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming; Cummins, Theodore R.

2017-01-01

Nav1.6 and Nav1.6 mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6 mediated resurgent currents by isoforms of Fibroblast growth Factor Homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas, FHF2B enhances resurgent currents. Overall our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies. PMID:27999940

A Novel Therapy to Attenuate Acute Kidney Injury and Ischemic Allograft Damage after Allogenic Kidney Transplantation in Mice

PubMed Central

Gueler, Faikah; Shushakova, Nelli; Mengel, Michael; Hueper, Katja; Chen, Rongjun; Liu, Xiaokun; Park, Joon-Keun; Haller, Hermann

2015-01-01

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20–50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells. PMID:25617900

A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

PubMed

Gueler, Faikah; Shushakova, Nelli; Mengel, Michael; Hueper, Katja; Chen, Rongjun; Liu, Xiaokun; Park, Joon-Keun; Haller, Hermann; Wensvoort, Gert; Rong, Song

2015-01-01

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

Propagation effects on radio range and noise in earth-space telecommunications

NASA Technical Reports Server (NTRS)

Flock, W. L.; Slobin, S. D.; Smith, E. K.

1982-01-01

Attention is given to the propagation effects on radio range and noise in earth-space telecommunications. The use of higher frequencies minimizes ionospheric effects on propagation, but tropospheric effects often increase or dominate. For paths of geostationary satellites, and beyond, the excess range delay caused by the ionosphere and plasmasphere is proportional to the total electron content along the path and inversely proportional to frequency squared. The delay due to dry air is usually of the order of a few meters while the delay due to water vapor (a few tens of centimeters) is responsible for most of the temporal variation in the range delay for clean air. For systems such as that of the Voyager spacecraft, and for attenuation values up to about 10 dB, increased sky noise degrades the received signal-to-noise ratio more than does the reduction in signal level due to attenuation.

Diffuse dispersive delay and the time convolution/attenuation of transients

NASA Technical Reports Server (NTRS)

Bittner, Burt J.

1991-01-01

Test data and analytic evaluations are presented to show that relatively poor 100 KHz shielding of 12 Db can effectively provide an electromagnetic pulse transient reduction of 100 Db. More importantly, several techniques are shown for lightning surge attenuation as an alternative to crowbar, spark gap, or power zener type clipping which simply reflects the surge. A time delay test method is shown which allows CW testing, along with a convolution program to define transient shielding effectivity where the Fourier phase characteristics of the transient are known or can be broadly estimated.

IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses

PubMed Central

Gazit, Neta; Vertkin, Irena; Shapira, Ilana; Helm, Martin; Slomowitz, Edden; Sheiba, Maayan; Mor, Yael; Rizzoli, Silvio; Slutsky, Inna

2016-01-01

Summary The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer’s disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca2+ transients, while promoting spontaneous transmission and resting Ca2+ level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca2+ buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer’s disease. Video Abstract PMID:26804996

Dietary Ziziphus jujuba Fruit Influence on Aberrant Crypt Formation and Blood Cells in Colitis-Associated Colorectal Cancer in Mice.

PubMed

Periasamy, Srinivasan; Liu, Chung-Teng; Wu, Wang-Hung; Chien, Se-Ping; Liu, Ming-Yie

2015-01-01

Ziziphus jujuba (ZJ) fruit is rich in bioactive functional components such as polysaccharides, triterpenoid acid, flavonoids and oleamide. It has been commonly used in the treatment of various diseases including diabetes, digestive disorders, diarrhea, skin infections, liver and urinary complaints. However, dietary effects with regard to chemoprevention of colon cancer have not been studied. The present study was performed to evaluate the protective effects of dietary ZJ against colitis-associated colon carcinogenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. AOM was injected (10 mg/kg b.wt., i.p.) and three cycles of 2% DSS in drinking water for 7 days with 14 days of normal drinking water in-between were administered to induce colitis-associated colon cancer. ZJ fruit was supplemented into feed at levels of 5 and 10%. Dietary ZJ significantly attenuated aberrant crypt foci (ACF) formation and also decreased the progression of hyperplasia to dysplasia. In addition, it significantly reduced circulating white blood cells, lymphocytes, neutrophils, monocytes, eosinophils, basophils and platelets compared to colon cancer mice. We conclude that ZJ supplementation may delay the progression of colon cancer from hyperplasia to dysplasia and ultimately adenocarcinoma and cancer. In addition, it decreased circulating tumor-related leukocytes, main regulators of cancer inflammation. Dietary consumption of ZJ fruit attenuated the formation of ACF and delayed the progression of colon cancer.

Communication-dependent mineralization of osteoblasts via gap junctions.

PubMed

Hashida, Yukihiko; Nakahama, Ken-ichi; Shimizu, Kaori; Akiyama, Masako; Harada, Kiyoshi; Morita, Ikuo

2014-04-01

Connexin43 (Cx43) is a major gap junction (GJ) protein in bone and plays a critical role in osteoblast differentiation. Several studies show that osteoblast differentiation is delayed by Cx43 ablation. However, the precise mechanism underlying the role of Cx43 in osteoblast differentiation is not fully understood. Firstly, we analyzed the phenotype of a conditional knockout mouse, which was generated by mating of an osterix promoter-driven Cre expressing mouse with a Cx43-floxed mouse. As expected, delayed ossification was observed. Secondly, we demonstrated that the cell communication via gap junctions played an important role in osteoblast differentiation using a tamoxifen-inducible knockout system in vitro. Genetic ablation of Cx43 resulted in both the disruption of cell-communications and the attenuation of osteoblast mineralization induced by BMP-2, but not by ascorbic acid. Moreover, restoring full-length Cx43 (382aa) expression rescued the impairment of osteoblast cell-communication and osteoblast mineralization; however, the expression of the Cx43 N-terminal mutant (382aaG2V) did not rescue either of them. Comparing the gene expression profiles, the genes directly regulated by BMP-2 were attenuated by Cx43 gene ablation. These results suggested that the cell-communication mediated by gap junctions was indispensable for normal differentiation of osteoblast induced by BMP-2. Copyright © 2013 Elsevier Inc. All rights reserved.

Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model.

PubMed

Kurdián, Melania; Herrero-Fresneda, Inmaculada; Lloberas, Nuria; Gimenez-Bonafe, Pepita; Coria, Virginia; Grande, María T; Boggia, José; Malacrida, Leonel; Torras, Joan; Arévalo, Miguel A; González-Martínez, Francisco; López-Novoa, José M; Grinyó, Josep; Noboa, Oscar

2012-01-01

The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats. This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation. Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model. Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin.

Delayed mTOR Inhibition with Low Dose of Everolimus Reduces TGFβ Expression, Attenuates Proteinuria and Renal Damage in the Renal Mass Reduction Model

PubMed Central

Kurdián, Melania; Herrero-Fresneda, Inmaculada; Lloberas, Nuria; Gimenez-Bonafe, Pepita; Coria, Virginia; Grande, María T.; Boggia, José; Malacrida, Leonel; Torras, Joan; Arévalo, Miguel A.; González-Martínez, Francisco; López-Novoa, José M.; Grinyó, Josep; Noboa, Oscar

2012-01-01

Background The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats. Methods This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation. Results Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model. Conclusion Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin. PMID:22427849

Micromachined silicon acoustic delay line with improved structural stability and acoustic directivity for real-time photoacoustic tomography

NASA Astrophysics Data System (ADS)

Cho, Young; Kumar, Akhil; Xu, Song; Zou, Jun

2017-03-01

Recent studies have shown that micromachined silicon acoustic delay lines can provide a promising solution to achieve real-time photoacoustic tomography without the need for complex transducer arrays and data acquisition electronics. However, as its length increases to provide longer delay time, the delay line becomes more vulnerable to structural instability due to reduced mechanical stiffness. In addition, the small cross-section area of the delay line results in a large acoustic acceptance angle and therefore poor directivity. To address these two issues, this paper reports the design, fabrication, and testing of a new silicon acoustic delay line enhanced with 3D printed polymer micro linker structures. First, mechanical deformation of the silicon acoustic delay line (with and without linker structures) under gravity was simulated by using finite element method. Second, the acoustic crosstalk and acoustic attenuation caused by the polymer micro linker structures were evaluated with both numerical simulation and ultrasound transmission testing. The result shows that the use of the polymer micro linker structures significantly improves the structural stability of the silicon acoustic delay lines without creating additional acoustic attenuation and crosstalk. In addition, a new tapered design for the input terminal of the delay line was also investigate to improve its acoustic directivity by reducing the acoustic acceptance angle. These two improvements are expected to provide an effective solution to eliminate current limitations on the achievable acoustic delay time and out-of-plane imaging resolution of micromachined silicon acoustic delay line arrays.

Micromachined silicon acoustic delay line with 3D-printed micro linkers and tapered input for improved structural stability and acoustic directivity

NASA Astrophysics Data System (ADS)

Cho, Y.; Kumar, A.; Xu, S.; Zou, J.

2016-10-01

Recent studies have shown that micromachined silicon acoustic delay lines can provide a promising solution to achieve real-time photoacoustic tomography without the need for complex transducer arrays and data acquisition electronics. To achieve deeper imaging depth and wider field of view, a longer delay time and therefore delay length are required. However, as the length of the delay line increases, it becomes more vulnerable to structural instability due to reduced mechanical stiffness. In this paper, we report the design, fabrication, and testing of a new silicon acoustic delay line enhanced with 3D printed polymer micro linker structures. First, mechanical deformation of the silicon acoustic delay line (with and without linker structures) under gravity was simulated by using finite element method. Second, the acoustic crosstalk and acoustic attenuation caused by the polymer micro linker structures were evaluated with both numerical simulation and ultrasound transmission testing. The result shows that the use of the polymer micro linker structures significantly improves the structural stability of the silicon acoustic delay lines without creating additional acoustic attenuation and crosstalk. In addition, the improvement of the acoustic acceptance angle of the silicon acoustic delay lines was also investigated to better suppress the reception of unwanted ultrasound signals outside of the imaging plane. These two improvements are expected to provide an effective solution to eliminate current limitations on the achievable acoustic delay time and out-of-plane imaging resolution of micromachined silicon acoustic delay line arrays.

Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

PubMed

Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

2016-12-01

Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (P<0.05). Both UTMD and delayed BMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both P<0.05). Histopathology demonstrated that UTMD combined with delayed BMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Zero-Extra-Dose PET Delayed Imaging with Data-Driven Attenuation Correction Estimation.

PubMed

Pang, Lifang; Zhu, Wentao; Dong, Yun; Lv, Yang; Shi, Hongcheng

2018-05-08

Delayed positron emission tomography (PET) imaging may improve sensitivity and specificity in lesion detection. We proposed a PET data-driven method to estimate the attenuation map (AM) for the delayed scan without an additional x-ray computed tomography (CT). An emission-attenuation-scatter joint estimation framework was developed. Several practical issues for clinical datasets were addressed. Particularly, the unknown scatter correction was incorporated in the joint estimation algorithm. The scaling problem was solved using prior information from the early CT scan. Fourteen patient datasets were added to evaluate the method. These patients went through two separate PET/CT scans. The delayed CT-based AM served as ground truth for the delayed scan. Standard uptake values (SUVmean and SUVmax) of lesion and normal tissue regions of interests (ROIs) in the early and delayed phase and the respective %DSUV (percentage change of SUVmean at two different time points) were analyzed, all with estimated and the true AM. Three radiologists participated in lesion detection tasks with images reconstructed with both AMs and rated scores for detectability. The mean relative difference of SUVmean in lesion and normal liver tissue were 3.30 and 6.69 %. The average lesion-to-background contrast (detectability) with delayed PET images using CT AM was 60 % higher than that of the earlier PET image, and was 64 % higher when using the data-based AM. %DSUV for lesions and liver backgrounds with CT-based AM were - 0.058 ± 0.25 and - 0.33 ± 0.08 while with data-based AM were - 0.00 ± 0.26 and - 0.28 ± 0.08. Only slight significance difference was found between using CT-based AM and using the data-based AM reconstruction delay phase on %DSUV of lesion. The scores associated with the two AMs matched well consistently. Our method may be used in delayed PET imaging, which allows no secondary CT radiation in delayed phase. The quantitative analysis for lesion detection purpose could be ensured.

Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

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

Yu, Xiao-Jing; Zhang, Dong-Mei; Jia, Lin-Lin

We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocytemore » diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines. • PVN inhibition of NF-κB attenuates PVN NF-κB p65 activity and oxidative stress.« less

Turning self-destructing Salmonella into a universal DNA vaccine delivery platform.

PubMed

Kong, Wei; Brovold, Matthew; Koeneman, Brian A; Clark-Curtiss, Josephine; Curtiss, Roy

2012-11-20

We previously developed a biological containment system using recombinant Salmonella Typhimurium strains that are attenuated yet capable of synthesizing protective antigens. The regulated delayed attenuation and programmed self-destructing features designed into these S. Typhimurium strains enable them to efficiently colonize host tissues and allow release of the bacterial cell contents after lysis. To turn such a recombinant attenuated Salmonella vaccine (RASV) strain into a universal DNA vaccine-delivery vehicle, our approach was to genetically modify RASV strains to display a hyperinvasive phenotype to maximize Salmonella host entry and host cell internalization, to enable Salmonella endosomal escape to release a DNA vaccine into the cytosol, and to decrease Salmonella-induced pyroptosis/apoptosis that allows the DNA vaccine time to traffic to the nucleus for efficient synthesis of encoded protective antigens. A DNA vaccine vector that encodes a domain that contributes to the arabinose-regulated lysis phenotype but has a eukaryotic promoter was constructed. The vector was then improved by insertion of multiple DNA nuclear-targeting sequences for efficient nuclear trafficking and gene expression, and by increasing nuclease resistance to protect the plasmid from host degradation. A DNA vaccine encoding influenza WSN virus HA antigen delivered by the RASV strain with the best genetic attributes induced complete protection to mice against a lethal influenza virus challenge. Adoption of these technological improvements will revolutionize means for effective delivery of DNA vaccines to stimulate mucosal, systemic, and cellular protective immunities, and lead to a paradigm shift in cost-effective control and prevention of a diversity of diseases.

Turning self-destructing Salmonella into a universal DNA vaccine delivery platform

PubMed Central

Kong, Wei; Brovold, Matthew; Koeneman, Brian A.; Clark-Curtiss, Josephine; Curtiss, Roy

2012-01-01

We previously developed a biological containment system using recombinant Salmonella Typhimurium strains that are attenuated yet capable of synthesizing protective antigens. The regulated delayed attenuation and programmed self-destructing features designed into these S. Typhimurium strains enable them to efficiently colonize host tissues and allow release of the bacterial cell contents after lysis. To turn such a recombinant attenuated Salmonella vaccine (RASV) strain into a universal DNA vaccine-delivery vehicle, our approach was to genetically modify RASV strains to display a hyperinvasive phenotype to maximize Salmonella host entry and host cell internalization, to enable Salmonella endosomal escape to release a DNA vaccine into the cytosol, and to decrease Salmonella-induced pyroptosis/apoptosis that allows the DNA vaccine time to traffic to the nucleus for efficient synthesis of encoded protective antigens. A DNA vaccine vector that encodes a domain that contributes to the arabinose-regulated lysis phenotype but has a eukaryotic promoter was constructed. The vector was then improved by insertion of multiple DNA nuclear-targeting sequences for efficient nuclear trafficking and gene expression, and by increasing nuclease resistance to protect the plasmid from host degradation. A DNA vaccine encoding influenza WSN virus HA antigen delivered by the RASV strain with the best genetic attributes induced complete protection to mice against a lethal influenza virus challenge. Adoption of these technological improvements will revolutionize means for effective delivery of DNA vaccines to stimulate mucosal, systemic, and cellular protective immunities, and lead to a paradigm shift in cost-effective control and prevention of a diversity of diseases. PMID:23129620

Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.

PubMed

Pang, Min-Hee; Kim, Nam-Soo; Kim, Il-Hwan; Kim, Hyun; Kim, Hyun-Taek; Choi, June-Seek

2010-09-01

Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected. Copyright 2010 Elsevier Inc. All rights reserved.

Forward masking as a mechanism of automatic gain control in odontocete biosonar: a psychophysical study.

PubMed

Supin, Alexander Ya; Nachtigall, Paul E; Breese, Marlee

2008-07-01

In a false killer whale Pseudorca crassidens, echo perception thresholds were measured using a go/no-go psychophysical paradigm and one-up-one-down staircase procedure. Computer controlled echoes were electronically synthesized pulses that were played back through a transducer and triggered by whale emitted biosonar pulses. The echo amplitudes were proportional to biosonar pulse amplitudes; echo levels were specified in terms of the attenuation of the echo sound pressure level near the animal's head relative to the source level of the biosonar pulses. With increasing echo delay, the thresholds (echo attenuation factor) decreased from -49.3 dB at 2 ms to -79.5 dB at 16 ms, with a regression slope of -9.5 dB per delay doubling (-31.5 dB per delay decade). At the longer delays, the threshold remained nearly constant around -80.4 dB. Levels of emitted pulses slightly increased with delay prolongation (threshold decrease), with a regression slope of 3.2 dB per delay doubling (10.7 dB per delay decade). The echo threshold dependence on delay is interpreted as a release from forward masking by the preceding emitted pulse. This release may compensate for the echo level decrease with distance, thus keeping the echo sensation level for the animal near constant within a certain distance range.

β1-adrenergic regulation of rapid component of delayed rectifier K+ currents in guinea-pig cardiac myocytes.

PubMed

Wang, Sen; Xu, Di; Wu, Ting-Ting; Guo, Yan; Chen, Yan-Hong; Zou, Jian-Gang

2014-05-01

Human ether-à-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current (IKr), which is crucial for repolarization of cardiac action potential. Patients with hERG‑associated long QT syndrome usually develop tachyarrhythmias during physical and/or emotional stress, both known to stimulate adrenergic receptors. The present study aimed to investigate a putative functional link between β1-adrenergic stimulation and IKr in guinea-pig left ventricular myocytes and to analyze how IKr is regulated following activation of the β1-adrenergic signaling pathway. The IKr current was measured using a whole-cell patch-clamp technique. A selective β1-adrenergic receptor agonist, xamoterol, at concentrations of 0.01-100 µM decreased IKr in a concentration-dependent manner. The 10 µM xamoterol-induced inhibition of IKr was attenuated by the protein kinase A (PKA) inhibitor KT5720, the protein kinase C (PKC) inhibitor chelerythrine, and the phospholipase (PLC) inhibitor U73122, indicating involvement of PKA, PKC and PLC in β1-adrenergic inhibition of IKr. The results of the present study indicate an association between IKr and the β1-adrenergic receptor in arrhythmogenesis, involving the activation of PKA, PKC and PLC.

Statistical Modelling and Characterization of Experimental mm-Wave Indoor Channels for Future 5G Wireless Communication Networks

PubMed Central

Al-Samman, A. M.; Rahman, T. A.; Azmi, M. H.; Hindia, M. N.; Khan, I.; Hanafi, E.

2016-01-01

This paper presents an experimental characterization of millimeter-wave (mm-wave) channels in the 6.5 GHz, 10.5 GHz, 15 GHz, 19 GHz, 28 GHz and 38 GHz frequency bands in an indoor corridor environment. More than 4,000 power delay profiles were measured across the bands using an omnidirectional transmitter antenna and a highly directional horn receiver antenna for both co- and cross-polarized antenna configurations. This paper develops a new path-loss model to account for the frequency attenuation with distance, which we term the frequency attenuation (FA) path-loss model and introduce a frequency-dependent attenuation factor. The large-scale path loss was characterized based on both new and well-known path-loss models. A general and less complex method is also proposed to estimate the cross-polarization discrimination (XPD) factor of close-in reference distance with the XPD (CIX) and ABG with the XPD (ABGX) path-loss models to avoid the computational complexity of minimum mean square error (MMSE) approach. Moreover, small-scale parameters such as root mean square (RMS) delay spread, mean excess (MN-EX) delay, dispersion factors and maximum excess (MAX-EX) delay parameters were used to characterize the multipath channel dispersion. Multiple statistical distributions for RMS delay spread were also investigated. The results show that our proposed models are simpler and more physically-based than other well-known models. The path-loss exponents for all studied models are smaller than that of the free-space model by values in the range of 0.1 to 1.4 for all measured frequencies. The RMS delay spread values varied between 0.2 ns and 13.8 ns, and the dispersion factor values were less than 1 for all measured frequencies. The exponential and Weibull probability distribution models best fit the RMS delay spread empirical distribution for all of the measured frequencies in all scenarios. PMID:27654703

Statistical Modelling and Characterization of Experimental mm-Wave Indoor Channels for Future 5G Wireless Communication Networks.

PubMed

Al-Samman, A M; Rahman, T A; Azmi, M H; Hindia, M N; Khan, I; Hanafi, E

This paper presents an experimental characterization of millimeter-wave (mm-wave) channels in the 6.5 GHz, 10.5 GHz, 15 GHz, 19 GHz, 28 GHz and 38 GHz frequency bands in an indoor corridor environment. More than 4,000 power delay profiles were measured across the bands using an omnidirectional transmitter antenna and a highly directional horn receiver antenna for both co- and cross-polarized antenna configurations. This paper develops a new path-loss model to account for the frequency attenuation with distance, which we term the frequency attenuation (FA) path-loss model and introduce a frequency-dependent attenuation factor. The large-scale path loss was characterized based on both new and well-known path-loss models. A general and less complex method is also proposed to estimate the cross-polarization discrimination (XPD) factor of close-in reference distance with the XPD (CIX) and ABG with the XPD (ABGX) path-loss models to avoid the computational complexity of minimum mean square error (MMSE) approach. Moreover, small-scale parameters such as root mean square (RMS) delay spread, mean excess (MN-EX) delay, dispersion factors and maximum excess (MAX-EX) delay parameters were used to characterize the multipath channel dispersion. Multiple statistical distributions for RMS delay spread were also investigated. The results show that our proposed models are simpler and more physically-based than other well-known models. The path-loss exponents for all studied models are smaller than that of the free-space model by values in the range of 0.1 to 1.4 for all measured frequencies. The RMS delay spread values varied between 0.2 ns and 13.8 ns, and the dispersion factor values were less than 1 for all measured frequencies. The exponential and Weibull probability distribution models best fit the RMS delay spread empirical distribution for all of the measured frequencies in all scenarios.

Good things come to those who wait: attenuated discounting of delayed rewards in aged Fischer 344 rats

PubMed Central

Simon, Nicholas W.; LaSarge, Candi L.; Montgomery, Karienn S.; Williams, Matthew T.; Mendez, Ian A.; Setlow, Barry; Bizon, Jennifer

2010-01-01

The ability to make advantageous choices among outcomes that differ in magnitude, probability, and delay until their arrival is critical for optimal survival and well-being across the lifespan. Aged individuals are often characterized as less impulsive in their choices than their young adult counterparts, demonstrating an increased ability to forgo immediate in favor of delayed (and often more beneficial) rewards. Such “wisdom” is usually characterized as a consequence of learning and life experience. However, aging is also associated with prefrontal cortical dysfunction and concomitant impairments in advantageous choice behavior. Animal models afford the opportunity to isolate the effects of biological aging on decision making from experiential factors. To model one critical component of decision making, young adult and aged Fischer 344 rats were trained on a two-choice delay discounting task in which one choice provided immediate delivery of a small reward and the other provided a large reward delivered after a variable delay period. Whereas young adult rats showed a characteristic pattern of choice behavior (choosing the large reward at short delays and shifting preference to the small reward as delays increased), aged rats maintained a preference for the large reward at all delays (i.e. – attenuated “discounting” of delayed rewards). This increased preference for the large reward in aged rats was not due to perceptual, motor, or motivational factors. The data strongly suggest that, independent of life experience, there are underlying neurobiological factors that contribute to age-related changes in decision making, and particularly the ability to delay gratification. PMID:18657883

Lycopene attenuates Aβ1-42 secretion and its toxicity in human cell and Caenorhabditis elegans models of Alzheimer disease.

PubMed

Chen, Wei; Mao, Liuqun; Xing, Huanhuan; Xu, Lei; Fu, Xiang; Huang, Liyingzi; Huang, Dongling; Pu, Zhijun; Li, Qinghua

2015-11-03

Growing evidence suggests concentration of lycopene was reduced in plasma of patients with Alzheimer disease (AD). Lycopene, a member of the carotenoid family, has been identified as an antioxidant to attenuate oxidative damage and has neuroprotective role in several AD models. However, whether lycopene is involved in the pathogenesis of AD and molecular underpinnings are elusive. In this study, we found that lycopene can significantly delay paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101. Lycopene treatment reduced Aβ1-42 secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found lycopene can down-regulate expression level of β-amyloid precursor protein(APP) in APPsw cells. Moreover, lycopene treatment can not change endogenous reactive oxygen species level and apoptosis in APPsw cells. However, lycopene treatment protected against H2O2-induced oxidative stress and copper-induced damage in APPsw cells. Collectively, our data support that elevated lycopene contributes to the lower pathogenesis of AD. Our findings suggest that increasing lycopene in neurons may be a novel approach to attenuate onset and development of AD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes

NASA Astrophysics Data System (ADS)

Hata, Kenji; Takashima, Rikako; Amano, Katsuhiko; Ono, Koichiro; Nakanishi, Masako; Yoshida, Michiko; Wakabayashi, Makoto; Matsuda, Akio; Maeda, Yoshinobu; Suzuki, Yutaka; Sugano, Sumio; Whitson, Robert H.; Nishimura, Riko; Yoneda, Toshiyuki

2013-11-01

Histone modification, a critical step for epigenetic regulation, is an important modulator of biological events. Sox9 is a transcription factor critical for endochondral ossification; however, proof of its epigenetic regulation remains elusive. Here we identify AT-rich interactive domain 5b (Arid5b) as a transcriptional co-regulator of Sox9. Arid5b physically associates with Sox9 and synergistically induces chondrogenesis. Growth of Arid5b-/- mice is retarded with delayed endochondral ossification. Sox9-dependent chondrogenesis is attenuated in Arid5b-deficient cells. Arid5b recruits Phf2, a histone lysine demethylase, to the promoter region of Sox9 target genes and stimulates H3K9me2 demethylation of these genes. In the promoters of chondrogenic marker genes, H3K9me2 levels are increased in Arid5b-/- chondrocytes. Finally, we show that Phf2 knockdown inhibits Sox9-induced chondrocyte differentiation. Our findings establish an epigenomic mechanism of skeletal development, whereby Arid5b promotes chondrogenesis by facilitating Phf2-mediated histone demethylation of Sox9-regulated chondrogenic gene promoters.

Effects of filtering of harmonics from biosonar echoes on delay acuity by big brown bats (Eptesicus fuscus).

PubMed

Bates, Mary E; Simmons, James A

2010-08-01

Big brown bats emit FM biosonar sounds containing two principal harmonics (FM1 approximately 55-22 kHz;FM2 approximately 105-45 kHz). To examine the role of harmonics, they were selectively filtered from stimuli in electronic-echo delay discrimination experiments. Positive stimuli were delayed by 3.16 ms (55 cm simulated target range); negative stimuli were by delayed by 3.96 ms (68 cm). This large 800-micros delay difference (nearly 14 cm) was easily discriminated for echoes containing equal-strength FM1 and FM2. Performance gradually decreased as highpass filters removed progressively larger segments from FM1. For echoes with FM2 alone, performance collapsed to chance, but performance remained good for lowpass echoes containing FM1 alone. Attenuation of FM2 by 3 dB relative to FM1 also decreased performance, but shortening electronic delay of the attenuated FM2 by 48 micros counteracted amplitude-latency trading and restored performance. Bats require the auditory representations of FM1 and FM2 to be in temporal register for high delay acuity. Misalignment of neuronal responses degrades acuity, but outright removal of FM2, leaving only FM1, causes little loss of acuity. Functional asymmetry of harmonics reflects lowpass effects from beaming and atmospheric propagation, which leave FM1 intact. It may cooperate with latency shifts to aid in suppression of clutter.

48 CFR 42.1304 - Government delay of work.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Government delay of work. 42.1304 Section 42.1304 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Government Delay of Work 42.1304 Government delay of work. (a) The clause at 52.242-17, Government Delay of...

48 CFR 42.1304 - Government delay of work.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Government delay of work. 42.1304 Section 42.1304 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Government Delay of Work 42.1304 Government delay of work. (a) The clause at 52.242-17, Government Delay of...

Apparatus and process for active pulse intensity control of laser beam

DOEpatents

Wilcox, Russell B.

1992-01-01

An optically controlled laser pulse energy control apparatus and process is disclosed wherein variations in the energy of a portion of the laser beam are used to vary the resistance of a photodetector such as a photoresistor through which a control voltage is fed to a light intensity controlling device through which a second portion of the laser beam passes. Light attenuation means are provided to vary the intensity of the laser light used to control the resistance of the photodetector. An optical delay path is provided through which the second portion of the beam travels before reaching the light intensity controlling device. The control voltage is supplied by a variable power supply. The apparatus may be tuned to properly attenuate the laser beam passing through the intensity controlling device by adjusting the power supply, the optical delay path, or the light attenuating means.

Inhibition of GSK-3β Rescues the Impairments in Bone Formation and Mechanical Properties Associated with Fracture Healing in Osteoblast Selective Connexin 43 Deficient Mice

PubMed Central

Loiselle, Alayna E.; Lloyd, Shane A. J.; Paul, Emmanuel M.; Lewis, Gregory S.; Donahue, Henry J.

2013-01-01

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/ Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair. PMID:24260576

Active doublet method for measuring small changes in physical properties

DOEpatents

Roberts, Peter M.; Fehler, Michael C.; Johnson, Paul A.; Phillips, W. Scott

1994-01-01

Small changes in material properties of a work piece are detected by measuring small changes in elastic wave velocity and attenuation within a work piece. Active, repeatable source generate coda wave responses from a work piece, where the coda wave responses are temporally displaced. By analyzing progressive relative phase and amplitude changes between the coda wave responses as a function of elapsed time, accurate determinations of velocity and attenuation changes are made. Thus, a small change in velocity occurring within a sample region during the time periods between excitation origin times (herein called "doublets") will produce a relative delay that changes with elapsed time over some portion of the scattered waves. This trend of changing delay is easier to detect than an isolated delay based on a single arrival and provides a direct measure of elastic wave velocity changes arising from changed material properties of the work piece.

Nitric-oxide synthase trafficking inducer is a pleiotropic regulator of endothelial cell function and signaling

PubMed Central

2017-01-01

Endothelial nitric-oxide synthase (eNOS) and its bioactive product, nitric oxide (NO), mediate many endothelial cell functions, including angiogenesis and vascular permeability. For example, vascular endothelial growth factor (VEGF)-mediated angiogenesis is inhibited upon reduction of NO bioactivity both in vitro and in vivo. Moreover, genetic disruption or pharmacological inhibition of eNOS attenuates angiogenesis during tissue repair, resulting in delayed wound closure. These observations emphasize that eNOS-derived NO can promote angiogenesis. Intriguingly, eNOS activity is regulated by nitric-oxide synthase trafficking inducer (NOSTRIN), which sequesters eNOS, thereby attenuating NO production. This has prompted significant interest in NOSTRIN's function in endothelial cells. We show here that NOSTRIN affects the functional transcriptome of endothelial cells by down-regulating several genes important for invasion and angiogenesis. Interestingly, the effects of NOSTRIN on endothelial gene expression were independent of eNOS activity. NOSTRIN also affected the expression of secreted cytokines involved in inflammatory responses, and ectopic NOSTRIN overexpression functionally restricted endothelial cell proliferation, invasion, adhesion, and VEGF-induced capillary tube formation. Furthermore, NOSTRIN interacted directly with TNF receptor-associated factor 6 (TRAF6), leading to the suppression of NFκB activity and inhibition of AKT activation via phosphorylation. Interestingly, TNF-α-induced NFκB pathway activation was reversed by NOSTRIN. We found that the SH3 domain of NOSTRIN is involved in the NOSTRIN-TRAF6 interaction and is required for NOSTRIN-induced down-regulation of endothelial cell proteins. These results have broad biological implications, as aberrant NOSTRIN expression leading to deactivation of the NFκB pathway, in turn triggering an anti-angiogenic cascade, might inhibit tumorigenesis and cancer progression. PMID:28235804

Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells.

PubMed

Papaconstantinou, John; Wang, Chen Z; Zhang, Min; Yang, San; Deford, James; Bulavin, Dmitry V; Ansari, Naseem H

2015-09-01

Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factorsi.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age-associated increase of p38α stress response signaling. This suggests that the maintenance of low levels of p38α activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38α mouse (DN-p38α(AF/+)) to demonstrate that in vivo attenuation of p38α activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16(Ink4a) and p19(Arf) tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38α activity promotes skeletal muscle aging and that the homeostasis of p38α impacts the maintenance of a beneficial healthspan.

Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up-regulating regulatory T cells.

PubMed

Liu, Xia; Ji, Baoju; Sun, Mengyi; Wu, Weijiang; Huang, Lili; Sun, Aihua; Zong, Yangyong; Xia, Sheng; Shi, Liyun; Qian, Hui; Xu, Wenrong; Shao, Qixiang

2015-07-01

Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-γ expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORγt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy. © 2015 British Society for Immunology.

Effects of filtering of harmonics from biosonar echoes on delay acuity by big brown bats (Eptesicus fuscus)

PubMed Central

Bates, Mary E.; Simmons, James A.

2010-01-01

Big brown bats emit FM biosonar sounds containing two principal harmonics (FM1∼55–22 kHz;FM2∼105–45 kHz). To examine the role of harmonics, they were selectively filtered from stimuli in electronic-echo delay discrimination experiments. Positive stimuli were delayed by 3.16 ms (55 cm simulated target range); negative stimuli were by delayed by 3.96 ms (68 cm). This large 800-μs delay difference (nearly 14 cm) was easily discriminated for echoes containing equal-strength FM1 and FM2. Performance gradually decreased as highpass filters removed progressively larger segments from FM1. For echoes with FM2 alone, performance collapsed to chance, but performance remained good for lowpass echoes containing FM1 alone. Attenuation of FM2 by 3 dB relative to FM1 also decreased performance, but shortening electronic delay of the attenuated FM2 by 48 μs counteracted amplitude-latency trading and restored performance. Bats require the auditory representations of FM1 and FM2 to be in temporal register for high delay acuity. Misalignment of neuronal responses degrades acuity, but outright removal of FM2, leaving only FM1, causes little loss of acuity. Functional asymmetry of harmonics reflects lowpass effects from beaming and atmospheric propagation, which leave FM1 intact. It may cooperate with latency shifts to aid in suppression of clutter. PMID:20707464

Inhibition of bleomycin-induced pulmonary fibrosis by bone marrow-derived mesenchymal stem cells might be mediated by decreasing MMP9, TIMP-1, INF-γ and TGF-β.

PubMed

Yu, Shi-huan; Liu, Li-jie; Lv, Bin; Che, Chun-li; Fan, Da-ping; Wang, Li-feng; Zhang, Yi-mei

2015-08-01

The study was aimed to investigate the mechanism and administration timing of bone marrow-derived mesenchymal stem cells (BMSCs) in bleomycin (BLM)-induced pulmonary fibrosis mice. Thirty-six mice were divided into six groups: control group (saline), model group (intratracheal administration of BLM), day 1, day 3 and day 6 BMSCs treatment groups and hormone group (hydrocortisone after BLM treatment). BMSCs treatment groups received BMSCs at day 1, 3 or 6 following BLM treatment, respectively. Haematoxylin and eosin and Masson staining were conducted to measure lung injury and fibrosis, respectively. Matrix metalloproteinase (MMP9), tissue inhibitor of metalloproteinase-1 (TIMP-1), γ-interferon (INF-γ) and transforming growth factor β1 (TGF-β) were detected in both lung tissue and serum. Histologically, the model group had pronounced lung injury, increased inflammatory cells and collagenous fibres and up-regulated MMP9, TIMP-1, INF-γ and TGF-β compared with control group. The histological appearance of lung inflammation and fibrosis and elevation of these parameters were inhibited in BMSCs treatment groups, among which, day 3 and day 6 treatment groups had less inflammatory cells and collagenous fibres than day 1 treatment group. BMSCs might suppress lung fibrosis and inflammation through down-regulating MMP9, TIMP-1, INF-γ and TGF-β. Delayed BMSCs treatment might exhibit a better therapeutic effect. Highlights are as follows: 1. BMSCs repair lung injury induced by BLM. 2. BMSCs attenuate pulmonary fibrosis induced by BLM. 3. BMSCs transplantation down-regulates MMP9 and TIMP-1. 4. BMSCs transplantation down-regulates INF-γ and TGF-β. 5. Delayed transplantation timing of BMSCs might exhibit a better effect against BLM. Copyright © 2015 John Wiley & Sons, Ltd.

Simultaneous Ka-Band Site Characterization: Goldstone, CA, White Sands, NM, and Guam, USA

NASA Technical Reports Server (NTRS)

Acosta, Roberto; Morse, Jacquelynne; Zemba, Michael; Nessel, James; Morabito, David; Caroglanian, Armen

2011-01-01

To statistically characterize atmospheric effects on Ka-band links at NASA operational sites, NASA has constructed site test interferometers (STI s) which directly measure the tropospheric phase stability and rain attenuation. These instruments observe an unmodulated beacon signal broadcast from a geostationary satellite (e.g., Anik F2) and measure the phase difference between the signals received by the two antennas and its signal attenuation. Three STI s have been deployed so far: the first one at the NASA Deep Space Network Tracking Complex in Goldstone, California (May 2007); the second at the NASA White Sands Complex, in Las Cruses, New Mexico (February 2009); and the third at the NASA Tracking and Data Relay Satellite (TDRS) Remote Ground Terminal (GRGT) complex in Guam (May 2010). Two station-years of simultaneous atmospheric phase fluctuation data have been collected at Goldstone and White Sands, while one year of data has been collected in Guam. With identical instruments operating simultaneously, we can directly compare the phase stability and rain attenuation at the three sites. Phase stability is analyzed statistically in terms of the root-mean-square (rms) of the tropospheric induced time delay fluctuations over 10 minute blocks. For two years, the time delay fluctuations at the DSN site in Goldstone, CA, have been better than 2.5 picoseconds (ps) for 90% of the time (with reference to zenith), meanwhile at the White Sands, New Mexico site, the time delay fluctuations have been better than 2.2 ps with reference to zenith) for 90% of time. For Guam, the time delay fluctuations have been better than 12 ps (reference to zenith) at 90% of the time, the higher fluctuations are as expected from a high humidity tropical rain zone. This type of data analysis, as well as many other site quality characteristics (e.g., rain attenuation, infrastructure, etc.) will be used to determine the suitability of all the sites for NASA s future communication services at Ka-band.

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

PubMed Central

Chauhan, Neha; Visram, Myriam; Cristobal-Sarramian, Alvaro; Sarkleti, Florian

2015-01-01

Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle–dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle–dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long-chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2ACdc55) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle. PMID:25713391

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression.

PubMed

Chauhan, Neha; Visram, Myriam; Cristobal-Sarramian, Alvaro; Sarkleti, Florian; Kohlwein, Sepp D

2015-03-10

Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long-chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A(Cdc55)) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.

Deep hypothermia therapy attenuates LPS-induced microglia neuroinflammation via the STAT3 pathway.

PubMed

Tong, G; Krauss, A; Mochner, J; Wollersheim, S; Soltani, P; Berger, F; Schmitt, K R L

2017-09-01

Deep hypothermia therapy (HT) is a standard method for neuroprotection during complex pediatric cardiac surgery involving extracorporeal circulation and deep hypothermic cardiac arrest. The procedure, however, can provoke systemic inflammatory response syndrome (SIRS), one of the most severe side effects associated with pediatric cardiac surgery. To date, the cellular inflammatory mechanisms induced by deep HT remain to be elucidated. Therefore, we investigated the effects of deep HT (17°C) and rewarming on the inflammatory response in lipopolysaccharide (LPS) stimulated BV-2 murine microglia. Additionally, we also investigated the application of Stattic, a signal transducer and activator of transcription 3 (STAT3) activation inhibitor, as an alternative to physical cooling to attenuate the LPS-induced inflammatory response. Deep HT had no cytotoxic effect but attenuated microglia migration. IκBα degradation was delayed by deep HT resulting in the attenuation of pNF-κB p65 migration into the nucleus and significant decreases in pro-inflammatory IL-6, TNF-α, and MCP-1 expressions and secretions, as well as decreased anti-inflammatory IL-10 and SOCS3 expressions. Additionally, pStat3 was significantly down regulated under deep hypothermic conditions, also corresponding with the significant reduction in IL-6 and TNF-α expressions. Similar to the effects of HT, the application of Stattic under normothermic conditions resulted in significantly reduced IL-6 and TNF-α expressions. Moreover, attenuation of the inflammatory response resulted in decreased apoptosis in a direct co-culture of microglia and neurons. HT reduces the inflammatory response in LPS-stimulated BV-2 microglial cells, alluding to a possible mechanism of therapeutic hypothermia-induced neuroprotection. In the future, attenuating the phospho-STAT3 pathway may lead to the development of a neuroprotectant with greater clinical efficacy. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Two-Phase Helical Computed Tomography Study of Salivary Gland Warthin Tumors: A Radiologic Findings and Surgical Applications

PubMed Central

Joo, Yeon Hee; Kim, Jin Pyeong; Park, Jung Je

2014-01-01

Objectives The goal of this study was to define the radiologic characteristics of two-phase computed tomography (CT) of salivary gland Warthin tumors and to compare them to pleomorphic adenomas. We also aimed to provide a foundation for selecting a surgical method on the basis of radiologic findings. Methods We prospectively enrolled 116 patients with parotid gland tumors, who underwent two-phase CT preoperatively. Early and delayed phase scans were obtained, with scanning delays of 30 and 120 seconds, respectively. The attenuation changes and enhancement patterns were analyzed. In cases when the attenuation changes were decreased, we presumed Warthin tumor preoperatively and performed extracapsular dissection. When the attenuation changes were increased, superficial parotidectomy was performed on the parotid gland tumors. We analyzed the operation times, incision sizes, complications, and recurrence rates. Results Attenuation of Warthin tumors was decreased from early to delayed scans. The ratio of CT numbers in Warthin tumors was also significantly different from other tumors. Warthin tumors were diagnosed with a sensitivity of 96.1% and specificity of 97% using two-phase CT. The mean operation time was 38 minutes and the mean incision size was 36.2 mm for Warthin tumors. However, for the other parotid tumors, the average operation time was 122 minutes and the average incision size was 91.8 mm (P<0.05). Conclusion Salivary Warthin tumor has a distinct pattern of contrast enhancement on two-phase CT, which can guide treatment decisions. The preoperative diagnosis of Warthin tumor made extracapsular dissection possible instead of superficial parotidectomy. PMID:25177439

Two-phase helical computed tomography study of salivary gland warthin tumors: a radiologic findings and surgical applications.

PubMed

Joo, Yeon Hee; Kim, Jin Pyeong; Park, Jung Je; Woo, Seung Hoon

2014-09-01

The goal of this study was to define the radiologic characteristics of two-phase computed tomography (CT) of salivary gland Warthin tumors and to compare them to pleomorphic adenomas. We also aimed to provide a foundation for selecting a surgical method on the basis of radiologic findings. We prospectively enrolled 116 patients with parotid gland tumors, who underwent two-phase CT preoperatively. Early and delayed phase scans were obtained, with scanning delays of 30 and 120 seconds, respectively. The attenuation changes and enhancement patterns were analyzed. In cases when the attenuation changes were decreased, we presumed Warthin tumor preoperatively and performed extracapsular dissection. When the attenuation changes were increased, superficial parotidectomy was performed on the parotid gland tumors. We analyzed the operation times, incision sizes, complications, and recurrence rates. Attenuation of Warthin tumors was decreased from early to delayed scans. The ratio of CT numbers in Warthin tumors was also significantly different from other tumors. Warthin tumors were diagnosed with a sensitivity of 96.1% and specificity of 97% using two-phase CT. The mean operation time was 38 minutes and the mean incision size was 36.2 mm for Warthin tumors. However, for the other parotid tumors, the average operation time was 122 minutes and the average incision size was 91.8 mm (P<0.05). Salivary Warthin tumor has a distinct pattern of contrast enhancement on two-phase CT, which can guide treatment decisions. The preoperative diagnosis of Warthin tumor made extracapsular dissection possible instead of superficial parotidectomy.

Antagonistic regulation, yet synergistic defense: effect of bergapten and protease inhibitor on development of cowpea bruchid Callosobruchus maculatus.

PubMed

Guo, Fengguang; Lei, Jiaxin; Sun, Yucheng; Chi, Yong Hun; Ge, Feng; Patil, Bhimanagouda S; Koiwa, Hisashi; Zeng, Rensen; Zhu-Salzman, Keyan

2012-01-01

The furanocoumarin compound bergapten is a plant secondary metabolite that has anti-insect function. When incorporated into artificial diet, it retarded cowpea bruchid development, decreased fecundity, and caused mortality at a sufficient dose. cDNA microarray analysis indicated that cowpea bruchid altered expression of 543 midgut genes in response to dietary bergapten. Among these bergapten-regulated genes, 225 have known functions; for instance, those encoding proteins related to nutrient transport and metabolism, development, detoxification, defense and various cellular functions. Such differential gene regulation presumably facilitates the bruchids' countering the negative effect of dietary bergapten. Many genes did not have homology (E-value cutoff 10(-6)) with known genes in a BlastX search (206), or had homology only with genes of unknown function (112). Interestingly, when compared with the transcriptomic profile of cowpea bruchids treated with dietary soybean cysteine protease inhibitor N (scN), 195 out of 200 coregulated midgut genes are oppositely regulated by the two compounds. Simultaneous administration of bergapten and scN attenuated magnitude of change in selected oppositely-regulated genes, as well as led to synergistic delay in insect development. Therefore, targeting insect vulnerable sites that may compromise each other's counter-defensive response has the potential to increase the efficacy of the anti-insect molecules.

Regulation of endocytosis via the oxygen-sensing pathway.

PubMed

Wang, Yi; Roche, Olga; Yan, Mathew S; Finak, Greg; Evans, Andrew J; Metcalf, Julie L; Hast, Bridgid E; Hanna, Sara C; Wondergem, Bill; Furge, Kyle A; Irwin, Meredith S; Kim, William Y; Teh, Bin T; Grinstein, Sergio; Park, Morag; Marsden, Philip A; Ohh, Michael

2009-03-01

Tumor hypoxia is associated with disease progression, resistance to conventional cancer therapies and poor prognosis. Hypoxia, by largely unknown mechanisms, leads to deregulated accumulation of and signaling via receptor tyrosine kinases (RTKs) that are critical for driving oncogenesis. Here, we show that hypoxia or loss of von Hippel-Lindau protein--the principal negative regulator of hypoxia-inducible factor (HIF)--prolongs the activation of epidermal growth factor receptor that is attributable to lengthened receptor half-life and retention in the endocytic pathway. The deceleration in endocytosis is due to the attenuation of Rab5-mediated early endosome fusion via HIF-dependent downregulation of a critical Rab5 effector, rabaptin-5, at the level of transcription. Primary kidney and breast tumors with strong hypoxic signatures show significantly lower expression of rabaptin-5 RNA and protein. These findings reveal a general role of the oxygen-sensing pathway in endocytosis and support a model in which tumor hypoxia or oncogenic activation of HIF prolongs RTK-mediated signaling by delaying endocytosis-mediated deactivation of receptors.

Regulation of EGF receptor signaling by the MARVEL domain-containing protein CKLFSF8.

PubMed

Jin, Caining; Ding, Peiguo; Wang, Ying; Ma, Dalong

2005-11-21

It is known that chemokine-like factor superfamily 8 (CKLFSF8), a member of the CKLF superfamily, has four putative transmembrane regions and a MARVEL domain. Its structure is similar to TM4SF11 (plasmolipin) and widely distributed in normal tissue. However, its function is not yet known. We show here that CKLFSF8 is associated with the epidermal growth factor receptor (EGFR) and that ectopic expression of CKLFSF8 in several cell lines suppresses EGF-induced cell proliferation, whereas knockdown of CKLFSF8 by siRNA promotes cell proliferation. In cells overexpressing CKLFSF8, the initial activation of EGFR was not affected, but subsequent desensitization of EGF-induced signaling occurred rapidly. This attenuation was correlated with an increased rate of receptor endocytosis. In contrast, knockdown of CKLFSF8 by siCKLFSF8 delayed EGFR endocytosis. These results identify CKLFSF8 as a novel regulator of EGF-induced signaling and indicate that the association of EGFR with four transmembrane proteins is critical for EGFR desensitization.

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

Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.

Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/-more » mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.« less

48 CFR 3442.7003 - Delays clause.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Delays clause. 3442.7003 Section 3442.7003 Federal Acquisition Regulations System DEPARTMENT OF EDUCATION ACQUISITION REGULATION CONTRACT MANAGEMENT CONTRACT ADMINISTRATION Contract Monitoring 3442.7003 Delays clause. The contracting...

Modeling, Simulation, and Analysis of a Decoy State Enabled Quantum Key Distribution System

DTIC Science & Technology

2015-03-26

through the fiber , we assume Alice and Bob have correct basis alignment and timing control for reference frame correction and precise photon detection...optical components ( laser , polarization modulator, electronic variable optical attenuator, fixed optical attenuator, fiber channel, beamsplitter...generated by the laser in the CPG propagate through multiple optical components, each with a unique propagation delay before reaching the OPM. Timing

VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

PubMed

Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

2015-07-09

We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

Licochalcone E activates Nrf2/antioxidant response element signaling pathway in both neuronal and microglial cells: therapeutic relevance to neurodegenerative disease.

PubMed

Kim, Sa Suk; Lim, Juhee; Bang, Yeojin; Gal, Jiyeong; Lee, Sang-Uk; Cho, Young-Chang; Yoon, Goo; Kang, Bok Yun; Cheon, Seung Hoon; Choi, Hyun Jin

2012-10-01

Oxidative stress and neuroinflammation are hallmarks of neurodegenerative diseases, which do not play independently but work synergistically through complex interactions exacerbating neurodegeneration. Therefore, the mechanism that is directly implicated in controlling oxidative stress and inflammatory response could be an attractive strategy to prevent the onset and/or delay the progression of neurodegenerative diseases. The transcription factor nuclear factor-E2-related factor-2 (Nrf2) is the guardian of redox homeostasis by regulating a battery of antioxidant and phase II detoxification genes, which are relevant to defense mechanism against oxidative stress and inflammatory responses. In this study, we show that a recently identified Glycyrrhiza-inflata-derived chalcone, licochalcone E (Lico-E), attenuates lipopolysaccharide-induced inflammatory responses in microglial BV2 cells and protects dopaminergic SH-SY5Y cells from 6-hydroxydopamine cytotoxicity. Lico-E activates Nrf2-antioxidant response element (ARE) system and up-regulates downstream NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). Anti-inflammatory and cytoprotective effects of Lico-E are attenuated in siRNA-mediated Nrf2-silencing cells as well as in the presence with specific inhibitor of HO-1 or NQO1, respectively. Lico-E also has neuroprotective effect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal dopaminergic neurodegeneration in mice, with up-regulation of HO-1 and NQO1 in the substantia nigra of the brain. This study demonstrates that Lico-E is a potential activator of the Nrf2/ARE-dependent pathway and is therapeutically relevant not only to oxidative-stress-related neurodegeneration but also inflammatory responses of microglial cells both in vitro and in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

NDUFA4L2 protects against ischaemia/reperfusion-induced cardiomyocyte apoptosis and mitochondrial dysfunction by inhibiting complex I.

PubMed

Li, Jianhua; Bai, Caiyan; Guo, Junxia; Liang, Wanqian; Long, Jingning

2017-07-01

Myocardial ischaemia/reperfusion (I/R) injury may cause the apoptosis of cardiomyocytes as well as mitochondrial dysfunction. The aims of the present study were to investigate whether NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) on myocardial ischaemia-reperfusion (I/R) injury and the underlying molecular mechanism. The hypoxia-reperfusion (H/R) model was established in vitro using H9c2 cells to simulate I/R injury. NDUFA4L2 and complex I expression levels were detected using RT-PCR and western blot. The apoptosis of H9c2 cells was evaluated by flow cytometry and the expression of Bax and Bcl-2 was detected by western blot. The mitochondrial function was assessed by ATP concentration, mPTP opening and cytochrome c (cyto C) expression. Our data indicated that NDUFA4L2 expression was significantly down-regulated in myocardial H/R injury. Overexpression of NDUFA4L2 led to a dramatic prevention of H/R-induced apoptosis accompanied by a decrease in the expression of Bax and an increase in the expression of Bcl-2. Meanwhile, augmentation of NDUFA4L2 dramatically prevented mitochondrial dysfunction caused by H/R as reflecting in the increased ATP concentration, delayed mPTP opening, as well as down-regulated cyto C expression. Moreover, complex I activation was heightened and negatively regulated by NDUFA4L2. Silencing complex I conspicuously attenuated cell apoptosis and mitochondrial dysfunction. Taken together, our findings demonstrated that NDUFA4L2 protects against H/R injury by preventing myocardium apoptosis and mitochondrial dysfunction via the complex I, and may be a potential therapeutic approach for attenuating myocardial I/R injury. © 2017 John Wiley & Sons Australia, Ltd.

Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in vivo

PubMed Central

Esmaeili, Mohammad A.; Yadav, Shilpi; Gupta, Ravi Kr.; Waggoner, Garrett R.; Deloach, Abigail; Calingasan, Noel Y.; Beal, M. Flint; Kiaei, Mahmoud

2016-01-01

Neuroinflammation, immune reactivity and mitochondrial abnormalities are considered as causes and/or contributors to neuronal degeneration. Peroxisome proliferator-activated receptors (PPARs) regulate both inflammatory and multiple other pathways that are implicated in neurodegeneration. In the present study, we investigated the efficacy of fenofibrate (Tricor), a pan-PPAR agonist that activates PPAR-α as well as other PPARs. We administered fenofibrate to superoxide dismutase 1 (SOD1G93A) mice daily prior to any detectable phenotypes and then animal behavior, pathology and longevity were assessed. Treated animals showed a significant slowing of the progression of disease with weight loss attenuation, enhanced motor performance, delayed onset and survival extension. Histopathological analysis of the spinal cords showed that neuronal loss was significantly attenuated in fenofibrate-treated mice. Mitochondria were preserved as indicated by Cytochrome c immunostaining in the spinal cord, which maybe partly due to increased expression of the PPAR-γ co-activator 1-α. The total mRNA analysis revealed that neuroprotective and anti-inflammatory genes were elevated, while neuroinflammatory genes were down-regulated. This study demonstrates that the activation of PPAR-α action via fenofibrate leads to neuroprotection by both reducing neuroinflammation and protecting mitochondria, which leads to a significant increase in survival in SOD1G93A mice. Therefore, the development of therapeutic strategies to activate PPAR-α as well as other PPARs may lead to new therapeutic agents to slow or halt the progression of amyotrophic lateral sclerosis. PMID:26604138

Preventing Return of Fear in an Animal Model of Anxiety: Additive Effects of Massive Extinction and Extinction in Multiple Contexts

PubMed Central

Laborda, Mario A.; Miller, Ralph R.

2013-01-01

Fear conditioning and experimental extinction have been presented as models of anxiety disorders and exposure therapy, respectively. Moreover, the return of fear serves as a model of relapse after exposure therapy. Here we present two experiments, with rats as subjects in a lick suppression preparation, in which we assessed the additive effects of two different treatments to attenuate the return of fear. First, we evaluated whether two phenomena known to generate return of fear (i.e., spontaneous recovery and renewal) summate to produce a stronger reappearance of extinguished fear. At test, rats evaluated outside the extinction context following a long delay after extinction (i.e., a delayed context shift) exhibited greater return of extinguished fear than rats evaluated outside the extinction context alone, but return of extinguished fear following a delayed context shift did not significantly differ from the return of fear elicited in rats tested following a long delay after extinction alone. Additionally, extinction in multiple contexts and a massive extinction treatment each attenuated the strong return of fear produced by a delayed context shift. Moreover, the conjoint action of these treatments was significantly more successful in preventing the reappearance of extinguished fear, suggesting that extensive cue exposure administered in several different therapeutic settings has the potential to reduce relapse after therapy for anxiety disorders, more than either manipulation alone. PMID:23611075

Transfer of motor learning engages specific neural substrates during motor memory consolidation dependent on the practice structure.

PubMed

Kantak, Shailesh S; Sullivan, Katherine J; Fisher, Beth E; Knowlton, Barbara J; Winstein, Carolee J

2011-01-01

The authors investigated how brain activity during motor-memory consolidation contributes to transfer of learning to novel versions of a motor skill following distinct practice structures. They used 1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) immediately after constant or variable practice of an arm movement skill to interfere with primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC). The effect of interference was assessed through skill performance on two transfer targets: one within and one outside the range of practiced movement parameters for the variable practice group. For the control (no rTMS) group, variable practice benefited delayed transfer performance more than constant practice. The rTMS effect on delayed transfer performance differed for the two transfer targets. For the within-range target, rTMS interference had no significant affect on the delayed transfer after either practice structure. However, for the outside-range target, rTMS interference to DLPFC but not M1 attenuated delayed transfer benefit following variable practice. Additionally, for the outside-range target, rTMS interference to M1 but not DLPFC attenuated delayed transfer following constant practice. This suggests that variable practice may promote reliance on DLPFC for memory consolidation associated with outside-range transfer of learning, whereas constant practice may promote reliance on M1 for consolidation and long-term transfer.

Diabetes attenuates the inhibitory effects of endomorphin-2, but not endomorphin-1 on gastrointestinal transit in mice.

PubMed

Wang, Chang-lin; Diao, Yu-xiang; Xiang, Qiong; Ren, Yu-kun; Gu, Ning

2014-09-05

Diabetes affects the entire gastrointestinal tract from the esophagus to the anus. In the present study, the charcoal meal test was undertaken to evaluate and compare the effects of intracerebroventricular (i.c.v.) administration of endomorphins (EMs) on gastrointestinal transit in non-diabetic and diabetic mice. Significantly delayed gastrointestinal transit was found in both 4 and 8 weeks alloxan-induced diabetes compared to non-diabetes. Moreover, i.c.v. EM-1 and EM-2 dose-dependently delayed gastrointestinal transit in non-diabetes and diabetes. The EM-1-induced inhibitory effects of gastrointestinal transit in 4 weeks diabetes were qualitatively similar to those of non-diabetes. However, at higher doses, the EM-1-induced effects in 8 weeks diabetes were largely enhanced. Different to EM-1, the EM-2-induced inhibition of gastrointestinal transit in diabetic mice was significantly attenuated compared to non-diabetic mice. Moreover, these effects were further decreased in 8 weeks diabetes. The delayed gastrointestinal transit effects caused by EM-1 may be primarily mediated by μ2-opioid receptor in both non-diabetes and 4 weeks diabetes. Interestingly, in 8 weeks diabetes, these effects were mediated by μ2- and δ-receptors. However, the inhibitory effects of EM-2 were mediated by μ1-opioid receptor, which exerted a reduced function in diabetes. Also, poor blood glucose control might result in the attenuated effects of EM-2. Our present results demonstrated that diabetes attenuates the inhibitory effects of EM-2, but not EM-1 on gastrointestinal transit in mice. The different effects of EM-1 and EM-2 on gastrointestinal transit in diabetes may be due to changes of opioid receptor subtypes and their functional responses. Copyright © 2014 Elsevier B.V. All rights reserved.

Tissue identification by ultrasound

NASA Technical Reports Server (NTRS)

Lecroissette, D. H.; Heyser, R. C.; Gammell, P. M.; Wilson, R. L.

1978-01-01

The ultrasonic properties of animal and human soft tissue were measured over the frequency range of 1.5 to 10.0 MHz. The method employed a swept-frequency, coherent technique known as time delay spectrometry. Measurements of attenuation versus frequency on liver, backfat, kidney, pancreas, spleen, breast, and other tissue were made. Considerable attention was paid to tissue handling and in determining the effects of fixing on the attenuation of ultrasound in the tissue.

The newly identified K+ channel blocker talatisamine attenuates beta-amyloid oligomers induced neurotoxicity in cultured cortical neurons.

PubMed

Wang, Yanxia; Song, Mingke; Hou, Lina; Yu, Zhihua; Chen, Hongzhuan

2012-06-19

Loss of cytosolic K(+) through up-regulated delayed rectifier K(+) channels play an important role in beta-amyloid (Aβ) induced neurotoxicity. Potent K(+) channel blocker, particular specific for I(K) channels has been suggested as an attractive candidate for the treatment of Alzheimer's disease (AD). Talatisamine is a novel I(K) channel blocker discovered by virtual screening and electrophysiological characterization. In the present study, we examined the neuroprotective effect of talatisamine against Aβ oligomers induced cytotoxicity in primarily cultured cortical neurons. The neurotoxicity related to K(+) loss caused by Aβ40 oligomers included enhanced I(K) density, increased cell membrane permeability, reduced cell viability, and impaired mitochondrial transmembrane potential. Decreased Bcl-2 and increased Bax level, activation of Caspase-3 and Caspase-9 were also observed after Aβ40 oligomers incubation. Talatisamine (120 μM) and TEA (5mM) inhibited the enhanced I(K) caused by Aβ40 oligomers, attenuated cytotoxicity of Aβ oligomers by restoring cell viability and suppressing K(+) loss related apoptotic response. Our results suggested that talatisamine may become a leading compound as I(K) channel blocker for neuroprotection. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The Reduced Effectiveness of EGR to Mitigate Knock at High Loads in Boosted SI Engines

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

Szybist, James P.; Wagnon, Scott W.; Splitter, Derek A.

Numerous studies have demonstrated that exhaust gas recirculation (EGR) can attenuate knock propensity in spark ignition (SI) engines at naturally aspirated or lightly boosted conditions. In this paper, we investigate the role of cooled EGR under higher load conditions with multiple fuel compositions, where highly retarded combustion phasing typical of modern SI engines was used. It was found that under these conditions, EGR attenuation of knock is greatly reduced, where EGR doesn’t allow significant combustion phasing advance as it does under lighter load conditions. Detailed combustion analysis shows that when EGR is added, the polytropic coefficient increases causing the compressivemore » pressure and temperature to increase. At sufficiently highly boosted conditions, the increase in polytropic coefficient and additional trapped mass from EGR can sufficiently reduce fuel ignition delay to overcome knock attenuation effects. Kinetic modeling demonstrates that the effectiveness of EGR to mitigate knock is highly dependent on the pressure-temperature condition. Experiments at 2000 rpm have confirmed reduced fuel ignition delay under highly boosted conditions relevant to modern downsized boosted SI engines, where in-cylinder pressure is higher and the temperature is cooler. Finally, at these conditions, charge reactivity increases compared to naturally aspirated conditions, and attenuation of knock by EGR is reduced.« less

The Reduced Effectiveness of EGR to Mitigate Knock at High Loads in Boosted SI Engines

DOE PAGES

Szybist, James P.; Wagnon, Scott W.; Splitter, Derek A.; ...

2017-09-04

Numerous studies have demonstrated that exhaust gas recirculation (EGR) can attenuate knock propensity in spark ignition (SI) engines at naturally aspirated or lightly boosted conditions. In this paper, we investigate the role of cooled EGR under higher load conditions with multiple fuel compositions, where highly retarded combustion phasing typical of modern SI engines was used. It was found that under these conditions, EGR attenuation of knock is greatly reduced, where EGR doesn’t allow significant combustion phasing advance as it does under lighter load conditions. Detailed combustion analysis shows that when EGR is added, the polytropic coefficient increases causing the compressivemore » pressure and temperature to increase. At sufficiently highly boosted conditions, the increase in polytropic coefficient and additional trapped mass from EGR can sufficiently reduce fuel ignition delay to overcome knock attenuation effects. Kinetic modeling demonstrates that the effectiveness of EGR to mitigate knock is highly dependent on the pressure-temperature condition. Experiments at 2000 rpm have confirmed reduced fuel ignition delay under highly boosted conditions relevant to modern downsized boosted SI engines, where in-cylinder pressure is higher and the temperature is cooler. Finally, at these conditions, charge reactivity increases compared to naturally aspirated conditions, and attenuation of knock by EGR is reduced.« less

Analysis of a digital RF memory in a signal-delay application

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

Jelinek, D.A.

1992-03-01

Laboratory simulation of the approach of a radar fuze towards a target is an important factor in our ability to accurately measure the radar's performance. This simulation is achieved, in part, by dynamically delaying and attenuating the radar's transmitted pulse and sending the result back to the radar's receiver. Historically, the device used to perform the dynamic delay has been a limiting factor in the evaluation of a radar's performance and characteristics. A new device has been proposed that appears to have more capability than previous dynamic delay devices. This device is the digital RF memory. This report presents themore » results of an analysis of a digital RF memory used in a signal-delay application. 2 refs.« less

Pubertal Height Velocity and Associations with Pre-pubertal and Adult Heights in Cystic Fibrosis

PubMed Central

Zhang, Zhumin; Lindstrom, Mary J.; Lai, HuiChuan J.

2013-01-01

Objectives To test the hypothesis that pubertal peak height velocity (PHV) in cystic fibrosis (CF) has improved and is influenced by pre-pubertal growth and genetic potential. Study design PHV from 1862 children born in 1984–87 and documented in the 1986–2008 US CF Foundation Registry was determined by statistical modeling and classified into normal, delayed (2-SD > average age), attenuated (magnitude < 5th percentile), or both (D&A). Genetic potential for height was estimated by parental stature. Results PHV averaged 8.4 cm/y at age 14.0 y in boys and 7.0 cm/y at age 12.1 y in girls, ~6 mo delay and ~15% reduction compared with healthy children. PHV was normal in 60%, delayed in 9%, attenuated in 21% and D&A in 5%. Patients with delayed PHV reached similar adult height percentile (boys: 34th, girls: 46th) to those with normal PHV (boys: 33rd, girls: 34th); both were significantly taller than the attenuated (boys: 11th, girls: 19th) and D&A PHV subgroups (boys: 8th, girls: 14th). Pancreatic sufficient patients had taller pre-pubertal and adult heights but similar PHV compared with pancreatic insufficient or meconium ileus patients. Adjusting for genetic potential reduced adult height percentiles more in boys (25th to 16th) than girls (28th to 24th). Height at age 7 y, PHV age and magnitude, and parental stature significantly predicted adult height. Conclusions Pubertal PHV has improved in children with CF born after mid 1980s compared with older cohorts but remains below normal. Suboptimal pre-pubertal and pubertal growth led to adult height below genetic potential in CF. PMID:23535012

48 CFR 49.108-6 - Delay in settling subcontractor settlement proposals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Delay in settling subcontractor settlement proposals. 49.108-6 Section 49.108-6 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.108-6 Delay in...

Relations among Temperament, Self-regulatory Strategies and Gender in Predicting Delay of Gratification.

PubMed

Hong, Fang; Doan, Stacey N; Lopez, Angelica; Evans, Gary W

2017-01-01

Self-regulation is associated with many positive outcomes, but there is limited information about individual difference regarding children's spontaneous use of strategies to self-regulate and the relative success of those strategies. In the current study, we examined whether temperament and gender are associated with self-regulation and explored the types of spontaneous strategies children use during Mischel's delay of gratification protocol. In addition, we investigated whether spontaneous strategy use during the task could moderate the effects of temperament on self-regulation and whether temperament would mediate the effect of gender on self-regulation. Participants were 349 9-year-olds (182 boys, M age = 9.18, SD = 1.17). Mothers reported on children's temperament and the Delay of Gratification task was used to assess self-regulation. Both temperament and child's gender were significantly associated with children's delay time. Girls were able to delay longer than boys, and children scoring high on activity level were less able to delay. Activity level also mediated the relationship between gender and delay time. Finally, we found an interaction effect between activity level and certain strategies in relation to self-regulatory behavior.

Relations among Temperament, Self-regulatory Strategies and Gender in Predicting Delay of Gratification

PubMed Central

Hong, Fang; Doan, Stacey N.; Lopez, Angelica; Evans, Gary W.

2017-01-01

Self-regulation is associated with many positive outcomes, but there is limited information about individual difference regarding children’s spontaneous use of strategies to self-regulate and the relative success of those strategies. In the current study, we examined whether temperament and gender are associated with self-regulation and explored the types of spontaneous strategies children use during Mischel’s delay of gratification protocol. In addition, we investigated whether spontaneous strategy use during the task could moderate the effects of temperament on self-regulation and whether temperament would mediate the effect of gender on self-regulation. Participants were 349 9-year-olds (182 boys, Mage = 9.18, SD = 1.17). Mothers reported on children’s temperament and the Delay of Gratification task was used to assess self-regulation. Both temperament and child’s gender were significantly associated with children’s delay time. Girls were able to delay longer than boys, and children scoring high on activity level were less able to delay. Activity level also mediated the relationship between gender and delay time. Finally, we found an interaction effect between activity level and certain strategies in relation to self-regulatory behavior. PMID:29163300

Prognostic significance of contrast-enhanced CT attenuation value in extrahepatic cholangiocarcinoma.

PubMed

Asayama, Yoshiki; Nishie, Akihiro; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Okamoto, Daisuke; Fujita, Nobuhiro; Ohtsuka, Takao; Yoshizumi, Tomoharu; Aishima, Shinichi; Oda, Yoshinao; Honda, Hiroshi

2017-06-01

To determine whether washout characteristics of dynamic contrast-enhanced computed tomography (CT) could predict survival in patients with extrahepatic cholangiocarcinoma (EHC). This study collected 46 resected cases. All cases were examined by dynamic contrast study on multidetector-row CT. Region-of-interest measurements were obtained at the non-enhanced, portal venous phase and delayed phase in the tumour and were used to calculate the washout ratio as follows: [(attenuation value at portal venous phase CT - attenuation value at delayed enhanced CT)/(attenuation value at portal venous phase CT - attenuation value at unenhanced CT)] × 100. On the basis of the median washout ratio, we classified the cases into two groups, a high-washout group and low-washout group. Associations between overall survival and various factors including washout rates were analysed. The median washout ratio was 29.4 %. Univariate analysis revealed that a lower washout ratio, venous invasion, lymphatic permeation and lymph node metastasis were associated with shorter survival. Multivariate analysis identified the lower washout ratio as an independent prognostic factor (hazard ratio, 3.768; p value, 0.027). The washout ratio obtained from the contrast-enhanced CT may be a useful imaging biomarker for the prediction of survival of patients with EHC. • Dynamic contrast study can evaluate the aggressiveness of extrahepatic cholangiocarcinoma. • A lower washout ratio was an independent prognostic factor for overall survival. • CT can predict survival and inform decisions on surgical options or chemotherapy.

The binding protein BiP attenuates stress-induced cell death in soybean via modulation of the N-rich protein-mediated signaling pathway.

PubMed

Reis, Pedro A A; Rosado, Gustavo L; Silva, Lucas A C; Oliveira, Luciana C; Oliveira, Lucas B; Costa, Maximiller D L; Alvim, Fátima C; Fontes, Elizabeth P B

2011-12-01

The molecular chaperone binding protein (BiP) participates in the constitutive function of the endoplasmic reticulum (ER) and protects the cell against stresses. In this study, we investigated the underlying mechanism by which BiP protects plant cells from stress-induced cell death. We found that enhanced expression of BiP in soybean (Glycine max) attenuated ER stress- and osmotic stress-mediated cell death. Ectopic expression of BiP in transgenic lines attenuated the leaf necrotic lesions that are caused by the ER stress inducer tunicamycin and also maintained shoot turgidity upon polyethylene glycol-induced dehydration. BiP-mediated attenuation of stress-induced cell death was confirmed by the decreased percentage of dead cell, the reduced induction of the senescence-associated marker gene GmCystP, and reduced DNA fragmentation in BiP-overexpressing lines. These phenotypes were accompanied by a delay in the induction of the cell death marker genes N-RICH PROTEIN-A (NRP-A), NRP-B, and GmNAC6, which are involved in transducing a cell death signal generated by ER stress and osmotic stress through the NRP-mediated signaling pathway. The prosurvival effect of BiP was associated with modulation of the ER stress- and osmotic stress-induced NRP-mediated cell death signaling, as determined in transgenic tobacco (Nicotiana tabacum) lines with enhanced (sense) and suppressed (antisense) BiP levels. Enhanced expression of BiP prevented NRP- and NAC6-mediated chlorosis and the appearance of senescence-associated markers, whereas silencing of endogenous BiP accelerated the onset of leaf senescence mediated by NRPs and GmNAC6. Collectively, these results implicate BiP as a negative regulator of the stress-induced NRP-mediated cell death response.

The Binding Protein BiP Attenuates Stress-Induced Cell Death in Soybean via Modulation of the N-Rich Protein-Mediated Signaling Pathway1[C][W][OA

PubMed Central

Reis, Pedro A.A.; Rosado, Gustavo L.; Silva, Lucas A.C.; Oliveira, Luciana C.; Oliveira, Lucas B.; Costa, Maximiller D.L.; Alvim, Fátima C.; Fontes, Elizabeth P.B.

2011-01-01

The molecular chaperone binding protein (BiP) participates in the constitutive function of the endoplasmic reticulum (ER) and protects the cell against stresses. In this study, we investigated the underlying mechanism by which BiP protects plant cells from stress-induced cell death. We found that enhanced expression of BiP in soybean (Glycine max) attenuated ER stress- and osmotic stress-mediated cell death. Ectopic expression of BiP in transgenic lines attenuated the leaf necrotic lesions that are caused by the ER stress inducer tunicamycin and also maintained shoot turgidity upon polyethylene glycol-induced dehydration. BiP-mediated attenuation of stress-induced cell death was confirmed by the decreased percentage of dead cell, the reduced induction of the senescence-associated marker gene GmCystP, and reduced DNA fragmentation in BiP-overexpressing lines. These phenotypes were accompanied by a delay in the induction of the cell death marker genes N-RICH PROTEIN-A (NRP-A), NRP-B, and GmNAC6, which are involved in transducing a cell death signal generated by ER stress and osmotic stress through the NRP-mediated signaling pathway. The prosurvival effect of BiP was associated with modulation of the ER stress- and osmotic stress-induced NRP-mediated cell death signaling, as determined in transgenic tobacco (Nicotiana tabacum) lines with enhanced (sense) and suppressed (antisense) BiP levels. Enhanced expression of BiP prevented NRP- and NAC6-mediated chlorosis and the appearance of senescence-associated markers, whereas silencing of endogenous BiP accelerated the onset of leaf senescence mediated by NRPs and GmNAC6. Collectively, these results implicate BiP as a negative regulator of the stress-induced NRP-mediated cell death response. PMID:22007022

Differential roles of breakfast and supper in rats of a daily three-meal schedule upon circadian regulation and physiology.

PubMed

Wu, Tao; Sun, Lu; ZhuGe, Fen; Guo, Xichao; Zhao, Zhining; Tang, Ruiqi; Chen, Qinping; Chen, Lin; Kato, Hisanori; Fu, Zhengwei

2011-12-01

The timing of meals has been suggested to play an important role in circadian regulation and metabolic health. Three meals a day is a well-established human feeding habit, which in today's lifestyle may or may not be followed. The aim of this study was to test whether the absence of breakfast or supper significantly affects the circadian system and physiological function. The authors developed a rat model for their daily three meals study, whereby animals were divided into three groups (three meals, TM; no first meal, NF; no last meal, NL) all fed with the same amount of food every day. Rats in the NF group displayed significantly decreased levels of plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose in the activity phase, accompanied by delayed circadian phases of hepatic peripheral clock and downstream metabolic genes. Rats in the NL group showed lower concentration of plasma TC, HDL-C, and glucose in the rest phase, plus reduced adipose tissue accumulation and body weight gain. Real-time polymerase chain reaction (PCR) analysis indicated an attenuated rhythm in the food-entraining pathway, including down-regulated expression of the clock genes Per2, Bmal1, and Rev-erbα, which may further contribute to the delayed and decreased expression of FAS in lipogenesis in this group. Our findings are consistent with the conclusion that the daily first meal determines the circadian phasing of peripheral clocks, such as in the liver, whereas the daily last meal tightly couples to lipid metabolism and adipose tissue accumulation, which suggests differential physiological effects and function of the respective meal timings.

Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson’s is associated with histone acetylation and up-regulation of neurotrophic factors

PubMed Central

Harrison, Ian F; Crum, William R; Vernon, Anthony C; Dexter, David T

2015-01-01

Background and Purpose Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD. Experimental Approach The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague–Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. Key Results Despite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. Conclusions and Implications The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the results suggest that HDACIs could hold potential as disease-modifying agents in PD. PMID:26040297

Effect of Mas-related gene (Mrg) receptors on hyperalgesia in rats with CFA-induced inflammation via direct and indirect mechanisms.

PubMed

Jiang, Jianping; Wang, Dongmei; Zhou, Xiaolong; Huo, Yuping; Chen, Tingjun; Hu, Fenjuan; Quirion, Rémi; Hong, Yanguo

2013-11-01

Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in trigeminal and dorsal root ganglia (DRG). We investigated the effects of MrgC receptor activation on inflammatory hyperalgesia and its mechanisms. A selective MrgC receptor agonist, bovine adrenal medulla peptide 8-22 (BAM8-22) or melanocyte-stimulating hormone (MSH) or the μ-opioid receptor (MOR) antagonist CTAP was administered intrathecally (i.t.) in rats injected with complete Freund's adjuvant (CFA) in one hindpaw. Thermal and mechanical nociceptive responses were assessed. Neurochemicals were measured by immunocytochemistry, Western blot, ELISA and RT-PCR. CFA injection increased mRNA for MrgC receptors in lumbar DRG. BAM8-22 or MSH, given i.t., generated instant short and delayed long-lasting attenuations of CFA-induced thermal hyperalgesia, but not mechanical allodynia. These effects were associated with decreased up-regulation of neuronal NOS (nNOS), CGRP and c-Fos expression in the spinal dorsal horn and/or DRG. However, i.t. administration of CTAP blocked the induction by BAM8-22 of delayed anti-hyperalgesia and inhibition of nNOS and CGRP expression in DRG. BAM8-22 also increased mRNA for MORs and pro-opiomelanocortin, along with β-endorphin content in the lumbar spinal cord and/or DRG. MrgC receptors and nNOS were co-localized in DRG neurons. Activation of MrgC receptors suppressed up-regulation of pronociceptive mediators and consequently inhibited inflammatory pain, because of the activation of up-regulated MrgC receptors and subsequent endogenous activity at MORs. The uniquely distributed MrgC receptors could be a novel target for relieving inflammatory pain. © 2013 The British Pharmacological Society.

Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits.

PubMed

Zhu, Yujie; Ai, Xun; Oster, Robert A; Bers, Donald M; Pogwizd, Steven M

2013-06-01

Slow delayed rectifier potassium current (IKs) is important in action potential (AP) repolarization and repolarization reserve. We tested the hypothesis that there are sex-specific differences in IKs, AP, and their regulation by β-adrenergic receptors (β-AR's) using whole-cell patch-clamp. AP duration (APD90) was significantly longer in control female (F) than in control male (M) myocytes. Isoproterenol (ISO, 500 nM) shortened APD90 comparably in M and F, and was largely reversed by β1-AR blocker CGP 20712A (CGP, 300 nM). Inhibition of IKs with chromanol 293B (10 μM) resulted in less APD prolongation in F at baseline (3.0 vs 8.9 %, p < 0.05 vs M) and even in the presence of ISO (5.4 vs 20.9 %, p < 0.05). This suggests that much of the ISO-induced APD abbreviation in F is independent of IKs. In F, baseline IKs was 42 % less and was more weakly activated by ISO (19 vs 68 % in M, p < 0.01). ISO enhancement of IKs was comparably attenuated by CGP in M and F. After ovariectomy, IKs in F had greater enhancement by ISO (72 %), now comparable to control M. After orchiectomy, IKs in M was only slightly enhanced by ISO (23 %), comparable to control F. Pretreatment with thapsigargin (to block SR Ca release) had bigger impact on ISO-induced APD shortening in F than that in M (p < 0.01). In conclusion, we found that there are sex differences in IKs, AP, and their regulation by β-AR's that are modulated by sex hormones, suggesting the potential for sex-specific antiarrhythmic therapy.

12-Chloracetyl-PPD, a novel dammarane derivative, shows anti-cancer activity via delay the progression of cell cycle G2/M phase and reactive oxygen species-mediate cell apoptosis.

PubMed

Wang, Xu De; Sun, Yuan Yuan; Zhao, Chen; Qu, Fan Zhi; Zhao, Yu Qing

2017-03-05

(20R)-Dammarane-3β, 12β, 20, 25-tetrol (25-OH-PPD) is a ginsenoside isolated from Panax ginseng (C. A. Meyer). This compound exhibits anti-cancer activities on many human cancer cell lines. In this study, we investigated anti-cancer mechanisms of 12β-O-( L -Chloracetyl)-dammar-20(22)-ene-3β,25-diol(12-Chloracetyl-PPD), a modified 25-OH-PPD. We found that compound 12-Chloracetyl-PPD resulted in a concentration-dependent inhibition of viability in prostate, breast, and gastric cancer cells, without affecting the viability of normal cell (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line-HHDPC and rat myocardial cell line-H9C2). In MDA-MB-435 and C4-2B cancer cells, 12-Chloracetyl-PPD induced G2/M cell cycle arrest, down-regulated mouse double minute 2 (MDM2) expression, up-regulated p53 expression, triggered apoptosis, and stimulated reactive oxygen species production. Apoptosis can be attenuated by the reactive oxygen species scavenger N-acetylcysteine. Our results suggested that compound 12-Chloracetyl-PPD showed obvious anti-cancer activity based on delaying cell cycle arrest and inducing cell apoptosis by reactive oxygen species production, which supported development of 12-Chloracetyl-PPD as a potential agent for cancer chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model

PubMed Central

Takuma, K; Lee, E; Enomoto, R; Mori, K; Baba, A; Matsuda, T

2001-01-01

We examined the effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 – 100 μM significantly attenuated the H2O2-induced decrease in cell viability. Ibudilast inhibited the H2O2-induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3′,5′-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H2O2-induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H2O2-induced decrease in cell viability, while the cyclic AMP-dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D4 antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H2O2-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H2O2-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway. PMID:11454657

Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis

PubMed Central

Stewart, Adele; Maity, Biswanath; Wunsch, Amanda M.; Meng, Fantao; Wu, Qi; Wemmie, John A.; Fisher, Rory A.

2014-01-01

Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT1ARs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT1AR-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT1AR-expressing cells implicated in mood disorders. RGS6−/− mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT1AR blockade. Effects of the SSRI fluvoxamine and 5-HT1AR agonist 8-OH-DPAT were also potentiated in RGS6+/− mice. The phenotype of RGS6−/− mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gαi-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in RGS6−/− animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents.—Stewart, A., Maity, B., Wunsch, A. M., Meng, F., Wu, Q., Wemmie, J. A., Fisher, R. A. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis. PMID:24421401

Interocular suppression in strabismic amblyopia results in an attenuated and delayed hemodynamic response function in early visual cortex.

PubMed

Farivar, Reza; Thompson, Benjamin; Mansouri, Behzad; Hess, Robert F

2011-12-20

Factors such as strabismus or anisometropia during infancy can disrupt normal visual development and result in amblyopia, characterized by reduced visual function in an otherwise healthy eye and often associated with persistent suppression of inputs from the amblyopic eye by those from the dominant eye. It has become evident from fMRI studies that the cortical response to stimulation of the amblyopic eye is also affected. We were interested to compare the hemodynamic response function (HRF) of early visual cortex to amblyopic vs. dominant eye stimulation. In the first experiment, we found that stimulation of the amblyopic eye resulted in a signal that was both attenuated and delayed in its time to peak. We postulated that this delay may be due to suppressive effects of the dominant eye and, in our second experiment, measured the cortical response of amblyopic eye stimulation under two conditions--where the dominant eye was open and seeing a static pattern (high suppression) or where the dominant eye was patched and closed (low suppression). We found that the HRF in response to amblyopic eye stimulation depended on whether the dominant eye was open. This effect was manifested as both a delayed HRF under the suppressed condition and an amplitude reduction.

When Delays Improve Memory: Stabilizing Memory in Children May Require Time.

PubMed

Darby, Kevin P; Sloutsky, Vladimir M

2015-12-01

Memory is critical for learning, cognition, and cognitive development. Recent work has suggested that preschool-age children are vulnerable to catastrophic levels of memory interference, in which new learning dramatically attenuates memory for previously acquired knowledge. In the work reported here, we investigated the effects of consolidation on children's memory by introducing a 48-hr delay between learning and testing. In Experiment 1, the delay improved children's memory and eliminated interference. Results of Experiment 2 suggest that the benefit of this delay is limited to situations in which children are given enough information to form complex memory structures. These findings have important implications for understanding consolidation processes and memory development. © The Author(s) 2015.

Analysis of a digital RF memory in a signal-delay application

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

Jelinek, D.A.

1992-03-01

Laboratory simulation of the approach of a radar fuze towards a target is an important factor in our ability to accurately measure the radar`s performance. This simulation is achieved, in part, by dynamically delaying and attenuating the radar`s transmitted pulse and sending the result back to the radar`s receiver. Historically, the device used to perform the dynamic delay has been a limiting factor in the evaluation of a radar`s performance and characteristics. A new device has been proposed that appears to have more capability than previous dynamic delay devices. This device is the digital RF memory. This report presents themore » results of an analysis of a digital RF memory used in a signal-delay application. 2 refs.« less

Using in-cell SHAPE-Seq and simulations to probe structure–function design principles of RNA transcriptional regulators

PubMed Central

Takahashi, Melissa K.; Watters, Kyle E.; Gasper, Paul M.; Abbott, Timothy R.; Carlson, Paul D.; Chen, Alan A.

2016-01-01

Antisense RNA-mediated transcriptional regulators are powerful tools for controlling gene expression and creating synthetic gene networks. RNA transcriptional repressors derived from natural mechanisms called attenuators are particularly versatile, though their mechanistic complexity has made them difficult to engineer. Here we identify a new structure–function design principle for attenuators that enables the forward engineering of new RNA transcriptional repressors. Using in-cell SHAPE-Seq to characterize the structures of attenuator variants within Escherichia coli, we show that attenuator hairpins that facilitate interaction with antisense RNAs require interior loops for proper function. Molecular dynamics simulations of these attenuator variants suggest these interior loops impart structural flexibility. We further observe hairpin flexibility in the cellular structures of natural RNA mechanisms that use antisense RNA interactions to repress translation, confirming earlier results from in vitro studies. Finally, we design new transcriptional attenuators in silico using an interior loop as a structural requirement and show that they function as desired in vivo. This work establishes interior loops as an important structural element for designing synthetic RNA gene regulators. We anticipate that the coupling of experimental measurement of cellular RNA structure and function with computational modeling will enable rapid discovery of structure–function design principles for a diverse array of natural and synthetic RNA regulators. PMID:27103533

Associations between toddler-age communication and kindergarten-age self-regulatory skills.

PubMed

Aro, Tuija; Laakso, Marja-Leena; Määttä, Sira; Tolvanen, Asko; Poikkeus, Anna-Maija

2014-08-01

In this study, the authors aimed at gaining understanding on the associations of different types of early language and communication profiles with later self-regulation skills by using longitudinal data from toddler age to kindergarten age. Children with early language profiles representing expressive delay, broad delay (i.e., expressive, social, and/or symbolic), and typical language development were compared in domains of kindergarten-age executive and regulative skills (attentional/executive functions, regulation of emotions and behavioral activity, and social skills) assessed with parental questionnaires. Children with delay in toddler-age language development demonstrated poorer kindergarten-age self-regulation skills than children with typical early language development. Broad early language delays were associated with compromised social skills and attentional/executive functions, and early expressive delays were associated with a generally lower level of kindergarten-age executive and regulative skills. Regression analyses showed that both earlier and concurrent language had an effect especially on the attentional/executive functions. The findings suggest that different aspects of toddler-age language have differential associations with later self-regulation. Possible mechanisms linking early language development to later self-regulative development are discussed.

Integrable microwave filter based on a photonic crystal delay line.

PubMed

Sancho, Juan; Bourderionnet, Jerome; Lloret, Juan; Combrié, Sylvain; Gasulla, Ivana; Xavier, Stephane; Sales, Salvador; Colman, Pierre; Lehoucq, Gaelle; Dolfi, Daniel; Capmany, José; De Rossi, Alfredo

2012-01-01

The availability of a tunable delay line with a chip-size footprint is a crucial step towards the full implementation of integrated microwave photonic signal processors. Achieving a large and tunable group delay on a millimetre-sized chip is not trivial. Slow light concepts are an appropriate solution, if propagation losses are kept acceptable. Here we use a low-loss 1.5 mm-long photonic crystal waveguide to demonstrate both notch and band-pass microwave filters that can be tuned over the 0-50-GHz spectral band. The waveguide is capable of generating a controllable delay with limited signal attenuation (total insertion loss below 10 dB when the delay is below 70 ps) and degradation. Owing to the very small footprint of the delay line, a fully integrated device is feasible, also featuring more complex and elaborate filter functions.

Effects of Astaxanthin and Docosahexaenoic-Acid-Acylated Astaxanthin on Alzheimer's Disease in APP/PS1 Double-Transgenic Mice.

PubMed

Che, Hongxia; Li, Qian; Zhang, Tiantian; Wang, Dandan; Yang, Lu; Xu, Jie; Yanagita, Teruyoshi; Xue, Changhu; Chang, Yaoguang; Wang, Yuming

2018-05-16

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with the characteristics of senile plaques, neuroinflammation, neurofibrillary tangles, and destruction of synapse structure stability. Previous studies have verified the protective effects of astaxanthin (AST). However, whether synthesized docosahexaenoic-acid-acylated AST diesters (AST-DHA) could delay AD pathogenesis remains unclear. In the present study, APP/PSEN1 (APP/PS1) double-transgenic mice were administrated with AST and AST-DHA for 2 months. The results of radial 8-arm maze and Morris water maze tests showed that AST-DHA exerted more significant effects than AST in enhancing learning and memory levels of APP/PS1 mice. Further mechanical studies suggested that AST-DHA was superior to AST in regulating the parameters of oxidative stress, reducing tau hyperphosphorylation, suppressing neuroinflammation, and regulating inflammasome expression and activation in APP/PS1 mice. The findings suggested that AST-DHA attenuated cognitive disorders by reducing pathological features in APP/PS1 mice, suggesting that AST-DHA might be a potential therapeutic agent for AD.

Exogenous fibroblast growth factor 9 attenuates cartilage degradation and aggravates osteophyte formation in post-traumatic osteoarthritis.

PubMed

Zhou, S; Wang, Z; Tang, J; Li, W; Huang, J; Xu, W; Luo, F; Xu, M; Wang, J; Wen, X; Chen, L; Chen, H; Su, N; Shen, Y; Du, X; Xie, Y; Chen, L

2016-12-01

The aim of the present study is to investigate the effects of exogenous fibroblast growth factor (FGF)9 on the progression of post-traumatic osteoarthritis (OA). The expression of FGF9 in articular cartilage with OA is detected by immunohistochemistry (IHC). The effects of intra-articular exogenous FGF9 injection on post-traumatic OA induced by the destabilization of the medial meniscus (DMM) surgery are evaluated. Cartilage changes and osteophyte formation in knee joints are investigated by histological analysis. Changes in subchondral bone are evaluated by microcomputed tomography (micro-CT). The effect of exogenous FGF9 on an interleukin-1β (IL-1β)-induced ex vivo OA model of human articular cartilage tissues is also evaluated. FGF9 expression was down-regulated in articular chondrocytes of OA but ectopically induced at sites of osteophyte formation. Intra-articular injection of exogenous FGF9 attenuated articular cartilage degradation in mice after DMM surgery. Exogenous FGF9 suppressed collagen X and MMP13 expressions in OA cartilage, while promoted collagen II expression. Similar results were observed in IL-1β-induced ex vivo OA model. Intra-articular injection of FGF9 had no significant effect on the subchondral bone of knee joints after DMM surgery, but aggravated osteophyte formation. The expressions of SOX9 and collagen II, and cell proliferation were up-regulated at sites of initial osteophyte formation in mice with exogenous FGF9 treatment. Intra-articular injection of exogenous FGF9 delays articular cartilage degradation in post-traumatic OA, while aggravates osteophyte formation. Copyright © 2016. Published by Elsevier Ltd.

Living in the moment: Effects of time perspective and emotional valence of episodic thinking on delay discounting

PubMed Central

Lin, Henry; Epstein, Leonard H.

2014-01-01

Excessive delay discounting (DD) has been related to various maladaptive behaviors, and may stem from a myopic focus on immediate gratification. Neuroimaging studies have shown that episodic future thinking (EFT) – vivid mental simulation of future experiences – may reduce DD by promoting consideration of delayed outcomes. However, the EFT manipulations in these experiments may have induced positive affect, which could independently enhance executive functions that facilitate self-regulation. To clarify the mechanism of this effect, 87 participants were randomized to visualize neutral- or positive-valenced events expected to occur in the present or in the future while completing a standardized DD questionnaire. Working memory capacity, inhibitory control, the genotypes of 3 functional dopaminergic polymorphisms (DRD1 rs686, DRD2 rs1800497 and COMT rs4680), as well as an additive dopamine genetic risk score were assessed as potential moderators. The results indicate that EFT reduces DD primarily by shifting the time perspective of intertemporal decision-making, and that this effect is moderated by working memory capacity. In addition, positive episodic thinking may independently attenuate the protective effects of high working memory capacity, high inhibitory control, and lower dopamine genetic risk scores on DD. The current findings dovetail with previous research to suggest that the time perspective and emotional valence of episodic thinking may dynamically shape intertemporal choice, perhaps in part by transiently modulating executive function and dopaminergic neurotransmission. PMID:24512061

Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy

PubMed Central

Wang, Junru; Pathak, Rupak; Garg, Sarita; Hauer-Jensen, Martin

2017-01-01

AIM To determine the mechanistic role of fibrinogen, a key regulator of inflammation and fibrosis, in early and delayed radiation enteropathy. METHODS Fibrinogen wild-type (Fib+/+), fibrinogen heterozygous (Fib+/-), and fibrinogen knockout (Fib-/-) mice were exposed to localized intestinal irradiation and assessed for early and delayed structural changes in the intestinal tissue. A 5-cm segment of ileum of mice was exteriorized and exposed to 18.5 Gy of x-irradiation. Intestinal tissue injury was assessed by quantitative histology, morphometry, and immunohistochemistry at 2 wk and 26 wk after radiation. Plasma fibrinogen level was measured by enzyme-linked immunosorbent assay. RESULTS There was no difference between sham-irradiated Fib+/+ and Fib+/- mice in terms of fibrinogen concentration in plasma and intestinal tissue, intestinal histology, morphometry, intestinal smooth muscle cell proliferation, and neutrophil infiltration. Therefore, Fib+/- mice were used as littermate controls. Unlike sham-irradiated Fib+/+ and Fib+/- mice, no fibrinogen was detected in the plasma and intestinal tissue of sham-irradiated Fib-/- mice. Moreover, fibrinogen level was not elevated after irradiation in the intestinal tissue of Fib-/- mice, while significant increase in intestinal fibrinogen level was noticed in irradiated Fib+/+ and Fib+/- mice. Importantly, irradiated Fib-/- mice exhibited substantially less overall intestinal structural injury (RIS, P = 0.000002), intestinal wall thickness (P = 0.003), intestinal serosal thickness (P = 0.009), collagen deposition (P = 0.01), TGF-β immunoreactivity (P = 0.03), intestinal smooth muscle proliferation (P = 0.046), neutrophil infiltration (P = 0.01), and intestinal mucosal injury (P = 0.0003), compared to irradiated Fib+/+ and Fib+/- mice at both 2 wk and 26 wk. CONCLUSION These data demonstrate that fibrinogen deficiency directly attenuates development of early and delayed radiation enteropathy. Fibrinogen could be a novel target in treating intestinal damage. PMID:28765691

Influence of Time-Pickoff Circuit Parameters on LiDAR Range Precision

PubMed Central

Wang, Hongming; Yang, Bingwei; Huyan, Jiayue; Xu, Lijun

2017-01-01

A pulsed time-of-flight (TOF) measurement-based Light Detection and Ranging (LiDAR) system is more effective for medium-long range distances. As a key ranging unit, a time-pickoff circuit based on automatic gain control (AGC) and constant fraction discriminator (CFD) is designed to reduce the walk error and the timing jitter for obtaining the accurate time interval. Compared with Cramer–Rao lower bound (CRLB) and the estimation of the timing jitter, four parameters-based Monte Carlo simulations are established to show how the range precision is influenced by the parameters, including pulse amplitude, pulse width, attenuation fraction and delay time of the CFD. Experiments were carried out to verify the relationship between the range precision and three of the parameters, exclusing pulse width. It can be concluded that two parameters of the ranging circuit (attenuation fraction and delay time) were selected according to the ranging performance of the minimum pulse amplitude. The attenuation fraction should be selected in the range from 0.2 to 0.6 to achieve high range precision. The selection criterion of the time-pickoff circuit parameters is helpful for the ranging circuit design of TOF LiDAR system. PMID:29039772

Self-regulation strategies may enhance the acute effect of exercise on smoking delay.

PubMed

Hatzigeorgiadis, Antonis; Pappa, Vassiliki; Tsiami, Anastasia; Tzatzaki, Theodora; Georgakouli, Kalliopi; Zourbanos, Nikos; Goudas, Marios; Chatzisarantis, Nikos; Theodorakis, Yannis

2016-06-01

The present study examined the acute effect of a moderate intensity aerobic exercise session combined with self-regulation on smoking delay in physically inactive smokers. Participants were 11 adults (5 males and 6 females) that completed three experimental conditions: control, exercise, and exercise using self-regulation strategies (SR). Following the experimental treatment smoking for the two exercise conditions delayed significantly more than for the control condition; in addition exercise SR delayed smoking marginally more that the plain exercise condition. Findings supported previous research that acute exercise reduces cravings to smoke, and suggests that the use of self-regulation strategies may strengthen exercise for smoking cessation interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Memantine Attenuates Delayed Vasospasm after Experimental Subarachnoid Hemorrhage via Modulating Endothelial Nitric Oxide Synthase.

PubMed

Huang, Chih-Yuan; Wang, Liang-Chao; Shan, Yan-Shen; Pan, Chia-Hsin; Tsai, Kuen-Jer

2015-06-23

Delayed cerebral vasospasm is an important pathological feature of subarachnoid hemorrhage (SAH). The cause of vasospasm is multifactorial. Impairs nitric oxide availability and endothelial nitric oxide synthase (eNOS) dysfunction has been reported to underlie vasospasm. Memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) blocker has been proven to reduce early brain injury after SAH. This study investigated the effect of memantine on attenuation of vasospasm and restoring eNOS functionality. Male Sprague-Dawley rats weighing 350-450 g were randomly divided into three weight-matched groups, sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the severity of vasospasm and the expression of eNOS. Memantine effectively ameliorated cerebral vasospasm by restoring eNOS functionality. Memantine can prevent vasospasm in experimental SAH. Treatment strategies may help combat SAH-induced vasospasm in the future.

Using in-cell SHAPE-Seq and simulations to probe structure-function design principles of RNA transcriptional regulators.

PubMed

Takahashi, Melissa K; Watters, Kyle E; Gasper, Paul M; Abbott, Timothy R; Carlson, Paul D; Chen, Alan A; Lucks, Julius B

2016-06-01

Antisense RNA-mediated transcriptional regulators are powerful tools for controlling gene expression and creating synthetic gene networks. RNA transcriptional repressors derived from natural mechanisms called attenuators are particularly versatile, though their mechanistic complexity has made them difficult to engineer. Here we identify a new structure-function design principle for attenuators that enables the forward engineering of new RNA transcriptional repressors. Using in-cell SHAPE-Seq to characterize the structures of attenuator variants within Escherichia coli, we show that attenuator hairpins that facilitate interaction with antisense RNAs require interior loops for proper function. Molecular dynamics simulations of these attenuator variants suggest these interior loops impart structural flexibility. We further observe hairpin flexibility in the cellular structures of natural RNA mechanisms that use antisense RNA interactions to repress translation, confirming earlier results from in vitro studies. Finally, we design new transcriptional attenuators in silico using an interior loop as a structural requirement and show that they function as desired in vivo. This work establishes interior loops as an important structural element for designing synthetic RNA gene regulators. We anticipate that the coupling of experimental measurement of cellular RNA structure and function with computational modeling will enable rapid discovery of structure-function design principles for a diverse array of natural and synthetic RNA regulators. © 2016 Takahashi et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Separation attenuation in swept shock wave-boundary-layer interactions using different microvortex generator geometries

NASA Astrophysics Data System (ADS)

Martis, R. R.; Misra, A.

2017-09-01

A numerical study is conducted to determine the effectiveness of six different microvortex generator geometries in controlling swept shock wave/boundary-layer interactions. The geometries considered are base ramp, base ramp with declining angle of 45°, blunt ramp, split ramp, thick vanes, and ramped vanes. Microvortex generators with a gap were found to be better suited for delaying the separation. Thick vanes showed the largest delay in separation among the devices studied.

Apparatus and method for the determination of grain size in thin films

DOEpatents

Maris, Humphrey J

2000-01-01

A method for the determination of grain size in a thin film sample comprising the steps of measuring first and second changes in the optical response of the thin film, comparing the first and second changes to find the attenuation of a propagating disturbance in the film and associating the attenuation of the disturbance to the grain size of the film. The second change in optical response is time delayed from the first change in optical response.

Apparatus and method for the determination of grain size in thin films

DOEpatents

Maris, Humphrey J

2001-01-01

A method for the determination of grain size in a thin film sample comprising the steps of measuring first and second changes in the optical response of the thin film, comparing the first and second changes to find the attenuation of a propagating disturbance in the film and associating the attenuation of the disturbance to the grain size of the film. The second change in optical response is time delayed from the first change in optical response.

Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices

PubMed Central

Barrese, Vincenzo; Taglialatela, Maurizio; Greenwood, Iain A; Davidson, Colin

2015-01-01

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The Kv7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an ~6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected; western blot experiments showed a parallel reduction in Kv7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for Kv7.2 in modulating ischemia-evoked caudate damage. PMID:25966943

Cathepsin K Knockout Alleviates Pressure Overload–Induced Cardiac Hypertrophy

PubMed Central

Hua, Yinan; Xu, Xihui; Shi, Guo-Ping; Chicco, Adam J.; Ren, Jun; Nair, Sreejayan

2014-01-01

Evidence from human and animal studies has documented elevated levels of lysosomal cysteine protease cathepsin K in failing hearts. Here, we hypothesized that ablation of cathepsin K mitigates pressure overload–induced cardiac hypertrophy. Cathepsin K knockout mice and their wild-type littermates were subjected to abdominal aortic constriction, resulting in cardiac remodeling (heart weight, cardiomyocyte size, left ventricular wall thickness, and end diastolic and end systolic dimensions) and decreased fractional shortening, the effects of which were significantly attenuated or ablated by cathepsin K knockout. Pressure overload dampened cardiomyocyte contractile function along with decreased resting Ca2+ levels and delayed Ca2+ clearance, which were partly resolved by cathepsin K knockout. Cardiac mammalian target of rapamycin and extracellular signal-regulated kinases (ERK) signaling cascades were upregulated by pressure overload, the effects of which were attenuated by cathepsin K knockout. In cultured H9c2 myoblast cells, silencing of cathepsin K blunted, whereas cathepsin K transfection mimicked phenylephrine–induced hypertrophic response, along with elevated phosphorylation of mammalian target of rapamycin and ERK. In addition, cathepsin K protein levels were markedly elevated in human hearts of end-stage dilated cardiomyopathy. Collectively, our data suggest that cathepsin K ablation mitigates pressure overload–induced hypertrophy, possibly via inhibition of the mammalian target of rapamycin and ERK pathways. PMID:23529168

Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death.

PubMed

Calderone, Agata; Jover, Teresa; Mashiko, Toshihiro; Noh, Kyung-min; Tanaka, Hidenobu; Bennett, Michael V L; Zukin, R Suzanne

2004-11-03

Transient global ischemia induces a delayed rise in intracellular Zn2+, which may be mediated via glutamate receptor 2 (GluR2)-lacking AMPA receptors (AMPARs), and selective, delayed death of hippocampal CA1 neurons. The molecular mechanisms underlying Zn2+ toxicity in vivo are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn2+ chelator calcium EDTA (CaEDTA) at 30 min before ischemia (early CaEDTA) or at 48-60 hr (late CaEDTA), but not 3-6 hr, after ischemia, afforded robust protection of CA1 neurons in approximately 50% (late CaEDTA) to 75% (early CaEDTA) of animals. We also show that Zn2+ acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation (and, by inference, formation of Zn2+-permeable AMPARs), the delayed rise in Zn2+, and neuronal death. These findings suggest that Zn2+ acts at step(s) upstream from GluR2 gene downregulation and implicate Zn2+ in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with low pI), caspase-3 activity (but not procaspase-3 cleavage), p75NTR induction, and DNA fragmentation. These findings indicate that CaEDTA preserves the functional integrity of the mitochondrial outer membrane and arrests the caspase death cascade. Late injection of CaEDTA at a time when GluR2 is downregulated and caspase is activated inhibited the delayed rise in Zn2+, p75NTR induction, DNA fragmentation, and cell death. The finding of neuroprotection by late CaEDTA administration has striking implications for intervention in the delayed neuronal death associated with global ischemia.

Lactic acid delays the inflammatory response of human monocytes

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

Peter, Katrin, E-mail: katrin.peter@ukr.de; Rehli, Michael, E-mail: michael.rehli@ukr.de; RCI Regensburg Center for Interventional Immunology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg

2015-02-13

Lactic acid (LA) accumulates under inflammatory conditions, e.g. in wounds or tumors, and influences local immune cell functions. We previously noted inhibitory effects of LA on glycolysis and TNF secretion of human LPS-stimulated monocytes. Here, we globally analyze the influence of LA on gene expression during monocyte activation. To separate LA-specific from lactate- or pH-effects, monocytes were treated for one or four hours with LPS in the presence of physiological concentrations of LA, sodium lactate (NaL) or acidic pH. Analyses of global gene expression profiles revealed striking effects of LA during the early stimulation phase. Up-regulation of most LPS-induced genesmore » was significantly delayed in the presence of LA, while this inhibitory effect was attenuated in acidified samples and not detected after incubation with NaL. LA targets included genes encoding for important monocyte effector proteins like cytokines (e.g. TNF and IL-23) or chemokines (e.g. CCL2 and CCL7). LA effects were validated for several targets by quantitative RT-PCR and/or ELISA. Further analysis of LPS-signaling pathways revealed that LA delayed the phosphorylation of protein kinase B (AKT) as well as the degradation of IκBα. Consistently, the LPS-induced nuclear accumulation of NFκB was also diminished in response to LA. These results indicate that the broad effect of LA on gene expression and function of human monocytes is at least partially caused by its interference with immediate signal transduction events after activation. This mechanism might contribute to monocyte suppression in the tumor environment. - Highlights: • Lactic acid broadly delays LPS-induced gene expression in human monocytes. • Expression of important monocyte effector molecules is affected by lactic acid. • Interference of lactic acid with TLR signaling causes the delayed gene expression. • The profound effect of lactic acid might contribute to immune suppression in tumors.« less

Liraglutide attenuates the migration of retinal pericytes induced by advanced glycation end products.

PubMed

Lin, Wen-Jian; Ma, Xue-Fei; Hao, Ming; Zhou, Huan-Ran; Yu, Xin-Yang; Shao, Ning; Gao, Xin-Yuan; Kuang, Hong-Yu

2018-07-01

Retinal pericyte migration represents a novel mechanism of pericyte loss in diabetic retinopathy (DR), which plays a crucial role in the early impairment of the blood-retinal barrier (BRB). Glucagon-like peptide-1 (GLP-1) has been shown to protect the diabetic retina in the early stage of DR; however, the relationship between GLP-1 and retinal pericytes has not been discussed. In this study, advanced glycation end products (AGEs) significantly increased the migration of primary bovine retinal pericytes without influencing cell viability. AGEs also significantly enhanced phosphatidylinositol 3-kinase (PI3K)/Akt activation, and changed the expressions of migration-related proteins, including phosphorylated focal adhesion kinase (p-FAK), matrix metalloproteinase (MMP)-2 and vinculin. PI3K inhibition significantly attenuated the AGEs-induced migration of retinal pericytes and reversed the overexpression of MMP-2. Glucagon-like peptide-1 receptor (Glp1r) was expressed in retinal pericytes, and liraglutide, a GLP-1 analog, significantly attenuated the migration of pericytes by Glp1r and reversed the changes in p-Akt/Akt, p-FAK/FAK, vinculin and MMP-2 levels induced by AGEs, indicating that the protective effect of liraglutide was associated with the PI3K/Akt pathway. These results provided new insights into the mechanism underlying retinal pericyte migration. The early use of liraglutide exerts a potential bebefical effect on regulating pericyte migration, which might contribute to mechanisms that maintain the integrity of vascular barrier and delay the development of DR. Copyright © 2018 Elsevier Inc. All rights reserved.

Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors.

PubMed

Michalski, Dominik; Pitsch, Roman; Pillai, Deepu R; Mages, Bianca; Aleithe, Susanne; Grosche, Jens; Martens, Henrik; Schlachetzki, Felix; Härtig, Wolfgang

2017-01-01

Current stroke therapy is focused on recanalizing strategies, but neuroprotective co-treatments are still lacking. Modern concepts of the ischemia-affected neurovascular unit (NVU) and surrounding penumbra emphasize the complexity during the transition from initial damaging to regenerative processes. While early treatment with neurotrophic factors was shown to result in lesion size reduction and blood-brain barrier (BBB) stabilization, cellular consequences from these treatments are poorly understood. This study explored delayed cellular responses not only to ischemic stroke, but also to an early treatment with neurotrophic factors. Rats underwent 60 minutes of focal cerebral ischemia. Fluorescence labeling was applied to sections from brains perfused 7 days after ischemia. Analyses focused on NVU constituents including the vasculature, astrocytes and microglia in the ischemic striatum, the border zone and the contralateral hemisphere. In addition to histochemical signs of BBB breakdown, a strong up-regulation of collagen IV and microglia activation occurred within the ischemic core with simultaneous degradation of astrocytes and their endfeet. Activated astroglia were mainly depicted at the border zone in terms of a glial scar formation. Early treatment with pigment epithelium-derived factor (PEDF) resulted in an attenuation of the usually up-regulated collagen IV-immunoreactivity. However, glial activation was not influenced by treatment with PEDF or the epidermal growth factor (EGF). In conclusion, these data on ischemia-induced cellular reactions within the NVU might help to develop treatments addressing the transition from injury towards regeneration. Thereby, the integrity of the vasculature in close relation to neighboring structures like astrocytes appears as a promising target.

Is research ethics regulation really killing people?

PubMed

Hunter, David

2015-04-06

It has been argued that research ethics regulation is leading to loss of life by delaying life-saving research. For example, Whitney and Schneider argue that the delays to the ISIS-2 trial cost 6538 lives. This suggests that there are grounds for rejecting research ethics regulation. However, the methods adopted by critics are flawed because: they conflate regulatory delays with those due to genuine normative requirements that would be present even if the regulatory framework was not; and looking at the impact of regulation on a per-project basis is the wrong metric, because it neglects all the unsuccessful research and because delaying specific projects does not reduce the overall research done by researchers. Research ethics regulation does not lead to substantial losses of life, but we have strong obligations to make it as efficient as possible.

Short-term memory for responses: the "choose-small" effect.

PubMed Central

Fetterman, J G; MacEwen, D

1989-01-01

Pigeons' short-term memory for fixed-ratio requirements was assessed using a delayed symbolic matching-to-sample procedure. Different choices were reinforced after fixed-ratio 10 and fixed-ratio 40 requirements, and delays of 0, 5, or 20 s were sometimes placed between sample ratios and choice. All birds made disproportionate numbers of responses to the small-ratio choice alternative when delays were interposed between ratios and choice, and this bias increased as a function of delay. Preference for the small fixed-ratio alternative was also observed on "no-sample" trials, during which the choice alternatives were presented without a prior sample ratio. This "choose-small" bias is analogous to results obtained by Spetch and Wilkie (1983) with event duration as the discriminative stimulus. The choose-small bias was attenuated when the houselight was turned on during delays, but overall accuracy was not influenced systematically by the houselight manipulation. PMID:2584917

Estrogen receptor ERα plays a major role in ethanol-evoked myocardial oxidative stress and dysfunction in conscious female rats.

PubMed

Yao, Fanrong; Abdel-Rahman, Abdel A

2016-02-01

Our previous studies showed that ethanol elicited estrogen (E2)-dependent myocardial oxidative stress and dysfunction. In the present study we tested the hypothesis that E2 signaling via the estrogen receptor (ER), ERα, mediates this myocardial detrimental effect of alcohol. To achieve this goal, conscious female rats in proestrus phase (highest endogenous E2 level) received a selective ER antagonist (200 μg/kg; intra-venous [i.v.]) for ERα (MPP), ERβ (PHTPP) or GPER (G15) or saline 30 min before ethanol (1 g/kg; i.v.) or saline infusion. ERα blockade virtually abrogated ethanol-evoked myocardial dysfunction and hypotension, while ERβ blockade had little effect on the hypotensive response, but caused delayed attenuation of the ethanol-evoked reductions in left ventricular developed pressure and the rate of left ventricle pressure rise. GPER blockade caused delayed attenuation of all cardiovascular effects of ethanol. All three antagonists attenuated the ethanol-evoked increases in myocardial catalase and ALDH2 activities, Akt, ERK1/2, p38, eNOS, and nNOS phosphorylation, except for a lack of effect of PHTPP on p38. Finally, all three ER antagonists attenuated ethanol-evoked elevation in myocardial ROS, but this effect was most notable with ERα blockade. In conclusion, ERα plays a greater role in, and might serve as a molecular target for ameliorating, the E2-dependent myocardial oxidative stress and dysfunction caused by ethanol. Copyright © 2016 Elsevier Inc. All rights reserved.

Study of Relationship Between Illness Perception and Delay in Seeking Help for Breast Cancer Patients Based on Leventhal's Self-Regulation Model.

PubMed

Attari, Seyedeh Maryam; Ozgoli, Giti; Solhi, Mahnaz; Alavi Majd, Hamid

2016-01-01

One of the major causes of morbidity and mortality in breast cancer patients is delay in seeking help. Leventhal's self-regulation model provides an appropriate framework to assess delay in seeking help. The aim of this study was to investigate the relationship between "illness perception" and "help seeking delay" in breast cancer patients based on Leventhal's self-regulation model. In this correlational descriptive study with convenience sampling conducted in 2013, participants were 120 women with breast cancer who were diagnosed in the last year and referred to chemotherapy and radiotherapy centers in Rasht, Iran. Data collection scales included demographic data, Revised Illness Perception Questionnaire (IPQ-R)and a researcher made questionnaire to measure the delay in seeking help. Pre-hospital delay (help seeking delay) was evaluated in 3 phases (assessment, disease, behavior). The data were analyzed using SPSS-19. The mean (SD) age calculated for the patients was 47.3±10.2. Some 43% of the patients had a high school or higher education level and 82% were married. The "pre-hospital delay" was reported ≥3 months. Logistic regression analysis showed that none of the illness perception components were correlated with appraisal and behavioral delay phases. In the illness delay phase, "time line" (p-value =0.04) and "risk factors"(p-value=0.03) had significant effects on reducing and "psychological attributions" had significant effects on increasing the delay (p-value =0.01). "Illness coherence" was correlated with decreased pre-hospital patient delay (p-value<0.01). Women's perceptions of breast cancer influences delay in seeking help. In addition to verifying the validity of Leventhal's self-regulation model in explaining delay in seeking help, the results signify the importance of the "illness delay phase" (decision to seek help) and educational interventions-counseling for women in the community.

Comparing Active Delay and Procrastination from a Self-Regulated Learning Perspective

ERIC Educational Resources Information Center

Corkin, Danya M.; Yu, Shirley L.; Lindt, Suzanne F.

2011-01-01

Researchers have proposed that the act of postponing academic work may be divided into a traditional definition of procrastination, viewed as maladaptive, and adaptive forms of delay. Adaptive forms of delay may be more consistent with certain facets of self-regulated learning. The current study investigated this issue by examining whether the…

Melatonin attenuates postharvest physiological deterioration of cassava storage roots.

PubMed

Ma, Qiuxiang; Zhang, Ting; Zhang, Peng; Wang, Zhen-Yu

2016-05-01

Melatonin reportedly increases abiotic and biotic stress tolerance in plants, but information on its in vivo effects during postharvest physiological deterioration (PPD) in cassava is limited. In this study, we investigated the effect of melatonin in regulating cassava PPD. Treatment with 500 mg/L melatonin significantly delayed cassava PPD and reduced the accumulation of hydrogen peroxide (H2O2) while increasing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR), but not ascorbate peroxidase (APX). Transcript analysis further showed that expression of copper/zinc SOD (MeCu/ZnSOD), MeCAT1, glutathione peroxidase (MeGPX), peroxidase 3 (MePX3), and glutathione S-transferases (MeGST) was higher in cassava roots sliced treated with 500 mg/L melatonin than in those not exposed to exogenous melatonin. These data demonstrate that melatonin delays cassava PPD by directly or indirectly maintaining homoeostasis of cellular reactive oxygen species (ROS). We also found that accumulation of endogenous melatonin and the transcript levels of melatonin biosynthesis genes changed dynamically during the PPD process. This finding suggested that endogenous melatonin acts as a signal modulator for maintaining cassava PPD progression and that manipulation of melatonin biosynthesis genes through genetic engineering might prevent cassava root deterioration. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Monitored natural attenuation forum: MNA of metals and radionuclides

EPA Science Inventory

While the natural attenuation of many organic compounds is established and accepted by the regulated and regulatory communities, there is some debate whether monitored natural attenuation (MNA) of metals and radionuclides is a reasonable remedial alternative to consider. Do you...

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment.

PubMed

Yang, Tao; Grafe, Ingo; Bae, Yangjin; Chen, Shan; Chen, Yuqing; Bertin, Terry K; Jiang, Ming-Ming; Ambrose, Catherine G; Lee, Brendan

2013-04-30

TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro-TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1(-/-) mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1(-/-) osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1(-/-) osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1(-/-) calvaria exhibit an elevated mature TGF-β/pro-TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-β antibody, significantly improved the low bone mass of Esl-1(-/-) mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1(-/-) mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.

Protein kinase C epsilon mediates the inhibition of angiotensin II on the slowly activating delayed-rectifier potassium current through channel phosphorylation.

PubMed

Gou, Xiangbo; Wang, Wenying; Zou, Sihao; Qi, Yajuan; Xu, Yanfang

2018-03-01

The slowly activating delayed rectifier K + current (I Ks ) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates I Ks through the protein kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of I Ks by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record I Ks in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited I Ks in a concentration-dependent manner in native cardiomyocytes. A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by PKCε-selective peptide inhibitor εV1-2. However, direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) increased the cloned human I Ks in HEK293 cells. Similarly, the cPKC peptide activator significantly enhanced the current. In contrast, the PKCε peptide activator inhibited the current. Further evidence showed that PKCε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of cPKCs (PKCα and PKCβ) attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that PKCε isoenzyme mediates the inhibitory action of Ang II on I Ks and by phosphorylating distinct sites in KCNQ1/KCNE1, cPKC and PKCε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism underlying the modulation of the KCNQ1/KCNE1 channel. Copyright © 2018 Elsevier Ltd. All rights reserved.

Inherent Association Between Academic Delay of Gratification, Future Time Perspective, and Self-Regulated Learning

ERIC Educational Resources Information Center

Bembenutty, Hefer; Karabenick, Stuart A.

2004-01-01

We review the association between delay of gratification and future time perspective (FTP), which can be incorporated within the theoretical perspective of self-regulation of learning. We propose that delay of gratification in academic contexts, along with facilitative beliefs about the future, increase the likelihood of completing academic tasks.…

48 CFR 22.1014 - Delay over 60 days in bid opening or commencement of work.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Delay over 60 days in bid... ACQUISITION REGULATION SOCIOECONOMIC PROGRAMS APPLICATION OF LABOR LAWS TO GOVERNMENT ACQUISITIONS Service Contract Act of 1965, as Amended 22.1014 Delay over 60 days in bid opening or commencement of work. If a...

Cerebrospinal fluid enhancement on fluid attenuated inversion recovery images after carotid artery stenting with neuroprotective balloon occlusions: hemodynamic instability and blood-brain barrier disruption.

PubMed

Ogami, Ryo; Nakahara, Toshinori; Hamasaki, Osamu; Araki, Hayato; Kurisu, Kaoru

2011-10-01

A rare complication of carotid artery stenting (CAS), prolonged reversible neurological symptoms with delayed cerebrospinal fluid (CSF) space enhancement on fluid attenuated inversion recovery (FLAIR) images, is associated with blood-brain barrier (BBB) disruption. We prospectively identified patients who showed CSF space enhancement on FLAIR images. Nineteen patients-5 acute-phase and 14 scheduled-underwent 21 CAS procedures. Balloon catheters were navigated across stenoses, angioplasty was performed using a neuroprotective balloon, and stents were placed with after dilation under distal balloon protection. CSF space hyperintensity or obscuration on FLAIR after versus before CAS indicated CSF space enhancement. Correlations with clinical factors were examined. CSF space was enhanced on FLAIR in 12 (57.1%) cases. Postprocedural CSF space enhancement was significantly related to age, stenosis rate, acute-stage procedure, and total occlusion time. All acute-stage CAS patients showed delayed enhancement. Only age was associated with delayed CSF space enhancement in scheduled CAS patients. Ischemic intolerance for severe carotid artery stenosis and temporary neuroprotective balloon occlusion, causing reperfusion injury, seem to be the main factors that underlie BBB disruption with delayed CSF space enhancement shortly after CAS, rather than sudden poststenting hemodynamic change. Our results suggest that factors related to hemodynamic instability or ischemic intolerance seem to be associated with post-CAS BBB vulnerability. Patients at risk for hemodynamic instability or with ischemic intolerance, which decrease BBB integrity, require careful management to prevent intracranial hemorrhagic and other post-CAS complications.

Granulocyte-Colony Stimulating Factor (G-CSF) Accelerates Wound Healing in Hemorrhagic Shock Rats by Enhancing Angiogenesis and Attenuating Apoptosis

PubMed Central

Huang, Hong; Zhang, Qi; Liu, Jiejie; Hao, Haojie; Jiang, Chaoguang; Han, Weidong

2017-01-01

Background Following severe trauma, treatment of cutaneous injuries is often delayed by inadequate blood supply. The aim of the present study was to determine whether granulocyte-colony stimulating factor (G-CSF) protects endothelial cells (ECs) and enhances angiogenesis in a rat model of hemorrhagic shock (HS) combined with cutaneous injury after resuscitation. Material/Methods The HS rats with full-thickness defects were resuscitated and randomly divided into a G-CSF group (200 μg/kg body weight), a normal saline group, and a blank control group. Histological staining was to used estimate the recovery and apoptosis of skin. Apoptosis- and angiogenesis-related factors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot (WB). Scratch assay, tube formation, and WB experiments were performed to verify the functional effects of G-CSF on HUVECs in vitro. Results H&E staining and Masson trichrome staining showed earlier inflammation resolution and collagen synthesis in the G-CSF-treated group. Angiogenesis-related factors were elevated at mRNA and protein levels. TUNEL staining suggested fewer apoptotic cells in the G-CSF group. The apoptotic-related factors were down-regulated and anti-apoptotic factors were up-regulated in the G-CSF-treated group. Scratch assay and tube formation experiments revealed that G-CSF facilitated migration ability and angiogenic potential of HUVECs. The angiogenic and anti-apoptotic effects were also enhanced in vitro. Conclusions Our results suggest that G-CSF after resuscitation attenuates local apoptosis and accelerates angiogenesis. These findings hold great promise for improving therapy for cutaneous injury in severe trauma and ischemia diseases. PMID:28559534

Hedgehog signaling in the murine melanoma microenvironment.

PubMed

Geng, Ling; Cuneo, Kyle C; Cooper, Michael K; Wang, Hong; Sekhar, Konjeti; Fu, Allie; Hallahan, Dennis E

2007-01-01

The Hedgehog intercellular signaling pathway regulates cell proliferation and differentiation. This pathway has been implicated to play a role in the pathogenesis of cancer and in embryonic blood vessel development. In the current study, Hedgehog signaling in tumor related vasculature and microenvironment was examined using human umbilical vein endothelial cells and B16F0 (murine melanoma) tumors models. Use of exogenous Sonic hedgehog (Shh) peptide significantly increased BrdU incorporation in endothelial cells in vitro by a factor of 2 (P < 0.001). The Hedgehog pathway antagonist cyclopamine effectively reduced Shh-induced proliferation to control levels. To study Hedgehog signaling in vivo a hind limb tumor model with the B16F0 cell line was used. Treatment with 25 mg/kg cyclopamine significantly attenuated BrdU incorporation in tumor cells threefold (P < 0.001), in tumor related endothelial cells threefold (P = 0.004), and delayed tumor growth by 4 days. Immunohistochemistry revealed that the Hedgehog receptor Patched was localized to the tumor stroma and that B16F0 cells expressed Shh peptide. Furthermore, mouse embryonic fibroblasts required the presence of B16F0 cells to express Patched in a co-culture assay system. These studies indicate that Shh peptide produced by melanoma cells induces Patched expression in fibroblasts. To study tumor related angiogenesis a vascular window model was used to monitor tumor vascularity. Treatment with cyclopamine significantly attenuated vascular formation by a factor of 2.5 (P < 0.001) and altered vascular morphology. Furthermore, cyclopamine reduced tumor blood vessel permeability to FITC labeled dextran while having no effect on normal blood vessels. These studies suggest that Hedgehog signaling regulates melanoma related vascular formation and function.

Highly purified eicosapentaenoic acid ameliorates cardiac injury and adipose tissue inflammation in a rat model of metabolic syndrome

PubMed Central

Ito, S.; Sano, Y.; Nagasawa, K.; Matsuura, N.; Yamada, Y.; Uchinaka, A.; Murohara, T.

2016-01-01

Summary Introduction n‐3 Polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), which are abundant in fish oil, have been shown to delay the onset of cardiovascular events. We previously established DahlS.Z‐Lepr fa/Lepr fa (DS/obese) rats, which are derived from a cross between Dahl salt‐sensitive and Zucker rats, as a model of metabolic syndrome. This study has now explored the influence of highly purified EPA on cardiac and adipose tissue pathophysiology in this animal model. Materials and methods DS/obese rats were administered EPA (300 or 1,000 mg kg−1 d−1, per os) or vehicle from age 9 to 13 weeks. Homozygous lean (DahlS.Z‐Lepr +/Lepr +, or DS/lean) littermates were studied as controls. Results Whereas EPA had no effect on body weight, food intake or systolic blood pressure in DS/obese rats, it attenuated cardiac fibrosis, diastolic dysfunction, oxidative stress and inflammation in these animals. In addition, EPA did not affect insulin resistance but reduced adipocyte hypertrophy and inflammation in visceral fat of DS/obese rats. Moreover, EPA increased circulating levels of adiponectin as well as attenuated both the down‐regulation of AMP‐activated protein kinase phosphorylation and the up‐regulation of phosphorylation of the p65 subunit of nuclear factor‐kB in the heart of DS/obese rats. Conclusions Treatment of DS/obese rats with EPA did not affect hypertension but reduced cardiac fibrosis and diastolic dysfunction, with the latter effects being accompanied by AMP‐activated protein kinase activation and inactivation of nuclear factor‐kB signalling in the heart, possibly as a result of an increase in adiponectin secretion. EPA may be suitable for the treatment of cardiac injury associated with metabolic syndrome. PMID:27708849

Bioturbation delays attenuation of DDT by clean sediment cap but promotes sequestration by thin-layered activated carbon.

PubMed

Lin, Diana; Cho, Yeo-Myoung; Werner, David; Luthy, Richard G

2014-01-21

The effects of bioturbation on the performance of attenuation by sediment deposition and activated carbon to reduce risks from DDT-contaminated sediment were assessed for DDT sediment-water flux, biouptake, and passive sampler (PE) uptake in microcosm experiments with a freshwater worm, Lumbriculus variegatus. A thin-layer of clean sediment (0.5 cm) did not reduce the DDT flux when bioturbation was present, while a thin (0.3 cm) AC cap was still capable of reducing the DDT flux by 94%. Bioturbation promoted AC sequestration by reducing the 28-day DDT biouptake (66%) and DDT uptake into PE (>99%) compared to controls. Bioturbation further promoted AC-sediment contact by mixing AC particles into underlying sediment layers, reducing PE uptake (55%) in sediment compared to the AC cap without bioturbation. To account for the observed effects from bioturbation, a mass transfer model together with a biodynamic model were developed to simulate DDT flux and biouptake, respectively, and models confirmed experimental results. Both experimental measurements and modeling predictions imply that thin-layer activated carbon placement on sediment is effective in reducing the risks from contaminated sediments in the presence of bioturbation, while natural attenuation process by clean sediment deposition may be delayed by bioturbation.

Histopathologic diversity of gastric cancers: Relationship between enhancement pattern on dynamic contrast-enhanced CT and histological type.

PubMed

Tsurumaru, Daisuke; Miyasaka, Mitsutoshi; Muraki, Toshio; Nishie, Akihiro; Asayama, Yoshiki; Oki, Eiji; Oda, Yoshinao; Honda, Hiroshi

2017-12-01

To evaluate the diagnostic value of contrast-enhanced computed tomography gastrography (CE-CTG) to predict the histological type of gastric cancer. We analyzed 47 consecutive patients with resectable advanced gastric cancer preoperatively evaluated by multiphasic dynamic contrast-enhanced CT. Two radiologists independently reviewed the CT images and they determined the peak enhancement phase, and then measured the CT attenuation value of the gastric lesion for each phase. The histological types of gastric cancers were assigned to three groups as differentiated-type, undifferentiated-type, and mixed-type. We compared the peak enhancement phase of the three types and compared the CT attenuation values in each phase. The peak enhancement was significantly different between the three types of gastric cancers for both readers (reader 1, p=0.001; reader 2, p=0.009); most of the undifferentiated types had peak enhancement in the delayed phase. The CT attenuation values of undifferentiated type were significantly higher than those of differentiated or mixed type in the delayed phase according to both readers (reader 1, p=0.002; reader 2, p=0.004). CE-CTG could provide helpful information in diagnosing the histological type of gastric cancers preoperatively. Copyright © 2017 Elsevier B.V. All rights reserved.

Arctigenin, a potential anti-arrhythmic agent, inhibits aconitine-induced arrhythmia by regulating multi-ion channels.

PubMed

Zhao, Zhenying; Yin, Yongqiang; Wu, Hong; Jiang, Min; Lou, Jianshi; Bai, Gang; Luo, Guo'an

2013-01-01

Arctigenin possesses biological activities, but its underlying mechanisms at the cellular and ion channel levels are not completely understood. Therefore, the present study was designed to identify the anti-arrhythmia effect of arctigenin in vivo, as well as its cellular targets and mechanisms. A rat arrhythmia model was established via continuous aconitine infusion, and the onset times of ventricular premature contraction, ventricular tachycardia and death were recorded. The Action Potential Duration (APD), sodium current (I(Na)), L-type calcium current (I(Ca, L)) and transient outward potassium current (I(to)) were measured and analysed using a patch-clamp recording technique in normal rat cardiomyocytes and myocytes of arrhythmia aconitine-induced by. Arctigenin significantly delayed the arrhythmia onset in the aconitine-induced rat model. The 50% and 90% repolarisations (APD50 and APD90) were shortened by 100 µM arctigenin; the arctigenin dose also inhibited the prolongation of APD50 and APD90 caused by 1 µM aconitine. Arctigenin inhibited I(Na) and I(Ca,L) and attenuated the aconitine-increased I(Na) and I(Ca,L) by accelerating the activation process and delaying the inactivation process. Arctigenin enhanced Ito by facilitating the activation process and delaying the inactivation process, and recoverd the decreased Ito induced by aconitine. Arctigenin has displayed anti-arrhythmia effects, both in vivo and in vitro. In the context of electrophysiology, I(Na), I(Ca, L), and I(to) may be multiple targets of arctigenin, leading to its antiarrhythmic effect. © 2013 S. Karger AG, Basel.

Delayed Administration of Bone Marrow Mesenchymal Stem Cell Conditioned Medium Significantly Improves Outcome After Retinal Ischemia in Rats

PubMed Central

Dreixler, John C.; Poston, Jacqueline N.; Balyasnikova, Irina; Shaikh, Afzhal R.; Tupper, Kelsey Y.; Conway, Sineadh; Boddapati, Venkat; Marcet, Marcus M.; Lesniak, Maciej S.; Roth, Steven

2014-01-01

Purpose. Delayed treatment after ischemia is often unsatisfactory. We hypothesized that injection of bone marrow stem cell (BMSC) conditioned medium after ischemia could rescue ischemic retina, and in this study we characterized the functional and histological outcomes and mechanisms of this neuroprotection. Methods. Retinal ischemia was produced in adult Wistar rats by increasing intraocular pressure for 55 minutes. Conditioned medium (CM) from rat BMSCs or unconditioned medium (uCM) was injected into the vitreous 24 hours after the end of ischemia. Recovery was assessed 7 days after ischemia using electroretinography, at which time we euthanized the animals and then prepared 4-μm-thick paraffin-embedded retinal sections. TUNEL and Western blot were used to identify apoptotic cells and apoptosis-related gene expression 24 hours after injections; that is, 48 hours after ischemia. Protein content in CM versus uCM was studied using tandem mass spectrometry, and bioinformatics methods were used to model protein interactions. Results. Intravitreal injection of CM 24 hours after ischemia significantly improved retinal function and attenuated cell loss in the retinal ganglion cell layer. CM attenuated postischemic apoptosis and apoptosis-related gene expression. By spectral counting, 19 proteins that met stringent identification criteria were increased in the CM compared to uCM; the majority were extracellular matrix proteins that mapped into an interactional network together with other proteins involved in cell growth and adhesion. Conclusions. By restoring retinal function, attenuating apoptosis, and preventing retinal cell loss after ischemia, CM is a robust means of delayed postischemic intervention. We identified some potential candidate proteins for this effect. PMID:24699381

Causal relationships among academic delay of gratification, motivation, and self-regulated learning in elementary school children.

PubMed

Zhang, Lili; Maruno, Shun'ichi

2010-10-01

Academic delay of gratification refers to the postponement of immediate rewards by students and the pursuit of more important, temporally remote academic goals. A path model was designed to identify the causal relationships among academic delay of gratification and motivation, self-regulated learning strategies (as specified in the Motivated Strategies for Learning Questionnaire), and grades among 386 Chinese elementary school children. Academic delay of gratification was found to be positively related to motivation and metacognition. Cognitive strategy, resource management, and grades mediated these two factors and were indirectly related to academic delay of gratification.

Autophagy and cardiovascular aging: lesson learned from rapamycin.

PubMed

Nair, Sreejayan; Ren, Jun

2012-06-01

The biological aging process is commonly associated with increased risk of cardiovascular diseases. Several theories have been put forward for aging-associated deterioration in ventricular function, including attenuation of growth hormone (insulin-like growth factors and insulin) signaling, loss of DNA replication and repair, histone acetylation and accumulation of reactive oxygen species. Recent evidence has depicted a rather unique role of autophagy as another important pathway in the regulation of longevity and senescence. Autophagy is a predominant cytoprotective (rather than self-destructive) process. It carries a prominent role in determination of lifespan. Reduced autophagy has been associated with aging, leading to accumulation of dysfunctional or damaged proteins and organelles. To the contrary, measures such as caloric restriction and exercise may promote autophagy to delay aging and associated comorbidities. Stimulation of autophagy using rapamycin may represent a novel strategy to prolong lifespan and combat aging-associated diseases. Rapamycin regulates autophagy through inhibition of the nutrient-sensing molecule mammalian target of rapamycin (mTOR). Inhibition of mTOR through rapamycin and caloric restriction promotes longevity. The purpose of this review is to recapitulate some of the recent advances in an effort to better understand the interplay between rapamycin-induced autophagy and decelerating cardiovascular aging.

Relations between Self Regulation, Future Time Perspective and the Delay of Gratification in University Students

ERIC Educational Resources Information Center

Avci, Suleyman

2013-01-01

The present study was conducted on 508 (331 female, 144 male) first grade university students in order to investigate the relations between self regulation, the future time perspectives, and the delay of gratification in the academic field. A future time perspective scale, an academic delay of gratification scale and a motivational strategies for…

Xenon treatment attenuates early renal allograft injury associated with prolonged hypothermic storage in rats.

PubMed

Zhao, Hailin; Yoshida, Akira; Xiao, Wei; Ologunde, Rele; O'Dea, Kieran P; Takata, Masao; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

2013-10-01

Prolonged hypothermic storage elicits severe ischemia-reperfusion injury (IRI) to renal grafts, contributing to delayed graft function (DGF) and episodes of acute immune rejection and shortened graft survival. Organoprotective strategies are therefore needed for improving long-term transplant outcome. The aim of this study is to investigate the renoprotective effect of xenon on early allograft injury associated with prolonged hypothermic storage. Xenon exposure enhanced the expression of heat-shock protein 70 (HSP-70) and heme oxygenase 1 (HO-1) and promoted cell survival after hypothermia-hypoxia insult in human proximal tubular (HK-2) cells, which was abolished by HSP-70 or HO-1 siRNA. In the brown Norway to Lewis rat renal transplantation, xenon administered to donor or recipient decreased the renal tubular cell death, inflammation, and MHC II expression, while delayed graft function (DGF) was therefore reduced. Pathological changes associated with acute rejection, including T-cell, macrophage, and fibroblast infiltration, were also decreased with xenon treatment. Donors or recipients treated with xenon in combination with cyclosporin A had prolonged renal allograft survival. Xenon protects allografts against delayed graft function, attenuates acute immune rejection, and enhances graft survival after prolonged hypothermic storage. Furthermore, xenon works additively with cyclosporin A to preserve post-transplant renal function.

Different patterns of modality dominance across development.

PubMed

Barnhart, Wesley R; Rivera, Samuel; Robinson, Christopher W

2018-01-01

The present study sought to better understand how children, young adults, and older adults attend and respond to multisensory information. In Experiment 1, young adults were presented with two spoken words, two pictures, or two word-picture pairings and they had to determine if the two stimuli/pairings were exactly the same or different. Pairing the words and pictures together slowed down visual but not auditory response times and delayed the latency of first fixations, both of which are consistent with a proposed mechanism underlying auditory dominance. Experiment 2 examined the development of modality dominance in children, young adults, and older adults. Cross-modal presentation attenuated visual accuracy and slowed down visual response times in children, whereas older adults showed the opposite pattern, with cross-modal presentation attenuating auditory accuracy and slowing down auditory response times. Cross-modal presentation also delayed first fixations in children and young adults. Mechanisms underlying modality dominance and multisensory processing are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Reliance on auditory feedback in children with childhood apraxia of speech.

PubMed

Iuzzini-Seigel, Jenya; Hogan, Tiffany P; Guarino, Anthony J; Green, Jordan R

2015-01-01

Children with childhood apraxia of speech (CAS) have been hypothesized to continuously monitor their speech through auditory feedback to minimize speech errors. We used an auditory masking paradigm to determine the effect of attenuating auditory feedback on speech in 30 children: 9 with CAS, 10 with speech delay, and 11 with typical development. The masking only affected the speech of children with CAS as measured by voice onset time and vowel space area. These findings provide preliminary support for greater reliance on auditory feedback among children with CAS. Readers of this article should be able to (i) describe the motivation for investigating the role of auditory feedback in children with CAS; (ii) report the effects of feedback attenuation on speech production in children with CAS, speech delay, and typical development, and (iii) understand how the current findings may support a feedforward program deficit in children with CAS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

H. pylori attenuates TNBS-induced colitis via increasing mucosal Th2 cells in mice.

PubMed

Wu, Yi-Zhong; Tan, Gao; Wu, Fang; Zhi, Fa-Chao

2017-09-26

There is an epidemiological inverse relationship between Helicobacter pylori ( H. pylori ) infection and Crohn's disease (CD). However, whether H. pylori plays a protective role against CD remains unclear. Since 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis is thought to resemble CD, we investigated whether H. pylori can attenuate TNBS-induced colitis in mice. Here we show that H. pylori can attenuate the severity of TNBS-induced colitis. In addition, H. pylori not only down-regulates Th17 and Th1 cytokine expression, but can up-regulate Th2 cytokine expression and increase the Th2:Th17 ratio of CD4 + T in the colonic mucosa of TNBS-induced colitis. Our results indicate that H. pylori attenuates TNBS-induced colitis mainly through increasing Th2 cells in murine colonic mucosa. Our finding offers a novel view on the role of H. pylori in regulating gastrointestinal immunity, and may open a new avenue for development of therapeutic strategies in CD by making use of asymptomatic H. pylori colonization.

Too proud to regulate: The differential effect of pride versus joy on children's ability to delay gratification.

PubMed

Shimoni, Einav; Asbe, Marwa; Eyal, Tal; Berger, Andrea

2016-01-01

We examined the effect of the distinct positive emotions pride and joy on children's self-regulation, focusing on their ability to delay gratification (i.e., resist a temptation in favor of a long-term goal). We hypothesized that because pride corresponds to the attainment of long-term goals and joy corresponds to the attainment of immediate desires, the experience of pride may signal sufficient progress toward a long-term goal, resulting in less delay of gratification than the experience of joy. To test this hypothesis, we induced an experience of pride or joy in 8-year-old children. At this age, the ability to self-regulate--and to experience pride and joy distinctively--is relatively mature. We then measured performance in a delay discounting task. We found that, compared with the joy condition and a control condition, children who experienced pride performed worse on the delay discounting task (p=.045), indicating poorer self-regulation. This result suggests that emotions may function as cues for sufficient goal pursuit, thereby influencing self-regulation from a very young age. Copyright © 2015 Elsevier Inc. All rights reserved.

Physiological Profiles During Delay of Gratification: Associations with Emotionality, Self-regulation, and Adjustment Problems

PubMed Central

Wilson, Anna C.; Lengua, Liliana J.; Tininenko, Jennifer; Taylor, Adam; Trancik, Anika

2009-01-01

This longitudinal study utilized a community sample of children (N=91, 45% female, 8–11 years at time 1) to investigate physiological responses (heart rate reactivity [HRR] and electrodermal responding [EDR]) during delay of gratification in relation to emotionality, self-regulation, and adjustment problems. Cluster analyses identified three profiles among children who successfully delayed: children who waited easily with low EDR and moderate HRR, children who had difficulty waiting with high EDR and moderate HRR, and children who had difficulty waiting with low EDR and low HRR. The 3 clusters and children who did not wait were compared. Children with low EDR-low HRR had the lowest self-regulation, and like the no-wait group, demonstrated the greatest baseline adjustment problems. The high EDR-moderate HRR group demonstrated highest self-regulation and increases in depression across one year. Distinct profiles among children in delay contexts point to children who are over- and under-regulated with implications for adjustment problems. PMID:20046898

Inflammatory response to Escherichia coli urinary tract infection in the neurogenic bladder of the spinal cord injured host.

PubMed

Chaudhry, Rajeev; Madden-Fuentes, Ramiro J; Ortiz, Tara K; Balsara, Zarine; Tang, Yuping; Nseyo, Unwanaobong; Wiener, John S; Ross, Sherry S; Seed, Patrick C

2014-05-01

Urinary tract infections cause significant morbidity in patients with spinal cord injury. An in vivo spinal cord injured rat model of experimental Escherichia coli urinary tract infection mimics human disease with enhanced susceptibility to urinary tract infection compared to controls. We hypothesized that a dysregulated inflammatory response contributes to enhanced susceptibility to urinary tract infection. Spinal cord injured and sham injured rats were inoculated transurethrally with E. coli. Transcript levels of 84 inflammatory pathway genes were measured in bladder tissue of each group before infection, 24 hours after infection and after 5 days of antibiotic therapy. Before infection quantitative polymerase chain reaction array revealed greater than twofold up-regulation in the proinflammatory factor transcripts slc11a1, ccl4 and il1β, and down-regulation of the antimicrobial peptides lcn2 and mpo in spinal cord injured vs control bladders. At 24 hours after infection spinal cord injured bladders showed an attenuated innate immune response with decreased expression of il6, slc11a1, il1β and lcn2, and decreased il10 and slpi expression compared to controls. Despite clearance of bacteriuria with antibiotics spinal cord injured rats had delayed induction of il6 transcription and a delayed anti-inflammatory response with decreased il10 and slpi transcript levels relative to controls. Spinal cord injured bladders fail to mount a characteristic inflammatory response to E. coli infection and cannot suppress inflammation after infection is eliminated. This may lead to increased susceptibility to urinary tract infection and persistent chronic inflammation through neural mediated pathways, which to our knowledge remain to be defined. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Inactivation of Tgfbr2 in Osterix-Cre expressing Dental Mesenchyme Disrupts Molar Root Formation

PubMed Central

Coricor, George; MacDougall, Mary; Serra, Rosa

2013-01-01

It has been difficult to examine the role of TGF-ß in post-natal tooth development due to perinatal lethality in many of the signaling deficient mouse models. To address the role of Tgfbr2 in postnatal tooth development, we generated a mouse in which Tgfbr2 was deleted in odontoblast-and bone-producing mesenchyme. Osx-Cre;Tgfbr2fl/fl mice were generated (Tgfbr2cko) and postnatal tooth development was compared in Tgfbr2cko and control littermates. X-ray and μCT analysis showed that in Tgfbr2cko mice radicular dentin matrix density was reduced in the molars. Molar shape was abnormal and molar eruption was delayed in the mutant mice. Most significantly, defects in root formation, including failure of the root to elongate, were observed by postnatal day 10. Immunostaining for Keratin-14 (K14) was used to delineate Hertwig's epithelial root sheath (HERS). The results showed a delay in elongation and disorganization of the HERS in Tgfbr2cko mice. In addition, the HERS was maintained and the break up into epithelial rests was attenuated suggesting that Tgfbr2 acts on dental mesenchyme to indirectly regulate the formation and maintenance of the HERS. Altered odontoblast organization and reduced Dspp expression indicated that odontoblast differentiation was disrupted in the mutant mice likely contributing to the defect in root formation. Nevertheless, expression of Nfic, a key mesenchymal regulator of root development, was similar in Tgfbr2cko mice and controls. The number of osteoclasts in the bone surrounding the tooth was reduced and osteoblast differentiation was disrupted likely contributing to both root and eruption defects. We conclude that Tgfbr2 in dental mesenchyme and bone is required for tooth development particularly root formation. PMID:23933490

Differential Sensitivity to Ethanol-Induced Circadian Rhythm Disruption in Adolescent and Adult Mice

PubMed Central

Ruby, Christina L.; Palmer, Kaitlyn N.; Zhang, Jiawen; Risinger, Megan O.; Butkowski, Melissa A.; Swartzwelder, H. Scott

2016-01-01

Background Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether ethanol has similar effects on circadian regulation during adolescence. Methods General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12 h light, 12 h dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of ethanol (1.5 g/kg, i.p.) or equal volume saline 15 min prior to a 30-min light pulse at Zeitgeber Time 14 (2 h into the dark phase), then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age group received injections but no light pulse prior to DD. Results While adults showed the expected decrease in photic phase-delays induced by acute ethanol, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Conclusions Collectively, our results indicate that adolescent mice are less sensitive to the effect of ethanol on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults. PMID:27997028

Radiation-induced pulmonary gene expression changes are attenuated by the CTGF antibody Pamrevlumab.

PubMed

Sternlicht, Mark D; Wirkner, Ute; Bickelhaupt, Sebastian; Lopez Perez, Ramon; Tietz, Alexandra; Lipson, Kenneth E; Seeley, Todd W; Huber, Peter E

2018-01-18

Fibrosis is a delayed side effect of radiation therapy (RT). Connective tissue growth factor (CTGF) promotes the development of fibrosis in multiple settings, including pulmonary radiation injury. To better understand the cellular interactions involved in RT-induced lung injury and the role of CTGF in these responses, microarray expression profiling was performed on lungs of irradiated and non-irradiated mice, including mice treated with the anti-CTGF antibody pamrevlumab (FG-3019). Between group comparisons (Welch's t-tests) and principal components analyses were performed in Genespring. At the mRNA level, the ability of pamrevlumab to prolong survival and ameliorate RT-induced radiologic, histologic and functional lung deficits was correlated with the reversal of a clear enrichment in mast cell, macrophage, dendritic cell and mesenchymal gene signatures. Cytokine, growth factor and matrix remodeling genes that are likely to contribute to RT pneumonitis and fibrosis were elevated by RT and attenuated by pamrevlumab, and likely contribute to the cross-talk between enriched cell-types in injured lung. CTGF inhibition had a normalizing effect on select cell-types, including immune cells not typically regarded as being regulated by CTGF. These results suggest that interactions between RT-recruited cell-types are critical to maintaining the injured state; that CTGF plays a key role in this process; and that pamrevlumab can ameliorate RT-induced lung injury in mice and may provide therapeutic benefit in other immune and fibrotic disorders.

Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration.

PubMed

Romero, Juan Ignacio; Holubiec, Mariana Inés; Tornatore, Tamara Logica; Rivière, Stéphanie; Hanschmann, Eva-Maria; Kölliker-Frers, Rodolfo Alberto; Tau, Julia; Blanco, Eduardo; Galeano, Pablo; Rodríguez de Fonseca, Fernando; Lillig, Christopher Horst; Capani, Francisco

2017-01-01

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration

PubMed Central

Holubiec, Mariana Inés; Tornatore, Tamara Logica; Rivière, Stéphanie; Kölliker-Frers, Rodolfo Alberto; Tau, Julia; Blanco, Eduardo; Galeano, Pablo; Lillig, Christopher Horst

2017-01-01

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury. PMID:28706574

Executive functioning, emotion regulation, eating self-regulation, and weight status in low-income preschool children: How do they relate?

PubMed Central

Hughes, Sheryl O.; Power, Thomas G.; O’Connor, Teresia M.; Fisher, Jennifer Orlet

2016-01-01

The purpose of the present study was to examine relationships between child eating self-regulation, child non-eating self-regulation, and child BMIz in a low-income sample of Hispanic families with preschoolers. The eating in the absence of hunger task as well as parent-report of child satiety responsiveness and food responsiveness were used to assess child eating self-regulation. Two laboratory tasks assessing executive functioning, a parent questionnaire assessing child effortful control (a temperament dimension related to executive functioning), and the delay of gratification and gift delay tasks assessing child emotion regulation were used to assess child non-eating self-regulation. Bivariate correlations were run among all variables in the study. Hierarchical linear regression analyses assessed: 1) child eating self-regulation associations with the demographic, executive functioning, effortful control, and emotion regulation measures; and 2) child BMI z-scores associations with executive functioning, effortful control, emotion regulation measures, and eating self-regulation measures. Within child eating self-regulation, only the two parent-report measures were related. Low to moderate positive correlations were found between measures of executive functioning, effortful control, and emotion regulation. Only three relationships were found between child eating self-regulation and other forms of child self-regulation: eating in the absence of hunger was positively associated with delay of gratification, and poor regulation on the gift delay task was associated positively with maternal reports of food responsiveness and negatively with parent-reports of satiety responsiveness. Regression analyses showed that child eating self-regulation was associated with child BMIz but other forms of child self-regulation were not. Implications for understanding the role of self-regulation in the development of child obesity are discussed. PMID:25596501

Executive functioning, emotion regulation, eating self-regulation, and weight status in low-income preschool children: how do they relate?

PubMed

Hughes, Sheryl O; Power, Thomas G; O'Connor, Teresia M; Orlet Fisher, Jennifer

2015-06-01

The purpose of the present study was to examine relationships between child eating self-regulation, child non-eating self-regulation, and child BMIz in a low-income sample of Hispanic families with preschoolers. The eating in the absence of hunger task as well as parent-report of child satiety responsiveness and food responsiveness were used to assess child eating self-regulation. Two laboratory tasks assessing executive functioning, a parent questionnaire assessing child effortful control (a temperament dimension related to executive functioning), and the delay of gratification and gift delay tasks assessing child emotion regulation were used to assess child non-eating self-regulation. Bivariate correlations were run among all variables in the study. Hierarchical linear regression analyses assessed: (1) child eating self-regulation associations with the demographic, executive functioning, effortful control, and emotion regulation measures; and (2) child BMI z-score associations with executive functioning, effortful control, emotion regulation measures, and eating self-regulation measures. Within child eating self-regulation, only the two parent-report measures were related. Low to moderate positive correlations were found between measures of executive functioning, effortful control, and emotion regulation. Only three relationships were found between child eating self-regulation and other forms of child self-regulation: eating in the absence of hunger was positively associated with delay of gratification, and poor regulation on the gift delay task was associated positively with maternal reports of food responsiveness and negatively with parent-reports of satiety responsiveness. Regression analyses showed that child eating self-regulation was associated with child BMIz but other forms of child self-regulation were not. Implications for understanding the role of self-regulation in the development of child obesity are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reachable set estimation for Takagi-Sugeno fuzzy systems against unknown output delays with application to tracking control of AUVs.

PubMed

Zhong, Zhixiong; Zhu, Yanzheng; Ahn, Choon Ki

2018-07-01

In this paper, we address the problem of reachable set estimation for continuous-time Takagi-Sugeno (T-S) fuzzy systems subject to unknown output delays. Based on the reachable set concept, a new controller design method is also discussed for such systems. An effective method is developed to attenuate the negative impact from the unknown output delays, which likely degrade the performance/stability of systems. First, an augmented fuzzy observer is proposed to capacitate a synchronous estimation for the system state and the disturbance term owing to the unknown output delays, which ensures that the reachable set of the estimation error is limited via the intersection operation of ellipsoids. Then, a compensation technique is employed to eliminate the influence on the system performance stemmed from the unknown output delays. Finally, the effectiveness and correctness of the obtained theories are verified by the tracking control of autonomous underwater vehicles. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Delayed rectifier potassium channels are involved in SO2 derivative-induced hippocampal neuronal injury.

PubMed

Li, Guangke; Sang, Nan

2009-01-01

Recent studies implicate the possible neurotoxicity of SO(2), however, its mechanisms remain unclear. In the present study, we investigated SO(2) derivative-induced effect on delayed rectifier potassium channels (I(K)) and cellular death/apoptosis in primary cultured hippocampal neurons. The results demonstrate that SO(2) derivatives (NaHSO(3) and Na(2)SO(3), 3:1M/M) effectively augmented I(K) and promoted the activation of delayed rectifier potassium channels. Also, SO(2) derivatives increased neuronal death percentage and contributed to the formation of DNA ladder in concentration-dependent manners. Interestingly, the neuronal death and DNA ladder formation, caused by SO(2) derivatives, could be attenuated by the delayed rectifier potassium channel blocker (tetraethylammonium, TEA), but not by the transient outward potassium channel blocker (4-aminopyridine, 4-AP). It implies that stimulating delayed rectifier potassium channels were involved in SO(2) derivative-caused hippocampal neuronal insults, and blocking these channels might be one of the possibly clinical treatment for SO(2)-caused neuronal dysfunction.

Consensus for multi-agent systems with time-varying input delays

NASA Astrophysics Data System (ADS)

Yuan, Chengzhi; Wu, Fen

2017-10-01

This paper addresses the consensus control problem for linear multi-agent systems subject to uniform time-varying input delays and external disturbance. A novel state-feedback consensus protocol is proposed under the integral quadratic constraint (IQC) framework, which utilises not only the relative state information from neighbouring agents but also the real-time information of delays by means of the dynamic IQC system states for feedback control. Based on this new consensus protocol, the associated IQC-based control synthesis conditions are established and fully characterised as linear matrix inequalities (LMIs), such that the consensus control solution with optimal ? disturbance attenuation performance can be synthesised efficiently via convex optimisation. A numerical example is used to demonstrate the proposed approach.

Elimination of residual amplitude modulation in tunable diode laser wavelength modulation spectroscopy using an optical fiber delay line.

PubMed

Chakraborty, Arup Lal; Ruxton, Keith; Johnstone, Walter; Lengden, Michael; Duffin, Kevin

2009-06-08

A new fiber-optic technique to eliminate residual amplitude modulation in tunable diode laser wavelength modulation spectroscopy is presented. The modulated laser output is split to pass in parallel through the gas measurement cell and an optical fiber delay line, with the modulation frequency / delay chosen to introduce a relative phase shift of pi between them. The two signals are balanced using a variable attenuator and recombined through a fiber coupler. In the absence of gas, the direct laser intensity modulation cancels, thereby eliminating the high background. The presence of gas induces a concentration-dependent imbalance at the coupler's output from which the absolute absorption profile is directly recovered with high accuracy using 1f detection.

Simultaneous learning of instantaneous and time-delayed genetic interactions using novel information theoretic scoring technique

PubMed Central

2012-01-01

Background Understanding gene interactions is a fundamental question in systems biology. Currently, modeling of gene regulations using the Bayesian Network (BN) formalism assumes that genes interact either instantaneously or with a certain amount of time delay. However in reality, biological regulations, both instantaneous and time-delayed, occur simultaneously. A framework that can detect and model both these two types of interactions simultaneously would represent gene regulatory networks more accurately. Results In this paper, we introduce a framework based on the Bayesian Network (BN) formalism that can represent both instantaneous and time-delayed interactions between genes simultaneously. A novel scoring metric having firm mathematical underpinnings is also proposed that, unlike other recent methods, can score both interactions concurrently and takes into account the reality that multiple regulators can regulate a gene jointly, rather than in an isolated pair-wise manner. Further, a gene regulatory network (GRN) inference method employing an evolutionary search that makes use of the framework and the scoring metric is also presented. Conclusion By taking into consideration the biological fact that both instantaneous and time-delayed regulations can occur among genes, our approach models gene interactions with greater accuracy. The proposed framework is efficient and can be used to infer gene networks having multiple orders of instantaneous and time-delayed regulations simultaneously. Experiments are carried out using three different synthetic networks (with three different mechanisms for generating synthetic data) as well as real life networks of Saccharomyces cerevisiae, E. coli and cyanobacteria gene expression data. The results show the effectiveness of our approach. PMID:22691450

Sodium butyrate attenuates soybean oil-based lipid emulsion-induced increase in intestinal permeability of lipopolysaccharide by modulation of P-glycoprotein in Caco-2 cells

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

Yan, Jun-Kai; Gong, Zi-Zhen; Zhang, Tian

Down-regulation of intestinal P-glycoprotein (P-gp) by soybean oil-based lipid emulsion (SOLE) may cause elevated intestinal permeability of lipopolysaccharide (LPS) in patients with total parenteral nutrition, but the appropriate preventative treatment is currently limited. Recently, sodium butyrate (NaBut) has been demonstrated to regulate the expression of P-gp. Therefore, this study aimed to address whether treatment with NaBut could attenuate SOLE-induced increase in intestinal permeability of LPS by modulation of P-gp in vitro. Caco-2 cells were exposed to SOLE with or without NaBut. SOLE-induced down-regulation of P-gp was significantly attenuated by co-incubation with NaBut. Nuclear recruitment of FOXO 3a in response to NaButmore » was involved in P-gp regulation. Transport studies revealed that SOLE-induced increase in permeability of LPS was significantly attenuated by co-incubation with NaBut. Collectively, our results suggested that NaBut may be a potentially useful medication to prevent SOLE-induced increase in intestinal permeability of LPS. - Highlights: • Caco-2 cells were used as models for studying parenteral nutrition in vitro. • NaBut restored SOLE-induced down-regulation of P-gp in Caco-2 cells. • Regulation of P-gp by NaBut was mediated via nuclear recruitment of FOXO 3a. • NaBut modulated the permeability of LPS by P-gp function, not barrier function.« less

The upper mantle structure of the central Rio Grande rift region from teleseismic P and S wave travel time delays and attenuation

USGS Publications Warehouse

Slack, P.D.; Davis, P.M.; Baldridge, W.S.; Olsen, K.H.; Glahn, A.; Achauer, U.; Spence, W.

1996-01-01

The lithosphere beneath a continental rift should be significantly modified due to extension. To image the lithosphere beneath the Rio Grande rift (RGR), we analyzed teleseismic travel time delays of both P and S wave arrivals and solved for the attenuation of P and S waves for four seismic experiments spanning the Rio Grande rift. Two tomographic inversions of the P wave travel time data are given: an Aki-Christofferson-Husebye (ACH) block model inversion and a downward projection inversion. The tomographic inversions reveal a NE-SW to NNE-SSW trending feature at depths of 35 to 145 km with a velocity reduction of 7 to 8% relative to mantle velocities beneath the Great Plains. This region correlates with the transition zone between the Colorado Plateau and the Rio Grande rift and is bounded on the NW by the Jemez lineament, a N52??E trending zone of late Miocene to Holocene volcanism. S wave delays plotted against P wave delays are fit with a straight line giving a slope of 3.0??0.4. This correlation and the absolute velocity reduction imply that temperatures in the lithosphere are close to the solidus, consistent with, but not requiring, the presence of partial melt in the mantle beneath the Rio Grande rift. The attenuation data could imply the presence of partial melt. We compare our results with other geophysical and geologic data. We propose that any north-south trending thermal (velocity) anomaly that may have existed in the upper mantle during earlier (Oligocene to late Miocene) phases of rifting and that may have correlated with the axis of the rift has diminished with time and has been overprinted with more recent structure. The anomalously low-velocity body presently underlying the transition zone between the core of the Colorado Plateau and the rift may reflect processes resulting from the modern (Pliocene to present) regional stress field (oriented WNW-ESE), possibly heralding future extension across the Jemez lineament and transition zone.

Self-Regulation of Learning and Academic Delay of Gratification among Korean College Students

ERIC Educational Resources Information Center

Bembenutty, Hefer

2007-01-01

The goal of the present study was to examine the relationship between Korean students' motivation for learning, use of self-regulation of learning strategies, and delay of gratification Self-regulation of learning is a process that required students to get involved in their personal, behavioral, motivational, and cognitive learning tasks in order…

Functional blockage of EMMPRIN ameliorates atherosclerosis in apolipoprotein E-deficient mice.

PubMed

Liu, Hong; Yang, Li-xia; Guo, Rui-wei; Zhu, Guo-Fu; Shi, Yan-Kun; Wang, Xian-mei; Qi, Feng; Guo, Chuan-ming; Ye, Jin-shan; Yang, Zhi-hua; Liang, Xing

2013-10-09

Extracellular matrix metalloproteinase inducer (EMMPRIN), a 58-kDa cell surface glycoprotein, has been identified as a key receptor for transmitting cellular signals mediating metalloproteinase activities, as well as inflammation and oxidative stress. Clinical evidence has revealed that EMMPRIN is expressed in human atherosclerotic plaque; however, the relationship between EMMPRIN and atherosclerosis is unclear. To evaluate the functional role of EMMPRIN in atherosclerosis, we treated apolipoprotein E-deficient (ApoE(-/-)) mice with an EMMPRIN function-blocking antibody. EMMPRIN was found to be up-regulated in ApoE(-/-) mice fed a 12-week high-fat diet in contrast to 12 weeks of normal diet. Administration of a function-blocking EMMPRIN antibody (100 μg, twice per week for 4 weeks) to ApoE(-/-) mice, starting after 12 weeks of high-fat diet feeding caused attenuated and more stable atherosclerotic lesions, less reactive oxygen stress generation on plaque, as well as down-regulation of circulating interleukin-6 and monocyte chemotactic protein-1 in ApoE(-/-) mice. The benefit of EMMPRIN functional blockage was associated with reduced metalloproteinases proteolytic activity, which delayed the circulating monocyte transmigrating into atherosclerotic lesions. EMMPRIN antibody intervention ameliorated atherosclerosis in ApoE(-/-) mice by the down-regulation of metalloproteinase activity, suggesting that EMMPRIN may be a viable therapeutic target in atherosclerosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pulse stretcher

DOEpatents

Horton, J.A.

1994-05-03

Apparatus for increasing the length of a laser pulse to reduce its peak power without substantial loss in the average power of the pulse is disclosed. The apparatus uses a White cell having a plurality of optical delay paths of successively increasing number of passes between the field mirror and the objective mirrors. A pulse from a laser travels through a multi-leg reflective path between a beam splitter and a totally reflective mirror to the laser output. The laser pulse is also simultaneously injected through the beam splitter to the input mirrors of the optical delay paths. The pulses from the output mirrors of the optical delay paths go simultaneously to the laser output and to the input mirrors of the longer optical delay paths. The beam splitter is 50% reflective and 50% transmissive to provide equal attenuation of all of the pulses at the laser output. 6 figures.

Stabilization strategies of a general nonlinear car-following model with varying reaction-time delay of the drivers.

PubMed

Li, Shukai; Yang, Lixing; Gao, Ziyou; Li, Keping

2014-11-01

In this paper, the stabilization strategies of a general nonlinear car-following model with reaction-time delay of the drivers are investigated. The reaction-time delay of the driver is time varying and bounded. By using the Lyapunov stability theory, the sufficient condition for the existence of the state feedback control strategy for the stability of the car-following model is given in the form of linear matrix inequality, under which the traffic jam can be well suppressed with respect to the varying reaction-time delay. Moreover, by considering the external disturbance for the running cars, the robust state feedback control strategy is designed, which ensures robust stability and a smaller prescribed H∞ disturbance attenuation level for the traffic flow. Numerical examples are given to illustrate the effectiveness of the proposed methods. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

48 CFR 42.1304 - Government delay of work.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Government delay of work... CONTRACT MANAGEMENT CONTRACT ADMINISTRATION AND AUDIT SERVICES Suspension of Work, Stop-Work Orders, and Government Delay of Work 42.1304 Government delay of work. (a) The clause at 52.242-17, Government Delay of...

P3 amplitude attenuation secondary to increases in target-to-target interval (TTI) during spatial serial order recall: Implications for EEG models of working memory function.

PubMed

Hochberger, William C; Axelrod, Jenna L; Sarapas, Casey; Shankman, Stewart A; Hill, S Kristian

2018-06-08

Research suggests that increasing delays in stimulus read-out can trigger declines in serial order recall accuracy due to increases in cognitive demand imposed by the delay; however, the exact neural mechanisms associated with this decline are unclear. Changes in neural resource allocation present as the ideal target and can easily be monitored by examining changes in the amplitude of an ERP component known as the P3. Changes in P3 amplitude secondary to exogenous pacing of stimulus read-out via increased target-to-target intervals (TTI) during recall could reflect decreased neural resource allocation due to increased cognitive demand. This shift in resource allocation could result in working memory storage decay and the declines in serial order accuracy described by prior research. In order to examine this potential effect, participants were administered a spatial serial order processing task, with the recall series consisting of a series of correct ("match") or incorrect ("non-match" or "oddball") stimuli. Moreover, the recall series included either a brief (500ms) or extended (2000ms) delay between stimuli. Results were significant for the presence of a P3 response to non-match stimuli for both experimental conditions, and attenuation of P3 amplitude secondary to the increase in target-to-target interval (TTI). These findings suggest that extending the delay between target recognition could increase cognitive demand and trigger a decrease in neural resource allocation that results in a decay of working memory stores.

Cerebrospinal Fluid Enhancement on Fluid Attenuated Inversion Recovery Images After Carotid Artery Stenting with Neuroprotective Balloon Occlusions: Hemodynamic Instability and Blood-Brain Barrier Disruption

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

Ogami, Ryo, E-mail: ogami.r@mazda.co.jp; Nakahara, Toshinori; Hamasaki, Osamu

2011-10-15

Purpose: A rare complication of carotid artery stenting (CAS), prolonged reversible neurological symptoms with delayed cerebrospinal fluid (CSF) space enhancement on fluid attenuated inversion recovery (FLAIR) images, is associated with blood-brain barrier (BBB) disruption. We prospectively identified patients who showed CSF space enhancement on FLAIR images. Methods: Nineteen patients-5 acute-phase and 14 scheduled-underwent 21 CAS procedures. Balloon catheters were navigated across stenoses, angioplasty was performed using a neuroprotective balloon, and stents were placed with after dilation under distal balloon protection. CSF space hyperintensity or obscuration on FLAIR after versus before CAS indicated CSF space enhancement. Correlations with clinical factors weremore » examined. Results: CSF space was enhanced on FLAIR in 12 (57.1%) cases. Postprocedural CSF space enhancement was significantly related to age, stenosis rate, acute-stage procedure, and total occlusion time. All acute-stage CAS patients showed delayed enhancement. Only age was associated with delayed CSF space enhancement in scheduled CAS patients. Conclusions: Ischemic intolerance for severe carotid artery stenosis and temporary neuroprotective balloon occlusion, causing reperfusion injury, seem to be the main factors that underlie BBB disruption with delayed CSF space enhancement shortly after CAS, rather than sudden poststenting hemodynamic change. Our results suggest that factors related to hemodynamic instability or ischemic intolerance seem to be associated with post-CAS BBB vulnerability. Patients at risk for hemodynamic instability or with ischemic intolerance, which decrease BBB integrity, require careful management to prevent intracranial hemorrhagic and other post-CAS complications.« less

Delay in Apoptosome Formation Attenuates Apoptosis in Mouse Embryonic Stem Cell Differentiation

PubMed Central

Akbari-Birgani, Shiva; Hosseinkhani, Saman; Mollamohamadi, Sepideh; Baharvand, Hossein

2014-01-01

Differentiation is an inseparable process of development in multicellular organisms. Mouse embryonic stem cells (mESCs) represent a valuable research tool to conduct in vitro studies of cell differentiation. Apoptosis as a well known cell death mechanism shows some common features with cell differentiation, which has caused a number of ambiguities in the field. The research question here is how cells could differentiate these two processes from each other. We have investigated the role of the mitochondrial apoptotic pathway and cell energy level during differentiation of mESCs into the cardiomyocytes and their apoptosis. p53 expression, cytochrome c release, apoptosome formation, and caspase-3/7 activation are observed upon induction of both apoptosis and differentiation. However, remarkable differences are detected in time of cytochrome c appearance, apoptosome formation, and caspase activity upon induction of both processes. In apoptosis, apoptosome formation and caspase activity were observed rapidly following the cytochrome c release. Unlike apoptosis, the release of cytochrome c upon differentiation took more time, and the maximum caspase activity was also postponed for 24 h. This delay suggests that there is a regulatory mechanism during differentiation of mESCs into cardiomyocytes. The highest ATP content of cells was observed immediately after cytochrome c release 6 h after apoptosis induction and then decreased, but it was gradually increased up to 48 h after differentiation. These observations suggest that a delay in the release of cytochrome c or delay in ATP increase attenuate apoptosome formation, and caspase activation thereby discriminates apoptosis from differentiation in mESCs. PMID:24755221

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

PubMed Central

Yang, Tao; Grafe, Ingo; Bae, Yangjin; Chen, Shan; Chen, Yuqing; Bertin, Terry K.; Jiang, Ming-Ming; Ambrose, Catherine G.; Lee, Brendan

2013-01-01

TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro–TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1−/− mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1−/− osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1−/− osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast–osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1−/− calvaria exhibit an elevated mature TGF-β/pro–TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan–TGF-β antibody, significantly improved the low bone mass of Esl-1−/− mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1−/− mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast–osteoclast coupling. PMID:23589896

Spatiotemporal changes of seismic attenuation caused by injected CO2 at the Frio-II pilot site, Dayton, TX, USA

NASA Astrophysics Data System (ADS)

Zhu, Tieyuan; Ajo-Franklin, Jonathan B.; Daley, Thomas M.

2017-09-01

A continuous active source seismic monitoring data set was collected with crosswell geometry during CO2 injection at the Frio-II brine pilot, near Liberty, TX. Previous studies have shown that spatiotemporal changes in the P wave first arrival time reveal the movement of the injected CO2 plume in the storage zone. To further constrain the CO2 saturation, particularly at higher saturation levels, we investigate spatial-temporal changes in the seismic attenuation of the first arrivals. The attenuation changes over the injection period are estimated by the amount of the centroid frequency shift computed by local time-frequency analysis. We observe that (1) at receivers above the injection zone seismic attenuation does not change in a physical trend; (2) at receivers in the injection zone attenuation sharply increases following injection and peaks at specific points varying with distributed receivers, which is consistent with observations from time delays of first arrivals; then, (3) attenuation decreases over the injection time. The attenuation change exhibits a bell-shaped pattern during CO2 injection. Under Frio-II field reservoir conditions, White's patchy saturation model can quantitatively explain both the P wave velocity and attenuation response observed. We have combined the velocity and attenuation change data in a crossplot format that is useful for model-data comparison and determining patch size. Our analysis suggests that spatial-temporal attenuation change is not only an indicator of the movement and saturation of CO2 plumes, even at large saturations, but also can quantitatively constrain CO2 plume saturation when used jointly with seismic velocity.

Maternal low-protein diet-induced delayed reflex ontogeny is attenuated by moderate physical training during gestation in rats.

PubMed

Falcão-Tebas, Filippe; Bento-Santos, Adriano; Fidalgo, Marco Antônio; de Almeida, Marcelus Brito; dos Santos, José Antônio; Lopes de Souza, Sandra; Manhães-de-Castro, Raul; Leandro, Carol Góis

2012-02-01

We evaluated the effects of moderate- to low-intensity physical training during gestation on reflex ontogeny in neonate rats whose mothers were undernourished. Virgin female Wistar rats were divided into four groups as follows: untrained (NT, n 7); trained (T, n 7); untrained with a low-protein diet (NT+LP, n 7); trained with a low-protein diet (T+LP, n 4). Trained rats were subjected to a protocol of moderate physical training on a treadmill over a period of 4 weeks (5 d/week and 60 min/d, at 65 % of VO₂max). After confirming the pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8 % casein diet, and controls were provided with a 17 % casein diet. Their respective offspring were evaluated (during the 10th-17th days of postnatal life) in terms of physical feature maturation, somatic growth and reflex ontogeny. Pups born to mothers provided with the low-protein diet during gestation and lactation showed delayed physical feature and reflex maturation and a deficit in somatic growth when compared with controls. However, most of these deficiencies were attenuated in pups of undernourished mothers undergoing training. In conclusion, physical training during gestation attenuates the effects of perinatal undernutrition on some patterns of maturation in the central nervous system during development.

Delayed administration of parecoxib, a specific COX-2 inhibitor, attenuated postischemic neuronal apoptosis by phosphorylation Akt and GSK-3β.

PubMed

Ye, Zhi; Wang, Na; Xia, Pingping; Wang, E; Yuan, Yajing; Guo, Qulian

2012-02-01

Parecoxib is a recently described novel COX-2 inhibitor whose functional significance and neuroprotective mechanisms remain elusive. Therefore, in this study, we aimed to investigate whether delayed administration of parecoxib inhibited mitochondria-mediated neuronal apoptosis induced by ischemic reperfusion injury via phosphorylating Akt and its downstream target protein, glycogen synthase kinase 3β (GSK-3β). Adult male Sprague-Dawley rats were administered parecoxib (10 or 30 mg kg(-1), IP) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion (MCAO) for three consecutive days. Cerebral infarct volume, apoptotic neuron, caspase-3 immunoreactivity and the protein expression of p-Akt, p-GSK-3β and Cytochrome C in cerebral ischemic cortex were evaluated at 96 h after reperfusion. Parecoxib significantly diminished infarct volume and attenuated neuron apoptosis in a dose-independent manner, compared with MCAO group alone. Increased p-Akt and p-GSK-3β was observed in the ischemic penumbra of parecoxib group after stroke. Moreover, parecoxib also reduced the release of Cytochrome C from mitochondrial into cytosol and attenuated the caspase-3 immunoreactivity in the penumbra. Taken together, these results suggested that parecoxib ameliorated postischemic mitochondria-mediated neuronal apoptosis induced by focal cerebral ischemia in rats and this neuroprotective potential is involved in phosphorylation of Akt and GSK-3β.

In-line quincke tube muffler

NASA Astrophysics Data System (ADS)

Patrick, William P.; Bryant, Rebecca S.; Greenwald, Larry E.

2002-05-01

A unique low-pressure-drop muffler is described which has been designed to attenuate low frequency tonal noise in ducts. Flow through the muffler is divided into two noncommunicating paths in the cylindrical configuration which was designed, built, and tested. Half of the flow is ducted through a straight central annulus and the other half is ducted through a partitioned outer annulus which directs the flow in a spiral flow pattern around the inner annulus. Thus the outer flow has a longer path length and the sound within the outer annulus is phase-delayed relative to the inner flow causing destructive interference between the inner and outer waves with resulting strong attenuation at the tuned frequencies. A procedure will be described for designing a muffler (with flow) to produce high attenuation at the fundamental noise tone and all harmonics (up to the first cross mode). Results will be presented which show that the muffler achieved over 20 dB attenuation for the first five harmonics of the incident noise in a flowing duct.

Gaining Regulator Acceptance of Natural Attenuation as a Remediation Tool

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

Hughes, M.B.

Monitored natural attenuation (MNA) makes use of biological degradation, chemical reactions with natural materials, and other processes to clean up contaminated soils and groundwater. In the past, the regulatory community has been slow to accept natural attenuation due to a misperception that natural attenuation is a ''do nothing'' approach. Recently however, regulators have been more open to considering MNA as part of an overall clean-up plan that includes active treatment technologies to remove or contain the source of contamination at a site. MNA is currently being implemented at the Savannah River Site for remediation of selected contaminants. The South Carolinamore » Department of Health and Environmental Control, who has regulatory authority over these actions, has accepted this process. Significant overall cost savings are forecast. Additionally, there will be less disruption to the ecosystem, compared with engineered technologies. This paper describes the monitored natural attenuation concept as well as the process of constructive engagement with the regulators to achieve acceptance. Application to DOE, DOD, and commercial sites, as well as acceptability to other regulatory bodies, will be discussed with an emphasis on strategies to prevent false starts in the negotiation process and inventing options that result in mutual gains for all parties.« less

Zooming in on children's behavior during delay of gratification: Disentangling impulsigenic and volitional processes underlying self-regulation.

PubMed

Neuenschwander, Regula; Blair, Clancy

2017-02-01

When delaying gratification, both motivational and regulatory processes are likely to be at play; however, the relative contributions of motivational and regulatory influences on delay behavior are unclear. By examining behavioral responses during a delay task, this study sought to examine the motivational (anticipatory behavior) and regulatory mechanisms (executive function and self-control strategies) underlying children's self-regulation. The participants, 65 5- to 9-year-old children (M age =7.19years, SD=0.89), were video-recorded during a delay procedure and later coded for anticipatory behaviors (e.g., gazing intensely at the tablet) and self-control strategies. Children also completed two executive function (EF) tasks. We found that anticipatory behavior was curvilinearly related to delay time. Children showing either very low or very high levels of anticipatory behavior were not able to wait the entire time. Furthermore, our results indicated that anticipatory behavior interacted with EF to predict delay time. Specifically, anticipatory behavior was negatively related to delay time only if EF abilities were low. Finally, self-control strategies also interacted with EF to predict children's ability to delay. Spontaneous engagement in self-control strategies such as fidgeting and engagement in alternative activities were beneficial for children with low EF but were unrelated to delay time for children with high EF. Results indicate the value of examining motivational and regulatory influences on delay behavior. Lapses in self-regulation may be due to the combination of powerful impulsigenic (i.e., anticipatory behavior) and weak volitional processes (i.e., EF, self-control strategies). Copyright © 2016. Published by Elsevier Inc.

The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer

PubMed Central

Li, Yiwei; Wang, Zhiwei; Kong, Dejuan

2010-01-01

Multiple cellular signaling pathways have been involved in the processes of cancer cell invasion and metastasis. Among many signaling pathways, Wnt and Hedgehog (Hh) signaling pathways are critically involved in embryonic development, in the biology of cancer stem cells (CSCs) and in the acquisition of epithelial to mesenchymal transition (EMT), and thus this article will remain focused on Wnt and Hh signaling. Since CSCs and EMT are also known to be responsible for cancer cell invasion and metastasis, the Wnt and Hedgehog signaling pathways are also intimately associated with cancer invasion and metastasis. Emerging evidence suggests the beneficial role of chemopreventive agents commonly known as nutraceutical in cancer. Among many such agents, soy isoflavones, curcumin, green tea polyphenols, 3,3′-diindolylmethane, resveratrol, lycopene, vitamin D, etc. have been found to prevent, reverse, or delay the carcinogenic process. Interestingly, these agents have also shown to prevent or delay the progression of cancer, which could in part be due to their ability to attack CSCs or EMT-type cells by attenuating the Wnt and Hedgehog signaling pathways. In this review, we summarize the current state of our knowledge on the role of Wnt and Hedgehog signaling pathways, and their targeted inactivation by chemopreventive agents (nutraceuticals) for the prevention of tumor progression and/or treatment of human malignancies. PMID:20711635

Investigation of Hyporheic Thermal Flux and Downstream Attenuation Driven by Hydropeaking in the Colorado River, Austin, Texas

NASA Astrophysics Data System (ADS)

Watson, J. A.; Cardenas, M. B.; Neilson, B. T.; Bennett, P. C.

2015-12-01

Thermal flux related to regulated river hydropeaking has been extensively researched at the single-study site scale, but little work has been done quantifying the downstream attenuation of a single regulated flood pulse at multiple sites. In order to better understand this flood pulse attenuation we instrumented four sites with temperature probes along a 91 km stretch of the Colorado River downstream of longhorn dam, Austin, TX. Piezometer transects perpendicular to the river at each site were instrumented with HOBO thermistors over a 1.4m screened interval within the saturated zone at 20cm spacing. As flood pulses are attenuated downstream, temperature gradients and distance of lateral temperature pulse penetration into the bank are hypothesized to decrease. The data collected in this investigation will test this hypothesis by providing 2D temperature cross-sections along an attenuating flood pulse, providing detailed spatial data on temperature gradients adjacent to the river.

77 FR 41110 - Exemptive Order Regarding Compliance With Certain Swap Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-12

... delay compliance with certain entity-level requirements of the CEA (and Commission regulations promulgated thereunder), subject to specified conditions. Additionally, with respect to transaction-level.... major swap participants may delay compliance with certain entity-level requirements of the CEA (and...

Hydrogen Sulfide Attenuates the Recruitment of CD11b+Gr-1+ Myeloid Cells and Regulates Bax/Bcl-2 Signaling in Myocardial Ischemia Injury

PubMed Central

Zhang, Youen; Li, Hua; Zhao, Gang; Sun, Aijun; Zong, Nobel C.; Li, Zhaofeng; Zhu, Hongming; Zou, Yunzeng; Yang, Xiangdong; Ge, Junbo

2014-01-01

Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b+Gr-1+ myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b+Gr-1+ myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b+Gr-1+ myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling. PMID:24758901

Phospholipase Cε deficiency delays the early stage of cutaneous wound healing and attenuates scar formation in mice.

PubMed

Zhu, Xiaolong; Sun, Yue; Mu, Xin; Guo, Pan; Gao, Fei; Zhang, Jing; Zhu, Yunjuan; Zhang, Xianzhi; Chen, Lingling; Ning, Zhiwei; Bai, Yunfeng; Ren, Jiling; Man, Maoqiang; Liu, Peimei; Hu, Lizhi

2017-02-26

This study aimed to investigate the role of phospholipase Cε (PLCε) in the skin wound healing process. PLCε, an effect factor of Ras/Rap small G protein, plays a crucial role in skin inflammation by regulating inflammatory cytokines. Inflammatory responses are closely associated with wound healing. Full-thickness skin wounds were made in the PLCε knockout (KO) and wild-type (WT) mice, and the healing process was analyzed. The macroscopic wound closure rate declined in the PLCε KO mice on days 3, 4, and 5 after wounding, following the decreased expression of interleukin (IL)-6, chemokine (C-X-C motif) ligand (Cxcl)-1, Cxcl-2, and chemokine (C-C motif) ligand (Ccl) 20. The proliferation rate of epidermal keratinocytes was not affected by PLCε, but silencing of PLCε resulted in the delayed migration of keratinocytes. Moreover, the scars were found to be much smaller in the PLCε KO mice than in the WT mice. The mRNA expression of Ccl20, collagen (Col) 6a1, and Col17a1 decreased in the PLCε KO mice. These results were in agreement with a previous hypothesis that PLCε might delay the early stage of cutaneous wound healing by inhibiting the migration of keratinocytes, and decrease the expression of Col6a1, Col17a1, and Ccl20 by inhibiting the inflammatory response to reduce scar formation. This study shed light on a novel role of PLCε in wound healing and provided new therapeutic approaches to target PLCε for diminishing scar formation after injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Value of two-phase dynamic multidetector computed tomography in differential diagnosis of post-inflammatory strictures from esophageal cancer

PubMed Central

Karmazanovsky, Grigory G; Buryakina, Svetlana A; Kondratiev, Evgeny V; Yang, Qin; Ruchkin, Dmitry V; Kalinin, Dmitry V

2015-01-01

AIM: To characterize the computed tomography (CT) findings in patients with post-inflammatory esophageal strictures (corrosive and peptic) and reveal the optimal scanning phase protocols for distinguishing post-inflammatory esophageal stricture and esophageal cancer. METHODS: Sixty-five patients with esophageal strictures of different etiology were included in this study: 24 patients with 27 histopathologically confirmed corrosive strictures, 10 patients with 12 peptic strictures and 31 patients with esophageal cancer were evaluated with a two-phase dynamic contrast-enhanced MDCT. Arterial and venous phases at 10 and 35 s after the attenuation of 200 HU were obtained at the descending aorta, with a delayed phase at 6-8 min after the start of injection of contrast media. For qualitative analysis, CT scans of benign strictures were reviewed for the presence/absence of the following features: “target sign”, luminal mass, homogeneity of contrast medium uptake, concentric wall thickening, conically shaped suprastenotic dilatation, smooth boundaries of stenosis and smooth mucous membrane at the transition to stenosis, which were compared with a control group of 31 patients who had esophageal cancer. The quantitative analysis included densitometric parameter acquisition using regions-of-interest measurement of the zone of stenosis and normal esophageal wall and the difference between those measurements (ΔCT) at all phases of bolus contrast enhancement. Esophageal wall thickening, length of esophageal wall thickening and size of the regional lymph nodes were also evaluated. RESULTS: The presence of a concentric esophageal wall, conically shaped suprastenotic dilatation, smooth upper and lower boundaries, “target sign” and smooth mucous membrane at the transition to stenosis were suggestive of a benign cause, with sensitivities of 92.31%, 87.17%, 94.87%, 76.92% and 82.05%, respectively, and specificities of 70.96%, 89.66%, 80.65%, 96.77% and 93.55%, respectively. The features that were most suggestive of a malignant cause were eccentric esophageal wall thickening, tuberous upper and lower boundaries of stenosis, absence of mucous membrane visualization, rupture of the mucous membrane at the upper boundary of stenosis, cup-shaped suprastenotic dilatation, luminal mass and enlarged regional lymph nodes with specificities of 92.31% 94.87%, 67.86%, 100%, 97.44%, 94.87% and 82.86%, respectively and sensitivities of 70.97%, 80.65%, 96.77%, 80.65%, 54.84%, 87.10% and 60%, respectively. The highest tumor attenuation occurred in the arterial phase (mean attenuation 74.13 ± 17.42 HU), and the mean attenuation difference between the tumor and the normal esophageal wall (mean ΔCT) in the arterial phase was 23.86 ± 19.31 HU. Here, 11.5 HU of ΔCT in the arterial phase was the cut-off value used to differentiate esophageal cancer from post-inflammatory stricture (P = 0.000). The highest attenuation of post-inflammatory strictures occurred in the delayed phase (mean attenuation 71.66 ± 14.28 HU), and the mean ΔCT in delayed phase was 34.03 ± 15.94 HU. Here, 18.5 HU of ΔCT in delayed phase was the cut-off value used to differentiate post-inflammatory stricture from esophageal cancer (P < 0.0001). CONCLUSION: The described imaging findings reveal high diagnostic significance in the differentiation of benign strictures from esophageal cancer. PMID:26269677

Finite-time H∞ control for a class of discrete-time switched time-delay systems with quantized feedback

NASA Astrophysics Data System (ADS)

Song, Haiyu; Yu, Li; Zhang, Dan; Zhang, Wen-An

2012-12-01

This paper is concerned with the finite-time quantized H∞ control problem for a class of discrete-time switched time-delay systems with time-varying exogenous disturbances. By using the sector bound approach and the average dwell time method, sufficient conditions are derived for the switched system to be finite-time bounded and ensure a prescribed H∞ disturbance attenuation level, and a mode-dependent quantized state feedback controller is designed by solving an optimization problem. Two illustrative examples are provided to demonstrate the effectiveness of the proposed theoretical results.

Parental inconsistency, impulsive choice and neural value representations in healthy adolescents

PubMed Central

Schneider, S; Peters, J; Peth, J M; Büchel, C

2014-01-01

A well-characterized potential marker for addiction is impulsive choice, stably measured by delay discounting (DD) paradigms. While genetic influences partly account for inter-individual variance in impulsivity, environmental factors such as parenting practices may have an important role. The present study investigates how inconsistent fulfillment of delayed reward promises impacts on DD. A combined correlational and experimental functional magnetic resonance imaging (fMRI) design was performed in a sample of 48 healthy adolescents (13–15 years). More specifically, neural activation during a DD task was investigated at two assessment points (T0 and T1). Adolescents' self-reports of parenting and substance use were assessed at T0. Between assessment points, we experimentally varied the reliability of delayed reward promises, measuring the impact of this intervention on DD and neural value processing at T1. In the correlational part, same-sex parent reward inconsistency was associated with steeper DD and an attenuated subjective value (SV) representation in the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC). Steeper DD was in turn associated with alcohol use during the past year. In the experimental part, the reward inconsistency manipulation resulted in an attenuation of the NAcc SV representation, similar to the parental inconsistency effect. Together, our correlational and experimental findings raise new light on how parents may influence their children's degree of impulsivity, making parenting a potential target in addiction prevention. PMID:24736798

A modeling study on the influence of blood flow regulation on skin temperature pulsations

NASA Astrophysics Data System (ADS)

Tang, Yanliang; Mizeva, Irina; He, Ying

2017-04-01

Nowadays together with known optic techniques of microcirculation blood flow monitoring, skin temperature measurements are developed as well. In this paper, a simple one-dimensional bioheat transfer model was developed to analyse the heat wave transport in biological tissue, where an arteriole vessel with pulsatile blood is located. The simulated results show that the skin temperature oscillation amplitudes attenuate with the increase of blood flow oscillation frequency which gives the same tendency as that in the experiments. The parameter analyses further show that the amplitude of oscillation is also influenced by oscillation amplitude of blood and effective thermal conductivity. When oscillation amplitude of blood flow and effective thermal conductivity increase, the amplitude of skin temperature oscillation increases nonlinearly. Variation of effective thermal convective influence to the time delay of the thermal wave on the skin surface and distort it. Combination of two measurement techniques: one for estimation blood flow oscillations in the microvessels and other to the skin temperature measurement can produce additional information about the skin properties.

An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth.

PubMed

Uchimura, Tomoya; Hollander, Judith M; Nakamura, Daisy S; Liu, Zhiyi; Rosen, Clifford J; Georgakoudi, Irene; Zeng, Li

2017-10-01

Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an IGF2 mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the Igf2 null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the Igf2 null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities. © 2017. Published by The Company of Biologists Ltd.

Hfq Influences Multiple Transport Systems and Virulence in the Plant Pathogen Agrobacterium tumefaciens

PubMed Central

Wilms, Ina; Möller, Philip; Stock, Anna-Maria; Gurski, Rosemarie; Lai, Erh-Min

2012-01-01

The Hfq protein mediates gene regulation by small RNAs (sRNAs) in about 50% of all bacteria. Depending on the species, phenotypic defects of an hfq mutant range from mild to severe. Here, we document that the purified Hfq protein of the plant pathogen and natural genetic engineer Agrobacterium tumefaciens binds to the previously described sRNA AbcR1 and its target mRNA atu2422, which codes for the substrate binding protein of an ABC transporter taking up proline and γ-aminobutyric acid (GABA). Several other ABC transporter components were overproduced in an hfq mutant compared to their levels in the parental strain, suggesting that Hfq plays a major role in controlling the uptake systems and metabolic versatility of A. tumefaciens. The hfq mutant showed delayed growth, altered cell morphology, and reduced motility. Although the DNA-transferring type IV secretion system was produced, tumor formation by the mutant strain was attenuated, demonstrating an important contribution of Hfq to plant transformation by A. tumefaciens. PMID:22821981

Human replication protein Cdc6 is selectively cleaved by caspase 3 during apoptosis

PubMed Central

Pelizon, Cristina; d’Adda di Fagagna, Fabrizio; Farrace, Lorena; Laskey, Ronald A.

2002-01-01

In eukaryotes, the initiation of DNA replication involves the ordered assembly on chromatin of pre-replicative complexes (pre-RCs), including the origin recognition complex (ORC), Cdc6, Cdt1 and the minichromosome maintenance proteins (MCMs). In light of its indispensable role in the formation of pre-RCs, Cdc6 binding to chromatin represents a key step in the regulation of DNA replication and cell proliferation. Here, we study the human Cdc6 (HuCdc6) protein during programmed cell death (apoptosis). We find that HuCdc6, but not HuOrc2 (a member of the ORC) or HuMcm5 (one of the MCMs), is specifically cleaved in several human cell lines induced to undergo apoptosis by a variety of stimuli. Expression of caspase-uncleavable mutant HuCdc6 attenuates apoptosis, delaying cell death. Therefore, an important function for cleavage of HuCdc6 is to prevent a wounded cell from replicating and to facilitate death. PMID:12151338

Extracting rate changes in transcriptional regulation from MEDLINE abstracts.

PubMed

Liu, Wenting; Miao, Kui; Li, Guangxia; Chang, Kuiyu; Zheng, Jie; Rajapakse, Jagath C

2014-01-01

Time delays are important factors that are often neglected in gene regulatory network (GRN) inference models. Validating time delays from knowledge bases is a challenge since the vast majority of biological databases do not record temporal information of gene regulations. Biological knowledge and facts on gene regulations are typically extracted from bio-literature with specialized methods that depend on the regulation task. In this paper, we mine evidences for time delays related to the transcriptional regulation of yeast from the PubMed abstracts. Since the vast majority of abstracts lack quantitative time information, we can only collect qualitative evidences of time delays. Specifically, the speed-up or delay in transcriptional regulation rate can provide evidences for time delays (shorter or longer) in GRN. Thus, we focus on deriving events related to rate changes in transcriptional regulation. A corpus of yeast regulation related abstracts was manually labeled with such events. In order to capture these events automatically, we create an ontology of sub-processes that are likely to result in transcription rate changes by combining textual patterns and biological knowledge. We also propose effective feature extraction methods based on the created ontology to identify the direct evidences with specific details of these events. Our ontologies outperform existing state-of-the-art gene regulation ontologies in the automatic rule learning method applied to our corpus. The proposed deterministic ontology rule-based method can achieve comparable performance to the automatic rule learning method based on decision trees. This demonstrates the effectiveness of our ontology in identifying rate-changing events. We also tested the effectiveness of the proposed feature mining methods on detecting direct evidence of events. Experimental results show that the machine learning method on these features achieves an F1-score of 71.43%. The manually labeled corpus of events relating to rate changes in transcriptional regulation for yeast is available in https://sites.google.com/site/wentingntu/data. The created ontologies summarized both biological causes of rate changes in transcriptional regulation and corresponding positive and negative textual patterns from the corpus. They are demonstrated to be effective in identifying rate-changing events, which shows the benefits of combining textual patterns and biological knowledge on extracting complex biological events.

The movement of sequestrated CO2 revealed by seismic attenuation spatial and temporal changes in Frio-II site, USA

NASA Astrophysics Data System (ADS)

Zhu, T.; Ajo Franklin, J. B.; Daley, T. M.

2015-12-01

Continuous active source seismic measurements (CASSM) were collected in the crosswell geometry during scCO2 injection at the Frio-II brine pilot (Liberty, TX). Previous studies (Daley et.al. 2007, 2011) have demonstrated that spatial-temporal changes in the picked first arrival time after CO2 injection constrain the movement of the CO2 plume in the storage interval. To improve the quantitative constraints on plume saturation using this dataset, we investigate spatial-temporal changes in the seismic attenuation of the first arrivals. The attenuation changes over the injection period (~60 h) are estimated by the amount of the centroid frequency shift computed by the local time-frequency analysis. Our observations include: at receivers above the packer seismic attenuation does not change in a physical trend; at receivers below the packer attenuation sharply increases as the amount of CO2 plume increase at the first few hours and peaks at specific points varying with distributed receivers, which are consistent with observations from time delays of first arrivals. Then, attenuation decreases over the injection time with increased amount of CO2 plume. This bell-shaped attenuation response as a function of time in the experiment is consistent with White's patchy saturation model which predicts an attenuation peak at intermediate CO2 saturations. Our analysis suggests that spatial-temporal attenuation change is an indicator of the movement/saturation of CO2 plume at high saturations, a system state for which seismic measurements are typically only weakly sensitive to.

Describing-function analysis of a ripple regulator with slew-rate limits and time delays

NASA Technical Reports Server (NTRS)

Wester, Gene W.

1990-01-01

The effects of time delays and slew-rate limits on the steady-state operating points and performance of a free-running ripple regulator are evaluated using describing-function analysis. The describing function of an ideal comparator (no time delays or slew rate limits) has no phase shift and is independent of frequency. It is found that turn-on delay and turn-off delay have different effects on gain and phase and cannot be combined. Comparator hysteresis affects both gain and phase; likewise, time delays generally affect both gain and phase. It is found that the effective time delay around the feedback loop is one half the sum of turn-on and turn-off delays, regardless of whether the delays are caused by storage time or slew rate limits. Expressions are formulated for the switching frequency, switch duty ratio, dc output, and output ripple. For the case of no hysteresis, a simple, graphical solution for the switching frequency is possible, and the resulting switching frequency is independent of first-order variations of input or load.

A Neurophysiological Study of Semantic Processing in Parkinson's Disease.

PubMed

Angwin, Anthony J; Dissanayaka, Nadeeka N W; Moorcroft, Alison; McMahon, Katie L; Silburn, Peter A; Copland, David A

2017-01-01

Cognitive-linguistic impairments in Parkinson's disease (PD) have been well documented; however, few studies have explored the neurophysiological underpinnings of semantic deficits in PD. This study investigated semantic function in PD using event-related potentials. Eighteen people with PD and 18 healthy controls performed a semantic judgement task on written word pairs that were either congruent or incongruent. The mean amplitude of the N400 for new incongruent word pairs was similar for both groups, however the onset latency was delayed in the PD group. Further analysis of the data revealed that both groups demonstrated attenuation of the N400 for repeated incongruent trials, as well as attenuation of the P600 component for repeated congruent trials. The presence of N400 congruity and N400 repetition effects in the PD group suggests that semantic processing is generally intact, but with a slower time course as evidenced by the delayed N400. Additional research will be required to determine whether N400 and P600 repetition effects are sensitive to further cognitive decline in PD. (JINS, 2017, 23, 78-89).

Timing effects of antecedent- and response-focused emotion regulation strategies.

PubMed

Paul, Sandra; Simon, Daniela; Kniesche, Rainer; Kathmann, Norbert; Endrass, Tanja

2013-09-01

Distraction and cognitive reappraisal influence the emotion-generative process at early stages and have been shown to effectively attenuate emotional responding. Inhibiting emotion-expressive behavior is thought to be less beneficial due to later implementation, but empirical results are mixed. Thus, the current study examined the temporal dynamics of these emotion regulation strategies at attenuating the late positive potential (LPP) while participants were shown unpleasant pictures. Results revealed that all strategies successfully reduced the LPP and self-reported negative affect. We confirmed that distraction attenuated the LPP earlier than cognitive reappraisal. Surprisingly, expressive suppression affected emotional responding as early as distraction. This suggests that suppression was used preventively and disrupted the emotion-generative process from the very beginning instead of targeting the emotional response itself. Thus, the obtained results point to the importance of considering the point in time when response-focused emotion regulation strategies are being implemented. Copyright © 2013 Elsevier B.V. All rights reserved.

Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells

PubMed Central

Chan, Chu-Fang; Kuo, Tzu-Wei; Weng, Ju-Yun; Lin, Yen-Chu; Chen, Ting-Yu; Cheng, Jen-Kun; Lien, Cheng-Chang

2013-01-01

Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba2+- and bupivacaine-sensitive background K+ conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K+ conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function. PMID:23940377

Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice

PubMed Central

Hanes, William M; Olofsson, Peder S; Kwan, Kevin; Hudson, LaQueta K; Chavan, Sangeeta S; Pavlov, Valentin A; Tracey, Kevin J

2015-01-01

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach. PMID:26322849

48 CFR 52.242-17 - Government Delay of Work.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 false Government Delay of Work....242-17 Government Delay of Work. As prescribed in 42.1305(c), insert the following clause in... services, or for supplies that are commercial or modified-commercial items. Government Delay of Work (APR...

48 CFR 52.242-17 - Government Delay of Work.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Government Delay of Work....242-17 Government Delay of Work. As prescribed in 42.1305(c), insert the following clause in... services, or for supplies that are commercial or modified-commercial items. Government Delay of Work (APR...

48 CFR 52.242-17 - Government Delay of Work.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 2 2013-10-01 2013-10-01 false Government Delay of Work....242-17 Government Delay of Work. As prescribed in 42.1305(c), insert the following clause in... services, or for supplies that are commercial or modified-commercial items. Government Delay of Work (APR...

48 CFR 52.242-17 - Government Delay of Work.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 2 2014-10-01 2014-10-01 false Government Delay of Work....242-17 Government Delay of Work. As prescribed in 42.1305(c), insert the following clause in... services, or for supplies that are commercial or modified-commercial items. Government Delay of Work (APR...

Novel insights into a retinoic-acid-induced cleft palate based on Rac1 regulation of the fibronectin arrangement.

PubMed

Tang, Qinghuang; Li, Liwen; Lee, Min-Jung; Ge, Qing; Lee, Jong-Min; Jung, Han-Sung

2016-03-01

Retinoic acid (RA)-induced cleft palate results from both extrinsic obstructions by the tongue and internal factors within the palatal shelves. Our previous study showed that the spatiotemporal expression of Rac1 regulates the fibronectin (FN) arrangement through cell density alterations that play an important role in palate development. In this study, we investigate the involvement of the Rac1 regulation of the FN arrangement in RA-induced cleft palate. Our results demonstrate that RA-induced intrinsic alterations in palatal shelves, including a delayed progress of cell condensation, delay palate development, even after the removal of the tongue. Further analysis shows that RA treatment diminishes the region-distinctive expression of Rac1 within the palatal shelves, which reversely alters the fibrillar arrangement of FN. Furthermore, RA treatment disrupts the formation of lamellipodia, which are indicative structures of cell migration that are regulated by Rac1. These results suggest that the Rac1 regulation of the FN arrangement is involved in RA-induced cleft palate through the regulation of cell migration, which delays the progress of cell condensation and subsequently influences the FN arrangement, inducing a delay in palate development. Our study provides new insights into the RA-induced impairment of palatal shelf elevation based on cell migration dynamics.

Comprehensive Care for Joint Replacement Model (CJR); Delay of Effective Date. Final rule; delay of effective date.

PubMed

2017-05-19

This final rule finalizes May 20, 2017 as the effective date of the final rule titled "Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to the Comprehensive Care for Joint Replacement Model (CJR)" originally published in the January 3, 2017 Federal Register. This final rule also finalizes a delay of the applicability date of the regulations at 42 CFR part 512 from July 1, 2017 to January 1, 2018 and delays the effective date of the specific CJR regulations listed in the DATES section from July 1, 2017 to January 1, 2018.

Stability and Hopf bifurcation for a regulated logistic growth model with discrete and distributed delays

NASA Astrophysics Data System (ADS)

Fang, Shengle; Jiang, Minghui

2009-12-01

In this paper, we investigate the stability and Hopf bifurcation of a new regulated logistic growth with discrete and distributed delays. By choosing the discrete delay τ as a bifurcation parameter, we prove that the system is locally asymptotically stable in a range of the delay and Hopf bifurcation occurs as τ crosses a critical value. Furthermore, explicit algorithm for determining the direction of the Hopf bifurcation and the stability of the bifurcating periodic solutions is derived by normal form theorem and center manifold argument. Finally, an illustrative example is also given to support the theoretical results.

The thin hot plume beneath Iceland

USGS Publications Warehouse

Allen, R.M.; Nolet, G.; Morgan, W.J.; Vogfjord, K.; Bergsson, B.H.; Erlendsson, P.; Foulger, G.R.; Jakobsdottir, S.; Julian, B.R.; Pritchard, M.; Ragnarsson, S.; Stefansson, R.

1999-01-01

We present the results of a seismological investigation of the frequency-dependent amplitude variations across Iceland using data from the HOTSPOT array currently deployed there. The array is composed of 30 broad-band PASSCAL instruments. We use the parameter t(*), defined in the usual manner from spectral ratios (Halderman and Davis 1991), to compare observed S-wave amplitude variations with those predicted due to both anelastic attenuation and diffraction effects. Four teleseismic events at a range of azimuths are used to measure t(*). A 2-D vertical cylindrical plume model with a Gaussian-shaped velocity anomaly is used to model the variations. That part of t(*) caused by attenuation was estimated by tracing a ray through IASP91, then superimposing our plume model velocity anomaly and calculating the path integral of 1/vQ. That part of t(*) caused by diffraction was estimated using a 2-D finite difference code to generate synthetic seismograms. The same spectral ratio technique used for the data was then used to extract a predicted t(*). The t(*) variations caused by anelastic attenuation are unable to account for the variations we observe, but those caused by diffraction do. We calculate the t(*) variations caused by diffraction for different plume models and obtain our best-fit plume, which exhibits good agreement between the observed and measured t(*). The best-fit plume model has a maximum S-velocity anomaly of - 12 per cent and falls to 1/e of its maximum at 100 km from the plume centre. This is narrower than previous estimates from seismic tomography, which are broadened and damped by the methods of tomography. This velocity model would suggest greater ray theoretical traveltime delays than observed. However, we find that for such a plume, wave-front healing effects at frequencies of 0.03-0.175 Hz (the frequency range used to pick S-wave arrivals) causes a 40 per cent reduction in traveltime delay, reducing the ray theoretical delay to that observed.

The Putative E3 Ubiquitin Ligase ECERIFERUM9 Regulates Abscisic Acid Biosynthesis and Response during Seed Germination and Postgermination Growth in Arabidopsis1[W][OPEN

PubMed Central

Zhao, Huayan; Zhang, Huoming; Cui, Peng; Ding, Feng; Wang, Guangchao; Li, Rongjun; Jenks, Matthew A.; Lü, Shiyou; Xiong, Liming

2014-01-01

The ECERIFERUM9 (CER9) gene encodes a putative E3 ubiquitin ligase that functions in cuticle biosynthesis and the maintenance of plant water status. Here, we found that CER9 is also involved in abscisic acid (ABA) signaling in seeds and young seedlings of Arabidopsis (Arabidopsis thaliana). The germinated embryos of the mutants exhibited enhanced sensitivity to ABA during the transition from reversible dormancy to determinate seedling growth. Expression of the CER9 gene is closely related to ABA levels and displays a similar pattern to that of ABSCISIC ACID-INSENSITIVE5 (ABI5), which encodes a positive regulator of ABA responses in seeds. cer9 mutant seeds exhibited delayed germination that is independent of seed coat permeability. Quantitative proteomic analyses showed that cer9 seeds had a protein profile similar to that of the wild type treated with ABA. Transcriptomics analyses revealed that genes involved in ABA biosynthesis or signaling pathways were differentially regulated in cer9 seeds. Consistent with this, high levels of ABA were detected in dry seeds of cer9. Blocking ABA biosynthesis by fluridone treatment or by combining an ABA-deficient mutation with cer9 attenuated the phenotypes of cer9. Whereas introduction of the abi1-1, abi3-1, or abi4-103 mutation could completely eliminate the ABA hypersensitivity of cer9, introduction of abi5 resulted only in partial suppression. These results indicate that CER9 is a novel negative regulator of ABA biosynthesis and the ABA signaling pathway during seed germination. PMID:24812105

Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells

PubMed Central

Abe, Mariko; Pelus, Louis M.; Singh, Pratibha; Hirade, Tomohiro; Onishi, Chie; Purevsuren, Jamiyan; Taketani, Takeshi; Yamaguchi, Seiji; Fukuda, Seiji

2016-01-01

Internal tandem duplication (ITD) mutations in the Fms-related tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression. PMID:27387666

Transcriptome and proteome analysis of nitrogen starvation responses in Synechocystis 6803 ΔglgC, a mutant incapable of glycogen storage

DOE PAGES

Carrieri, Damian; Lombardi, Thomas; Paddock, Troy; ...

2016-11-17

Molecular mechanisms that regulate carbon flux are poorly understood in algae. The ΔglgC mutant of the cyanobacterium Synechocystis sp. PCC 6803 is incapable of glycogen storage and displays an array of physiological responses under nitrogen starvation that are different from wild-type (WT). These include non-bleaching phenotype and the redirection of photosynthetically fixed carbon towards excreted organic acids (overflow metabolism) without biomass growth. To understand the role of gene/protein expression in these responses, we followed the time course of transcripts by genome-scale microarrays and proteins by shotgun proteomics in ΔglgC and WT cells upon nitrogen starvation. Compared to WT, the degradationmore » of phycobilisome rod proteins was delayed and attenuated in the mutant, and the core proteins were less degraded; both contributed to the non-bleaching appearance despite the induction of nblA genes, suggesting the presence of a break in regulation of the phycobilisome degradation pathway downstream of nblA induction. The mutant displayed NtcA-mediated transcriptional response to nitrogen starvation, indicating that it is able to sense nitrogen status. Furthermore, some responses to nitrogen starvation appear to be stronger in the mutant, as shown by the increases in transcripts for the transcriptional regulator, rre37, which regulates central carbon metabolism. Accordingly, multiple proteins involved in photosynthesis, central carbon metabolism, and carbon storage and utilization showed lower abundance in the mutant. Furthermore, these results indicate that the transition in the central carbon metabolism from growth to overflow metabolism in ΔglgC does not require increases in expression of the overflow pathway enzymes; the transition and non-bleaching phenotype are likely regulated instead at the metabolite level.« less

Transcriptome and proteome analysis of nitrogen starvation responses in Synechocystis 6803 ΔglgC, a mutant incapable of glycogen storage

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

Carrieri, Damian; Lombardi, Thomas; Paddock, Troy

Molecular mechanisms that regulate carbon flux are poorly understood in algae. The ΔglgC mutant of the cyanobacterium Synechocystis sp. PCC 6803 is incapable of glycogen storage and displays an array of physiological responses under nitrogen starvation that are different from wild-type (WT). These include non-bleaching phenotype and the redirection of photosynthetically fixed carbon towards excreted organic acids (overflow metabolism) without biomass growth. To understand the role of gene/protein expression in these responses, we followed the time course of transcripts by genome-scale microarrays and proteins by shotgun proteomics in ΔglgC and WT cells upon nitrogen starvation. Compared to WT, the degradationmore » of phycobilisome rod proteins was delayed and attenuated in the mutant, and the core proteins were less degraded; both contributed to the non-bleaching appearance despite the induction of nblA genes, suggesting the presence of a break in regulation of the phycobilisome degradation pathway downstream of nblA induction. The mutant displayed NtcA-mediated transcriptional response to nitrogen starvation, indicating that it is able to sense nitrogen status. Furthermore, some responses to nitrogen starvation appear to be stronger in the mutant, as shown by the increases in transcripts for the transcriptional regulator, rre37, which regulates central carbon metabolism. Accordingly, multiple proteins involved in photosynthesis, central carbon metabolism, and carbon storage and utilization showed lower abundance in the mutant. Furthermore, these results indicate that the transition in the central carbon metabolism from growth to overflow metabolism in ΔglgC does not require increases in expression of the overflow pathway enzymes; the transition and non-bleaching phenotype are likely regulated instead at the metabolite level.« less

Impact of Parturition on Chemokine Homing Factor Expression in the Vaginal Distention Model of Stress Urinary Incontinence

PubMed Central

Lenis, Andrew T.; Kuang, Mei; Woo, Lynn L.; Hijaz, Adonis; Penn, Marc S.; Butler, Robert S.; Rackley, Raymond; Damaser, Margot S.; Wood, Hadley M.

2015-01-01

Purpose Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. Materials and Methods We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. Results Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1α and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. Conclusions Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1α and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia. PMID:23022009

The role of the brown adipose tissue in β3-adrenergic receptor activation-induced sleep, metabolic and feeding responses.

PubMed

Szentirmai, Éva; Kapás, Levente

2017-04-19

Brown adipose tissue (BAT) is regulated by the sympathetic nervous system via β3-adrenergic receptors (β3-AR). Here we tested the hypothesis that pharmacological stimulation of β3-ARs leads to increased sleep in mice and if this change is BAT dependent. In wild-type (WT) animals, administration of CL-316,243, a selective β3-AR agonist, induced significant increases in non-rapid-eye movement sleep (NREMS) lasting for 4-10 h. Simultaneously, electroencephalographic slow-wave activity (SWA) was significantly decreased and body temperature was increased with a delay of 5-6 h. In uncoupling protein 1 (UCP-1) knockout mice, the middle and highest doses of the β3-AR agonist increased sleep and suppressed SWA, however, these effects were significantly attenuated and shorter-lasting as compared to WT animals. To determine if somnogenic signals arising from BAT in response to β3-AR stimulation are mediated by the sensory afferents of BAT, we tested the effects of CL-316,243 in mice with the chemical deafferentation of the intra-scapular BAT pads. Sleep responses to CL-316,243 were attenuated by ~50% in intra-BAT capsaicin-treated mice. Present findings indicate that the activation of BAT via β3-AR leads to increased sleep in mice and that this effect is dependent on the presence of UCP-1 protein and sleep responses require the intact sensory innervation of BAT.

Velocity and attenuation of sound in arterial tissues

NASA Technical Reports Server (NTRS)

Rooney, J. A.; Gammell, P. M.; Hestenes, J. D.; Chin, H. P.; Blankenhorn, D. H.

1982-01-01

The velocity of sound in excised human and canine arterial tissues is measured in order to serve as a basis for the development and application of ultrasonic techniques for the diagnosis of atherosclerotic lesions. Measurements of sound velocity at different regions of 11 human and six canine aortas were made by a time delay spectrometer technique at frequencies from 2 to 10 MHz, and compared with ultrasonic attenuation parameters and the results of biochemical assays. Sound velocity is found to increase with increasing attenuation at all frequencies, and with increasing collagen content. A strong dependence of sound velocity on cholesterol content or low calcium contents is not observed, although velocities of up to 2000 m/sec are observed in highly organized calcified lesions. A decrease in velocity with decreasing temperature is also noted. It is thus concluded that it is principally the differences in tissue collagen levels that contribute to image formation according to sound velocity.

Modeling On-Body DTN Packet Routing Delay in the Presence of Postural Disconnections.

PubMed

Quwaider, Muhannad; Taghizadeh, Mahmoud; Biswas, Subir

2011-01-01

This paper presents a stochastic modeling framework for store-and-forward packet routing in Wireless Body Area Networks ( WBAN ) with postural partitioning. A prototype WBANs has been constructed for experimentally characterizing and capturing on-body topology disconnections in the presence of ultrashort range radio links, unpredictable RF attenuation, and human postural mobility. Delay modeling techniques for evaluating single-copy on-body DTN routing protocols are then developed. End-to-end routing delay for a series of protocols including opportunistic, randomized, and two other mechanisms that capture multiscale topological localities in human postural movements have been evaluated. Performance of the analyzed protocols are then evaluated experimentally and via simulation to compare with the results obtained from the developed model. Finally, a mechanism for evaluating the topological importance of individual on-body sensor nodes is developed. It is shown that such information can be used for selectively reducing the on-body sensor-count without substantially sacrificing the packet delivery delay.

Modeling On-Body DTN Packet Routing Delay in the Presence of Postural Disconnections

PubMed Central

Quwaider, Muhannad; Taghizadeh, Mahmoud; Biswas, Subir

2014-01-01

This paper presents a stochastic modeling framework for store-and-forward packet routing in Wireless Body Area Networks (WBAN) with postural partitioning. A prototype WBANs has been constructed for experimentally characterizing and capturing on-body topology disconnections in the presence of ultrashort range radio links, unpredictable RF attenuation, and human postural mobility. Delay modeling techniques for evaluating single-copy on-body DTN routing protocols are then developed. End-to-end routing delay for a series of protocols including opportunistic, randomized, and two other mechanisms that capture multiscale topological localities in human postural movements have been evaluated. Performance of the analyzed protocols are then evaluated experimentally and via simulation to compare with the results obtained from the developed model. Finally, a mechanism for evaluating the topological importance of individual on-body sensor nodes is developed. It is shown that such information can be used for selectively reducing the on-body sensor-count without substantially sacrificing the packet delivery delay. PMID:25530749

Gene end-like sequences within the 3' non-coding region of the Nipah virus genome attenuate viral gene transcription.

PubMed

Sugai, Akihiro; Sato, Hiroki; Yoneda, Misako; Kai, Chieko

2017-08-01

The regulation of transcription during Nipah virus (NiV) replication is poorly understood. Using a bicistronic minigenome system, we investigated the involvement of non-coding regions (NCRs) in the transcriptional re-initiation efficiency of NiV RNA polymerase. Reporter assays revealed that attenuation of NiV gene expression was not constant at each gene junction, and that the attenuating property was controlled by the 3' NCR. However, this regulation was independent of the gene-end, gene-start and intergenic regions. Northern blot analysis indicated that regulation of viral gene expression by the phosphoprotein (P) and large protein (L) 3' NCRs occurred at the transcription level. We identified uridine-rich tracts within the L 3' NCR that are similar to gene-end signals. These gene-end-like sequences were recognized as weak transcription termination signals by the viral RNA polymerase, thereby reducing downstream gene transcription. Thus, we suggest that NiV has a unique mechanism of transcriptional regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Connected cruise control: modelling, delay effects, and nonlinear behaviour

NASA Astrophysics Data System (ADS)

Orosz, Gábor

2016-08-01

Connected vehicle systems (CVS) are considered in this paper where vehicles exchange information using wireless vehicle-to-vehicle (V2V) communication. The concept of connected cruise control (CCC) is established that allows control design at the level of individual vehicles while exploiting V2V connectivity. Due to its high level of modularity the proposed design can be applied to large heterogeneous traffic systems. The dynamics of a simple CVS is analysed in detail while taking into account nonlinearities in the vehicle dynamics as well as in the controller. Time delays that arise due to intermittencies and packet drops in the communication channels are also incorporated. The results are summarised using stability charts which allow one to select control gains to maintain stability and ensure disturbance attenuation when the delay is below a critical value.

Physiological Profiles during Delay of Gratification: Associations with Emotionality, Self-Regulation, and Adjustment Problems

ERIC Educational Resources Information Center

Wilson, Anna C.; Lengua, Liliana J.; Tininenko, Jennifer; Taylor, Adam; Trancik, Anika

2009-01-01

This longitudinal study utilized a community sample of children (N = 91, 45% female, 8-11 years at time 1) to investigate physiological responses (heart rate reactivity [HRR] and electrodermal responding [EDR]) during delay of gratification in relation to emotionality, self-regulation, and adjustment problems. Cluster analyses identified three…

GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells.

PubMed

Wang, Chang-Ying; Huang, An-Qi; Zhou, Meng-Hua; Mei, Yan-Ai

2014-05-15

GDF15 (growth/differentiation factor 15), a novel member of the TGFβ (transforming growth factor β) superfamily, plays critical roles in the central and peripheral nervous systems, but the signal transduction pathways and receptor subtypes involved are not well understood. In the present paper, we report that GDF15 specifically increases the IK (delayed-rectifier outward K+ current) in rat CGNs (cerebellar granule neurons) in time- and concentration-dependent manners. The GDF15-induced amplification of the IK is mediated by the increased expression and reduced lysosome-dependent degradation of the Kv2.1 protein, the main α-subunit of the IK channel. Exposure of CGNs to GDF15 markedly induced the phosphorylation of ERK (extracellular-signal-regulated kinase), Akt and mTOR (mammalian target of rapamycin), but the GDF15-induced IK densities and increased expression of Kv2.1 were attenuated only by Akt and mTOR, and not ERK, inhibitors. Pharmacological inhibition of the Src-mediated phosphorylation of TGFβR2 (TGFβ receptor 2), not TGFβR1, abrogated the effect of GDF15 on IK amplification and Kv2.1 induction. Immunoprecipitation assays showed that GDF15 increased the tyrosine phosphorylation of TGFβRII in the CGN lysate. The results of the present study reveal a novel regulation of Kv2.1 by GDF15 mediated through the TGFβRII-activated Akt/mTOR pathway, which is a previously uncharacterized Smad-independent mechanism of GDF15 signalling.

Directional gamma detector

DOEpatents

LeVert, Francis E.; Cox, Samson A.

1981-01-01

An improved directional gamma radiation detector has a collector sandwiched etween two layers of insulation of varying thicknesses. The collector and insulation layers are contained within an evacuated casing, or emitter, which releases electrons upon exposure to gamma radiation. Delayed electrons and electrons entering the collector at oblique angles are attenuated as they pass through the insulation layers on route to the collector.

Determination of the time delay in the case of two-path propagation on the basis of the attenuation characteristics for two adjacent frequencies

NASA Technical Reports Server (NTRS)

Gilroi, H. G.

1979-01-01

Pronounced fading occurring in the line of sight radio links at frequencies below 10 GHz can be traced to the effects of multipath propagation. Modulation disturbances depend on travel time differences between the direct wave and the wave which is reflected at atmospheric layers. A method described for the determination of the time delay is based on an indirect approach which utilizes the difference in fading at various frequencies. The method was employed in measurements involving a distance of 181 km. The results obtained in the measurement are discussed.

Attenuation of MUC4 potentiates the anticancer activity of auranofin via regulation of the Her2/Akt/FOXO3 pathway in ovarian cancer cells.

PubMed

Bae, Jun Sang; Lee, Jongsung; Park, Yoonkook; Park, Kyungmoon; Kim, Jung Ryul; Cho, Dong Hyu; Jang, Kyu Yun; Park, See-Hyoung

2017-10-01

Previously, we reported that auranofin induces apoptosis in SKOV3 cells via regulation of the IKKβ/FOXO3 pathway. In the present study, we reveal that the anticancer activity of auranofin in SKOV3 cells could be enhanced by the attenuation of MUC4 through the regulation of the Her2/Akt/FOXO3 pathway. Compared to the control-siRNA, siRNA transfection against MUC4 into SKOV3 cells accelerated the protein degradation of Her2. Under the same conditions, the expression level of phosphorylated Akt was also downregulated leading to an increase of FOXO3 in the nucleus. Notably, auranofin treatment in SKOV3 cells also resulted in the downregulation of the expression levels of both Her2 and phosphorylated Akt. Thus, Her2 was identified as the common molecular target protein by siRNA transfection against MUC4. Western blot analysis of total and nuclear fraction lysates from SKOV3 cells revealed that attenuation of MUC4 combined with auranofin treatment in SKOV3 cells synergistically activated FOXO3 translocation from the cytoplasm to the nucleus through the regulation of the Her2/Akt/FOXO3 pathway. Attenuation of MUC4 by siRNA transfection potentiated the antitumor effect of auranofin which was examined by performing in vitro assays such as WST-1, cell counting, colony formation, TUNEL and Annexin V staining. In addition, western blot analysis of the apoptosis‑related proteins such as PARP1, caspase-3, Bim extra large (EL), Bax and Bcl2 revealed that the attenuation of MUC4 by siRNA transfection potentiates the pro-apoptotic activity of auranofin in SKOV3 cells. Collectively, auranofin could regulate the Her2/Akt/FOXO3 signaling pathway in SKOV3 cells and be used as a potential antitumor agent considering the expression of MUC4 in ovarian cancer patients.

Discovery of time-delayed gene regulatory networks based on temporal gene expression profiling

PubMed Central

Li, Xia; Rao, Shaoqi; Jiang, Wei; Li, Chuanxing; Xiao, Yun; Guo, Zheng; Zhang, Qingpu; Wang, Lihong; Du, Lei; Li, Jing; Li, Li; Zhang, Tianwen; Wang, Qing K

2006-01-01

Background It is one of the ultimate goals for modern biological research to fully elucidate the intricate interplays and the regulations of the molecular determinants that propel and characterize the progression of versatile life phenomena, to name a few, cell cycling, developmental biology, aging, and the progressive and recurrent pathogenesis of complex diseases. The vast amount of large-scale and genome-wide time-resolved data is becoming increasing available, which provides the golden opportunity to unravel the challenging reverse-engineering problem of time-delayed gene regulatory networks. Results In particular, this methodological paper aims to reconstruct regulatory networks from temporal gene expression data by using delayed correlations between genes, i.e., pairwise overlaps of expression levels shifted in time relative each other. We have thus developed a novel model-free computational toolbox termed TdGRN (Time-delayed Gene Regulatory Network) to address the underlying regulations of genes that can span any unit(s) of time intervals. This bioinformatics toolbox has provided a unified approach to uncovering time trends of gene regulations through decision analysis of the newly designed time-delayed gene expression matrix. We have applied the proposed method to yeast cell cycling and human HeLa cell cycling and have discovered most of the underlying time-delayed regulations that are supported by multiple lines of experimental evidence and that are remarkably consistent with the current knowledge on phase characteristics for the cell cyclings. Conclusion We established a usable and powerful model-free approach to dissecting high-order dynamic trends of gene-gene interactions. We have carefully validated the proposed algorithm by applying it to two publicly available cell cycling datasets. In addition to uncovering the time trends of gene regulations for cell cycling, this unified approach can also be used to study the complex gene regulations related to the development, aging and progressive pathogenesis of a complex disease where potential dependences between different experiment units might occurs. PMID:16420705

Emotion regulation strategies and childhood obesity in high risk preschoolers.

PubMed

Power, Thomas G; Olivera, Yadira A; Hill, Rachael A; Beck, Ashley D; Hopwood, Veronica; Garcia, Karina Silva; Ramos, Guadalupe G; Fisher, Jennifer Orlet; O'Connor, Teresia M; Hughes, Sheryl O

2016-12-01

The current study examined the relationships between the specific strategies that preschool children use to regulate their emotions and childhood weight status to see if emotion regulation strategies would predict childhood weight status over and above measures of eating self-regulation. 185 4- to 5-year-old Latino children were recruited through Head Start centers in a large city in the southeastern U.S. Children completed both a delay of gratification task (emotion regulation) and an eating in the absence of hunger task (eating regulation). Eating regulation also was assessed by maternal reports. Four emotion regulation strategies were examined in the delay of gratification task: shut out stimuli, prevent movement, distraction, and attention to reward. Hierarchical linear regressions predicting children's weight status showed that both measures of eating regulation negatively predicted child obesity, and the use of prevent movement negatively predicted child obesity. Total wait time during the delay of gratification tasks was not a significant predictor. The current findings are consistent with studies showing that for preschool children, summary measures of emotion regulation (e.g., wait time) are not concurrently associated with child obesity. In contrast, the use of emotion regulation strategies was a significant predictor of lower child weight status. These findings help identify emotion regulation strategies that prevention programs can target for helping children regulate their emotions and decrease their obesity risk. Copyright © 2016 Elsevier Ltd. All rights reserved.

Emotion Regulation Strategies and Childhood Obesity in High Risk Preschoolers

PubMed Central

Power, Thomas G.; Olivera, Yadira A.; Hill, Rachael A.; Beck, Ashley D.; Hopwood, Veronica; Garcia, Karina Silva; Ramos, Guadalupe G.; Fisher, Jennifer Orlet; O’Connor, Teresia M.; Hughes, Sheryl O.

2016-01-01

The current study examined the relationships between the specific strategies that preschool children use to regulate their emotions and childhood weight status to see if emotion regulation strategies would predict childhood weight status over and above measures of eating self-regulation. 185 4- to 5-year-old Latino children were recruited through Head Start centers in a large city in the southeastern U.S. Children completed both a delay of gratification task (emotion regulation) and an eating in the absence of hunger task (eating regulation). Eating regulation also was assessed by maternal reports. Four emotion regulation strategies were examined in the delay of gratification task: shut out stimuli, prevent movement, distraction, and attention to reward. Hierarchical linear regressions predicting children’s weight status showed that both measures of eating regulation negatively predicted child obesity, and the use of prevent movement negatively predicted child obesity. Total wait time during the delay of gratification tasks was not a significant predictor. The current findings are consistent with studies showing that for preschool children, summary measures of emotion regulation (e.g., wait time) are not concurrently associated with child obesity. In contrast, the use of emotion regulation strategies was a significant predictor of lower child weight status. These findings help identify emotion regulation strategies that prevention programs can target for helping children regulate their emotions and decrease their obesity risk. PMID:27620645

33 CFR 117.9 - Delaying opening of a draw.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Delaying opening of a draw. 117.9... DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.9 Delaying opening of a draw. No person shall unreasonably delay the opening of a draw after the signals required by § 117.15 have been given. Note: Trains...

Attenuating Staphylococcus aureus Virulence Gene Regulation: A Medicinal Chemistry Perspective

PubMed Central

2013-01-01

Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this Perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA–DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections. PMID:23294220

Prolactin receptor attenuation induces zinc pool redistribution through ZnT2 and decreases invasion in MDA-MB-453 breast cancer cells

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

Bostanci, Zeynep, E-mail: zbostanci@hmc.psu.edu; The Pennsylvania State University Milton S. Hershey Medical Center, Department of Surgery, 500 University Dr., Hershey, PA 17033; Alam, Samina, E-mail: sra116@psu.edu

2014-02-15

Prolactin receptor (PRL-R) activation regulates cell differentiation, proliferation, cell survival and motility of breast cells. Prolactin (PRL) and PRL-R over-expression are strongly implicated in breast cancer, particularly contributing to tumor growth and invasion in the more aggressive estrogen-receptor negative (ER−) disease. PRL-R antagonists have been suggested as potential therapeutic agents; however, mechanisms through which PRL-R antagonists exert their actions are not well-understood. Zinc (Zn) is a regulatory factor for over 10% of the proteome, regulating critical cell processes such as proliferation, cell signaling, transcription, apoptosis and autophagy. PRL-R signaling regulates Zn metabolism in breast cells. Herein we determined effects ofmore » PRL-R attenuation on cellular Zn metabolism and cell function in a model of ER-, PRL-R over-expressing breast cancer cells (MDA-MB-453). PRL-R attenuation post-transcriptionally increased ZnT2 abundance and redistributed intracellular Zn pools into lysosomes and mitochondria. ZnT2-mediated lysosomal Zn sequestration was associated with reduced matrix metalloproteinase 2 (MMP-2) activity and decreased invasion. ZnT2-mediated Zn accumulation in mitochondria was associated with increased mitochondrial oxidation. Our results suggest that PRL-R antagonism in PRL-R over-expressing breast cancer cells may reduce invasion through the redistribution of intracellular Zn pools critical for cellular function. - Highlights: • PRL-R attenuation increased ZnT2 expression. • PRL-R attenuation increased lysosomal and mitochondrial Zn accumulation. • PRL-R attenuation decreased MMP-2 and invasion. • PRL-R antagonists may modulate lysosomal and mitochondrial Zn pools.« less

49 CFR 236.831 - Time, delay.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Time, delay. 236.831 Section 236.831 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Time, delay. As applied to an automatic train stop or train control system, the time which elapses...

Examining P-Wave Arrivals of Low-Frequency Earthquakes for Evidence of Attenuation and its Effects on Moment-Duration Scaling

NASA Astrophysics Data System (ADS)

Gerzina, J.; Rubin, A. M.

2017-12-01

Bostock et. al. (2015) found that low-frequency earthquake (LFE) duration is nearly independent of moment, a result that is surprising enough to warrant investigating whether it might be an artifact of attenuation. Bostock et. al. (2017) found that bulk crustal attenuation could not be the culprit, but suggested that near-source attenuation might cause pronounced depletion of high frequency S-waves. Despite their lower signal-to noise ratio, looking at the P-waves might be enlightening because they aren't expected to attenuate as much as S-waves in the high Vp/Vs region near the tremor source. We have examined P-wave arrivals of LFEs that occurred during episodic tremor in the Cascadia subduction zone with the goal of refining the relationship between LFE magnitude and duration.Bostock et. al's duration measurements were made on stacked templates rather than individual arrivals. Because members of Bostock's LFE families vary in location, and therefore in P-S delay time, aligning the stacks primarily on the S arrival may artificially widen the P pulse. To circumvent this, we used cross-station cross correlations on Bostock's detections to identify and stack events with similar locations and therefore similar P-S delay times, until P arrivals became visible. We then stacked these stacks based on cross-correlating the optimal P component in a small window surrounding the P arrival. Although this procedure narrowed both the P and S pulse widths, it did not dramatically narrow P in relation to S, nor did we observe different P pulse widths for small and large events.We also compared the frequency spectra of small windows around the expected P and S arrivals for each amplitude bin. Although there is more high-frequency content in P-waves than S-waves, we have not yet been able to resolve a difference in P-wave corner frequency for different event sizes. Thus our preliminary results support the notion that LFEs are intrinsically low frequency.

Involvement of {gamma}-secretase in postnatal angiogenesis

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

Hayashi, Hiroki; Nakagami, Hironori; Takami, Yoichi

2007-11-23

{gamma}-Secretase cleaves the transmembrane domains of several integral membrane proteins involved in vasculogenesis. Here, we investigated the role of {gamma}-secretase in the regulation of postnatal angiogenesis using {gamma}-secretase inhibitors (GSI). In endothelial cell (EC), {gamma}-secretase activity was up-regulated under hypoxia or the treatment of vascular endothelial growth factor (VEGF). The treatment of GSI significantly attenuated growth factor-induced EC proliferation and migration as well as c-fos promoter activity in a dose-dependent manner. In vascular smooth muscle cell (VSMC), treatment of GSI significantly attenuated growth factor-induced VEGF and fibroblast growth factor-2 (FGF-2) expression. Indeed, GSI attenuated VEGF-induced tube formation and inhibited FGF-2-inducedmore » angiogenesis on matrigel in mice as quantified by FITC-lectin staining of EC. Overall, we demonstrated that {gamma}-secretase may be key molecule in postnatal angiogenesis which may be downstream molecule of growth factor-induced growth and migration in EC, and regulate the expression of angiogenic growth factors in VSMC.« less

Caffeic acid attenuates rat liver reperfusion injury through sirtuin 3-dependent regulation of mitochondrial respiratory chain.

PubMed

Mu, Hong-Na; Li, Quan; Pan, Chun-Shui; Liu, Yu-Ying; Yan, Li; Hu, Bai-He; Sun, Kai; Chang, Xin; Zhao, Xin-Rong; Fan, Jing-Yu; Han, Jing-Yan

2015-08-01

Sirtuin 3 (Sirt3) plays critical roles in regulating mitochondrial oxidative metabolism. However, whether Sirt3 is involved in liver ischemia and reperfusion (I/R) injury remains elusive. Caffeic acid (CA) is a natural antioxidant derived from Salvia miltiorrhiza. Whether CA protects against liver I/R injury through regulating Sirt3 and the mitochondrial respiratory chain (MRC) is unclear. This study investigated the effect of CA on liver I/R injury, microcirculatory disturbance, and potential mechanisms, particularly focusing on Sirt3-dependent MRC. Liver I/R of male Sprague-Dawley rats was established by occlusion of portal area vessels for 30 min followed by 120 min of reperfusion. CA (15 mg/kg/h) was continuously infused via the femoral vein starting 30 min before ischemia. After I/R, Sirt3 expression, and MRC activity decreased, acetylation of NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 and succinate dehydrogenase complex, subunit A, flavoprotein variant provoked, and the liver microcirculatory disturbance and injury were observed. Treatment with CA attenuated liver injury, inhibited Sirt3 down-expression, and up-regulated MRC activity. CA attenuated rat liver microcirculatory disturbance and oxidative injury through regulation of Sirt3 and the mitochondrial respiratory chain. Copyright © 2015 Elsevier Inc. All rights reserved.

Test Anxiety and Academic Delay of Gratification

ERIC Educational Resources Information Center

Bembenutty, Hefer

2009-01-01

The present study examined the relationship between college students' willingness to delay gratification, motivation, self-regulation of learning, and their level of test anxiety (N = 364). Academic delay of gratification refers to students' postponement of immediately available opportunities to satisfy impulses in favor of pursuing academic…

Clustering of mutations within the inverted repeat regions of a serially-passaged attenuated gallid herpesvirus type 2 strain.

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is the leading cause of losses in chicken production in the world. Over the past 40 years significant progress has been made in the control of MD through the use of vaccines which reduce or delay tumor formation in vaccinated flocks. However, these vaccines fail to induce an imm...

Age-Related Occipito-Temporal Hypoactivation during Visual Search: Relationships between mN2pc Sources and Performance

ERIC Educational Resources Information Center

Lorenzo-Lopez, L.; Gutierrez, R.; Moratti, S.; Maestu, F.; Cadaveira, F.; Amenedo, E.

2011-01-01

Recently, an event-related potential (ERP) study (Lorenzo-Lopez et al., 2008) provided evidence that normal aging significantly delays and attenuates the electrophysiological correlate of the allocation of visuospatial attention (N2pc component) during a feature-detection visual search task. To further explore the effects of normal aging on the…

Delayed-onset Reversible Cortical Blindness after Resuscitation from Cardiac Arrest

PubMed Central

de Souza, Aaron; de Souza, Rainha J.; Pai Kakode, Varun R.

2017-01-01

We present a patient who presented with cortical blindness (CB) 1 week after repeated cardiac arrest while undergoing treatment for an acute myocardial infarction. He had been revived within 5 min in each instance and was apparently neurologically normal until presentation. Magnetic resonance imaging showed subtle hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging in both temporooccipital cortices. A rapid recovery over the next 2 weeks was remarkable for the appearance of metamorphopsia. CB may present even days to weeks after hypoxic-ischemic encephalopathy following cardiac arrest, even in patients apparently without immediate neurological sequelae. The pathogenesis of this phenomenon remains to be fully elucidated, but is likely to be due to delayed effects of anoxia on the occipital cortex and may be analogous to the previously described syndrome of delayed posthypoxic leukoencephalopathy. Prognosis for visual recovery appears to be good. PMID:28936091

Acute ethanol effects on neural encoding of reward size and delay in the nucleus accumbens

PubMed Central

Gutman, Andrea L.

2016-01-01

Acute ethanol administration can cause impulsivity, resulting in increased preference for immediately available rewards over delayed but more valuable alternatives. The manner in which reward size and delay are represented in neural firing is not fully understood, and very little is known about ethanol effects on this encoding. To address this issue, we used in vivo electrophysiology to characterize neural firing in the core of the nucleus accumbens (NAcc) in rats responding for rewards that varied in size or delay after vehicle or ethanol administration. The NAcc is a central element in the circuit that governs decision-making and importantly, promotes choice of delayed rewards. We found that NAcc firing in response to reward-predictive cues encoded anticipated reward value after vehicle administration, but ethanol administration disrupted this encoding, resulting in a loss of discrimination between immediate and delayed rewards in cue-evoked neural responses. In addition, NAcc firing occurring at the time of the operant response (lever pressing) was inversely correlated with behavioral response latency, such that increased firing rates were associated with decreased latencies to lever press. Ethanol administration selectively attenuated this lever press-evoked firing when delayed but not immediate rewards were expected. These effects on neural firing were accompanied by increased behavioral latencies to respond for delayed rewards. Our results suggest that ethanol effects on NAcc cue- and lever press-evoked encoding may contribute to ethanol-induced impulsivity. PMID:27169507

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression.

PubMed

Chen, Diyu; Zuo, Yangjin; Zhang, Xinhua; Ye, Yuhua; Bao, Xiuqin; Huang, Haiyan; Tepakhan, Wanicha; Wang, Lijuan; Ju, Junyi; Chen, Guangfu; Zheng, Mincui; Liu, Dun; Huang, Shuodan; Zong, Lu; Li, Changgang; Chen, Yajun; Zheng, Chenguang; Shi, Lihong; Zhao, Quan; Wu, Qiang; Fucharoen, Supan; Zhao, Cunyou; Xu, Xiangmin

2017-07-06

A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for β-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of β-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from β-thalassemia persons. The present study demonstrates that this common rSNP in the proximal A γ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of β-hemoglobinopathy. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

GATA4 negatively regulates bone sialoprotein expression in osteoblasts.

PubMed

Song, Insun; Jeong, Byung-Chul; Choi, Yong Jun; Chung, Yoon-Sok; Kim, Nacksung

2016-06-01

GATA4 has been reported to act as a negative regulator in osteoblast differentiation by inhibiting the Dlx5 transactivation of Runx2 via the attenuation of the binding ability of Dlx5 to the Runx2 promoter region. Here, we determine the role of GATA4 in the regulation of bone sialoprotein (Bsp) in osteoblasts. We observed that the overexpression of Runx2 or Sox9 induced the Bsp expression in osteoblastic cells. Silencing GATA4 further enhanced the Runx2- and Sox9-mediated Bsp promoter activity, whereas GATA4 overexpression down-regulated Bsp promoter activity mediated by Runx2 and Sox9. GATA4 also interacted with Runx2 and Sox9, by attenuating the binding ability of Runx2 and Sox9 to the Bsp promoter region. Our data suggest that GATA4 acts as a negative regulator of Bsp expression in osteoblasts. [BMB Reports 2016; 49(6): 343-348].

The effect of activation rate on left atrial bipolar voltage in patients with paroxysmal atrial fibrillation.

PubMed

Williams, Steven E; Linton, Nick; O'Neill, Louisa; Harrison, James; Whitaker, John; Mukherjee, Rahul; Rinaldi, Christopher A; Gill, Jaswinder; Niederer, Steven; Wright, Matthew; O'Neill, Mark

2017-09-01

Bipolar voltage is used during electroanatomic mapping to define abnormal myocardium, but the effect of activation rate on bipolar voltage is not known. We hypothesized that bipolar voltage may change in response to activation rate. By examining corresponding unipolar signals we sought to determine the mechanisms of such changes. LA extrastimulus mapping was performed during CS pacing in 10 patients undergoing first time paroxysmal atrial fibrillation ablation. Bipolar and unipolar electrograms were recorded using a PentaRay catheter (4-4-4 spacing) and indifferent IVC electrode, respectively. An S1S2 pacing protocol was delivered with extrastimulus coupling interval reducing from 350 to 200 milliseconds. At each recording site (119 ± 37 per LA), bipolar peak-to-peak voltage, unipolar peak to peak voltage and activation delay between unipole pairs was measured. Four patterns of bipolar voltage/extrastimulus coupling interval curves were seen: voltage attenuation with plateau voltage >1 mV (48 ± 15%) or <1 mV (22 ± 15%), and voltage unaffected by coupling interval with plateau voltage >1 mV (17 ± 10%) or <1 mV (13 ± 8%). Electrograms showing bipolar voltage attenuation were associated with significantly greater unipolar voltage attenuation at low (25 ± 28 mV/s vs. 9 ± 11 mV/s) and high (23 ± 29 mV/s vs. 6 ± 12 mV/s) plateau voltage sites (P < 0.001). There was a small but significant increase in conduction delay between unipole pairs at sites showing bipolar voltage attenuation (P = 0.026). Bipolar electrogram voltage is dependent on activation rate at a significant proportion of sites. Changes in unipolar voltage and timing underlie these effects. These observations have important implications for use of voltage mapping to delineate abnormal atrial substrate. © 2017 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals, Inc.

The effect of activation rate on left atrial bipolar voltage in patients with paroxysmal atrial fibrillation

PubMed Central

Linton, Nick; O'Neill, Louisa; Harrison, James; Whitaker, John; Mukherjee, Rahul; Rinaldi, Christopher A.; Gill, Jaswinder; Niederer, Steven; Wright, Matthew; O'Neill, Mark

2017-01-01

Abstract Introduction Bipolar voltage is used during electroanatomic mapping to define abnormal myocardium, but the effect of activation rate on bipolar voltage is not known. We hypothesized that bipolar voltage may change in response to activation rate. By examining corresponding unipolar signals we sought to determine the mechanisms of such changes. Methods and results LA extrastimulus mapping was performed during CS pacing in 10 patients undergoing first time paroxysmal atrial fibrillation ablation. Bipolar and unipolar electrograms were recorded using a PentaRay catheter (4‐4‐4 spacing) and indifferent IVC electrode, respectively. An S1S2 pacing protocol was delivered with extrastimulus coupling interval reducing from 350 to 200 milliseconds. At each recording site (119 ± 37 per LA), bipolar peak‐to‐peak voltage, unipolar peak to peak voltage and activation delay between unipole pairs was measured. Four patterns of bipolar voltage/extrastimulus coupling interval curves were seen: voltage attenuation with plateau voltage >1 mV (48 ± 15%) or <1 mV (22 ± 15%), and voltage unaffected by coupling interval with plateau voltage >1 mV (17 ± 10%) or <1 mV (13 ± 8%). Electrograms showing bipolar voltage attenuation were associated with significantly greater unipolar voltage attenuation at low (25 ± 28 mV/s vs. 9 ± 11 mV/s) and high (23 ± 29 mV/s vs. 6 ± 12 mV/s) plateau voltage sites (P < 0.001). There was a small but significant increase in conduction delay between unipole pairs at sites showing bipolar voltage attenuation (P = 0.026). Conclusions Bipolar electrogram voltage is dependent on activation rate at a significant proportion of sites. Changes in unipolar voltage and timing underlie these effects. These observations have important implications for use of voltage mapping to delineate abnormal atrial substrate. PMID:28639747

Tissue inhibitor of metalloproteinases 1 enhances rod survival in the rd1 mouse retina.

PubMed

Kim, Hwa Sun; Vargas, Andrew; Eom, Yun Sung; Li, Justin; Yamamoto, Kyra L; Craft, Cheryl Mae; Lee, Eun-Jin

2018-01-01

Retinitis pigmentosa (RP), an inherited retinal degenerative disease, is characterized by a progressive loss of rod photoreceptors followed by loss of cone photoreceptors. Previously, when tissue inhibitor of metalloproteinase 1 (TIMP1), a key extracellular matrix (ECM) regulator that binds to and inhibits activation of Matrix metallopeptidase 9 (MMP9) was intravitreal injected into eyes of a transgenic rhodopsin rat model of RP, S334ter-line3, we discovered cone outer segments are partially protected. In parallel, we reported that a specific MMP9 and MMP2 inhibitor, SB-3CT, interferes with mechanisms leading to rod photoreceptor cell death in an MMP9 dependent manner. Here, we extend our initial rat studies to examine the potential of TIMP1 as a treatment in retinal degeneration by investigating neuroprotective effects in a classic mouse retinal degeneration model, rdPde6b-/- (rd1). The results clearly demonstrate that intravitreal injections of TIMP1 produce extended protection to delay rod photoreceptor cell death. The mean total number of rods in whole-mount retinas was significantly greater in TIMP-treated rd1 retinas (postnatal (P) 30, P35 (P<0.0001) and P45 (P<0.05) than in saline-treated rd1 retinas. In contrast, SB-3CT did not delay rod cell death, leading us to further investigate alternative pathways that do not involve MMPs. In addition to inducing phosphorylated ERK1/2, TIMP1 significantly reduces BAX activity and delays attenuation of the outer nuclear layer (ONL). Physiological responses using scotopic electroretinograms (ERG) reveal b-wave amplitudes from TIMP1-treated retinas are significantly greater than from saline-treated rd1 retinas (P<0.05). In later degenerative stages of rd1 retinas, photopic b-wave amplitudes from TIMP1-treated rd1 retinas are significantly larger than from saline-treated rd1 retinas (P<0.05). Our findings demonstrate that TIMP1 delays photoreceptor cell death. Furthermore, this study provides new insights into how TIMP1 works in the mouse animal model of RP.

The Putative E3 Ubiquitin Ligase ECERIFERUM9 Regulates Abscisic Acid Biosynthesis and Response during Seed Germination and Postgermination Growth in Arabidopsis.

PubMed

Zhao, Huayan; Zhang, Huoming; Cui, Peng; Ding, Feng; Wang, Guangchao; Li, Rongjun; Jenks, Matthew A; Lü, Shiyou; Xiong, Liming

2014-07-01

The ECERIFERUM9 (CER9) gene encodes a putative E3 ubiquitin ligase that functions in cuticle biosynthesis and the maintenance of plant water status. Here, we found that CER9 is also involved in abscisic acid (ABA) signaling in seeds and young seedlings of Arabidopsis (Arabidopsis thaliana). The germinated embryos of the mutants exhibited enhanced sensitivity to ABA during the transition from reversible dormancy to determinate seedling growth. Expression of the CER9 gene is closely related to ABA levels and displays a similar pattern to that of ABSCISIC ACID-INSENSITIVE5 (ABI5), which encodes a positive regulator of ABA responses in seeds. cer9 mutant seeds exhibited delayed germination that is independent of seed coat permeability. Quantitative proteomic analyses showed that cer9 seeds had a protein profile similar to that of the wild type treated with ABA. Transcriptomics analyses revealed that genes involved in ABA biosynthesis or signaling pathways were differentially regulated in cer9 seeds. Consistent with this, high levels of ABA were detected in dry seeds of cer9. Blocking ABA biosynthesis by fluridone treatment or by combining an ABA-deficient mutation with cer9 attenuated the phenotypes of cer9. Whereas introduction of the abi1-1, abi3-1, or abi4-103 mutation could completely eliminate the ABA hypersensitivity of cer9, introduction of abi5 resulted only in partial suppression. These results indicate that CER9 is a novel negative regulator of ABA biosynthesis and the ABA signaling pathway during seed germination. © 2014 American Society of Plant Biologists. All Rights Reserved.

Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish.

PubMed

Lee, Yeon-Joo; Choi, Hyeon-Son; Seo, Min-Jung; Jeon, Hui-Jeon; Kim, Kui-Jin; Lee, Boo-Yong

2015-08-01

Kaempferol is a flavonoid present in Kaempferia galanga and Opuntia ficus indica var. saboten. Recent studies have suggested that it has anti-oxidant, anti-inflammatory, anti-cancer, and anti-obesity effects. In this study, we focused on the anti-adipogenic effects of kaempferol during adipocyte differentiation. The results showed that kaempferol inhibits lipid accumulation in adipocytes and zebrafish. Oil Red O and Nile Red staining showed that the number of intracellular lipid droplets decreased in adipocytes and zebrafish treated with kaempferol. LPAATθ (lysophosphatidic acid acyltransferase), lipin1, and DGAT1 (triglyceride synthetic enzymes) and FASN and SREBP-1C (fatty acid synthetic proteins) showed decreased expression levels in the presence of kaempferol. In addition, treatment of kaempferol showed an inhibitory activity on cell cycle progression. Kaempferol delayed cell cycle progression from the S to G2/M phase through the regulation of cyclins in a dose-dependent manner. Kaempferol blocked the phosphorylation of AKT (protein kinase B) and mammalian target of rapamycin (mTOR) signaling pathway during the early stages of adipogenesis. In addition, kaempferol down-regulated pro-early adipogenic factors such as CCAAT-enhancer binding proteins β (C/EBPβ), and Krüppel-like factors (KLFs) 4 and 5, while anti-early adipogenic factors, such as KLF2 and pref-1(preadipocyte factor-1), were upregulated. These kaempferol-mediated regulations of early adipogenic factors resulted in the attenuation of late adipogenic factors such as C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ). These results were supported in zebrafish based on the decrease in lipid accumulation and expression of adipogenic factors. Our results indicated that kaempferol might have an anti-obesity effect by regulating lipid metabolism.

Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

PubMed Central

Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

2014-01-01

The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

Epidermal UV-A absorbance and whole-leaf flavonoid composition in pea respond more to solar blue light than to solar UV radiation.

PubMed

Siipola, Sari M; Kotilainen, Titta; Sipari, Nina; Morales, Luis O; Lindfors, Anders V; Robson, T Matthew; Aphalo, Pedro J

2015-05-01

Plants synthesize phenolic compounds in response to certain environmental signals or stresses. One large group of phenolics, flavonoids, is considered particularly responsive to ultraviolet (UV) radiation. However, here we demonstrate that solar blue light stimulates flavonoid biosynthesis in the absence of UV-A and UV-B radiation. We grew pea plants (Pisum sativum cv. Meteor) outdoors, in Finland during the summer, under five types of filters differing in their spectral transmittance. These filters were used to (1) attenuate UV-B; (2) attenuate UV-B and UV-A < 370 nm; (3) attenuate UV-B and UV-A; (4) attenuate UV-B, UV-A and blue light; and (5) as a control not attenuating these wavebands. Attenuation of blue light significantly reduced the flavonoid content in leaf adaxial epidermis and reduced the whole-leaf concentrations of quercetin derivatives relative to kaempferol derivatives. In contrast, UV-B responses were not significant. These results show that pea plants regulate epidermal UV-A absorbance and accumulation of individual flavonoids by perceiving complex radiation signals that extend into the visible region of the solar spectrum. Furthermore, solar blue light instead of solar UV-B radiation can be the main regulator of phenolic compound accumulation in plants that germinate and develop outdoors. © 2014 John Wiley & Sons Ltd.

Touch Attenuates Infants' Physiological Reactivity to Stress

ERIC Educational Resources Information Center

Feldman, Ruth; Singer, Magi; Zagoory, Orna

2010-01-01

Animal studies demonstrate that maternal touch and contact regulate infant stress, and handling during periods of maternal deprivation attenuates the stress response. To measure the effects of touch on infant stress reactivity during simulated maternal deprivation, 53 dyads were tested in two paradigms: still-face (SF) and still-face with maternal…

Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP-mediated p53 activation.

PubMed

Nishimura, Kazuho; Kumazawa, Takuya; Kuroda, Takao; Katagiri, Naohiro; Tsuchiya, Mai; Goto, Natsuka; Furumai, Ryohei; Murayama, Akiko; Yanagisawa, Junn; Kimura, Keiji

2015-03-03

The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Sympathetic nervous system influences on the kidney. Role in hypertension.

PubMed

DiBona, G F

1989-03-01

Efferent renal sympathetic nerve activity (ERSNA) is elevated in human essential hypertension as well as several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow and glomerular filtration rate, renal tubular sodium and water reabsorption, and renin secretion rate that are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of ERSNA, two environmental factors, dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in ERSNA and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration.

PubMed

Friedman, Alexander; Lax, Elad; Dikshtein, Yahav; Abraham, Lital; Flaumenhaft, Yakov; Sudai, Einav; Ben-Tzion, Moshe; Yadid, Gal

2011-01-01

The lateral habenula (LHb) plays a role in prediction of negative reinforcement, punishment and aversive responses. In the current study, we examined the role that the LHb plays in regulation of negative reward responses and aversion. First, we tested the effect of intervention in LHb activity on sucrose reinforcing behavior. An electrode was implanted into the LHb and rats were trained to self-administer sucrose (20%; 16 days) until at least three days of stable performance were achieved (as represented by the number of active lever presses in self-administration cages). Rats subsequently received deep brain stimulation (DBS) of the LHb, which significantly reduced sucrose self-administration levels. In contrast, lesion of the LHb increased sucrose-seeking behavior, as demonstrated by a delayed extinction response to substitution of sucrose with water. Furthermore, in a modified non-rewarding conditioned-place-preference paradigm, DBS of the LHb led to aversion to the context associated with stimulation of this brain region. We postulate that electrical stimulation of the LHb attenuates positive reward-associated reinforcement by natural substances. Copyright © 2010 Elsevier Ltd. All rights reserved.

Pulse stretcher

DOEpatents

Horton, James A.

1994-01-01

Apparatus (20) for increasing the length of a laser pulse to reduce its peak power without substantial loss in the average power of the pulse. The apparatus (20) uses a White cell (10) having a plurality of optical delay paths (18a-18d) of successively increasing number of passes between the field mirror (13) and the objective mirrors (11 and 12). A pulse (26) from a laser (27) travels through a multi-leg reflective path (28) between a beam splitter (21) and a totally reflective mirror (24) to the laser output (37). The laser pulse (26) is also simultaneously injected through the beam splitter (21) to the input mirrors (14a-14d) of the optical delay paths (18a-18d). The pulses from the output mirrors (16a-16d) of the optical delay paths (18a-18d) go simultaneously to the laser output (37) and to the input mirrors ( 14b-14d) of the longer optical delay paths. The beam splitter (21) is 50% reflective and 50% transmissive to provide equal attenuation of all of the pulses at the laser output (37).

Transport delay compensation for computer-generated imagery systems

NASA Technical Reports Server (NTRS)

Mcfarland, Richard E.

1988-01-01

In the problem of pure transport delay in a low-pass system, a trade-off exists with respect to performance within and beyond a frequency bandwidth. When activity beyond the band is attenuated because of other considerations, this trade-off may be used to improve the performance within the band. Specifically, transport delay in computer-generated imagery systems is reduced to a manageable problem by recognizing frequency limits in vehicle activity and manual-control capacity. Based on these limits, a compensation algorithm has been developed for use in aircraft simulation at NASA Ames Research Center. For direct measurement of transport delays, a beam-splitter experiment is presented that accounts for the complete flight simulation environment. Values determined by this experiment are appropriate for use in the compensation algorithm. The algorithm extends the bandwidth of high-frequency flight simulation to well beyond that of normal pilot inputs. Within this bandwidth, the visual scene presentation manifests negligible gain distortion and phase lag. After a year of utilization, two minor exceptions to universal simulation applicability have been identified and subsequently resolved.

31 CFR 560.515 - 30-day delayed effective date for pre-May 7, 1995 trade contracts involving Iran.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false 30-day delayed effective date for pre-May 7, 1995 trade contracts involving Iran. 560.515 Section 560.515 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY IRANIAN TRANSACTIONS REGULATIONS...

31 CFR 538.506 - 30-day delayed effective date for pre-November 4, 1997 trade contracts involving Sudan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false 30-day delayed effective date for pre-November 4, 1997 trade contracts involving Sudan. 538.506 Section 538.506 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY SUDANESE SANCTIONS REGULATIONS...

31 CFR 538.506 - 30-day delayed effective date for pre-November 4, 1997 trade contracts involving Sudan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false 30-day delayed effective date for pre-November 4, 1997 trade contracts involving Sudan. 538.506 Section 538.506 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY SUDANESE SANCTIONS REGULATIONS...

31 CFR 538.506 - 30-day delayed effective date for pre-November 4, 1997 trade contracts involving Sudan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false 30-day delayed effective date for pre-November 4, 1997 trade contracts involving Sudan. 538.506 Section 538.506 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY SUDANESE SANCTIONS REGULATIONS...

31 CFR 560.515 - 30-day delayed effective date for pre-May 7, 1995 trade contracts involving Iran.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false 30-day delayed effective date for pre-May 7, 1995 trade contracts involving Iran. 560.515 Section 560.515 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY IRANIAN TRANSACTIONS REGULATIONS...

The effects of oral d-amphetamine on impulsivity in smoked and intranasal cocaine users.

PubMed

Reed, Stephanie Collins; Evans, Suzette M

2016-06-01

Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Effects of Oral d-Amphetamine on Impulsivity in Smoked and Intranasal Cocaine Users

PubMed Central

Reed, Stephanie Collins; Evans, Suzette M.

2016-01-01

BACKGROUND Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. METHODS The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20 mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. RESULTS Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). CONCLUSIONS Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. PMID:27114203

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia.

PubMed

Asp, Michelle L; Tian, Min; Kliewer, Kara L; Belury, Martha A

2011-12-01

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia.

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia

PubMed Central

Asp, Michelle L.; Tian, Min; Kliewer, Kara L.

2011-01-01

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia. PMID:22104958

Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols

PubMed Central

2010-01-01

Background Multidrug resistance (MDR) is a major obstacle in cancer treatment and is often the result of overexpression of the drug efflux protein, P-glycoprotein (P-gp), as a consequence of hyperactivation of NFκB, AP1 and Nrf2 transcription factors. In addition to effluxing chemotherapeutic drugs, P-gp also plays a specific role in blocking caspase-dependent apoptotic pathways. One feature that cytotoxic treatments of cancer have in common is activation of the transcription factor NFκB, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NFκB inhibitors may promote apoptosis in cancer cells and could be used to overcome resistance to chemotherapeutic agents. Results Although the natural withanolide withaferin A and polyphenol quercetin, show comparable inhibition of NFκB target genes (involved in inflammation, angiogenesis, cell cycle, metastasis, anti-apoptosis and multidrug resistance) in doxorubicin-sensitive K562 and -resistant K562/Adr cells, only withaferin A can overcome attenuated caspase activation and apoptosis in K562/Adr cells, whereas quercetin-dependent caspase activation and apoptosis is delayed only. Interestingly, although withaferin A and quercetin treatments both decrease intracellular protein levels of Bcl2, Bim and P-Bad, only withaferin A decreases protein levels of cytoskeletal tubulin, concomitantly with potent PARP cleavage, caspase 3 activation and apoptosis, at least in part via a direct thiol oxidation mechanism. Conclusions This demonstrates that different classes of natural NFκB inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis. PMID:20438634

Minocycline reduces neuronal death and attenuates microglial response after pediatric asphyxial cardiac arrest.

PubMed

Tang, Minke; Alexander, Henry; Clark, Robert S B; Kochanek, Patrick M; Kagan, Valerian E; Bayir, Hülya

2010-01-01

The mechanisms leading to delayed neuronal death after asphyxial cardiac arrest (ACA) in the developing brain are unknown. This study aimed at investigating the possible role of microglial activation in neuronal death in developing brain after ACA. Postnatal day-17 rats were subjected to 9 mins of ACA followed by resuscitation. Rats were randomized to treatment with minocycline, (90 mg/kg, intraperitoneally (i.p.)) or vehicle (saline, i.p.) at 1 h after return of spontaneous circulation. Thereafter, minocycline (22.5 mg/kg, i.p.) was administrated every 12 h until sacrifice. Microglial activation (evaluated by immunohistochemistry using ionized calcium-binding adapter molecule-1 (Iba1) antibody) coincided with DNA fragmentation and neurodegeneration in CA1 hippocampus and cortex (assessed by deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL), Fluoro-Jade-B and Nissl stain). Minocycline significantly decreased both the microglial response and neuronal degeneration compared with the vehicle. Asphyxial CA significantly enhanced proinflammatory cytokine and chemokine levels in hippocampus versus control (assessed by multiplex bead array assay), specifically tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), regulated upon activation, normal T-cell expressed and secreted (RANTES), and growth-related oncogene (GRO-KC) (P<0.05). Minocycline attenuated ACA-induced increases in MIP-1alpha and RANTES (P<0.05). These data show that microglial activation and cytokine production are increased in immature brain after ACA. The beneficial effect of minocycline suggests an important role for microglia in selective neuronal death after pediatric ACA, and a possible therapeutic target.

Proteomics of red and white corolla limbs in petunia reveals a novel function of the anthocyanin regulator ANTHOCYANIN1 in determining flower longevity.

PubMed

Prinsi, Bhakti; Negri, Alfredo S; Quattrocchio, Francesca M; Koes, Ronald E; Espen, Luca

2016-01-10

The Petunia hybrida ANTHOCYANIN1 (AN1) gene encodes a transcription factor that regulates both the expression of genes involved in anthocyanin synthesis and the acidification of the vacuolar lumen in corolla epidermal cells. In this work, the comparison between the red flowers of the R27 line with the white flowers of the isogenic an1 mutant line W225 showed that the AN1 gene has further pleiotropic effects on flavonoid biosynthesis as well as on distant physiological traits. The proteomic profiling showed that the an1 mutation was associated to changes in accumulation of several proteins, affecting both anthocyanin synthesis and primary metabolism. The flavonoid composition study confirmed that the an1 mutation provoked a broad attenuation of the entire flavonoid pathway, probably by indirect biochemical events. Moreover, proteomic changes and variation of biochemical parameters revealed that the an1 mutation induced a delay in the onset of flower senescence in W225, as supported by the enhanced longevity of the W225 flowers in planta and the loss of sensitivity of cut flowers to sugar. This study suggests that AN1 is possibly involved in the perception and/or transduction of ethylene signal during flower senescence. Copyright © 2015 Elsevier B.V. All rights reserved.

Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression.

PubMed

Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

2016-05-05

Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2(f/f);Bmp4(f/f)ameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling.

Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression

PubMed Central

Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H.; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

2016-01-01

Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2f/f;Bmp4f/fameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling. PMID:27146352

Anti-CXCL4 monoclonal antibody accelerates telogen to anagen transition and attenuates apoptosis of the hair follicle in mice

PubMed Central

Guan, Wen; Yu, Xiaolan; Li, Jingjing; Deng, Qing; Zhang, Yang; Gao, Jing; Xia, Peng; Yuan, Yunsheng; Gao, Jin; Zhou, Liang; Han, Wei; Yu, Yan

2017-01-01

Although hair loss or alopecia is a common disease, its exact mechanisms are not yet well understood. The present study investigated the hypothesis that the homeostatic regulation of genes during hair regeneration may participate in hair loss, based on the cyclicity of hair growth. A cluster of such genes was identified by an expression gene-array from the dorsal skin in a depilated mouse model, and CXCL4 was identified as a significantly regulated gene during the hair regeneration process. To elucidate the function of CXCL4 in hair growth, CXCL4 activity was blocked by the administration of an anti-CXCL4 monoclonal antibody (mAb). Histomorphometric analysis indicated that anti-CXCL4 mAb induced an earlier anagen phase and delayed hair follicle regression, in contrast with that in the control group. Moreover, CXCL4 mAb upregulated the transcription levels of several hair growth-related genes, including Lef1, Wnt10b, Bmp4 and Bmp2. In addition, CXCL4 mAb increased the levels of the proliferation-related protein PCNA and Bcl-2 during the anagen phase, while it reduced the expression of pro-apoptotic protein Bax and cleaved caspase-3 during the catagen phase. These findings reveal that CXCL4 plays an important role in hair growth, and that blockade of CXCL4 activity promotes hair growth. PMID:28810552

Anti-CXCL4 monoclonal antibody accelerates telogen to anagen transition and attenuates apoptosis of the hair follicle in mice.

PubMed

Guan, Wen; Yu, Xiaolan; Li, Jingjing; Deng, Qing; Zhang, Yang; Gao, Jing; Xia, Peng; Yuan, Yunsheng; Gao, Jin; Zhou, Liang; Han, Wei; Yu, Yan

2017-08-01

Although hair loss or alopecia is a common disease, its exact mechanisms are not yet well understood. The present study investigated the hypothesis that the homeostatic regulation of genes during hair regeneration may participate in hair loss, based on the cyclicity of hair growth. A cluster of such genes was identified by an expression gene-array from the dorsal skin in a depilated mouse model, and CXCL4 was identified as a significantly regulated gene during the hair regeneration process. To elucidate the function of CXCL4 in hair growth, CXCL4 activity was blocked by the administration of an anti-CXCL4 monoclonal antibody (mAb). Histomorphometric analysis indicated that anti-CXCL4 mAb induced an earlier anagen phase and delayed hair follicle regression, in contrast with that in the control group. Moreover, CXCL4 mAb upregulated the transcription levels of several hair growth-related genes, including Lef1, Wnt10b, Bmp4 and Bmp2. In addition, CXCL4 mAb increased the levels of the proliferation-related protein PCNA and Bcl-2 during the anagen phase, while it reduced the expression of pro-apoptotic protein Bax and cleaved caspase-3 during the catagen phase. These findings reveal that CXCL4 plays an important role in hair growth, and that blockade of CXCL4 activity promotes hair growth.

Phototropin 1 and dim-blue light modulate the red light de-etiolation response.

PubMed

Wang, Yihai; M Folta, Kevin

2014-01-01

Light signals regulate seedling morphological changes during de-etiolation through the coordinated actions of multiple light-sensing pathways. Previously we have shown that red-light-induced hypocotyl growth inhibition can be reversed by addition of dim blue light through the action of phototropin 1 (phot1). Here we further examine the fluence-rate relationships of this blue light effect in short-term (hours) and long-term (days) hypocotyl growth assays. The red stem-growth inhibition and blue promotion is a low-fluence rate response, and blue light delays or attenuates both the red light and far-red light responses. These de-etiolation responses include blue light reversal of red or far-red induced apical hook opening. This response also requires phot1. Cryptochromes (cry1 and cry2) are activated by higher blue light fluence-rates and override phot1's influence on hypocotyl growth promotion. Exogenous application of auxin transport inhibitor naphthylphthalamic acid abolished the blue light stem growth promotion in both hypocotyl growth and hook opening. Results from the genetic tests of this blue light effect in auxin transporter mutants, as well as phytochrome kinase substrate mutants indicated that aux1 may play a role in blue light reversal of red light response. Together, the phot1-mediated adjustment of phytochrome-regulated photomorphogenic events is most robust in dim blue light conditions and is likely modulated by auxin transport through its transporters.

STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) Interacts with Protein Kinase SnRK1.

PubMed

Nietzsche, Madlen; Guerra, Tiziana; Alseekh, Saleh; Wiermer, Marcel; Sonnewald, Sophia; Fernie, Alisdair R; Börnke, Frederik

2018-02-01

Sucrose nonfermenting related kinase1 (SnRK1) is a conserved energy sensor kinase that regulates cellular adaptation to energy deficit in plants. Activation of SnRK1 leads to the down-regulation of ATP-consuming biosynthetic processes and the stimulation of energy-generating catabolic reactions by transcriptional reprogramming and posttranslational modifications. Although considerable progress has been made during the last years in understanding the SnRK1 signaling pathway, many of its components remain unidentified. Here, we show that the catalytic α-subunits KIN10 and KIN11 of the Arabidopsis ( Arabidopsis thaliana ) SnRK1 complex interact with the STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) inside the plant cell nucleus. Overexpression of STKR1 in transgenic Arabidopsis plants led to reduced growth, a delay in flowering, and strongly attenuated senescence. Metabolite profiling revealed that the transgenic lines exhausted their carbohydrates during the dark period to a greater extent than the wild type and accumulated a range of amino acids. At the global transcriptome level, genes affected by STKR1 overexpression were broadly associated with systemic acquired resistance, and transgenic plants showed enhanced resistance toward a virulent strain of the biotrophic oomycete pathogen Hyaloperonospora arabidopsidis Noco2. We discuss a possible connection of STKR1 function, SnRK1 signaling, and plant immunity. © 2018 American Society of Plant Biologists. All Rights Reserved.

Glucocorticoid action in human corneal epithelial cells establishes roles for corticosteroids in wound healing and barrier function of the eye.

PubMed

Kadmiel, Mahita; Janoshazi, Agnes; Xu, Xiaojiang; Cidlowski, John A

2016-11-01

Glucocorticoids play diverse roles in almost all physiological systems of the body, including both anti-inflammatory and immunosuppressive roles. Synthetic glucocorticoids are one of the most widely prescribed drugs and are used in the treatment of conditions such as autoimmune diseases, allergies, ocular disorders and certain types of cancers. In the interest of investigating glucocorticoid actions in the cornea of the eye, we established that multiple cell types in mouse corneas express functional glucocorticoid receptor (GR) with corneal epithelial cells having robust expression. To define glucocorticoid actions in a cell type-specific manner, we employed immortalized human corneal epithelial (HCE) cell line to define the glucocorticoid transcriptome and elucidated its functions in corneal epithelial cells. Over 4000 genes were significantly regulated within 6 h of dexamethasone treatment, and genes associated with cell movement, cytoskeletal remodeling and permeability were highly regulated. Real-time in vitro wound healing assays revealed that glucocorticoids delay wound healing by attenuating cell migration. These functional alterations were associated with cytoskeletal remodeling at the wounded edge of a scratch-wounded monolayer. However, glucocorticoid treatment improved the organization of tight-junction proteins and enhanced the epithelial barrier function. Our results demonstrate that glucocorticoids profoundly alter corneal epithelial gene expression and many of these changes likely impact both wound healing and epithelial cell barrier function. Published by Elsevier Ltd.

STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) Interacts with Protein Kinase SnRK11[OPEN

PubMed Central

Nietzsche, Madlen; Guerra, Tiziana; Fernie, Alisdair R.

2018-01-01

Sucrose nonfermenting related kinase1 (SnRK1) is a conserved energy sensor kinase that regulates cellular adaptation to energy deficit in plants. Activation of SnRK1 leads to the down-regulation of ATP-consuming biosynthetic processes and the stimulation of energy-generating catabolic reactions by transcriptional reprogramming and posttranslational modifications. Although considerable progress has been made during the last years in understanding the SnRK1 signaling pathway, many of its components remain unidentified. Here, we show that the catalytic α-subunits KIN10 and KIN11 of the Arabidopsis (Arabidopsis thaliana) SnRK1 complex interact with the STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) inside the plant cell nucleus. Overexpression of STKR1 in transgenic Arabidopsis plants led to reduced growth, a delay in flowering, and strongly attenuated senescence. Metabolite profiling revealed that the transgenic lines exhausted their carbohydrates during the dark period to a greater extent than the wild type and accumulated a range of amino acids. At the global transcriptome level, genes affected by STKR1 overexpression were broadly associated with systemic acquired resistance, and transgenic plants showed enhanced resistance toward a virulent strain of the biotrophic oomycete pathogen Hyaloperonospora arabidopsidis Noco2. We discuss a possible connection of STKR1 function, SnRK1 signaling, and plant immunity. PMID:29192025

Dynamics of the mean signal amplitude of a crystal oscillator with a nonlinear resonator and low drives

NASA Astrophysics Data System (ADS)

Shmaliy, Yuriy S.; Rosales, Juan

2004-09-01

Dynamics of the mean amplitude of oscillations of a crystal oscillator with a linear feedback is outlined for low drives when the losses (friction) of a resonator become large and nonlinear after a long storage. The drive-level-dependence (DLD) of the crystal resonator losses is assumed to change inversely to the piezoelectric current. A stochastic differential equation for the mean amplitude is derived and solved in a sense of Ito. The development and attenuation processes are learned and it is shown that attenuation finishes at some non-zero level associated with the effect termed "sleeping sickness." The critical value of the friction is calculated and the conditions are discussed to avoid attenuation. Based upon, we show in that (1) if the value of the DLD coefficient of the resonator losses ranges below the critical point, the effect occurs primarilly in a delay of self-excitation; (2) contrary, noise drives the crystal oscillator.

NAC-NOR mutations in tomato Penjar accessions attenuate multiple metabolic processes and prolong the fruit shelf life.

PubMed

Kumar, Rakesh; Tamboli, Vajir; Sharma, Rameshwar; Sreelakshmi, Yellamaraju

2018-09-01

Several Penjar accessions of tomato grown in the Mediterranean exhibit prolonged shelf life and harbor alcobaca mutation. To uncover the metabolic basis underlying shelf life, we compared four Penjar accessions to Ailsa Craig. Three accessions bore alcobaca mutation, whereas the fourth was a novel NAC-NOR allele. Cuticle composition of Penjars varied widely during fruit ripening. All Penjars exhibited delayed ripening, prolonged on-vine and off-vine shelf life, low ethylene emission, and carotenoid levels. Metabolic profiling revealed shifts in Krebs cycle intermediates, amino acids, and γ-aminobutyric acid levels indicating the attenuation of respiration in Penjars during post-harvest storage. Penjar fruits also showed concerted downregulation of several cell-wall modifying genes and related metabolites. The high ABA and sucrose levels at the onset of senescence in Penjar fruits likely contribute to reduced water loss. Our analyses reveal that the attenuation of various metabolic processes by NAC-NOR mutation likely prolongs the shelf life of Penjar fruits. Copyright © 2018 Elsevier Ltd. All rights reserved.

Output regulation control for switched stochastic delay systems with dissipative property under error-dependent switching

NASA Astrophysics Data System (ADS)

Li, L. L.; Jin, C. L.; Ge, X.

2018-01-01

In this paper, the output regulation problem with dissipative property for a class of switched stochastic delay systems is investigated, based on an error-dependent switching law. Under the assumption that none subsystem is solvable for the problem, a sufficient condition is derived by structuring multiple Lyapunov-Krasovskii functionals with respect to multiple supply rates, via designing error feedback regulators. The condition is also established when dissipative property reduces to passive property. Finally, two numerical examples are given to demonstrate the feasibility and efficiency of the present method.

78 FR 43148 - Takes of Marine Mammals Incidental to Specified Activities; Taking Marine Mammals Incidental to a...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-19

.... Section 101(a)(5)(D) establishes a 45-day time limit for NMFS review of an application followed by a 30... concurrently and only one impact hammer rig was operated at a time. Due to delays in beginning construction..., Coleman, 2011, Caltrans, 2012). The variability in attenuation levels is due to variation in design, as...

The stationary phase sigma factor, RpoS, regulates the production of a carbapenem antibiotic, a bioactive prodigiosin and virulence in the enterobacterial pathogen Serratia sp. ATCC 39006.

PubMed

Wilf, Nabil M; Salmond, George P C

2012-03-01

Serratia sp. ATCC 39006 (S39006) is a Gram-negative bacterium that is virulent in plant (potato) and invertebrate animal (Caenorhabditis elegans) models. It produces two secondary metabolite antibiotics, a prodigiosin and a carbapenem, and the exoenzymes pectate lyase and cellulase. We showed previously that deletion of the RNA chaperone Hfq abolished antibiotic production and attenuated virulence in both animal and plant hosts. Hfq and dependent small RNAs (sRNAs) are known to regulate the post-transcriptional expression of rpoS, which encodes σ(S), the stationary phase sigma factor subunit of RNA polymerase. An S39006 hfq deletion mutant showed decreased transcript levels of rpoS. Therefore, in this study we investigated whether the phenotypes regulated by Hfq were mediated through its control of rpoS. Whereas loss of Hfq abolished prodigiosin and carbapenem production and attenuated virulence in both C. elegans and potato, characterization of an S39006 rpoS mutant showed unexpectedly elevated prodigiosin and carbapenem production. Furthermore, the rpoS mutant exhibited attenuated animal pathogenesis, but not plant pathogenesis. Additionally, a homologue of the Hfq-dependent sRNA, RprA, was identified and shown to regulate prodigiosin production in a manner consistent with its role in positively regulating translation of rpoS mRNA. Combined, these results demonstrate that Hfq regulation of secondary metabolism and plant pathogenesis is independent of RpoS and establishes RpoS and RprA as regulators of antibiotic production.

Backscatter and attenuation characterization of ventricular myocardium

NASA Astrophysics Data System (ADS)

Gibson, Allyson Ann

2009-12-01

This Dissertation presents quantitative ultrasonic measurements of the myocardium in fetal hearts and adult human hearts with the goal of studying the physics of sound waves incident upon anisotropic and inhomogeneous materials. Ultrasound has been used as a clinical tool to assess heart structure and function for several decades. The clinical usefulness of this noninvasive approach has grown with our understanding of the physical mechanisms underlying the interaction of ultrasonic waves with the myocardium. In this Dissertation, integrated backscatter and attenuation analyses were performed on midgestational fetal hearts to assess potential differences in the left and right ventricular myocardium. The hearts were interrogated using a 50 MHz transducer that enabled finer spatial resolution than could be achieved at more typical clinical frequencies. Ultrasonic data analyses demonstrated different patterns and relative levels of backscatter and attenuation from the myocardium of the left ventricle and the right ventricle. Ultrasonic data of adult human hearts were acquired with a clinical imaging system and quantified by their magnitude and time delay of cyclic variation of myocardial backscatter. The results were analyzing using Bayes Classification and ROC analysis to quantify potential advantages of using a combination of two features of cyclic variation of myocardial backscatter over using only one or the other feature to distinguish between groups of subjects. When the subjects were classified based on hemoglobin A1c, the homeostasis model assessment of insulin resistance, and the ratio of triglyceride to high-density lipoprotein-cholesterol, differences in the magnitude and normalized time delay of cyclic variation of myocardial backscatter were observed. The cyclic variation results also suggested a trend toward a larger area under the ROC curve when information from magnitude and time delay of cyclic variation is combined using Bayes classification than when each feature is analyzed individually. Ultrasound continues to be a powerful tool that enables noninvasive quantification of material properties. The studies in this Dissertation show that understanding the physical mechanisms behind the interaction of sound waves with myocardium can reveal new information about the structure, composition and overall state of the heart.

Effects of delay and noise in a negative feedback regulatory motif

NASA Astrophysics Data System (ADS)

Palassini, Matteo; Dies, Marta

2009-03-01

The small copy number of the molecules involved in gene regulation can induce nontrivial stochastic phenomena such as noise-induced oscillations. An often neglected aspect of regulation dynamics are the delays involved in transcription and translation. Delays introduce analytical and computational complications because the dynamics is non-Markovian. We study the interplay of noise and delays in a negative feedback model of the p53 core regulatory network. Recent experiments have found pronounced oscillations in the concentrations of proteins p53 and Mdm2 in individual cells subjected to DNA damage. Similar oscillations occur in the Hes-1 and NK-kB systems, and in circadian rhythms. Several mechanisms have been proposed to explain this oscillatory behaviour, such as deterministic limit cycles, with and without delay, or noise-induced excursions in excitable models. We consider a generic delayed Master Equation incorporating the activation of Mdm2 by p53 and the Mdm2-promoted degradation of p53. In the deterministic limit and for large delays, the model shows a Hopf bifurcation. Via exact stochastic simulations, we find strong noise-induced oscillations well outside the limit-cycle region. We propose that this may be a generic mechanism for oscillations in gene regulatory systems.

How long can fisheries management delay action in response to ecosystem and climate change?

PubMed

Brown, Christopher J; Fulton, Elizabeth A; Possingham, Hugh P; Richardson, Anthony J

2012-01-01

Sustainable management of fisheries is often compromised by management delaying implementation of regulations that reduce harvest, in order to maintain higher catches in the short-term. Decreases or increases in fish population growth rate driven by environmental change, including ecosystem and climate change, affect the harvest that can be taken sustainably. If not acted on rapidly, environmental change could result in unsustainable fishing or missed opportunity for higher catches. Using simulation models of harvested fish populations influenced by environmental change, we explore how long fisheries managers can afford to wait before changing harvest regulations in response to changes in population growth. If environmental change causes population declines, delays greater than five years increase the probability of population collapse. Species with fast and highly variable population growth rates are more susceptible to collapse under delays and should be a priority for revised management where delays occur. Generally, the long-term cost of delay, in terms of lost fishing opportunity, exceeds the short-term benefits of overfishing. Lowering harvest limits and monitoring for environmental change can alleviate the impact of delays; however, these measures may be more costly than reducing delays. We recommend that management systems that allow rapid responses to population growth changes be enacted for fisheries management to adapt to ecosystem and climate change.

Camptothecin Attenuates Cytochrome P450 3A4 Induction by Blocking the Activation of Human Pregnane X ReceptorS⃞

PubMed Central

Chen, Yakun; Tang, Yong; Robbins, Gregory T.

2010-01-01

Differential regulation of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in cancer therapy. Due to the extremely important role of cytochrome P450 3A4 (CYP3A4) in drug metabolism and the dominant regulation of human pregnane X receptor (hPXR) on CYP3A4, finding inhibitors for hPXR could provide a unique tool to control drug efficacies in cancer therapy. Camptothecin (CPT) was demonstrated as a novel and potent inhibitor (IC50 = 0.58 μM) of an hPXR-mediated transcriptional regulation on CYP3A4 in this study. In contrast, one of its analogs, irinotecan (CPT-11), was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 but had effects on neither the competition of ligand binding nor the formation of the hPXR and retinoid X receptor α heterodimer, nor the interaction between the regulatory complex and DNA-responsive elements. CPT treatment resulted in delayed metabolism of nifedipine in human hepatocytes treated with rifampicin, suggesting a potential prevention of drug-drug interactions between CYP3A4 inducers and CYP3A4-metabolized drugs. Because CPT is the leading compound of topoisomerase I inhibitors, which comprise a quickly developing class of anticancer agents, the findings indicate the potential of a new class of compounds to modify hPXR activity as agonists/inhibitors and are important in the development of CPT analogs. PMID:20504912

Air Traffic Control: Economics of Flight

NASA Technical Reports Server (NTRS)

Murphy, James R.

2004-01-01

Contents include the following: 1. Commercial flight is a partnership. Airlines. Pilots. Air traffic control. 2. Airline schedules and weather problems can cause delays at the airport. Delays are inevitable in de-regulated industry due to simple economics. 3.Delays can be mitigated. Build more runways/technology. Increase airspace supply. 4. Cost/benefit analysis determine justification.

78 FR 29652 - Institutional Eligibility Under the Higher Education Act of 1965, as Amended; Delay of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-21

... DEPARTMENT OF EDUCATION 34 CFR Part 600 RIN 1840-AD02 Institutional Eligibility Under the Higher Education Act of 1965, as Amended; Delay of Implementation Date AGENCY: Office of Postsecondary Education, Department of Education. ACTION: Final regulations; delay of implementation date. SUMMARY: This document...

Self-Regulation of Learning in the 21st Century: Understanding the Role of Academic Delay of Gratification.

ERIC Educational Resources Information Center

Bembenutty, Hefer

This study examined college students' motivational tendencies as predictors of academic outcomes and tested how students' goal orientations and academic delay of gratification mediated these associations. The study used data, previously analyzed in 1999, on academic delay of gratification, personal achievement goal orientations, self-efficacy,…

Spherical body protein 2 truncated copy 11 as a specific babesia bovis attenuation marker

USDA-ARS?s Scientific Manuscript database

Background: Spherical body protein 2 (SBP-2) truncated copies 7, 9 and 11, gene transcripts in Babesia bovis, were recently reported to be significantly up-regulated in two geographically distinct attenuated B. bovis strains. Results: Sequence comparisons between the sbp2t7, 9 and 11 genes among geo...

Post-transcriptional regulation tends to attenuate the mRNA noise and to increase the mRNA gain

NASA Astrophysics Data System (ADS)

Shi, Changhong; Wang, Shuqiang; Zhou, Tianshou; Jiang, Yiguo

2015-10-01

Post-transcriptional regulation is ubiquitous in prokaryotic and eukaryotic cells, but how it impacts gene expression remains to be fully explored. Here, we analyze a simple gene model in which we assume that mRNAs are produced in a constitutive manner but are regulated post-transcriptionally by a decapping enzyme that switches between the active state and the inactive state. We derive the analytical mRNA distribution governed by a chemical master equation, which can be well used to analyze the mechanism of how post-transcription regulation influences the mRNA expression level including the mRNA noise. We demonstrate that the mean mRNA level in the stochastic case is always higher than that in the deterministic case due to the stochastic effect of the enzyme, but the size of the increased part depends mainly on the switching rates between two enzyme states. More interesting is that we find that in contrast to transcriptional regulation, post-transcriptional regulation tends to attenuate noise in mRNA. Our results provide insight into the role of post-transcriptional regulation in controlling the transcriptional noise.

Lessons from the 'Humanitarian Golden Rice' project: regulation prevents development of public good genetically engineered crop products.

PubMed

Potrykus, Ingo

2010-11-30

Compared to a non-Genetically Engineered (GE) variety, the deployment of Golden Rice has suffered from a delay of at least ten years. The cause of this delay is exclusively GE-regulation. Considering the potential impact of Golden Rice on the reduction in vitamin A-malnutrition, this delay is responsible for an unjustifiable loss of millions of lives, mostly children and women. GE-regulation is also responsible for the fact that no public institution can deliver a public good GE-product and that thus we have a de facto monopoly in favour of a few potent industries. Considering the forgone benefits from prevented public good GE-products, GE-regulation is responsible for hundreds of millions of lives, all of them, of course, in developing countries. As there is no scientific justification for present GE-regulation, and as it has, so far, not prevented any harm, our society has the urgent responsibility to reconsider present regulation, which is based on an extreme interpretation of the precautionary principle, and change it to science-based regulation on the basis of traits instead of technology. GE-technology has an unprecedented safety record and is far more precise and predictable than any other 'traditional' and unregulated breeding technology. Not to change GE-regulation to a scientific basis is considered by the author 'a crime against humanity'. Copyright © 2010 Elsevier B.V. All rights reserved.

Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling.

PubMed

Wu, Chia-Lun; Buszard, Bree; Teng, Chun-Hung; Chen, Wei-Lin; Warr, Coral G; Tiganis, Tony; Meng, Tzu-Ching

2011-10-01

PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR.

CK1/Doubletime activity delays transcription activation in the circadian clock

PubMed Central

O'Neil, Jenna L; Merz, Gregory E; Dusad, Kritika; Crane, Brian R; Young, Michael W

2018-01-01

In the Drosophila circadian clock, Period (PER) and Timeless (TIM) proteins inhibit Clock-mediated transcription of per and tim genes until PER is degraded by Doubletime/CK1 (DBT)-mediated phosphorylation, establishing a negative feedback loop. Multiple regulatory delays within this feedback loop ensure ~24 hr periodicity. Of these delays, the mechanisms that regulate delayed PER degradation (and Clock reactivation) remain unclear. Here we show that phosphorylation of certain DBT target sites within a central region of PER affect PER inhibition of Clock and the stability of the PER/TIM complex. Our results indicate that phosphorylation of PER residue S589 stabilizes and activates PER inhibitory function in the presence of TIM, but promotes PER degradation in its absence. The role of DBT in regulating PER activity, stabilization and degradation ensures that these events are chronologically and biochemically linked, and contributes to the timing of an essential delay that influences the period of the circadian clock. PMID:29611807

Investigation of stability in a two-delay model of the ultradian oscillations in glucose-insulin regulation

NASA Astrophysics Data System (ADS)

Huard, B.; Easton, J. F.; Angelova, M.

2015-09-01

In this paper, a two-delay model for the ultradian oscillatory behaviour of the glucose-insulin regulation system is studied. Hill functions are introduced to model nonlinear physiological interactions within this system and ranges on parameters reproducing biological oscillations are determined on the basis of analytical and numerical considerations. Local and global stability are investigated and delay-dependent conditions are obtained through the construction of Lyapunov-Krasovskii functionals. The effect of Hill parameters on these conditions, as well as the boundary of the stability region in the delay domain, are established for the first time. Numerical simulations demonstrate that the model with Hill functions represents well the oscillatory behaviour of the system with the advantage of incorporating new meaningful parameters. The influence of the time delays on the period of oscillations and the sensitivity of the latter to model parameters, in particular glucose infusion, are investigated. The model can contribute to the better understanding and treatment of diabetes.

Implementation of High Time Delay Accuracy of Ultrasonic Phased Array Based on Interpolation CIC Filter

PubMed Central

Liu, Peilu; Li, Xinghua; Li, Haopeng; Su, Zhikun; Zhang, Hongxu

2017-01-01

In order to improve the accuracy of ultrasonic phased array focusing time delay, analyzing the original interpolation Cascade-Integrator-Comb (CIC) filter, an 8× interpolation CIC filter parallel algorithm was proposed, so that interpolation and multichannel decomposition can simultaneously process. Moreover, we summarized the general formula of arbitrary multiple interpolation CIC filter parallel algorithm and established an ultrasonic phased array focusing time delay system based on 8× interpolation CIC filter parallel algorithm. Improving the algorithmic structure, 12.5% of addition and 29.2% of multiplication was reduced, meanwhile the speed of computation is still very fast. Considering the existing problems of the CIC filter, we compensated the CIC filter; the compensated CIC filter’s pass band is flatter, the transition band becomes steep, and the stop band attenuation increases. Finally, we verified the feasibility of this algorithm on Field Programming Gate Array (FPGA). In the case of system clock is 125 MHz, after 8× interpolation filtering and decomposition, time delay accuracy of the defect echo becomes 1 ns. Simulation and experimental results both show that the algorithm we proposed has strong feasibility. Because of the fast calculation, small computational amount and high resolution, this algorithm is especially suitable for applications with high time delay accuracy and fast detection. PMID:29023385

Implementation of High Time Delay Accuracy of Ultrasonic Phased Array Based on Interpolation CIC Filter.

PubMed

Liu, Peilu; Li, Xinghua; Li, Haopeng; Su, Zhikun; Zhang, Hongxu

2017-10-12

In order to improve the accuracy of ultrasonic phased array focusing time delay, analyzing the original interpolation Cascade-Integrator-Comb (CIC) filter, an 8× interpolation CIC filter parallel algorithm was proposed, so that interpolation and multichannel decomposition can simultaneously process. Moreover, we summarized the general formula of arbitrary multiple interpolation CIC filter parallel algorithm and established an ultrasonic phased array focusing time delay system based on 8× interpolation CIC filter parallel algorithm. Improving the algorithmic structure, 12.5% of addition and 29.2% of multiplication was reduced, meanwhile the speed of computation is still very fast. Considering the existing problems of the CIC filter, we compensated the CIC filter; the compensated CIC filter's pass band is flatter, the transition band becomes steep, and the stop band attenuation increases. Finally, we verified the feasibility of this algorithm on Field Programming Gate Array (FPGA). In the case of system clock is 125 MHz, after 8× interpolation filtering and decomposition, time delay accuracy of the defect echo becomes 1 ns. Simulation and experimental results both show that the algorithm we proposed has strong feasibility. Because of the fast calculation, small computational amount and high resolution, this algorithm is especially suitable for applications with high time delay accuracy and fast detection.

Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin

PubMed Central

Zamolodchikov, Daria

2012-01-01

Alzheimer disease is characterized by the presence of increased levels of the β-amyloid peptide (Aβ) in the brain parenchyma and cerebral blood vessels. This accumulated Aβ can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that Aβ42 specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, Aβ42-induced structural changes cannot be the sole mechanism of delayed lysis because Aβ overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that Aβ interferes with the binding of plasminogen to fibrin, which could impair plasmin generation and fibrin degradation. Indeed, plasmin generation by tissue plasminogen activator (tPA), but not streptokinase, is slowed in fibrin clots containing Aβ42, and clot lysis by plasmin, but not trypsin, is delayed. Notably, plasmin and tPA activities, as well as tPA-dependent generation of plasmin in solution, are not decreased in the presence of Aβ42. Our results indicate the existence of 2 mechanisms of Aβ42 involvement in delayed fibrinolysis: (1) through the induction of a tighter fibrin network composed of thinner fibers, and (2) through inhibition of plasmin(ogen)–fibrin binding. PMID:22238323

Cognitive person variables in the delay of gratification of older children at risk.

PubMed

Rodriguez, M L; Mischel, W; Shoda, Y

1989-08-01

The components of self-regulation were analyzed, extending the self-imposed delay of gratification paradigm to older children with social adjustment problems. Delay behavior was related to a network of conceptually relevant cognitive person variables, consisting of attention deployment strategies during delay, knowledge of delay rules, and intelligence. A positive relationship was demonstrated between concurrent indexes of intelligence, attention deployment, and actual delay time. Moreover, attention deployment, measured as an individual differences variable during the delay process, had a direct, positive effect on delay behavior. Specifically, as the duration of delay and the frustration of the situation increased, children who spent a higher proportion of the time distracting themselves from the tempting elements of the delay situation were able to delay longer. The effect of attention deployment on delay behavior was significant even when age, intelligence, and delay rule knowledge were controlled. Likewise, delay rule knowledge significantly predicted delay time, even when age, attention deployment, and intelligence were controlled.

Variation in vocal-motor development in infant siblings of children with autism.

PubMed

Iverson, Jana M; Wozniak, Robert H

2007-01-01

In this study we examined early motor, vocal, and communicative development in a group of younger siblings of children diagnosed with autism (Infant Siblings). Infant Siblings and no-risk comparison later-born infants were videotaped at home with a primary caregiver each month from 5 to 14 months, with follow-up at 18 months. As a group, Infant Siblings were delayed in the onset of early developmental milestones and spent significantly less time in a greater number of postures, suggestive of relative postural instability. In addition, they demonstrated attenuated patterns of change in rhythmic arm activity around the time of reduplicated babble onset; and they were highly likely to exhibit delayed language development at 18 months.

Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology.

PubMed

Meyer, Michael Andrew

2013-01-01

Delayed post-hypoxic leukoencephalopathy is a rare clinical phenomenon usually observed in a small number of carbon monoxide poisoning survivors. A similar phenomenon is reported here in a patient who successfully recovered from a large overdose of diazepam and methadone, but then abruptly declined 3 weeks after the initial event. Magnetic resnance revealed confluent white matter hyperintensity on fluid-attenuated inversion recovery and T2 weighted sequences, and spectroscopy revealed elevated peaks in choline, creatinine, and lactate. Analysis and review of the literature suggests this phenomenon occurs on average about 19 days after the initial event. Although the pathophysiology remains obscure, it is noted here that the mean lucid interval coincides approximately with the replacement half-life for myelin related lipids and proteins.

Use of EDTA in modified kinetic testing for contaminated drainage prediction from waste rocks: case of the Lac Tio mine.

PubMed

Plante, Benoît; Benzaazoua, Mostafa; Bussière, Bruno; Kandji, El-Hadji-Babacar; Chopard, Aurélie; Bouzahzah, Hassan

2015-05-01

The tools developed for acid mine drainage (AMD) prediction were proven unsuccessful to predict the geochemical behavior of mine waste rocks having a significant chemical sorption capacity, which delays the onset of contaminated neutral drainage (CND). The present work was performed in order to test a new approach of water quality prediction, by using a chelating agent solution (0.03 M EDTA, or ethylenediaminetetraacetic acid) in kinetic testing used for the prediction of the geochemical behavior of geologic material. The hypothesis underlying the proposed approach is that the EDTA solution should chelate the metals as soon as they are released by sulfide oxidation, inhibiting their sorption or secondary precipitation, and therefore reproduce a worst-case scenario where very low metal attenuation mechanisms are present in the drainage waters. Fresh and weathered waste rocks from the Lac Tio mine (Rio tinto, Iron and Titanium), which are known to generate Ni-CND at the field scale, were submitted to small-scale humidity cells in control tests (using deionized water) and using an EDTA solution. Results show that EDTA effectively prevents the metals to be sorbed or to precipitate as secondary minerals, therefore enabling to bypass the delay associated with metal sorption in the prediction of water quality from these materials. This work shows that the use of a chelating agent solution is a promising novel approach of water quality prediction and provides general guidelines to be used in further studies, which will help both practitioners and regulators to plan more efficient management and disposal strategies of mine wastes.

Inhibition of non-NMDA ionotropic glutamate receptors delays the retinal degeneration in rd10 mouse.

PubMed

Xiang, Zongqin; Bao, Yiqin; Zhang, Jia; Liu, Chao; Xu, Di; Liu, Feng; Chen, Hui; He, Liumin; Ramakrishna, Seeram; Zhang, Zaijun; Vardi, Noga; Xu, Ying

2018-06-22

Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by neurodegeneration of photoreceptors. Retinal ganglion cells (RGCs) in animal models of RP exhibit an abnormally high spontaneous activity that interferes with signal processing. Blocking AMPA/Kainate receptors by bath application of CNQX decreases the spontaneous firing, suggesting that inhibiting these receptors in vivo may help maintain the function of inner retinal neurons in rd10 mice experiencing photoreceptor degeneration. To test this, rd10 mice were i.p. injected with CNQX or GYKI 52466 (an AMPA receptor antagonist) for 1-2 weeks, and examined for their retinal morphology (by immunocytochemistry), function (by MEA recordings) and visual behaviors (using a black/white box). Our data show that iGluRs were up-regulated in the inner plexiform layer (IPL) of rd10 retinas. Application of CNQX at low doses both in vitro and in vivo, attenuated the abnormal spontaneous spiking in RGCs, and increased the light-evoked response of ON RGCs, whereas GYKI 52466 had little effect. CNQX application also improved the behavioral performance. Interestingly, in vivo administration of CNQX delayed photoreceptor degeneration, evidenced by the increased cell number and restored structure. CNQX also improved the structure of bipolar cells. Together, we demonstrated that during photoreceptor degeneration, blockade of the non-NMDA iGluRs decelerates the progression of RGCs dysfunction, possibly by dual mechanisms including slowing photoreceptor degeneration and modulating signal processing within the IPL. Accordingly, this strategy may effectively extend the time window for treating RP. Copyright © 2018. Published by Elsevier Ltd.

Detection of contraband using microwave radiation

DOEpatents

Toth, Richard P.; Loubriel, Guillermo M.; Bacon, Larry D.; Watson, Robert D.

2002-01-01

The present invention relates to a method and system for using microwave radiation to detect contraband hidden inside of a non-metallic container, such as a pneumatic vehicle tire. The method relies on the attenuation, retardation, time delay, or phase shift of microwave radiation as it passes through the container plus the contraband. The method is non-invasive, non-destructive, low power, and does not require physical contact with the container.

Wound Trauma Mediated Inflammatory Signaling Attenuates a Tissue Regenerative Response in MRL/MpJ Mice

DTIC Science & Technology

2010-01-01

multi-system organ failure, and remote organ injury at sites such as the lung, liver , small intestines, and brain, representing major causes of...inflammatory components. The development of systemic inflammation following severe thermal injury has been implicated in immune dysfunction, delayed wound...healing, multi-system organ failure and increased mortality. Methods: In this study, we examined the impact of thermal injury -induced systemic

Attenuation of ischemia/reperfusion-induced inhibition of the rapid component of delayed rectifier potassium current by Isosteviol through scavenging reactive oxygen species.

PubMed

Yin, Chunxia; Chen, Yaoxu; Wu, Huanlin; Xu, Danping; Tan, Wen

2017-12-01

Isosteviol has been demonstrated to play a protective role during ischemia reperfusion (I/R) myocardial infarction. However, the underlying electrophysiological mechanisms of isosteviol are still unknown. Our previous study showed that the rapid component of the delayed rectifier potassium channel (I Kr ) plays an important role in the prolongation of I/R-induced QT interval-related arrhythmia. This study aimed to investigate whether isosteviol could attenuate I/R-induced prolongation of the action potential duration (APD) along with inhibition of I Kr , and we aimed to clarify the electrophysiological mechanism of isosteviol to determine its cardioprotective effects in guinea pigs. We observed that the APD 90 were 298.5±41.6ms in control, 528.6±56.7ms during I/R, and reduced to 327.8±40.5ms after 10μmol/L of isosteviol treatment. The I Kr currents were 1.44±0.06 pA·pF -1 in the control group, 0.50±0.07pA·pF -1 during I/R, and recovered to 1.20±0.12pA·pF -1 after 10μmol/L of isoteviol treatment. Moreover, isosteviol reduced the over-production of reactive oxygen species (ROS) during I/R. Importantly, isosteviol does not affect the I Kr and human ether-a-go-go-related gene currents of normal cardiomyocytes. It attenuated the I/R-induced inhibition of I Kr due to reduced over-production of ROS. Furthermore, isosteviol is safe and has no cardiotoxicity, and it might be beneficial for coronary reperfusion therapy. Copyright © 2017. Published by Elsevier B.V.

miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice.

PubMed

Zeng, Ping; Han, Wanhong; Li, Changyin; Li, Hu; Zhu, Dahai; Zhang, Yong; Liu, Xiaohong

2016-09-01

Skeletal muscle mass and homeostasis during postnatal muscle development and regeneration largely depend on adult muscle stem cells (satellite cells). We recently showed that global overexpression of miR-378 significantly reduced skeletal muscle mass in mice. In the current study, we used miR-378 transgenic (Tg) mice to assess the in vivo functional effects of miR-378 on skeletal muscle growth and regeneration. Cross-sectional analysis of skeletal muscle tissues showed that the number and size of myofibers were significantly lower in miR-378 Tg mice than in wild-type mice. Attenuated cardiotoxin-induced muscle regeneration in miR-378 Tg mice was found to be associated with delayed satellite cell activation and differentiation. Mechanistically, miR-378 was found to directly target Igf1r in muscle cells both in vitro and in vivo These miR-378 Tg mice may provide a model for investigating the physiological and pathological roles of skeletal muscle in muscle-associated diseases in humans, particularly in sarcopenia. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Antinociceptive and Anti-Inflammatory Activities of Leaf Methanol Extract of Cotyledon orbiculata L. (Crassulaceae).

PubMed

Amabeoku, George J; Kabatende, Joseph

2012-01-01

Leaf methanol extract of C. orbiculata L. was investigated for antinociceptive and anti-inflammatory activities using acetic acid writhing and hot-plate tests and carrageenan-induced oedema test in mice and rats, respectively. C. orbiculata (100-400 mg/kg, i.p.) significantly inhibited acetic acid-induced writhing and significantly delayed the reaction time of mice to the hot-plate-induced thermal stimulation. Paracetamol (300 mg/kg, i.p.) significantly inhibited the acetic acid-induced writhing in mice. Morphine (10 mg/kg, i.p.) significantly delayed the reaction time of mice to the thermal stimulation produced with hot plate. Leaf methanol extract of C. orbiculata (50-400 mg/kg, i.p.) significantly attenuated the carrageenan-induced rat paw oedema. Indomethacin (10 mg/kg, p.o.) also significantly attenuated the carrageenan-induced rat paw oedema. The LD(50) value obtained for the plant species was greater than 4000 mg/kg (p.o.). The data obtained indicate that C. orbiculata has antinociceptive and anti-inflammatory activities, justifying the folklore use of the plant species by traditional medicine practitioners in the treatment of painful and inflammatory conditions. The relatively high LD(50) obtained shows that C. orbiculata may be safe in or nontoxic to mice.

JACALIN-LECTIN LIKE1 Regulates the Nuclear Accumulation of GLYCINE-RICH RNA-BINDING PROTEIN7, Influencing the RNA Processing of FLOWERING LOCUS C Antisense Transcripts and Flowering Time in Arabidopsis1[OPEN

PubMed Central

Xiao, Jun; Li, Chunhua; Xu, Shujuan; Xing, Lijing; Xu, Yunyuan; Chong, Kang

2015-01-01

Lectins selectively recognize sugars or glycans for defense in living cells, but less is known about their roles in the development process and the functional network with other factors. Here, we show that Arabidopsis (Arabidopsis thaliana) JACALIN-LECTIN LIKE1 (AtJAC1) functions in flowering time control. Loss of function of AtJAC1 leads to precocious flowering, whereas overexpression of AtJAC1 causes delayed flowering. AtJAC1 influences flowering through regulation of the key flowering repressor gene FLOWERING LOCUS C (FLC). Genetic analysis revealed that AtJAC1’s function is mostly dependent on GLYCINE-RICH RNA-BINDING PROTEIN7 (GRP7), an upstream regulator of FLC. Biochemical and cell biological data indicated that AtJAC1 interacted physically with GRP7 specifically in the cytoplasm. AtJAC1 influences the nucleocytoplasmic distribution of GRP7, with predominant nuclear localization of GRP7 when AtJAC1 function is lost but retention of GRP7 in the cytoplasm when AtJAC1 is overexpressed. A temporal inducible assay suggested that AtJAC1’s regulation of flowering could be compromised by the nuclear accumulation of GRP7. In addition, GRP7 binds to the antisense precursor messenger RNA of FLC through a conserved RNA motif. Loss of GRP7 function leads to the elevation of total FLC antisense transcripts and reduced proximal-distal polyadenylation ratio, as well as histone methylation changes in the FLC gene body region and increased total functional sense FLC transcript. Attenuating the direct binding of GRP7 with competing artificial RNAs leads to changes of FLC antisense precursor messenger RNA processing and flowering transition. Taken together, our study indicates that AtJAC1 coordinates with GRP7 in shaping plant development through the regulation of RNA processing in Arabidopsis. PMID:26392261

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein-Coupled Estrogen Receptor.

PubMed

Gros, Robert; Hussain, Yasin; Chorazyczewski, Jozef; Pickering, J Geoffrey; Ding, Qingming; Feldman, Ross D

2016-11-01

Estrogens are important regulators of cardiovascular function. Some of estrogen's cardiovascular effects are mediated by a G-protein-coupled receptor mechanism, namely, G-protein-coupled estrogen receptor (GPER). Estradiol-mediated regulation of vascular cell programmed cell death reflects the balance of the opposing actions of GPER versus estrogen receptor α (ERα). However, the significance of these opposing actions on the regulation of vascular smooth muscle cell proliferation or migration in vitro is unclear, and the significance in vivo is unknown. To determine the effects of GPER activation in vitro, we studied rat aortic vascular smooth muscle cells maintained in primary culture. GPER was reintroduced using adenoviral gene transfer. Both estradiol and G1, a GPER agonist, inhibited both proliferation and cell migration effects that were blocked by the GPER antagonist, G15. To determine the importance of the GPER-ERα balance in regulating vascular remodeling in a rat model of carotid ligation, we studied the effects of upregulation of GPER expression versus downregulation of ERα. Reintroduction of GPER significantly attenuated the extent of medial hypertrophy and attenuated the extent of CD45 labeling. Downregulation of ERα expression comparably attenuated the extent of medial hypertrophy and inflammation after carotid ligation. These studies demonstrate that the balance between GPER and ERα regulates vascular remodeling. Receptor-specific modulation of estrogen's effects may be an important new approach in modifying vascular remodeling in both acute settings like vascular injury and perhaps in longer term regulation like in hypertension. © 2016 American Heart Association, Inc.

Positive parenting mitigates the effects of poor self-regulation on body mass index trajectories from ages 4-15 years.

PubMed

Connell, Lauren E; Francis, Lori A

2014-08-01

This study sought to determine whether parenting style moderates the effects of delay of gratification on body mass index (BMI) trajectories from ages 4-15 years. Longitudinal data were analyzed for 778 children drawn from the Study of Early Child Care and Youth Development. Parenting style (i.e., authoritative, authoritarian, permissive, and neglectful) was created from measures of mothers' sensitivity and expectations for self-control when children were age 4 years. Self-regulation was also measured at 4 years using a well-known delay of gratification protocol. BMI was calculated from measured height and weight at each time point. Mixed modeling was used to test the interaction of parenting styles and ability to delay gratification on BMI trajectories from 4-15 years. There was a significant interaction effect of parenting and ability to delay on BMI growth from 4-15 years for boys. Boys who had authoritarian mothers and failed to delay gratification had a significantly steeper rate of growth in BMI from childhood through adolescence than children in any other parenting by delay group. Authoritative and permissive parenting styles were protective against more rapid BMI gains for boys who could not delay gratification. Ability to delay gratification was protective against BMI gains for boys who had parents with authoritarian or neglectful parenting styles.

Positive parenting mitigates the effects of poor self-regulation on BMI trajectories from age 4 to 15 years

PubMed Central

Connell, Lauren E.; Francis, Lori A.

2014-01-01

Objective This study sought to determine whether parenting style moderated the effects of delay of gratification on BMI trajectories from age 4 to 15 years. Methods Longitudinal data were analyzed on 778 children drawn from the Study of Early Child Care and Youth Development. Parenting style (authoritative, authoritarian, permissive, neglectful) was created from measures of mothers’ sensitivity and expectations for self-control when children were age 4 years. Self-regulation was also measured at 4 years using a well-known delay of gratification protocol. BMI was calculated from measured height and weight at each time point. Mixed modeling was used to test the interaction of parenting styles and ability to delay gratification on BMI trajectories from 4 to 15 years. Results There was a significant interaction effect of parenting and ability to delay on BMI growth from 4 to 15 years for boys. Boys who had authoritarian mothers and failed to delay gratification had a significantly steeper rate of growth in BMI from childhood through adolescence than children in any other parenting x delay group. Conclusions Authoritative and permissive parenting styles were protective against more rapid BMI gains for boys who could not delay gratification. Ability to delay gratification was protective against BMI gains for boys who had parents with authoritarian or neglectful parenting styles. PMID:23977874

--RNA Polymerase II Transcription Attenuation at the Yeast DNA Repair Gene, DEF1, Involves Sen1-Dependent and Polyadenylation Site-Dependent Termination.

PubMed

Whalen, Courtney; Tuohy, Christine; Tallo, Thomas; Kaufman, James W; Moore, Claire; Kuehner, Jason N

2018-04-23

Termination of RNA Polymerase II (Pol II) activity serves a vital cellular function by separating ubiquitous transcription units and influencing RNA fate and function. In the yeast Saccharomyces cerevisiae , Pol II termination is carried out by cleavage and polyadenylation factor (CPF-CF) and Nrd1-Nab3-Sen1 (NNS) complexes, which operate primarily at mRNA and non-coding RNA genes, respectively. Premature Pol II termination (attenuation) contributes to gene regulation, but there is limited knowledge of its prevalence and biological significance. In particular, it is unclear how much crosstalk occurs between CPF-CF and NNS complexes and how Pol II attenuation is modulated during stress adaptation. In this study, we have identified an attenuator in the DEF1 DNA repair gene, which includes a portion of the 5'-untranslated region (UTR) and upstream open reading frame (ORF). Using a plasmid-based reporter gene system, we conducted a genetic screen of 14 termination mutants and their ability to confer Pol II read-through defects. The DEF1 attenuator behaved as a hybrid terminator, relying heavily on CPF-CF and Sen1 but without Nrd1 and Nab3 involvement. Our genetic selection identified 22 cis -acting point mutations that clustered into four regions, including a polyadenylation site efficiency element that genetically interacts with its cognate binding-protein Hrp1. Outside of the reporter gene context, a DEF1 attenuator mutant increased mRNA and protein expression, exacerbating the toxicity of a constitutively active Def1 protein. Overall, our data support a biologically significant role for transcription attenuation in regulating DEF1 expression, which can be modulated during the DNA damage response. Copyright © 2018, G3: Genes, Genomes, Genetics.

Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation

PubMed Central

2011-01-01

Background Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. Methods Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L6 transverse process; (2) ligated (Group L), which underwent left L5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 μl). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). Results Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p < 0.01) and thermal hyperalgesia (p < 0.001), attenuated Nav1.3 up-regulation (p = 0.003), and mitigated spinal microglial activation (p = 0.026) by inhibiting phosphorylation (activation) of p38 MAP kinase (p = 0.034). p38 activation was also suppressed on POD7 (p = 0.002). Conclusions Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain. PMID:21676267

A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in ADHD boys and siblings

PubMed Central

Sonuga-Barke, Edmund J. S.; Kumsta, Robert; Schlotz, Wolff; Lasky-Su, Jessica; Marco, Rafaela; Miranda, Ana; Mulas, Fernando; Oades, Robert D.; Banaschewski, Tobias; Mueller, Ueli; Andreou, Penny; Christiansen, Hanna; Gabriels, Isabel; Uebel, Henrik; Kuntsi, Jonna; Franke, Barbara; Buitelaar, Jan; Ebstein, Richard; Gill, Michael; Anney, Richard; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Asherson, Philip; Faraone, Stephen V.

2011-01-01

Background Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in Attention Deficit/Hyperactivity Disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion with serotonin regulating genes. Methods IDIR and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) using a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter 5-HTTLPR polymorphism and a DAT1 (SLC6A3) 40-base pair VNTR located in the 3`-untranslated region of the gene. Results There was no effect of DAT1 on IDIR. As predicted 5-HTTLPR s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G SNP and were independent of age, IQ and ODD symptoms. Conclusions The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented. PMID:21497794

TRAP binding to the Bacillus subtilis trp leader region RNA causes efficient transcription termination at a weak intrinsic terminator

PubMed Central

Potter, Kristine D.; Merlino, Natalie M.; Jacobs, Timothy; Gollnick, Paul

2011-01-01

The Bacillus subtilis trpEDCFBA operon is regulated by a transcription attenuation mechanism controlled by the trp RNA-binding attenuation protein (TRAP). TRAP binds to 11 (G/U)AG repeats in the trp leader transcript and prevents formation of an antiterminator, which allows formation of an intrinsic terminator (attenuator). Previously, formation of the attenuator RNA structure was believed to be solely responsible for signaling RNA polymerase (RNAP) to halt transcription. However, base substitutions that prevent formation of the antiterminator, and thus allow the attenuator structure to form constitutively, do not result in efficient transcription termination. The observation that the attenuator requires the presence of TRAP bound to the nascent RNA to cause efficient transcription termination suggests TRAP has an additional role in causing termination at the attenuator. We show that the trp attenuator is a weak intrinsic terminator due to low GC content of the hairpin stem and interruptions in the U-stretch following the hairpin. We also provide evidence that termination at the trp attenuator requires forward translocation of RNA polymerase and that TRAP binding to the nascent transcript can induce this activity. PMID:21097886

TRAP binding to the Bacillus subtilis trp leader region RNA causes efficient transcription termination at a weak intrinsic terminator.

PubMed

Potter, Kristine D; Merlino, Natalie M; Jacobs, Timothy; Gollnick, Paul

2011-03-01

The Bacillus subtilis trpEDCFBA operon is regulated by a transcription attenuation mechanism controlled by the trp RNA-binding attenuation protein (TRAP). TRAP binds to 11 (G/U)AG repeats in the trp leader transcript and prevents formation of an antiterminator, which allows formation of an intrinsic terminator (attenuator). Previously, formation of the attenuator RNA structure was believed to be solely responsible for signaling RNA polymerase (RNAP) to halt transcription. However, base substitutions that prevent formation of the antiterminator, and thus allow the attenuator structure to form constitutively, do not result in efficient transcription termination. The observation that the attenuator requires the presence of TRAP bound to the nascent RNA to cause efficient transcription termination suggests TRAP has an additional role in causing termination at the attenuator. We show that the trp attenuator is a weak intrinsic terminator due to low GC content of the hairpin stem and interruptions in the U-stretch following the hairpin. We also provide evidence that termination at the trp attenuator requires forward translocation of RNA polymerase and that TRAP binding to the nascent transcript can induce this activity.

Huperzine A attenuates cognitive deficits and hippocampal neuronal damage after transient global ischemia in gerbils.

PubMed

Zhou, J; Zhang, H Y; Tang, X C

2001-11-09

The protective effects of huperzine A on transient global ischemia in gerbils were investigated. Five min of global ischemia in gerbils results in working memory impairments shown by increased escape latency in a water maze and reduced time spent in the target quadrant. These signs of dysfunction are accompanied by delayed degeneration of pyramidal hippocampal CA1 neurons and by decrease in acetylcholinesterase activity in the hippocampus. Subchronic oral administration of huperzine A (0.1 mg/kg, twice per day for 14 days) after ischemia significantly reduced the memory impairment, reduced neuronal degeneration in the CA1 region, and partially restored hippocampal choline acetyltransferase activity. The ability of huperzine A to attenuate memory deficits and neuronal damage after ischemia might be beneficial in cerebrovascular type dementia.

Adaptive control system for line-commutated inverters

NASA Technical Reports Server (NTRS)

Dolland, C. R.; Bailey, D. A. (Inventor)

1983-01-01

A control system for a permanent magnet motor driven by a multiphase line commutated inverter is provided with integration for integrating the back EMF of each phase of the motor. This is used in generating system control signals for an inverter gate logic using a sync and firing angle (alpha) control generator connected to the outputs of the integrators. A precision full wave rectifier provides a speed control feedback signal to a phase delay rectifier via a gain and loop compensation circuit and to the integrators for adaptive control of the attenuation of low frequencies by the integrators as a function of motor speed. As the motor speed increases, the attenuation of low frequency components by the integrators is increased to offset the gain of the integrators to spurious low frequencies.

Delay of Gratification: A Comparison Study of Children with Down Syndrome, Moderate Intellectual Disability and Typical Development

ERIC Educational Resources Information Center

Cuskelly, M.; Gilmore, L.; Glenn, S.; Jobling, A.

2016-01-01

Background: Self-regulation has been found to be an important contributor to a range of outcomes, with delay of gratification (a self-regulatory skill) predicting better academic, social and personal functioning. There is some evidence that individuals with Down syndrome have difficulty with delay of gratification. We investigated the question of…

The Role of Strategic Attention Deployment in Development of Self-Regulation: Predicting Preschoolers' Delay of Gratification from Mother-Toddler Interactions.

ERIC Educational Resources Information Center

Sethi, Anita; Mischel, Walter; Aber, J. Lawrence; Shoda, Yuichi; Rodriguez, Monica Larrea

2000-01-01

Examined role of toddlers' attention deployment strategies in predicting 5-year-olds' delay-of-gratification strategies. Found that toddlers' use of effective attention deployment strategies to cope with separation from mother and with maternal behavior (controlling or noncontrolling) predicted effective delay-of-gratification strategies at age 5,…

Associations of advanced glycation end-products with cognitive functions in individuals with and without type 2 diabetes: the maastricht study.

PubMed

Spauwen, P J J; van Eupen, M G A; Köhler, S; Stehouwer, C D A; Verhey, F R J; van der Kallen, C J H; Sep, S J S; Koster, A; Schaper, N C; Dagnelie, P C; Schalkwijk, C G; Schram, M T; van Boxtel, M P J

2015-03-01

Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus. The objective of the study was to examine associations between AGEs and cognitive functions. This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus. We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition. After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = -0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = -0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = -0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes. We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression.

Circadian phase resetting in older people by ocular bright light exposure.

PubMed

Klerman, E B; Duffy, J F; Dijk, D J; Czeisler, C A

2001-01-01

Aging is associated with frequent complaints about earlier bedtimes and waketimes. These changes in sleep timing are associated with an earlier timing of multiple endogenous rhythms, including core body temperature (CBT) and plasma melatonin, driven by the circadian pacemaker. One possible cause of the age-related shift of endogenous circadian rhythms and the timing of sleep relative to clock time is a change in the phase-shifting capacity of the circadian pacemaker in response to the environmental light-dark cycle, the principal synchronizer of the human circadian system. We studied the response of the circadian system of 24 older men and women and 23 young men to scheduled exposure to ocular bright light stimuli. Light stimuli were 5 hours in duration, administered for 3 consecutive days at an illuminance of approximately 10,000 lux. Light stimuli were scheduled 1.5 or 3.5 hours after the CBT nadir to induce shifts of endogenous circadian pacemaker to an earlier hour (phase advances) or were scheduled 1.5 hours before the CBT nadir to induce shifts to a later hour (phase delays). The rhythms of CBT and plasma melatonin assessed under constant conditions served as markers of circadian phase. Bright light stimuli elicited robust responses of the circadian timing system in older people; both phase advances and phase delays were induced. The magnitude of the phase delays did not differ significantly between older and younger individuals, but the phase advances were significantly attenuated in older people. The attenuated response to light stimuli that induce phase advances does not explain the advanced phase of the circadian pacemaker in older people. The maintained responsiveness of the circadian pacemaker to light implies that scheduled bright light exposure can be used to treat circadian phase disturbances in older people.

Seismic random noise removal by delay-compensation time-frequency peak filtering

NASA Astrophysics Data System (ADS)

Yu, Pengjun; Li, Yue; Lin, Hongbo; Wu, Ning

2017-06-01

Over the past decade, there has been an increasing awareness of time-frequency peak filtering (TFPF) due to its outstanding performance in suppressing non-stationary and strong seismic random noise. The traditional approach based on time-windowing achieves local linearity and meets the unbiased estimation. However, the traditional TFPF (including the improved algorithms with alterable window lengths) could hardly relieve the contradiction between removing noise and recovering the seismic signal, and this situation is more obvious in wave crests and troughs, even for alterable window lengths (WL). To improve the efficiency of the algorithm, the following TFPF in the time-space domain is applied, such as in the Radon domain and radial trace domain. The time-space transforms obtain a reduced-frequency input to reduce the TFPF error and stretch the desired signal along a certain direction, therefore the time-space development brings an improvement by both enhancing reflection events and attenuating noise. It still proves limited in application because the direction should be matched as a straight line or quadratic curve. As a result, waveform distortion and false seismic events may appear when processing the complex stratum record. The main emphasis in this article is placed on the time-space TFPF applicable expansion. The reconstructed signal in delay-compensation TFPF, which is generated according to the similarity among the reflection events, overcomes the limitation of the direction curve fitting. Moreover, the reconstructed signal just meets the TFPF linearity unbiased estimation and integrates signal reservation with noise attenuation. Experiments on both the synthetic model and field data indicate that delay-compensation TFPF has a better performance over the conventional filtering algorithms.

Effect of 4-Week Ingestion of Tomato-Based Carotenoids on Exercise-Induced Inflammation, Muscle Damage, and Oxidative Stress in Endurance Runners.

PubMed

Nieman, David C; Capps, Courtney L; Capps, Christopher R; Shue, Zack L; McBride, Jennifer E

2018-05-03

This double-blind, randomized, placebo-controlled crossover trial determined if ingestion of a supplement containing a tomato complex with lycopene, phytoene, and phytofluene (T-LPP) and other compounds for 4 weeks would attenuate inflammation, muscle damage, and oxidative stress postexercise and during recovery from a 2-hr running bout that included 30 min of -10% downhill running. Study participants ingested the T-LPP supplement or placebo with the evening meal for 4 weeks prior to running 2 hr at high intensity. Blood samples and delayed onset muscle soreness ratings were taken pre- and post-4-week supplementation, and immediately following the 2-hr run, and then 1-hr, 24-hr, and 48-hr postrun. After a 2-week washout period, participants crossed over to the opposite treatment and repeated all procedures. Plasma lycopene, phytoene, and phytofluene increased significantly in T-LPP compared with placebo (p < .001 for each). Significant time effects were shown for serum creatine kinase, delayed onset muscle soreness, C-reactive protein, myoglobin, 9- and 13-hydroxyoctadecadienoic acids, ferric reducing ability of plasma, and six plasma cytokines (p < .001 for each). The pattern of increase for serum myoglobin differed between T-LPP and placebo (interaction effect, p = .016, with lower levels in T-LPP), but not for creatine kinase, delayed onset muscle soreness, C-reactive protein, the six cytokines, 9- and 13-hydroxyoctadecadienoic acids, and ferric reducing ability of plasma. No significant time or interaction effects were measured for plasma-oxidized low-density lipoprotein or serum 8-hydroxy-2'-deoxyguanosine. In summary, supplementation with T-LPP over a 4-week period increased plasma carotenoid levels 73% and attenuated postexercise increases in the muscle damage biomarker myoglobin, but not inflammation and oxidative stress.

Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats.

PubMed

He, Meixia; Xing, Shihui; Yang, Bo; Zhao, Liqun; Hua, Haiying; Liang, Zhijian; Zhou, Wenliang; Zeng, Jinsheng; Pei, Zhong

2007-11-21

Oxidative DNA damage has been proposed to be a major contributor to focal cerebral ischemic injury. However, little is known about the role of oxidative DNA damage in remote damage secondary to the primary infarction. In the present study, we investigated oxidative damage within the ventroposterior nucleus (VPN) after distal middle cerebral artery occlusion (MCAO) in hypertensive rats. We also examined the possible protective effect of ebselen, one glutathione peroxidase mimic, on delayed degeneration in the VPN after distal MCAO. Neuronal damage in the ipsilateral VPN was examined by Nissl staining. Oxidative DNA damage and base repair enzyme activity were assessed by analyzing immunoreactivity of 8-hydroxy-2'-deoxyguanosine (8-ohdG) and 8-oxoguanine DNA glycosylase (OGG1), respectively. The number of intact neurons in the ipsilateral VPN decreased by 52% compared to the contralateral side in ischemia group 2 weeks after distal cerebral cortical infarction. The immunoreactivity of 8-ohdG significantly increased while OGG1 immunoreactivity significantly decreased in the ipsilateral VPN 2 weeks after distal cortical infarction (all p<0.01). Compared with vehicle treatment, ebselen significantly attenuated the neuron loss, ameliorated ischemia-induced increase in 8-ohdG level as well as decrease in OGG1 level within the ipsilateral VPN (all p<0.01). OGG1 was further demonstrated to mainly express in neurons. These findings strongly suggest that oxidative DNA damage may be involved in the delayed neuronal death in the VPN region following distal MCAO. Furthermore, ebselen protects against the delayed damage in the VPN when given at 24 h following distal MCAO.

Diagnostic value of three-dimensional magnetic resonance imaging of inner ear after intratympanic gadolinium injection, and clinical application of magnetic resonance imaging scoring system in patients with delayed endolymphatic hydrops.

PubMed

Gu, X; Fang, Z-M; Liu, Y; Lin, S-L; Han, B; Zhang, R; Chen, X

2014-01-01

Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging of the inner ear after intratympanic injection of gadolinium, together with magnetic resonance imaging scoring of the perilymphatic space, were used to investigate the positive identification rate of hydrops and determine the technique's diagnostic value for delayed endolymphatic hydrops. Twenty-five patients with delayed endolymphatic hydrops underwent pure tone audiometry, bithermal caloric testing, vestibular-evoked myogenic potential testing and three-dimensional magnetic resonance imaging of the inner ear after bilateral intratympanic injection of gadolinium. The perilymphatic space of the scanned images was analysed to investigate the positive identification rate of endolymphatic hydrops. According to the magnetic resonance imaging scoring of the perilymphatic space and the diagnostic standard, 84 per cent of the patients examined had endolymphatic hydrops. In comparison, the positive identification rates for vestibular-evoked myogenic potential and bithermal caloric testing were 52 per cent and 72 per cent respectively. Three-dimensional magnetic resonance imaging after intratympanic injection of gadolinium is valuable in the diagnosis of delayed endolymphatic hydrops and its classification. The perilymphatic space scoring system improved the diagnostic accuracy of magnetic resonance imaging.

Hepatocellular carcinoma in cirrhotic patients at multidetector CT: hepatic venous phase versus delayed phase for the detection of tumour washout

PubMed Central

Furlan, A; Marin, D; Vanzulli, A; Patera, G Palermo; Ronzoni, A; Midiri, M; Bazzocchi, M; Lagalla, R; Brancatelli, G

2011-01-01

Objectives Our aim was to compare retrospectively hepatic venous and delayed phase images for the detection of tumour washout during multiphasic multidetector row CT (MDCT) of the liver in patients with hepatocellular carcinoma (HCC). Methods 30 cirrhotic patients underwent multiphasic MDCT in the 90 days before liver transplantation. MDCT was performed before contrast medium administration and during hepatic arterial hepatic venous and delayed phases, images were obtained at 12, 55 and 120 s after trigger threshold. Two radiologists qualitatively evaluated images for lesion attenuation. Tumour washout was evaluated subjectively and objectively. Tumour-to-liver contrast (TLC) was measured for all pathologically proven HCCs. Results 48 HCCs were detected at MDCT. 46 of the 48 tumours (96%) appeared as either hyper- or isoattenuating during the hepatic arterial phase subjective washout was present in 15 HCCs (33%) during the hepatic venous phase and in 35 (76%) during the delayed phase (p<0.001, McNemar’s test). Objective washout was present in 30 of the 46 HCCs (65%) during the hepatic venous phase and in 42 of the HCCs (91%) during the delayed phase (p=0.001). The delayed phase yielded significantly higher mean TLC absolute values compared with the hepatic venous phase (−16.1±10.8 HU vs −10.5±10.2 HU; p<0.001). Conclusions The delayed phase is superior to the hepatic venous phase for detection of tumour washout of pathologically proven HCC in cirrhotic patients. PMID:21081569

Chromatin Remodeling Factors Isw2 and Ino80 Regulate Checkpoint Activity and Chromatin Structure in S Phase

PubMed Central

Lee, Laura; Rodriguez, Jairo; Tsukiyama, Toshio

2015-01-01

When cells undergo replication stress, proper checkpoint activation and deactivation are critical for genomic stability and cell survival and therefore must be highly regulated. Although mechanisms of checkpoint activation are well studied, mechanisms of checkpoint deactivation are far less understood. Previously, we reported that chromatin remodeling factors Isw2 and Ino80 attenuate the S-phase checkpoint activity in Saccharomyces cerevisiae, especially during recovery from hydroxyurea. In this study, we found that Isw2 and Ino80 have a more pronounced role in attenuating checkpoint activity during late S phase in the presence of methyl methanesulfonate (MMS). We therefore screened for checkpoint factors required for Isw2 and Ino80 checkpoint attenuation in the presence of MMS. Here we demonstrate that Isw2 and Ino80 antagonize checkpoint activators and attenuate checkpoint activity in S phase in MMS either through a currently unknown pathway or through RPA. Unexpectedly, we found that Isw2 and Ino80 increase chromatin accessibility around replicating regions in the presence of MMS through a novel mechanism. Furthermore, through growth assays, we provide additional evidence that Isw2 and Ino80 partially counteract checkpoint activators specifically in the presence of MMS. Based on these results, we propose that Isw2 and Ino80 attenuate S-phase checkpoint activity through a novel mechanism. PMID:25701287

Kisspeptin regulates ovarian steroidogenesis during delayed embryonic development in the fruit bat, Cynopterus sphinx.

PubMed

Anuradha; Krishna, Amitabh

2017-11-01

Cynopterus sphinx, a fruit bat, undergoes delayed embryonic development during the winter months, a period that corresponds to low levels of progesterone and estradiol synthesis by the ovary. Kisspeptins (KPs) are a group of neuropeptide hormones that act via G-protein coupled receptor 54 (GPR54) to stimulate hypothalamic secretion of Gonadotropin-releasing hormone, thereby regulating ovarian steroidogenesis, folliculogenesis, and ovulation. GPR54 is also expressed in the ovary, suggesting a direct role for KPs in ovarian steroidogenesis. The aim of present study was to determine if a low serum level of KP is responsible for reduced progesterone and estradiol levels during the period of delayed embryonic development in C. sphinx. Indeed, low serum KP abundance corresponded to reduced expression of GPR54 in ovarian luteal cells during the period of delayed development compared to normal development. In vitro and in vivo treatment with KP increased GPR54 abundance, via Extracellular signal regulated kinase and its downstream mediators, leading to increased progesterone synthesis in the ovary during delayed embryonic development. KP treatment also increased cholesterol uptake and elevated expression of Luteinizing hormone receptor and Steroid acute regulatory protein in the ovary, suggesting that elevation in circulating KP during delayed embryonic development may reactivate luteal activity. KPs may also enhance cell survival (BCL-2, reduced Caspase 3 activity) and angiogenesis (Vascular endothelium growth factor) during this period. The findings of this study thus demonstrate a regulatory role for KPs in the maintenance of luteal steroidogenesis during pregnancy in C. sphinx. © 2017 Wiley Periodicals, Inc.

Passive Heating Attenuates Post-exercise Cardiac Autonomic Recovery in Healthy Young Males

PubMed Central

Peçanha, Tiago; Forjaz, Cláudia L. de Moraes; Low, David A.

2017-01-01

Post-exercise heart rate (HR) recovery (HRR) presents a biphasic pattern, which is mediated by parasympathetic reactivation and sympathetic withdrawal. Several mechanisms regulate these post-exercise autonomic responses and thermoregulation has been proposed to play an important role. The aim of this study was to test the effects of heat stress on HRR and HR variability (HRV) after aerobic exercise in healthy subjects. Twelve healthy males (25 ± 1 years, 23.8 ± 0.5 kg/m2) performed 14 min of moderate-intensity cycling exercise (40–60% HRreserve) followed by 5 min of loadless active recovery in two conditions: heat stress (HS) and normothermia (NT). In HS, subjects dressed in a whole-body water-perfused tube-lined suit to increase internal temperature (Tc) by ~1°C. In NT, subjects did not wear the suit. HR, core and skin temperatures (Tc and Tsk), mean arterial pressure (MAP) skin blood flow (SKBF), and cutaneous vascular conductance (CVC) were measured throughout and analyzed during post-exercise recovery. HRR was assessed through calculations of HR decay after 60 and 300 s of recovery (HRR60s and HRR300s), and the short- and long-term time constants of HRR (T30 and HRRt). Post-exercise HRV was examined via calculations of RMSSD (root mean square of successive RR intervals) and RMS (root mean square residual of RR intervals). The HS protocol promoted significant thermal stress and hemodynamic adjustments during the recovery (HS-NT differences: Tc = +0.7 ± 0.3°C; Tsk = +3.2 ± 1.5°C; MAP = −12 ± 14 mmHg; SKBF = +90 ± 80 a.u; CVC = +1.5 ± 1.3 a.u./mmHg). HRR and post-exercise HRV were significantly delayed in HS (e.g., HRR60s = 27 ± 9 vs. 44 ± 12 bpm, P < 0.01; HRR300s = 39 ± 12 vs. 59 ± 16 bpm, P < 0.01). The effects of heat stress (e.g., the HS-NT differences) on HRR were associated with its effects on thermal and hemodynamic responses. In conclusion, heat stress delays HRR, and this effect seems to be mediated by an attenuated parasympathetic reactivation and sympathetic withdrawal after exercise. In addition, the impact of heat stress on HRR is related to the magnitude of the heat stress-induced thermal stress and hemodynamic changes. PMID:29311799

Shenqi detoxification granule combined with P311 inhibits epithelial-mesenchymal transition in renal fibrosis via TGF-β1-Smad-ILK pathway.

PubMed

Cai, Pingping; Liu, Xiang; Xu, Yuan; Qi, Fanghua; Si, Guomin

2017-01-01

Shenqi detoxification granule (SDG), a traditional Chinese herbal formula, has been shown to have nephroprotective and anti-fibrotic activities in patients with chronic kidney disease (CKD). However, its mechanisms in renal fibrosis and the progression of CKD remain largely unknown. P311, a highly conserved 8-kDa intracellular protein, plays a key role in renal fibrosis by regulating epithelial-mesenchymal transition (EMT). Previously, we found P311 might be involved in the pathogenesis of renal fibrosis by inhibiting EMT via the TGF-β1-Smad-ILK pathway. We also found SDG combined with P311 could ameliorate renal fibrosis by regulating the expression of EMT markers. Here we further examined the effect and mechanism of SDG combined with P311 on TGF-β1-mediated EMT in a rat model of unilateral ureteral occlusion (UUO) renal fibrosis. After establishment of the UUO model successfully, the rats were gavaged with SDG daily and/or injected with recombinant adenovirus p311 (also called Ad-P311) through the tail vein each week for 4 weeks. Serum creatinine (Cr), blood urea nitrogen (BUN) and albumin (ALB) levels were tested to observe renal function, and hematoxylin eosin (HE) and Masson staining were performed to observe kidney histopathology. Furthermore, the expression of EMT markers (E-cadherin and α-smooth muscle actin (α-SMA)) and EMT-related molecules TGF-β1, pSmad2/3, Smad7 and ILK were observed using immunohistochemical staining and Western blot analysis. Treatment with SDG and P311 improved renal function and histopathological abnormalities, as well as reversing the changes of EMT markers and EMT-related molecules, which indicated SDG combined with P311 could attenuate renal fibrosis in UUO rats, and the underlying mechanism might involve TGF-β1-mediated EMT and the TGF-β1-Smad-ILK signaling pathway. Therefore, SDG might be a novel alternative therapy for treating renal fibrosis and delaying the progression of CKD. Furthermore, SDG combined with P311 might have a synergistic effect on attenuating renal fibrosis.

Role of Adaptor Protein Toll-Like Interleukin Domain Containing Adaptor Inducing Interferon β in Toll-Like Receptor 3- and 4-Mediated Regulation of Hepatic Drug Metabolizing Enzyme and Transporter Genes.

PubMed

Shah, Pranav; Omoluabi, Ozozoma; Moorthy, Bhagavatula; Ghose, Romi

2016-01-01

The expressions and activities of hepatic drug-metabolizing enzymes and transporters (DMETs) are altered during infection and inflammation. Inflammatory responses in the liver are mediated primarily by Toll-like receptor (TLR)-signaling, which involves recruitment of Toll/interleukin (IL)-1 receptor (TIR) domain containing adaptor protein (TIRAP) and TIR domain containing adaptor inducing interferon (IFN)-β (TRIF) that eventually leads to induction of proinflammatory cytokines and mitogen-activated protein kinases (MAPKs). Lipopolysaccharide (LPS) activates the Gram-negative bacterial receptor TLR4 and polyinosinic:polycytidylic acid (polyI:C) activates the viral receptor TLR3. TLR4 signaling involves TIRAP and TRIF, whereas TRIF is the only adaptor protein involved in the TLR3 pathway. We have shown previously that LPS-mediated downregulation of DMETs is independent of TIRAP. To determine the role of TRIF, we treated TRIF(+/+) and TRIF(-/-) mice with LPS or polyI:C. LPS downregulated (∼40%-60%) Cyp3a11, Cyp2a4, Ugt1a1, Mrp2 mRNA levels, whereas polyI:C downregulated (∼30%-60%) Cyp3a11, Cyp2a4, Cyp1a2, Cyp2b10, Ugt1a1, Mrp2, and Mrp3 mRNA levels in TRIF(+/+) mice. This downregulation was not attenuated in TRIF(-/-) mice. Induction of cytokines by LPS was observed in both TRIF(+/+) and TRIF(-/-) mice. Cytokine induction was delayed in polyI:C-treated TRIF(-/-) mice, indicating that multiple mechanisms mediating polyI:C signaling exist. To assess the role of MAPKs, primary hepatocytes were pretreated with specific inhibitors before treatment with LPS/polyI:C. We found that only the c-jun-N-terminal kinase (JNK) inhibitor attenuated the down-regulation of DMETs. These results show that TRIF-independent pathways can be involved in the downregulation of DMETs through TLR4 and 3. JNK-dependent mechanisms likely mediate this downregulation. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics.

PubMed

Kou, Xianjuan; Li, Jie; Liu, Xingran; Chang, Jingru; Zhao, Qingxia; Jia, Shaohui; Fan, Jingjing; Chen, Ning

2017-06-01

microRNAs (miRNAs) have been reported to be involved in many neurodegenerative diseases. To explore the regulatory role of miR-34a in aging-related diseases such as Alzheimer's disease (AD) during exercise intervention, we constructed a rat model with d-galactose (d-gal)-induced oxidative stress and cognitive impairment coupled with dysfunctional autophagy and abnormal mitochondrial dynamics, determined the mitigation of cognitive impairment of d-gal-induced aging rats during swimming intervention, and evaluated miR-34a-mediated functional status of autophagy and abnormal mitochondrial dynamics. Meanwhile, whether the upregulation of miR-34a can lead to dysfunctional autophagy and abnormal mitochondrial dynamics was confirmed in human SH-SY5Y cells with silenced miR-34a by the transfection of a miR-34a inhibitor. Results indicated that swimming intervention could significantly attenuate cognitive impairment, prevent the upregulation of miR-34a, mitigate the dysfunctional autophagy, and inhibit the increase of dynamin-related protein 1 (DRP1) in d-gal-induced aging model rats. In contrast, the miR-34a inhibitor in cell model not only attenuated D-gal-induced the impairment of autophagy but also decreased the expression of DRP1 and mitofusin 2 (MFN2). Therefore, swimming training can delay brain aging of d-gal-induced aging rats through attenuating the impairment of miR-34a-mediated autophagy and abnormal mitochondrial dynamics, and miR-34a could be the novel therapeutic target for aging-related diseases such as AD. NEW & NOTEWORTHY In the present study, we have found that the upregulation of miR-34a is the hallmark of aging or aging-related diseases, which can result in dysfunctional autophagy and abnormal mitochondrial dynamics. In contrast, swimming intervention can delay the aging process by rescuing the impaired functional status of autophagy and abnormal mitochondrial dynamics via the suppression of miR-34a. Copyright © 2017 the American Physiological Society.

Arabidopsis AGAMOUS Regulates Sepal Senescence by Driving Jasmonate Production

PubMed Central

Jibran, Rubina; Tahir, Jibran; Cooney, Janine; Hunter, Donald A.; Dijkwel, Paul P.

2017-01-01

The signal that initiates the age-regulated senescence program in flowers is still unknown. Here we propose for the ephemeral Arabidopsis thaliana flower that it dies because of continued expression of the MADS-box transcription factor AGAMOUS (AG). AG is necessary for specifying the reproductive structures of the flower. Flowers of ag-1, which lack AG, exhibited delayed sepal senescence and abscission. The flowers also had reduced jasmonic acid (JA) content. Other anther-defective sterile mutants deficient in JA, defective in anther dehiscence 1 (dad1) and delayed dehiscence 2 (dde2), exhibited delayed sepal senescence and abscission as well. Manually pollinated dad1 flowers produced siliques but still had delayed senescence, demonstrating that absence of pollination does not cause delayed senescence. When ag-1, dad1 and dde2 flowers were sprayed with 100 μM methyl jasmonate, the sepal senescence and abscission phenotypes were rescued, suggesting that JA has a role in these processes. Our study uncovers a novel role for AG in determining the timing of death of the flower it helps develop and highlights a role for JA in sepal senescence. PMID:29312374

Three-dimensional Q -1 model of the Coso Hot Springs Known Geothermal Resource Area

NASA Astrophysics Data System (ADS)

Young, Chi-Yuh; Ward, Ronald W.

1980-05-01

Observations of teleseismic P waves above geothermal systems exhibit travel time delays and anomalously high seismic attenuation, which is extremely useful in estimating the thermal regime and the potential of the system. A regional telemetered network of sixteen stations was operated by the U.S. Geological Survey in the Coso Hot Springs Known Geothermal Resources Area (KGRA) for such studies from September 1975 to October 1976. Subsequently, they deployed a portable Centipede array of 26 three-component stations near the center of the anomaly. The seismograms of 44 events recorded by the telemetered array and nine events by the Centipede array were analyzed using the reduced spectral ratio technique to determine the differential attenuation factor δt* for the events recorded with the highest signal-to-noise ratio. The δt* variation observed across the Coso Hot Springs KGRA were small (<0.2 s). A three-dimensional generalized linear inversion of the δt* observations was performed using a three-layer model. A shallow zone of high attenuation exists within the upper 5 km in a region bounded by Coso Hot Springs, Devils Kitchen, and Sugarloaf Mountain probably corresponding to a shallow vapor liquid mixture or `lossy' near surface lithology. No zones of significantly high attenuation occur between 5- and 12- km depth. Between the depth of 12-20 km a thick zone of high attenuation (Q <50) exists, offset toward the east from the surface anomaly.

PPARα autocrine regulation of Ca²⁺-regulated exocytosis in guinea pig antral mucous cells: NO and cGMP accumulation.

PubMed

Tanaka, Saori; Sugiyama, Nanae; Takahashi, Yuko; Mantoku, Daiki; Sawabe, Yukinori; Kuwabara, Hiroko; Nakano, Takashi; Shimamoto, Chikao; Matsumura, Hitoshi; Marunaka, Yoshinori; Nakahari, Takashi

2014-12-15

In antral mucous cells, acetylcholine (ACh, 1 μM) activates Ca(2+)-regulated exocytosis, consisting of a peak in exocytotic events that declines rapidly (initial phase) followed by a second slower decline (late phase) lasting during ACh stimulation. GW7647 [a peroxisome proliferation activation receptor α (PPARα) agonist] enhanced the ACh-stimulated initial phase, and GW6471 (a PPARα antagonist) abolished the GW7647-induced enhancement. However, GW6471 produced the delayed, but transient, increase in the ACh-stimulated late phase, and it also decreased the initial phase and produced the delayed increase in the late phase during stimulation with ACh alone. A similar delayed increase in the ACh-stimulated late phase is induced by an inhibitor of the PKG, Rp8BrPETcGMPS, suggesting that GW6471 inhibits cGMP accumulation. An inhibitor of nitric oxide synthase 1 (NOS1), N(5)-[imino(propylamino)methyl]-L-ornithine hydrochloride (N-PLA), also abolished the GW7647-induced-enhancement of ACh-stimulated initial phase but produced the delayed increase in the late phase. However, in the presence of N-PLA, an NO donor or 8BrcGMP enhanced the ACh-stimulated initial phase and abolished the delayed increase in the late phase. Moreover, GW7647 and ACh stimulated NO production and cGMP accumulation in antral mucosae, which was inhibited by GW6471 or N-PLA. Western blotting and immunohistochemistry revealed that NOS1 and PPARα colocalize in antral mucous cells. In conclusion, during ACh stimulation, a PPARα autocrine mechanism, which accumulates NO via NOS1 leading to cGMP accumulation, modulates the Ca(2+)-regulated exocytosis in antral mucous cells. Copyright © 2014 the American Physiological Society.

AgRP to Kiss1 neuron signaling links nutritional state and fertility

PubMed Central

Padilla, Stephanie L.; Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Smith, Arik W.; Whiddon, Benjamin B.; Rønnekleiv, Oline K.; Kelly, Martin J.; Palmiter, Richard D.

2017-01-01

Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons. PMID:28196880

Dual conception of risk in the Iowa Gambling Task: effects of sleep deprivation and test-retest gap.

PubMed

Singh, Varsha

2013-01-01

Risk in the Iowa Gambling Task (IGT) is often understood in terms of intertemporal choices, i.e., preference for immediate outcomes in favor of delayed outcomes is considered risky decision making. According to behavioral economics, healthy decision makers are expected to refrain from choosing the short-sighted immediate gain because, over time (10 trials of the IGT), the immediate gains result in a long term loss (net loss). Instead decision makers are expected to maximize their gains by choosing options that, over time (10 trials), result in delayed or long term gains (net gain). However, task choices are sometimes made on the basis of the frequency of reward and punishment such that frequent rewards/infrequent punishments are favored over infrequent rewards/frequent punishments. The presence of these two attributes (intertemporality and frequency of reward) in IGT decision making may correspond to the emotion-cognition dichotomy and reflect a dual conception of risk. Decision making on the basis of the two attributes was tested under two conditions: delay in retest and sleep deprivation. An interaction between sleep deprivation and time delay was expected to attenuate the difference between the two attributes. Participants were 40 male university students. Analysis of the effects of IGT attribute type (intertemporal vs. frequency of reinforcement), sleep deprivation (sleep deprivation vs. no sleep deprivation), and test-retest gap (short vs. long delay) showed a significant within-subjects effect of IGT attribute type thus confirming the difference between the two attributes. Sleep deprivation had no effect on the attributes, but test-retest gap and the three-way interaction between attribute type, test-retest gap, and sleep deprivation were significantly different. Post-hoc tests revealed that sleep deprivation and short test-retest gap attenuated the difference between the two attributes. Furthermore, the results showed an expected trend of increase in intertemporal decision making at retest suggesting that intertemporal decision making benefited from repeated task exposure. The present findings add to understanding of the emotion-cognition dichotomy. Further, they show an important time-dependent effect of a universally experienced constraint (sleep deprivation) on decision making. It is concluded that risky decision making in the IGT is contingent on the attribute under consideration and is affected by factors such as time elapsed and constraint experienced before the retest.

Down-regulation of inflammatory cytokines by berberine attenuates Riemerella anatipestifer infection in ducks

USDA-ARS?s Scientific Manuscript database

Riemerella anatipestifer an important infectious bacterium affecting the duck industry, has 5-75% mortality, depending on strain virulence. We previously demonstrated that proinflammatory cytokines are involved in inflammation during, and regulating susceptibility to, R. anatipestifer infection We i...

Biosafety considerations for attenuated measles virus vectors used in virotherapy and vaccination.

PubMed

Baldo, Aline; Galanis, Evanthia; Tangy, Frédéric; Herman, Philippe

2016-05-03

Attenuated measles virus (MV) is one of the most effective and safe vaccines available, making it attractive candidate vector to prevent infectious diseases. Attenuated MV have acquired the ability to use the complement regulator CD46 as a major receptor to mediate virus entry and intercellular fusion. Therefore, attenuated MV strains preferentially infect and destroy a wide variety of cancer cells making them also attractive oncolytic vectors. The use of recombinant MV vector has to comply with various regulatory requirements, particularly relating to the assessment of potential risks for human health and the environment. The present article highlights the main characteristics of MV and recombinant MV vectors used for vaccination and virotherapy and discusses these features from a biosafety point of view.

Effect of histochrome on the severity of delayed effects of prenatal exposure to lead nitrate in the rat brain.

PubMed

Ryzhavsky, B Ya; Lebedko, O A; Belolubskaya, D S

2008-08-01

The effects of histochrome on the severity of delayed effects of prenatal exposure to lead nitrate were studied in the rat brain. Exposure of pregnant rats to lead nitrate during activation of free radical oxidation reduced activity of NADH- and NADPH-dehydrogenases in cortical neurons of their 40-day-old progeny, reduced the number of neurons in a visual field, increased the number of pathologically modified neurons, and stimulated rat motor activity in an elevated plus-maze. Two intraperitoneal injections of histochrome in a dose of 0.1 mg/kg before and after lead citrate challenge attenuated the manifestations of oxidative stress and prevented the changes in some morphological and histochemical parameters of the brain, developing under the effect of lead exposure.

Tissue characterization with ballistic photons: counting scattering and/or absorption centres

NASA Astrophysics Data System (ADS)

Corral, F.; Strojnik, M.; Paez, G.

2015-03-01

We describe a new method to separate ballistic from the scattered photons for optical tissue characterization. It is based on the hypothesis that the scattered photons acquire a phase delay. The photons passing through the sample without scattering or absorption preserve their coherence so they may participate in interference. We implement a Mach-Zehnder experimental setup where the ballistic photons pass through the sample with the delay caused uniquely by the sample indices of refraction. We incorporate a movable mirror on the piezoelectric actuator in the sample arm to detect the amplitude of the modulation term. We present the theory that predicts the path-integrated (or total) concentration of the scattering and absorption centres. The proposed technique may characterize samples with transmission attenuation of ballistic photons by a factor of 10-14.

Aging and insulin signaling differentially control normal and tumorous germline stem cells.

PubMed

Kao, Shih-Han; Tseng, Chen-Yuan; Wan, Chih-Ling; Su, Yu-Han; Hsieh, Chang-Che; Pi, Haiwei; Hsu, Hwei-Jan

2015-02-01

Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC-male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease.

PubMed

Sagredo, Onintza; Pazos, M Ruth; Satta, Valentina; Ramos, José A; Pertwee, Roger G; Fernández-Ruiz, Javier

2011-09-01

We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies. Copyright © 2011 Wiley-Liss, Inc.

Regulation of p53, nuclear factor {kappa}B and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin

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

Kalra, Neetu; Bhui, Kulpreet; Roy, Preeti

2008-01-01

Bromelain is a pharmacologically active compound, present in stems and immature fruits of pineapples (Ananas cosmosus), which has been shown to have anti-edematous, anti-inflammatory, anti-thrombotic and anti-metastatic properties. In the present study, antitumorigenic activity of bromelain was recorded in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted 2-stage mouse skin model. Results showed that bromelain application delayed the onset of tumorigenesis and reduced the cumulative number of tumors, tumor volume and the average number of tumors/mouse. To establish a cause and effect relationship, we targeted the proteins involved in the cell death pathway. Bromelain treatment resulted in upregulation of p53 and Bax andmore » subsequent activation of caspase 3 and caspase 9 with concomitant decrease in antiapoptotic protein Bcl-2 in mouse skin. Since persistent induction of cyclooxygenase-2 (Cox-2) is frequently implicated in tumorigenesis and is regulated by nuclear factor-kappa B (NF-{kappa}B), we also investigated the effect of bromelain on Cox-2 and NF-{kappa}B expression. Results showed that bromelain application significantly inhibited Cox-2 and inactivated NF-{kappa}B by blocking phosphorylation and subsequent degradation of I{kappa}B{alpha}. In addition, bromelain treatment attenuated DMBA-TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), mitogen-activated protein kinase (MAPK) and Akt. Taken together, we conclude that bromelain induces apoptosis-related proteins along with inhibition of NF-{kappa}B-driven Cox-2 expression by blocking the MAPK and Akt/protein kinase B signaling in DMBA-TPA-induced mouse skin tumors, which may account for its anti-tumorigenic effects.« less

RovA, a global regulator of Yersinia pestis, specifically required for bubonic plague.

PubMed

Cathelyn, Jason S; Crosby, Seth D; Lathem, Wyndham W; Goldman, William E; Miller, Virginia L

2006-09-05

The pathogenic species of Yersinia contain the transcriptional regulator RovA. In Yersinia pseudotuberculosis and Yersinia enterocolitica, RovA regulates expression of the invasion factor invasin (inv), which mediates translocation across the intestinal epithelium. A Y. enterocolitica rovA mutant has a significant decrease in virulence by LD(50) analysis and an altered rate of dissemination compared with either wild type or an inv mutant, suggesting that RovA regulates multiple virulence factors. Here, we show the involvement of RovA in the virulence of Yersinia pestis, which naturally lacks a functional inv gene. A Y. pestis DeltarovA mutant is attenuated approximately 80-fold by LD(50) and is defective in dissemination/colonization of spleens and lungs after s.c. inoculation. However, the DeltarovA mutant is only slightly attenuated when given via an intranasal or i.p. route, indicating a more important role for RovA in bubonic plague than pneumonic plague or systemic infection. Microarray analysis was used to define the RovA regulon. The psa locus was among the most highly down-regulated loci in the DeltarovA mutant. A DeltapsaA mutant had a significant dissemination defect after s.c. infection but only slight attenuation by the pneumonic-disease model, closely mimicking the virulence defect seen with the DeltarovA mutant. DNA-binding studies revealed that RovA specifically interacts with the psaE and psaA promoter regions, indicating a direct role for RovA in regulating this locus. Thus, RovA appears to be a global transcription factor in Y. pestis and, through its regulatory influence on genes such as psaEFABC, contributes to the virulence of Y. pestis.

Saxagliptin Induces β-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α In Vivo and In Vitro.

PubMed

Li, Chun-Jun; Sun, Bei; Fang, Qian-Hua; Ding, Min; Xing, Yun-Zhi; Chen, Li-Ming; Yu, De-Min

2017-01-01

Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on β-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1α (SDF-1α), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting β-cell survival. Here, we speculate that SDF-1α might mediate the effect of saxagliptin on improving β-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased β-cell to α-cell areas ratio were observed. Saxagliptin significantly induced β-cell proliferation and upregulated the expression of proliferation-related factors including c-myc and cyclind D1 determined with western blotting from the isolated islets. The expression/activity of DPP-4 was significantly reduced and paralleled with the restoration of SDF-1α levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, β-catenin, and AKT were activated. However, the effect of saxagliptin inducing β-cell proliferation was attenuated when we silenced the SDF-1α receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1α mediates the protective effect of saxagliptin on β-cell proliferation, suggesting that DPP-4 inhibitors have the potential role on delaying β-cell failure and SDF-1α could be a therapeutic target of β-cell regeneration.

Saxagliptin Induces β-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α In Vivo and In Vitro

PubMed Central

Li, Chun-Jun; Sun, Bei; Fang, Qian-Hua; Ding, Min; Xing, Yun-Zhi; Chen, Li-Ming; Yu, De-Min

2017-01-01

Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on β-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1α (SDF-1α), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting β-cell survival. Here, we speculate that SDF-1α might mediate the effect of saxagliptin on improving β-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased β-cell to α-cell areas ratio were observed. Saxagliptin significantly induced β-cell proliferation and upregulated the expression of proliferation-related factors including c-myc and cyclind D1 determined with western blotting from the isolated islets. The expression/activity of DPP-4 was significantly reduced and paralleled with the restoration of SDF-1α levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, β-catenin, and AKT were activated. However, the effect of saxagliptin inducing β-cell proliferation was attenuated when we silenced the SDF-1α receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1α mediates the protective effect of saxagliptin on β-cell proliferation, suggesting that DPP-4 inhibitors have the potential role on delaying β-cell failure and SDF-1α could be a therapeutic target of β-cell regeneration. PMID:29230196

Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia.

PubMed

Kinsella, Sinéad; König, Hans-Georg; Prehn, Jochen H M

2016-01-01

Mutations in the superoxide dismutase 1 (SOD1) gene contribute to motoneuron degeneration and are evident in 20% of familial amyotrophic lateral sclerosis cases. Mutant SOD1 induces microglial activation through a stimulation of Toll-like receptors 2 and 4 (TLR2 and TLR4). In the present study, we identified the proapoptotic Bcl-2 family protein Bid as a positive regulator of mutant SOD1-induced TLR-nuclear factor-κB (NF-κB) signaling in microglia. bid-deficient primary mouse microglia showed reduced NF-κB signaling in response to TLR4 activation or exposure to conditioned medium derived from SOD1 (G93A) expressing NSC-34 cells. Attenuation of NF-κB signaling in bid-deficient microglia was associated with lower levels of phosphorylated IKKα/β and p65, with a delayed degradation of IκBα and enhanced degradation of Peli1. Upstream of IKK, we found that Bid interacted with, and promoted, the K63-linked polyubiquitination of the E3 ubiquitin ligase tumor necrosis factor receptor associated factor 6 (TRAF6) in microglia. Our study suggests a key role for Bid in the regulation of TLR4-NF-κB proinflammatory signaling during mutant SOD1-induced disease pathology. Bid promotes TLR4-NF-κB signaling by interacting with TRAF6 and promoting TRAF6 K63-linked polyubiquitination in microglia.

Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia123

PubMed Central

Kinsella, Sinéad

2016-01-01

Mutations in the superoxide dismutase 1 (SOD1) gene contribute to motoneuron degeneration and are evident in 20% of familial amyotrophic lateral sclerosis cases. Mutant SOD1 induces microglial activation through a stimulation of Toll-like receptors 2 and 4 (TLR2 and TLR4). In the present study, we identified the proapoptotic Bcl-2 family protein Bid as a positive regulator of mutant SOD1-induced TLR-nuclear factor-κB (NF-κB) signaling in microglia. bid-deficient primary mouse microglia showed reduced NF-κB signaling in response to TLR4 activation or exposure to conditioned medium derived from SOD1 G93A expressing NSC-34 cells. Attenuation of NF-κB signaling in bid-deficient microglia was associated with lower levels of phosphorylated IKKα/β and p65, with a delayed degradation of IκBα and enhanced degradation of Peli1. Upstream of IKK, we found that Bid interacted with, and promoted, the K63-linked polyubiquitination of the E3 ubiquitin ligase tumor necrosis factor receptor associated factor 6 (TRAF6) in microglia. Our study suggests a key role for Bid in the regulation of TLR4-NF-κB proinflammatory signaling during mutant SOD1-induced disease pathology. Bid promotes TLR4-NF-κB signaling by interacting with TRAF6 and promoting TRAF6 K63-linked polyubiquitination in microglia. PMID:27257617

Phototropin 1 and dim-blue light modulate the red light de-etiolation response

PubMed Central

Wang, Yihai; M Folta, Kevin

2014-01-01

Light signals regulate seedling morphological changes during de-etiolation through the coordinated actions of multiple light-sensing pathways. Previously we have shown that red-light-induced hypocotyl growth inhibition can be reversed by addition of dim blue light through the action of phototropin 1 (phot1). Here we further examine the fluence-rate relationships of this blue light effect in short-term (hours) and long-term (days) hypocotyl growth assays. The red stem-growth inhibition and blue promotion is a low-fluence rate response, and blue light delays or attenuates both the red light and far-red light responses. These de-etiolation responses include blue light reversal of red or far-red induced apical hook opening. This response also requires phot1. Cryptochromes (cry1 and cry2) are activated by higher blue light fluence-rates and override phot1's influence on hypocotyl growth promotion. Exogenous application of auxin transport inhibitor naphthylphthalamic acid abolished the blue light stem growth promotion in both hypocotyl growth and hook opening. Results from the genetic tests of this blue light effect in auxin transporter mutants, as well as phytochrome kinase substrate mutants indicated that aux1 may play a role in blue light reversal of red light response. Together, the phot1-mediated adjustment of phytochrome-regulated photomorphogenic events is most robust in dim blue light conditions and is likely modulated by auxin transport through its transporters. PMID:25482790

Hypoxic preconditioning facilitates acclimatization to hypobaric hypoxia in rat heart.

PubMed

Singh, Mrinalini; Shukla, Dhananjay; Thomas, Pauline; Saxena, Saurabh; Bansal, Anju

2010-12-01

Acute systemic hypoxia induces delayed cardioprotection against ischaemia-reperfusion injury in the heart. As cobalt chloride (CoCl₂) is known to elicit hypoxia-like responses, it was hypothesized that this chemical would mimic the preconditioning effect and facilitate acclimatization to hypobaric hypoxia in rat heart. Male Sprague-Dawley rats treated with distilled water or cobalt chloride (12.5 mg Co/kg for 7 days) were exposed to simulated altitude at 7622 m for different time periods (1, 2, 3 and 5 days). Hypoxic preconditioning with cobalt appreciably attenuated hypobaric hypoxia-induced oxidative damage as observed by a decrease in free radical (reactive oxygen species) generation, oxidation of lipids and proteins. Interestingly, the observed effect was due to increased expression of the antioxidant proteins hemeoxygenase and metallothionein, as no significant change was observed in antioxidant enzyme activity. Hypoxic preconditioning with cobalt increased hypoxia-inducible factor 1α (HIF-1α) expression as well as HIF-1 DNA binding activity, which further resulted in increased expression of HIF-1 regulated genes such as erythropoietin, vascular endothelial growth factor and glucose transporter. A significant decrease was observed in lactate dehydrogenase activity and lactate levels in the heart of preconditioned animals compared with non-preconditioned animals exposed to hypoxia. The results showed that hypoxic preconditioning with cobalt induces acclimatization by up-regulation of hemeoxygenase 1 and metallothionein 1 via HIF-1 stabilization. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

Androgen therapy for delayed male puberty.

PubMed

Ambler, Geoffrey R

2009-06-01

Delayed puberty in men is a commonly presenting problem to paediatricians and an understanding of the available evidence on cause, treatments and outcomes is important to guide practice. Understanding of the regulation of the onset of puberty is gradually unfolding, although the genetic factors that dictate the timing of puberty in individuals and families remain poorly elucidated. Mutations and polymorphisms in candidate genes are being actively studied and it is likely that there is significant overlap between traditional diagnostic categories. Also, environmental endocrine disruptors may interact with the genetic regulation of puberty. Delayed puberty may not always be a benign condition, with increased risks of failing to achieve target height, adverse psychological and educational consequences, delayed sexual and psychosocial integration into society and effects on skeletal proportions and bone mass reported. Appropriate evaluation and follow-up is needed to guide clinical practice, particularly to distinguish constitutional delay in growth and puberty from that associated with other medical disease or permanent disorders. In milder cases of delayed puberty, treatment is often not required; however, considerable evidence exists for the efficacy and safety of short courses of low-dose testosterone therapy for appropriately selected individuals. This treatment is associated with high levels of patient satisfaction. There is not yet sufficient evidence for the routine use of other therapies (e.g. growth hormone, aromatase inhibitors) for constitutional delay in growth and puberty and better characterization of cause may lead to more targeted individual therapy.

Down-regulation of microRNA-142-5p attenuates oxygen-glucose deprivation and reoxygenation-induced neuron injury through up-regulating Nrf2/ARE signaling pathway.

PubMed

Wang, Ning; Zhang, Lingmin; Lu, Yang; Zhang, Mingxin; Zhang, Zhenni; Wang, Kui; Lv, Jianrui

2017-05-01

MicroRNAs (miRNAs) play vital roles in regulating neuron survival during cerebral ischemia/reperfusion injury. miR-142-5p is reported to be an important regulator of cellular survival. However, little is known about the role of miR-142-5p in regulating neuron survival during cerebral ischemia/reperfusion injury. In this study, we aimed to investigate the precise function and mechanism of miR-142-5p in the regulation of neuron ischemia/reperfusion injury using a cellular model of oxygen-glucose deprivation and reoxygenation (OGD/R)-induced injury in hippocampal neurons in vitro. We found that miR-142-5p was induced in hippocampal neurons with OGD/R treatment. The inhibition of miR-142-5p attenuated OGD/R-induced cell injury and oxidative stress, whereas the overexpression of miR-142-5p aggravated them. Nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as a target gene of miR-142-5p. Moreover, miR-142-5p regulated Nrf2 expression and downstream signaling. Knockdown of Nrf2 abolished the protective effects of miR-142-5p suppression. In addition, we showed an inverse correlation relationship between miR-142-5p and Nrf2 in an in vivo model of middle cerebral artery occlusion in rats. Taken together, these results suggest that miR-142-5p contributes to OGD/R-induced cell injury and the down-regulation of miR-142-5p attenuates OGD/R-induced neuron injury through promoting Nrf2 expression. Our study provides a novel insight into understanding the molecular pathogenesis of cerebral ischemia/reperfusion injury and indicates a potential therapeutic target for the treatment of cerebral ischemia/reperfusion injury. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

Lin, S.; Key Laboratory for Physical Electronics and Devices of the Ministry of Education, Xi'an Jiaotong University, Xi'an 710049; Beeson, S.

Self-induced gaseous plasma is evaluated as active opening switch medium for pulsed high power microwave radiation. The self-induced plasma switch is investigated for N{sub 2} and Ar environments under pressure conditions ranging from 25 to 700 Torr. A multi-pass TE{sub 111} resonator is used to significantly reduce the delay time inherently associated with plasma generation. The plasma forms under the pulsed excitation of a 4 MW magnetron inside the central dielectric tube of the resonator, which isolates the inner atmospheric gas from the outer vacuum environment. The path from the power source to the load is designed such that the pulse passesmore » through the plasma twice with a 35 ns delay between these two passes. In the first pass, initial plasma density is generated, while the second affects the transition to a highly reflective state with as much as 30 dB attenuation. Experimental data revealed that virtually zero delay time may be achieved for N{sub 2} at 25 Torr. A two-dimensional fluid model was developed to study the plasma formation times for comparison with experimental data. The delay time predicted from this model agrees well with the experimental values in the lower pressure regime (error < 25%), however, due to filamentary plasma formation at higher pressures, simulated delay times may be underestimated by as much as 50%.« less

Effects of Vitamin K2 on the Development of Osteopenia in Rats as the Models of Osteoporosis

PubMed Central

Takeda, Tsuyoshi; Sato, Yoshihiro

2006-01-01

Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest. PMID:16642543

Global Attenuation Tomography and Implications for Upper-Mantle Thermal Structure

NASA Astrophysics Data System (ADS)

Dalton, C. A.; Ekström, G.; Dziewonski, A. M.

2007-12-01

Observation of seismic-wave attenuation provides a direct measure of the Earth's anelasticity. The sensitivity of attenuation to temperature, composition, partial melt, and water content is different from that of seismic velocity, and joint interpretation of elastic and anelastic models may be used to improve constraints on these properties throughout the Earth. Historically, the development of attenuation models has lagged behind velocity models. However, the availability of large seismic datasets and improved techniques to treat these data have recently led to better and higher-resolution attenuation models. We have developed a new 3-D global model of shear attenuation in the upper mantle. This new model, QRFSI12, is derived from > 30,000 fundamental-mode Rayleigh wave amplitude measurements at each period (period range 50-250 s). The amplitudes are inverted simultaneously for the coefficients of the 3-D model as well as frequency-dependent amplitude correction factors for each source and receiver. We have found that focusing by elastic heterogeneity can significantly influence surface-wave amplitudes and that this effect can be modeled at long periods using ray-theoretical approximations. We therefore subtract focusing effects from the data prior to inversion by using phase-velocity maps determined from jointly inverting amplitude and phase-delay datasets. In the shallow mantle, QRFSI12 exhibits a strong correlation with tectonic features, and different tectonic provinces are characterized by distinct attenuative properties. At depths > 250 km, the model is dominated by high attenuation beneath the southeastern Pacific and eastern Africa and low attenuation associated with subduction zones in the western Pacific. Comparison of QRFSI12 with global shear-velocity models shows a strong anti-correlation throughout the upper mantle. At 100-km depth, a clear trend of increasing velocity and decreasing attenuation with increasing age of the seafloor is apparent, and tectonically active continental areas are associated with slower velocities and higher attenuation than stable continental interiors. At depths of 150 and 200 km, oceanic regions exhibit a larger decrease in attenuation per fractional increase in velocity than stable continental regions do, suggesting differences in the mechanisms that influence the seismic properties within these two regions. Comparison with recent laboratory measurements (Faul and Jackson, 2005) of attenuation and velocity for olivine helps to quantify the extent to which temperature alone can explain the observed variability. We find that the mineral-physics predictions agree well with the global seismic models for the oceanic regions between 150- and 250-km depth, but that the cratonic areas cannot be fit.

Cinnamon extract attenuates TNF-alpha-induced intestinal lipoprotein ApoB48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes

USDA-ARS?s Scientific Manuscript database

We evaluated whether a water extract of cinnamon (CE = Cinnulin PF®) attenuates the dyslipidemia induced by TNF-alpha in Triton WR-1339-treated hamsters, and whether CE inhibited the over-secretion of apoB48-induced by TNF-alpha in enterocytes in a 35S-labelling study. In vivo, oral treatment with C...

Jasmonate response decay and defense metabolite accumulation contributes to age-regulated dynamics of plant insect resistance

PubMed Central

Mao, Ying-Bo; Liu, Yao-Qian; Chen, Dian-Yang; Chen, Fang-Yan; Fang, Xin; Hong, Gao-Jie; Wang, Ling-Jian; Wang, Jia-Wei; Chen, Xiao-Ya

2017-01-01

Immunity deteriorates with age in animals but comparatively little is known about the temporal regulation of plant resistance to herbivores. The phytohormone jasmonate (JA) is a key regulator of plant insect defense. Here, we show that the JA response decays progressively in Arabidopsis. We show that this decay is regulated by the miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE9 (SPL9) group of proteins, which can interact with JA ZIM-domain (JAZ) proteins, including JAZ3. As SPL9 levels gradually increase, JAZ3 accumulates and the JA response is attenuated. We provide evidence that this pathway contributes to insect resistance in young plants. Interestingly however, despite the decay in JA response, older plants are still comparatively more resistant to both the lepidopteran generalist Helicoverpa armigera and the specialist Plutella xylostella, along with increased accumulation of glucosinolates. We propose a model whereby constitutive accumulation of defense compounds plays a role in compensating for age-related JA-response attenuation during plant maturation. PMID:28067238

Oxymatrine attenuated isoproterenol-induced heart failure in rats via regulation of COX-2/PGI2 pathway.

PubMed

Zhou, Ru; Xu, Qingbin; Xu, Yehua; Xiong, Aiqin; Wang, Yang; Ma, Ping

2016-12-01

Oxymatrine (OMT) is an active constituent of traditional Chinese herb Sophora japonica Ait which has been shown to exert potent anti-inflammatory,anti-oxidant and anti-fibrosis properties. Our previous studies have demonstrated that OMT has protective effects on isoproterenol-induced heart failure in rats through regulation of DDAH/ADMA metabolism pathway.In this study,we further investigated whether OMT could attenuate isoproterenol-induced heart failure through the regulation of COX-2/PGI 2 pathway. Heart failure was induced in Sprague-Dawley rats by 5mg/kg isoproterenol subcutaneous injection for 7days. The rats were maintained on normal diet and randomly divided into five groups: control, isoproterenol, isoproterenol with OMT (50, 100mg/kg), and OMT alone groups (n=12 in each group). Serum brain natruretic peptide (BNP, a heart failure biomarker), histopathological variables, expression of Cytosolic phospholipase A 2 (cPLA 2 ), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and Prostacyclin synthase (PGIS) were analysed. Administration of OMT significantly reduced the increased BNP in plasm of isoproterenol-induced rats, attenuated cardiac fibrosis,suppressed overexpression of myocardial COX-1 expression, up-regulated COX-2 and PGIS expression, but had no effects on isoproterenol-induced elevated protein cPLA 2 . And compared with control group, any indexes in sham rats treated with OMT (100mg/kg) alone were unaltered. These results demonstrated that OMT has cardioprotective effects on isoproterenol-induced heart failure in rats by regulating COX-2/PGI 2 pathway. Copyright © 2016. Published by Elsevier Masson SAS.

Alantolactone suppresses APOC3 expression and alters lipid homeostasis in L02 liver cells.

PubMed

Yang, Meiting; Zhao, Hanhan; Ai, Huihan; Zhu, Hongbin; Wang, Shuyue; Bao, Yongli; Li, Yuxin

2018-06-05

A high level of APOC3 expression is an independent risk factor for some lipid metabolism-related diseases, such as cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD) and atherosclerosis (AS). This suggests that down-regulating APOC3 expression is a potential way of regulating lipid levels. In this study, we used luciferase reporter screening to identify a natural compound, alantolactone (ALA), that can inhibit the promoter activity of APOC3. ALA decreased APOC3 expression at both mRNA and protein levels. Then we pretreated L02 liver cells with oxLDL to investigate the function of ALA in lipid homeostasis. Intriguingly, ALA attenuated oxLDL-induced foam cell formation by reducing total cholesterol (TC) and triglyceride (TG) contents. Furthermore, these results could be reversed by overexpressing APOC3 protein. ALA inhibited tyrosine phosphorylation (Tyr705pho) of STAT3 to down-regulate APOC3 expression. Intriguingly, overexpression of a wild-type STAT3 or a constitutively active form of STAT3 (STAT3-C) up-regulated APOC3 expression and partly reversed the effect of ALA in oxLDL-induced L02 cells. Overexpression of wild-type STAT3 also increased TC but not TG contents in L02 cells. However, overexpression of STAT3-C significantly increased TC and TG contents, and the effect of ALA was partly attenuated by STAT3-C, although this was not statistically significant. These results suggest that ALA attenuates lipid accumulation through down-regulation of APOC3 expression, at least in part by inhibiting STAT3 signaling. Copyright © 2018 Elsevier B.V. All rights reserved.

Default mode network abnormalities during state switching in attention deficit hyperactivity disorder.

PubMed

Sidlauskaite, J; Sonuga-Barke, E; Roeyers, H; Wiersema, J R

2016-02-01

Individuals with attention deficit hyperactivity disorder (ADHD) display excess levels of default mode network (DMN) activity during goal-directed tasks, which are associated with attentional disturbances and performance decrements. One hypothesis is that this is due to attenuated down-regulation of this network during rest-to-task switching. A second related hypothesis is that it may be associated with right anterior insula (rAI) dysfunction - a region thought to control the actual state-switching process. These hypotheses were tested in the current fMRI study in which 19 adults with ADHD and 21 typically developing controls undertook a novel state-to-state switching paradigm. Advance cues signalled upcoming switches between rest and task periods and switch-related anticipatory modulation of DMN and rAI was measured. To examine whether rest-to-task switching impairments may be a specific example of a more general state regulation deficit, activity upon task-to-rest cues was also analysed. Against our hypotheses, we found that the process of down-regulating the DMN when preparing to switch from rest to task was unimpaired in ADHD and that there was no switch-specific deficit in rAI modulation. However, individuals with ADHD showed difficulties up-regulating the DMN when switching from task to rest. Rest-to-task DMN attenuation seems to be intact in adults with ADHD and thus appears unrelated to excess DMN activity observed during tasks. Instead, individuals with ADHD exhibit attenuated up-regulation of the DMN, hence suggesting disturbed re-initiation of a rest state.

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man.

PubMed

Kalafatakis, K; Russell, G M; Harmer, C J; Munafo, M R; Marchant, N; Wilson, A; Brooks, J C; Durant, C; Thakrar, J; Murphy, P; Thai, N J; Lightman, S L

2018-04-24

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

Sympathetic neural control of the kidney in hypertension.

PubMed

DiBona, G F

1992-01-01

Efferent renal sympathetic nerve activity is elevated in human essential hypertension as well as in several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow, the glomerular filtration rate, renal tubular sodium and water reabsorption, and the renin secretion rate, which are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of efferent renal sympathetic nerve activity, two environmental factors, a high dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in efferent renal sympathetic nerve activity and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

10 CFR 950.14 - Standby Support Contract: Covered events, exclusions, covered delay and covered cost provisions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... environmental laws or regulations such as those related to pollution abatement or human health and the... a covered event(s) is determined to be the cause of delay in attainment of full power operation...

10 CFR 950.14 - Standby Support Contract: Covered events, exclusions, covered delay and covered cost provisions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... environmental laws or regulations such as those related to pollution abatement or human health and the... a covered event(s) is determined to be the cause of delay in attainment of full power operation...

10 CFR 950.14 - Standby Support Contract: Covered events, exclusions, covered delay and covered cost provisions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... environmental laws or regulations such as those related to pollution abatement or human health and the... a covered event(s) is determined to be the cause of delay in attainment of full power operation...

10 CFR 950.14 - Standby Support Contract: Covered events, exclusions, covered delay and covered cost provisions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... environmental laws or regulations such as those related to pollution abatement or human health and the... a covered event(s) is determined to be the cause of delay in attainment of full power operation...

Marine polysaccharides attenuate metabolic syndrome by fermentation products and altering gut microbiota: An overview.

PubMed

Wang, Xueliang; Wang, Xin; Jiang, Hao; Cai, Chao; Li, Guoyun; Hao, Jiejie; Yu, Guangli

2018-09-01

Marine polysaccharides (MPs), including plant, animal, and microbial-derived polysaccharides, can alleviate metabolic syndrome (MetS) by different regulation mechanisms. MPs and their derivatives can attenuate MetS by vary cellular signal pathways, such as peroxisome proliferator-activated receptor, 5' adenosine monophosphate-activated protein kinase, and CCAAT/enhancer binding protein-α. Also, most of MPs cannot be degraded by human innate enzymes, but they can be degraded and fermented by human gut microbiota. The final metabolic products of these polysaccharides are usually short-chain fatty acids (SCFAs), which can change the gut microbiota ecology by altering the existing percentage of special microorganisms. In addition, the SCFAs and changed gut microbiota can regulate enteroendocrine hormone secretion, blood glucose, lipid metabolism levels, and other MetS symptoms. Here, we summarize the up-to-date findings on the effects of MPs, particularly marine microbial-derived polysaccharides, and their metabolites on attenuating MetS. Copyright © 2018 Elsevier Ltd. All rights reserved.

PKACs attenuate innate antiviral response by phosphorylating VISA and priming it for MARCH5-mediated degradation

PubMed Central

Yan, Bing-Ru; Zhou, Lu; Hu, Ming-Ming; Li, Mi; Lin, Heng; Yang, Yan; Wang, Yan-Yi

2017-01-01

Sensing of viral RNA by RIG-I-like receptors initiates innate antiviral response, which is mediated by the central adaptor VISA. How the RIG-I-VISA-mediated antiviral response is terminated at the late phase of infection is enigmatic. Here we identified the protein kinase A catalytic (PKAC) subunits α and β as negative regulators of RNA virus-triggered signaling in a redundant manner. Viral infection up-regulated cellular cAMP levels and activated PKACs, which then phosphorylated VISA at T54. This phosphorylation abrogated virus-induced aggregation of VISA and primed it for K48-linked polyubiquitination and degradation by the E3 ligase MARCH5, leading to attenuation of virus-triggered induction of downstream antiviral genes. PKACs-deficiency or inactivation by the inhibitor H89 potentiated innate immunity to RNA viruses in cells and mice. Our findings reveal a critical mechanism of attenuating innate immune response to avoid host damage at the late phase of viral infection by the house-keeping PKA kinase. PMID:28934360

PKACs attenuate innate antiviral response by phosphorylating VISA and priming it for MARCH5-mediated degradation.

PubMed

Yan, Bing-Ru; Zhou, Lu; Hu, Ming-Ming; Li, Mi; Lin, Heng; Yang, Yan; Wang, Yan-Yi; Shu, Hong-Bing

2017-09-01

Sensing of viral RNA by RIG-I-like receptors initiates innate antiviral response, which is mediated by the central adaptor VISA. How the RIG-I-VISA-mediated antiviral response is terminated at the late phase of infection is enigmatic. Here we identified the protein kinase A catalytic (PKAC) subunits α and β as negative regulators of RNA virus-triggered signaling in a redundant manner. Viral infection up-regulated cellular cAMP levels and activated PKACs, which then phosphorylated VISA at T54. This phosphorylation abrogated virus-induced aggregation of VISA and primed it for K48-linked polyubiquitination and degradation by the E3 ligase MARCH5, leading to attenuation of virus-triggered induction of downstream antiviral genes. PKACs-deficiency or inactivation by the inhibitor H89 potentiated innate immunity to RNA viruses in cells and mice. Our findings reveal a critical mechanism of attenuating innate immune response to avoid host damage at the late phase of viral infection by the house-keeping PKA kinase.

Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features.

PubMed

Steinfeld, Hallie; Cho, Megan T; Retterer, Kyle; Person, Rick; Schaefer, G Bradley; Danylchuk, Noelle; Malik, Saleem; Wechsler, Stephanie Burns; Wheeler, Patricia G; van Gassen, Koen L I; Terhal, P A; Verhoeven, Virginie J M; van Slegtenhorst, Marjon A; Monaghan, Kristin G; Henderson, Lindsay B; Chung, Wendy K

2016-07-01

Human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay.

Haem oxygenase delays programmed cell death in wheat aleurone layers by modulation of hydrogen peroxide metabolism

PubMed Central

Wu, Mingzhu; Huang, Jingjing; Xu, Sheng; Ling, Tengfang; Xie, Yanjie; Shen, Wenbiao

2011-01-01

Haem oxygenase-1 (HO-1) confers protection against a variety of oxidant-induced cell and tissue injury in animals and plants. In this report, it is confirmed that programmed cell death (PCD) in wheat aleurone layers is stimulated by GA and prevented by ABA. Meanwhile, HO activity and HO-1 protein expression exhibited lower levels in GA-treated layers, whereas the hydrogen peroxide (H2O2) content was apparently increased. The pharmacology approach illustrated that scavenging or accumulating H2O2 either delayed or accelerated GA-induced PCD. Furthermore, pretreatment with the HO-1 specific inhibitor, zinc protoporphyrin IX (ZnPPIX), before exposure to GA, not only decreased HO activity but also accelerated GA-induced PCD significantly. The application of the HO-1 inducer, haematin, and the enzymatic reaction product of HO, carbon monoxide (CO) aqueous solution, both of which brought about a noticeable induction of HO expression, substantially prevented GA-induced PCD. These effects were reversed when ZnPPIX was added, suggesting that HO in vivo played a role in delaying PCD. Meanwhile, catalase (CAT) and ascorbate peroxidase (APX) activities or transcripts were enhanced by haematin, CO, or bilirubin (BR), the catalytic by-product of HO. This enhancement resulted in a decrease in H2O2 production and a delay in PCD. In addition, the antioxidants butylated hydroxytoluene (BHT), dithiothreitol (DTT), and ascorbic acid (AsA) were able not only to delay PCD but also to mimic the effects of haematin and CO on HO up-regulation. Overall, the above results suggested that up-regulation of HO expression delays PCD through the down-regulation of H2O2 production. PMID:20797999

FTY720 ameliorates murine sclerodermatous chronic graft-versus-host disease by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into skin.

PubMed

Huu, Doanh Le; Matsushita, Takashi; Jin, Guihua; Hamaguchi, Yasuhito; Hasegawa, Minoru; Takehara, Kazuhiko; Fujimoto, Manabu

2013-06-01

Sphingosine 1-phosphate (S1P) exerts a variety of activities in immune, inflammatory, and vascular systems. S1P plays an important role in systemic sclerosis (SSc) pathogenesis. Regulation of S1P in fibrotic diseases as well as in SSc was recently reported. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases. Murine sclerodermatous chronic graft-versus-host disease (GVHD) is a model for human sclerodermatous chronic GVHD and SSc. We undertook this study to investigate the effects of FTY720 in murine sclerodermatous chronic GVHD. FTY720 was orally administered to allogeneic recipient mice from day 0 to day 20 (short-term, early-treatment group), from day 0 to day 42 (full-term, early-treatment group), or from day 22 to day 42 (delayed-treatment group) after bone marrow transplantation. Delayed administration of FTY720 attenuated, and early administration of FTY720 inhibited, the severity and fibrosis in murine sclerodermatous chronic GVHD. With early treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, Treg cells, and Breg cells. Vascular damage in chronic GVHD was inhibited by FTY720 through down-regulating serum levels of S1P and soluble E-selectin. FTY720 inhibited infiltration of immune cells into skin. Moreover, FTY720 diminished the expression of messenger RNA for monocyte chemotactic protein 1, macrophage inflammatory protein 1α, RANTES, tumor necrosis factor α, interferon-γ, interleukin-6 (IL-6), IL-10, IL-17A, and transforming growth factor β1 in the skin. FTY720 suppressed the immune response by promoting the expansion of regulatory cells and reducing vascular damage and infiltration of immune cells into the skin. Taken together, these results have important implications for the potential use of FTY720 in the treatment of sclerodermatous chronic GVHD and SSc in humans. Copyright © 2013 by the American College of Rheumatology.

Perturbation of nucleo-cytoplasmic transport affects size of nucleus and nucleolus in human cells.

PubMed

Ganguly, Abira; Bhattacharjee, Chumki; Bhave, Madhura; Kailaje, Vaishali; Jain, Bhawik K; Sengupta, Isha; Rangarajan, Annapoorni; Bhattacharyya, Dibyendu

2016-03-01

Size regulation of human cell nucleus and nucleolus are poorly understood subjects. 3D reconstruction of live image shows that the karyoplasmic ratio (KR) increases by 30-80% in transformed cell lines compared to their immortalized counterpart. The attenuation of nucleo-cytoplasmic transport causes the KR value to increase by 30-50% in immortalized cell lines. Nucleolus volumes are significantly increased in transformed cell lines and the attenuation of nucleo-cytoplasmic transport causes a significant increase in the nucleolus volume of immortalized cell lines. A cytosol and nuclear fraction swapping experiment emphasizes the potential role of unknown cytosolic factors in nuclear and nucleolar size regulation. © 2016 Federation of European Biochemical Societies.

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

PubMed Central

Das, Sudip; Lindemann, Claudia; Young, Bernadette C.; Muller, Julius; Österreich, Babett; Ternette, Nicola; Winkler, Ann-Cathrin; Paprotka, Kerstin; Reinhardt, Richard; Allen, Elizabeth; Flaxman, Amy; Yamaguchi, Yuko; Rollier, Christine S.; van Diemen, Pauline; Blättner, Sebastian; Remmele, Christian W.; Selle, Martina; Dittrich, Marcus; Müller, Tobias; Vogel, Jörg; Ohlsen, Knut; Crook, Derrick W.; Massey, Ruth; Wilson, Daniel J.; Rudel, Thomas; Wyllie, David H.; Fraunholz, Martin J.

2016-01-01

Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection. PMID:27185949

Inhibition of oxytocin-induced but not angiotensin-induced rat uterine contractions following exposure to sodium sulfide

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

Hayden, L.J.; Franklin, K.J.; Roth, S.H.

1989-01-01

Low concentrations of sodium sulfide reversibly attenuate the contractile response of the isolate rat uterus to oxytocin without affecting angiotensin II responsiveness. These findings suggest that functionally important disulfide bonds in the rat uterine oxytocin receptor, but not the angiotensin receptor, are sensitive to hydrosulfide ion. Reduction of oxytocin receptors by hydrosulfide ion may be a mechanism by which low level of H{sub 2}S delay parturition in rats.

The Suppression of Beta Oscillations in the Primate Supplementary Motor Complex Reflects a Volatile State During the Updating of Action Sequences.

PubMed

Hosaka, Ryosuke; Nakajima, Toshi; Aihara, Kazuyuki; Yamaguchi, Yoko; Mushiake, Hajime

2016-08-01

The medial motor areas play crucial but flexible roles in the temporal organizations of multiple movements. The beta oscillation of local field potentials is the predominant oscillatory activity in the motor areas, but the manner in which increases and decreases in beta power contribute to updating of multiple action plans is not yet fully understood. In the present study, beta and high-gamma activities in the supplementary motor area (SMA) and pre-SMA of monkeys were analyzed during performance of a bimanual motor sequence task that required updating and maintenance of the memory of action sequences. Beta power was attenuated during early delay periods of updating trials but was increased during maintenance trials, while there was a reciprocal increase in high-gamma power during updating trials. Moreover, transient attenuation of beta power during maintenance trials resulted in the erroneous selection of an action sequence. Therefore, it was concluded that the suppression of beta power during the early delay period reflects volatility of neural representation of the action sequence. This neural representation would be properly updated to the appropriate instructed action sequence via increases in high-gamma power in updating trials whereas it would be erroneously updated without the appropriate updating signal in maintenance trials. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Heart-Brain Interactions in the MR Environment: Characterization of the Ballistocardiogram in EEG Signals Collected During Simultaneous fMRI.

PubMed

Marino, Marco; Liu, Quanying; Del Castello, Mariangela; Corsi, Cristiana; Wenderoth, Nicole; Mantini, Dante

2018-05-01

The ballistocardiographic (BCG) artifact is linked to cardiac activity and occurs in electroencephalographic (EEG) recordings acquired inside the magnetic resonance (MR) environment. Its variability in terms of amplitude, waveform shape and spatial distribution over subject's scalp makes its attenuation a challenging task. In this study, we aimed to provide a detailed characterization of the BCG properties, including its temporal dependency on cardiac events and its spatio-temporal dynamics. To this end, we used high-density EEG data acquired during simultaneous functional MR imaging in six healthy volunteers. First, we investigated the relationship between cardiac activity and BCG occurrences in the EEG recordings. We observed large variability in the delay between ECG and subsequent BCG events (ECG-BCG delay) across subjects and non-negligible epoch-by-epoch variations at the single subject level. The inspection of spatial-temporal variations revealed a prominent non-stationarity of the BCG signal. We identified five main BCG waves, which were common across subjects. Principal component analysis revealed two spatially distinct patterns to explain most of the variance (85% in total). These components are possibly related to head rotation and pulse-driven scalp expansion, respectively. Our results may inspire the development of novel, more effective methods for the removal of the BCG, capable of isolating and attenuating artifact occurrences while preserving true neuronal activity.

Sources of image degradation in fundamental and harmonic ultrasound imaging using nonlinear, full-wave simulations.

PubMed

Pinton, Gianmarco F; Trahey, Gregg E; Dahl, Jeremy J

2011-04-01

A full-wave equation that describes nonlinear propagation in a heterogeneous attenuating medium is solved numerically with finite differences in the time domain (FDTD). This numerical method is used to simulate propagation of a diagnostic ultrasound pulse through a measured representation of the human abdomen with heterogeneities in speed of sound, attenuation, density, and nonlinearity. Conventional delay-andsum beamforming is used to generate point spread functions (PSF) that display the effects of these heterogeneities. For the particular imaging configuration that is modeled, these PSFs reveal that the primary source of degradation in fundamental imaging is reverberation from near-field structures. Reverberation clutter in the harmonic PSF is 26 dB higher than the fundamental PSF. An artificial medium with uniform velocity but unchanged impedance characteristics indicates that for the fundamental PSF, the primary source of degradation is phase aberration. An ultrasound image is created in silico using the same physical and algorithmic process used in an ultrasound scanner: a series of pulses are transmitted through heterogeneous scattering tissue and the received echoes are used in a delay-and-sum beamforming algorithm to generate images. These beamformed images are compared with images obtained from convolution of the PSF with a scatterer field to demonstrate that a very large portion of the PSF must be used to accurately represent the clutter observed in conventional imaging. © 2011 IEEE

Resolution and quantification accuracy enhancement of functional delay and sum beamforming for three-dimensional acoustic source identification with solid spherical arrays

NASA Astrophysics Data System (ADS)

Chu, Zhigang; Yang, Yang; Shen, Linbang

2017-05-01

Functional delay and sum (FDAS) is a novel beamforming algorithm introduced for the three-dimensional (3D) acoustic source identification with solid spherical microphone arrays. Being capable of offering significantly attenuated sidelobes with a fast speed, the algorithm promises to play an important role in interior acoustic source identification. However, it presents some intrinsic imperfections, specifically poor spatial resolution and low quantification accuracy. This paper focuses on conquering these imperfections by ridge detection (RD) and deconvolution approach for the mapping of acoustic sources (DAMAS). The suggested methods are referred to as FDAS+RD and FDAS+RD+DAMAS. Both computer simulations and experiments are utilized to validate their effects. Several interesting conclusions have emerged: (1) FDAS+RD and FDAS+RD+DAMAS both can dramatically ameliorate FDAS's spatial resolution and at the same time inherit its advantages. (2) Compared to the conventional DAMAS, FDAS+RD+DAMAS enjoys the same super spatial resolution, stronger sidelobe attenuation capability and more than two hundred times faster speed. (3) FDAS+RD+DAMAS can effectively conquer FDAS's low quantification accuracy. Whether the focus distance is equal to the distance from the source to the array center or not, it can quantify the source average pressure contribution accurately. This study will be of great significance to the accurate and quick localization and quantification of acoustic sources in cabin environments.

Ketoconazole attenuates radiation-induction of tumor necrosis factor

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

Hallahan, D.E.; Virudachalam, S.; Kufe, D.W.

1994-07-01

Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2more » inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.« less

Stimulus-Dependent Dopamine Release in Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Sikstrom, Sverker; Soderlund, Goran

2007-01-01

Attention-deficit/hyperactivity disorder (ADHD) is related to an attenuated and dysfunctional dopamine system. Normally, a high extracellular dopamine level yields a tonic dopaminergic input that down-regulates stimuli-evoked phasic dopamine responses through autoreceptors. Abnormally low tonic extracellular dopamine in ADHD up-regulates the…

Short-term fasting attenuates the response of the HPG axis to kisspeptin challenge in the adult male rhesus monkey (Macaca mulatta).

PubMed

Wahab, Fazal; Aziz, Farzana; Irfan, Shahzad; Zaman, Waheed-Uz; Shahab, Muhammad

2008-11-07

In primates, changes in nutritional status affect the hypothalamic-pituitary-gonadal (HPG) axis by still poorly understood mechanisms. Recently, hypothalamic kisspeptin-GPR54 signaling has emerged as a significant regulator of this neuroendocrine axis. The present study was designed to examine whether suppression of the reproductive function by acute food-restriction in a non-human primate is mediated by decreased responsiveness of the HPG axis to endogenous kisspeptin drive. Five intact adult male rhesus monkeys habituated to chair-restraint, received intravenous boli of human kisspeptin-10 (KP10, 50 microg), hCG (50 IU), and vehicle (1 ml) in both fed and 48-h fasting conditions. Plasma concentrations of glucose, cortisol and testosterone (T) were measured by using enzymatic and specific RIAs, respectively. The acute 48-h fasting decreased plasma glucose (P<0.01) and T (P<0.005) levels, and increased cortisol levels (P<0.05). KP10 administration caused a robust stimulation of T secretion in both fed and fasted monkeys. However, mean T concentration and T AUC after KP10 administration were significantly (P<0.01-0.005) reduced in fasted monkeys. Likewise, the time of the first significant increase in post-KP10 T levels was also significantly (P<0.01) delayed. T response to hCG stimulation was similar in fed and fasted monkeys. The present results indicate that under fasting conditions the KP10 induced T response is delayed and suppressed. These data support the notion that fasting-induced suppression of the HPG axis in the adult male rhesus monkey may involve, at least in part, a reduction in the sensitivity of the GnRH neuronal network to endogenous kisspeptin stimulation.

Activation of Neuregulin 1/ErbB Signaling Is Involved in the Development of TOCP-Induced Delayed Neuropathy.

PubMed

Xu, Hai-Yang; Wang, Pan; Sun, Ying-Jian; Xu, Ming-Yuan; Zhu, Li; Wu, Yi-Jun

2018-01-01

Organophosphate-induced delayed neuropathy (OPIDN) is characterized by progressive axonal degeneration and demyelination of the spinal cord and sciatic nerves. The neuregulin 1/epidermal growth factor receptor (ErbB) signaling pathway is crucial for axonal myelination. In this study, we investigated whether the neuregulin 1/ErbB signaling pathway mediated the progression of OPIDN. Adult hens were given tri- o -cresyl phosphate (TOCP), a typical neuropathic organophosphorus compound, to induce OPIDN. The ErbB inhibitor lapatinib was administered to hens 4 h prior to and 4 days after TOCP exposure. The neuregulin 1/ErbB signaling pathway was examined for their role in maintaining spinal cord and sciatic nerve fiber integrity. Schwann cell line sNF96.2 was used as the in vitro cell model. The in vivo results showed that TOCP (750 mg/kg body weight, p.o .) induced prominent ataxia and significant axon degeneration in the spinal cord and sciatic nerves. Lapatinib (25 mg/kg body weight, p.o .) treatment attenuated OPIDN clinically and histopathlogically and partially prevented the TOCP-induced activation of neuregulin 1/ErbB signaling pathway. Lapatinib also prevented the TOCP-induced inhibition of neuropathy target esterase (NTE), a key enzyme during the development of OPIDN, and the disturbed metabolism of phosphatidylcholine in sciatic nerves. In addition, lapatinib was shown, in vitro , to protect sNF96.2 cells from TOCP-induced dedifferentiation through neuregulin 1/ErbB signaling. Our results suggest that neuregulin 1/ErbB, through regulation of NTE activity in the peripheral nervous system, mediates the progression of OPIDN. Thus, this signal may serve as a potential target for the treatment of OPIDN.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

PubMed

Isherwood, Sarah N; Robbins, Trevor W; Nicholson, Janet R; Dalley, Jeffrey W; Pekcec, Anton

2017-09-01

Metabotropic glutamate receptor 4 (mGluR4) and dopamine D 2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D 2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D 2 receptor antagonist eticlopride, on two distinct forms of impulsivity. Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. These findings demonstrate that mGluR4s, in conjunction with D 2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II

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

Kawiak, Anna; Piosik, Jacek; Stasilojc, Grzegorz

2007-09-15

Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topomore » II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin.« less

Senescence-Induced Serotonin Biosynthesis and Its Role in Delaying Senescence in Rice Leaves1[C][W][OA

PubMed Central

Kang, Kiyoon; Kim, Young-Soon; Park, Sangkyu; Back, Kyoungwhan

2009-01-01

Serotonin, which is well known as a pineal hormone in mammals, plays a key role in conditions such as mood, eating disorders, and alcoholism. In plants, although serotonin has been suggested to be involved in several physiological roles, including flowering, morphogenesis, and adaptation to environmental changes, its regulation and functional roles are as yet not characterized at the molecular level. In this study, we found that serotonin is greatly accumulated in rice (Oryza sativa) leaves undergoing senescence induced by either nutrient deprivation or detachment, and its synthesis is closely coupled with transcriptional and enzymatic induction of the tryptophan biosynthetic genes as well as tryptophan decarboxylase (TDC). Transgenic rice plants that overexpressed TDC accumulated higher levels of serotonin than the wild type and showed delayed senescence of rice leaves. However, transgenic rice plants, in which expression of TDC was suppressed through an RNA interference (RNAi) system, produced less serotonin and senesced faster than the wild type, suggesting that serotonin is involved in attenuating leaf senescence. The senescence-retarding activity of serotonin is associated with its high antioxidant activity compared to either tryptophan or chlorogenic acid. Results of TDC overexpression and TDC RNAi plants suggest that TDC plays a rate-limiting role for serotonin accumulation, but the synthesis of serotonin depends on an absolute amount of tryptophan accumulation by the coordinate induction of the tryptophan biosynthetic genes. In addition, immunolocalization analysis revealed that serotonin was abundant in the vascular parenchyma cells, including companion cells and xylem-parenchyma cells, suggestive of its involvement in maintaining the cellular integrity of these cells for facilitating efficient nutrient recycling from senescing leaves to sink tissues during senescence. PMID:19439571

Dephosphorylation of juxtamembrane serines and threonines of the NPR2 guanylyl cyclase is required for rapid resumption of oocyte meiosis in response to luteinizing hormone

PubMed Central

Shuhaibar, Leia C.; Egbert, Jeremy R.; Edmund, Aaron B.; Uliasz, Tracy F.; Dickey, Deborah M.; Yee, Siu-Pok; Potter, Lincoln R.; Jaffe, Laurinda A.

2016-01-01

The meiotic cell cycle of mammalian oocytes starts during embryogenesis and then pauses until luteinizing hormone (LH) acts on the granulosa cells of the follicle surrounding the oocyte to restart the cell cycle. An essential event in this process is a decrease in cyclic GMP in the granulosa cells, and part of the cGMP decrease results from dephosphorylation and inactivation of the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase, also known as guanylyl cyclase B. However, it is unknown whether NPR2 dephosphorylation is essential for LH-induced meiotic resumption. Here, we prevented NPR2 dephosphorylation by generating a mouse line in which the seven regulatory serines and threonines of NPR2 were changed to the phosphomimetic amino acid glutamate (Npr2–7E). Npr2–7E/7E follicles failed to show a decrease in enzyme activity in response to LH, and the cGMP decrease was attenuated; correspondingly, LH-induced meiotic resumption was delayed. Meiotic resumption in response to EGF receptor activation was likewise delayed, indicating that NPR2 dephosphorylation is a component of the pathway by which EGF receptor activation mediates LH signaling. We also found that most of the NPR2 protein in the follicle was present in the mural granulosa cells. These findings indicate that NPR2 dephosphorylation in the mural granulosa cells is essential for the normal progression of meiosis in response to LH and EGF receptor activation. In addition, these studies provide the first demonstration that a change in phosphorylation of a transmembrane guanylyl cyclase regulates a physiological process, a mechanism that may also control other developmental events. PMID:26522847

Genome expression analyses revealing the modulation of the Salmonella Rcs regulon by the attenuator IgaA.

PubMed

Mariscotti, Javier F; García-del Portillo, Francisco

2009-03-01

Intracellular growth attenuator A (IgaA) was identified as a Salmonella enterica regulator limiting bacterial growth inside fibroblasts. Genetic evidence further linked IgaA to repression of the RcsCDB regulatory system, which responds to envelope stress. How IgaA attenuates this system is unknown. Here, we present genome expression profiling data of S. enterica serovar Typhimurium igaA mutants grown at high osmolarity and displaying exacerbated Rcs responses. Transcriptome data revealed that IgaA attenuates gene expression changes requiring phosphorylated RcsB (RcsB~P) activity. Some RcsB-regulated genes, yciGFE and STM1862 (pagO)-STM1863-STM1864, were equally expressed in wild-type and igaA strains, suggesting a maximal expression at low levels of RcsB ~P. Other genes, such as metB, ypeC, ygaC, glnK, glnP, napA, glpA, and nirB, were shown for the first time and by independent methods to be regulated by the RcsCDB system. Interestingly, IgaA-deficient strains with reduced RcsC or RcsD levels exhibited different Rcs responses and distinct virulence properties. spv virulence genes were differentially expressed in most of the analyzed strains. spvA expression required RcsB and IgaA but, unexpectedly, was also impaired upon stimulation of the RcsC-->RcsD-->RcsB phosphorelay. Overproduction of either RcsB(+) or a nonphosphorylatable RcsB(D56Q) variant in strains displaying low spvA expression unveiled that both dephosphorylated RcsB and RcsB~P are required for optimal spvA expression. Taken together, our data support a model with IgaA attenuating the RcsCDB system by favoring the switch of RcsB~P to the dephosphorylated state. This role of IgaA in constantly fine-tuning the RcsB~P/RcsB ratio may ensure the proper expression of important virulence factors, such as the Spv proteins.

Biosafety considerations for attenuated measles virus vectors used in virotherapy and vaccination

PubMed Central

Baldo, Aline; Galanis, Evanthia; Tangy, Frédéric; Herman, Philippe

2016-01-01

ABSTRACT Attenuated measles virus (MV) is one of the most effective and safe vaccines available, making it attractive candidate vector to prevent infectious diseases. Attenuated MV have acquired the ability to use the complement regulator CD46 as a major receptor to mediate virus entry and intercellular fusion. Therefore, attenuated MV strains preferentially infect and destroy a wide variety of cancer cells making them also attractive oncolytic vectors. The use of recombinant MV vector has to comply with various regulatory requirements, particularly relating to the assessment of potential risks for human health and the environment. The present article highlights the main characteristics of MV and recombinant MV vectors used for vaccination and virotherapy and discusses these features from a biosafety point of view. PMID:26631840

Short-term dopaminergic regulation of GABA release in dopamine deafferented caudate-putamen is not directly associated with glutamic acid decarboxylase gene expression.

PubMed

O'Connor, W T; Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H; Ungerstedt, U

1991-07-08

In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of gamma-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 microM) for 3 h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.

The calcium-binding protein ALG-2 regulates protein secretion and trafficking via interactions with MISSL and MAP1B proteins.

PubMed

Takahara, Terunao; Inoue, Kuniko; Arai, Yumika; Kuwata, Keiko; Shibata, Hideki; Maki, Masatoshi

2017-10-13

Mobilization of intracellular calcium is essential for a wide range of cellular processes, including signal transduction, apoptosis, and vesicular trafficking. Several lines of evidence have suggested that apoptosis-linked gene 2 (ALG-2, also known as PDCD6 ), a calcium-binding protein, acts as a calcium sensor linking calcium levels with efficient vesicular trafficking, especially at the endoplasmic reticulum (ER)-to-Golgi transport step. However, how ALG-2 regulates these processes remains largely unclear. Here, we report that M APK1- i nteracting and s pindle- s tabilizing (MISS)- l ike (MISSL), a previously uncharacterized protein, interacts with ALG-2 in a calcium-dependent manner. Live-cell imaging revealed that upon a rise in intracellular calcium levels, GFP-tagged MISSL (GFP-MISSL) dynamically relocalizes in a punctate pattern and colocalizes with ALG-2. MISSL knockdown caused disorganization of the components of the ER exit site, the ER-Golgi intermediate compartment, and Golgi. Importantly, knockdown of either MISSL or ALG-2 attenuated the secretion of se creted a lkaline p hosphatase (SEAP), a model secreted cargo protein, with similar reductions in secretion by single- and double-protein knockdowns, suggesting that MISSL and ALG-2 act in the same pathway to regulate the secretion process. Furthermore, ALG-2 or MISSL knockdown delayed ER-to-Golgi transport of procollagen type I. We also found that ALG-2 and MISSL interact with microtubule-associated protein 1B (MAP1B) and that MAP1B knockdown reverts the reduced secretion of SEAP caused by MISSL or ALG-2 depletion. These results suggest that a change in the intracellular calcium level plays a role in regulation of the secretory pathway via interaction of ALG-2 with MISSL and MAP1B. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia–Reperfusion Injury in Mice

PubMed Central

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Zhang, Xiaoyan; Bosnjak, Zeljko J.; Liang, Mingyu; Ding, Xiaoqiang

2015-01-01

Background MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Methods Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Results Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti–miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti–miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. Conclusions These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning. PMID:23681145

miR-21 contributes to xenon-conferred amelioration of renal ischemia-reperfusion injury in mice.

PubMed

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Zhang, Xiaoyan; Bosnjak, Zeljko J; Liang, Mingyu; Ding, Xiaoqiang

2013-09-01

MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti-miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti-miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.

31 CFR 361.1 - Scope of regulations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 361.1 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE... (hereafter consignors). Failure by any consignor or agent or employee thereof to comply with these regulations may delay recoveries, preclude reimbursement from the fund for the payment of Government losses in...

Effects of regulation on drug launch and pricing in interdependent markets.

PubMed

Danzon, Patricia M; Epstein, Andrew J

2012-01-01

This study examines the effect of price regulation and competition on launch timing and pricing of new drugs. Our data cover launch experience in 15 countries from 1992 to 2003 for drugs in 12 major therapeutic classes. We estimate a two-equation model of launch hazard and launch price of new drugs. We find that launch timing and prices of new drugs are related to a country's average prices of established products in a class. Thus to the extent that price regulation reduces price levels, such regulation directly contributes to launch delay in the regulating country. Regulation by external referencing, whereby high-price countries reference low-price countries, also has indirect or spillover effects, contributing to launch delay and higher launch prices in low-price referenced countries. Referencing policies adopted in high-price countries indirectly impose welfare loss on low-price countries. These findings have implications for US proposals to constrain pharmaceutical prices through external referencing and drug importation.

pyr RNA binding to the Bacillus caldolyticus PyrR attenuation protein. Characterization and regulation by uridine and guanosine nucleotides

PubMed Central

Jørgensen, Casper Møller; Fields, Christopher J.; Chander, Preethi; Watt, Desmond; Burgner, John W.; Smith, Janet L.; Switzer, Robert L.

2011-01-01

Summary The PyrR protein regulates expression of pyrimidine biosynthetic (pyr) genes in many bacteria. PyrR binds to specific sites in the 5’ leader RNA of target operons and favors attenuation of transcription. Filter binding and gel mobility assays were used to characterize the binding of PyrR from Bacillus caldolyticus to RNA sequences (binding loops) from the three attenuation regions of the B. caldolyticus pyr operon. Binding of PyrR to the three binding loops and modulation of RNA binding by nucleotides was similar for all three RNAs. Apparent dissociation constants at 0° C ranged from 0.13 to 0.87 nM in the absence of effectors; dissociation constants were decreased by 3 to 12 fold by uridine nucleotides and increased by 40 to 200 fold by guanosine nucleotides. The binding data suggest that pyr operon expression is regulated by the ratio of intracellular uridine nucleotides to guanosine nucleotides; the effects of nucleoside addition to the growth medium on aspartate transcarbamylase (pyrB) levels in B. subtilis cells in vivo supported this conclusion. Analytical ultracentrifugation established that RNA binds to dimeric PyrR, even though the tetrameric form of unbound PyrR predominates in solution at the concentrations studied. PMID:18190533

Luteolin attenuates TGF-β1-induced epithelial-mesenchymal transition of lung cancer cells by interfering in the PI3K/Akt-NF-κB-Snail pathway.

PubMed

Chen, Kun-Chieh; Chen, Chiu-Yuan; Lin, Chih-Ru; Lin, Chih-Ju; Yang, Tsung-Ying; Chen, Tzu-Hsiu; Wu, Li-Chen; Wu, Chun-Chi

2013-12-05

Luteolin is a natural flavonoid that possesses a variety of pharmacological activities, such as anti-inflammatory and anti-cancer abilities. Whether luteolin regulates the transformation ability of lung cancer cells remains unclear. The current study aims to uncover the effects and underlying mechanisms of luteolin in regulation of and epithelial-mesenchymal transition of lung cancer cells. The lung adenocarcinoma A549 cells were used in this experiment; the cells were pretreated with luteolin followed by administration with TGF-β1. The expression levels of various cadherin and related upstream regulatory modules were examined. Pretreatment of luteolin prevented the morphological change and downregulation of E-cadherin of A549 cells induced by TGF-β1. In addition, the activation of PI3K-Akt-IκBa-NF-κB-Snail pathway which leads to the decline of E-cadherin induced by TGF-β1 was also attenuated under the pretreatment of luteolin. We provide the mechanisms about how luteolin attenuated the epithelial-mesenchymal transition of A549 lung cancer cells induced by TGF-β1. This finding will strengthen the anti-cancer effects of flavonoid compounds via the regulation of migration/invasion and EMT ability of various cancer cells. © 2013.

Adolescent Changes in the Homeostatic and Circadian Regulation of Sleep

PubMed Central

Hagenauer, M.H.; Perryman, J.I.; Lee, T.M.; Carskadon, M.A.

2009-01-01

Sleep deprivation among adolescents is epidemic. We argue that this sleep deprivation is due in part to pubertal changes in the homeostatic and circadian regulation of sleep. These changes promote a delayed sleep phase that is exacerbated by evening light exposure and incompatible with aspects of modern society, notably early school start times. In this review of human and animal literature, we demonstrate that delayed sleep phase during puberty is likely a common phenomenon in mammals, not specific to human adolescents, and we provide insight into the mechanisms underlying this phenomenon. PMID:19546564

Monitoring of KrF excimer laser ablation for burn scars: a comparative study of transient reflection measurement and time-resolved photography of ablation plume

NASA Astrophysics Data System (ADS)

Nakajima, Akio; Arai, Tsunenori; Kikuchi, Makoto; Iwaya, Akimi; Arai, Katsuyuki; Inazaki, Satoshi; Takaoka, Takatsugu; Kato, Masayoshi

1995-05-01

A simple laser ablation monitoring during burn scar removal by KrF laser irradiation was studied to control laser fluence in real-time. Because, to obtain suitable surface for auto skin-graft, the laser fluence should be precisely controlled at each laser shot. We employed simple probe transmission method which could detect ejected material/phenomena from irradiated surface. The time-course of measured probe intensity contained a couple of attenuated peaks, which might corresponded to a shock wave front and debris plume. The delay time from laser irradiation to the debris plume peak appearance varied with the ablation fluence. The delay time of 1 J/cm2 (near ablation threshold) case prolonged 25% from 8 J/cm2 (far above threshold) case. Therefore, we think the delay time measurement by means of the simple probe transmission method may be available to attain the laser fluence control for nonuniform burn scar removal. The time-resolved photography and probe reflection method were also studied to understand the measured time-course of the transmitted probe intensity.

Effect of centrally administered C75, a fatty acid synthase inhibitor, on gastric emptying and gastrointestinal transit in mice.

PubMed

Li, Lai-Fu; Lu, Yan-Yu; Xiong, Wei; Liu, Juan-Ying; Chen, Qiang

2008-10-24

The central or systemic administration of 3-carboxy-4-octyl-2-methylenebutyrolactone (C75), a synthetic inhibitor of fatty acid synthase (FAS), causes anorexia and profound weight loss in rodents. The amount of food intake and gastrointestinal mobility are closely related. In this study, an attempt has been made to investigate the effects and mechanisms of C75 on gastric emptying and gastrointestinal transit after intracerebroventricular (i.c.v.) injection in mice. Our data showed that C75 (1, 5, 10 microg/mouse) dose-dependently delayed gastric emptying and gastrointestinal transit in fasted mice. 10 microg C75 delayed gastric emptying by about 21.4% and reduced gastrointestinal transit by about 31.0% compared with vehicle control group. Administration (i.c.v.) of 5-(tetradecyloxy)-2-furoic acid (TOFA, an acetyl-CoA carboxylase (ACC) inhibitor) or ghrelin attenuated the delayed gastrointestinal mobility effect induced by 10 microg C75. Taken together, C75 is able to decrease gastrointestinal mobility and it seems possible that malonyl-CoA and ghrelin might play an intermediary role in these processes.

A rare case of short stature: Say Meyer syndrome.

PubMed

Karthik, T S; Prasad, N Rajendra; Rani, P Radha; Maheshwari, Rushikesh; Reddy, P Amaresh; Chakradhar, B V S; Menon, Bindu

2013-10-01

Say Meyer syndrome is rare X linked condition characterized by developmental delay, short stature and metopic suture synostosis. We are reporting a case of Say Meyer syndrome presented to our hospital for short stature and developmental delay at age 3½ years. A 3½-year-old boy presented to our hospital for decreased growth velocity from the age of 1 year. History revealed the boy had a birth weight of 2.3 kg, had an episode of seizures in the neonatal period. He was born to non-consanguineous marriage. He had global developmental delay and there was a lack of bowel and bladder control. History did not reveal any hearing or visual impairment. No history of any chronic systemic illnesses. Magnetic resonance imaging (MRI) brain revealed mild diffuse frontotemporal atrophy with multiple irregular gliotic areas in bilateral frontal lobes. Diffuse white matter volume loss in bilateral cerebral hemispheres. Diffuse thinning of corpus callosum. Diffuse periventricular hyper intensity on T2W and fluid attenuated inversion recovery sequences. Say Meyer syndrome is rare X linked condition characterized by developmental delay, short stature and metopic suture synostosis. Characteristic MRI brain findings include diffuse frontotemporal atrophy with multiple gliotic areas in frontal lobes. Diffuse white matter volume loss in bilateral cerebral hemispheres.

A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in attention-deficit/hyperactivity disorder boys and siblings.

PubMed

Sonuga-Barke, Edmund J S; Kumsta, Robert; Schlotz, Wolff; Lasky-Su, Jessica; Marco, Rafaela; Miranda, Ana; Mulas, Fernando; Oades, Robert D; Banaschewski, Tobias; Mueller, Ueli; Andreou, Penny; Christiansen, Hanna; Gabriels, Isabel; Uebel, Henrik; Kuntsi, Jonna; Franke, Barbara; Buitelaar, Jan; Ebstein, Richard; Gill, Michael; Anney, Richard; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Asherson, Philip; Faraone, Stephen V

2011-08-01

Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in attention-deficit/hyperactivity disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion would be associated with serotonin-regulating genes. Impulsive drive for immediate reward and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) with a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter serotonin-transporter-linked polymorphic region polymorphism and a DAT1 (SLC6A3) 40-base pair variable number tandem repeat located in the 3'-untranslated region of the gene. There was no effect of dopamine transporter (DAT)1 on IDIR. As predicted, serotonin-transporter-linked polymorphic region s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G single nucleotide polymorphism and were independent of age, IQ, and oppositional defiant disorder symptoms. The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

CT Evaluation of the progression of hypoattenuating nodular lesions in virus-related chronic liver disease.

PubMed

Takayasu, Kenichi; Muramatsu, Yukio; Mizuguchi, Yasunori; Okusaka, Takuji; Shimada, Kazuaki; Takayama, Tadatoshi; Sakamoto, Michiie

2006-08-01

The purpose of this study was to clarify the natural outcomes of hypoattenuating nodular lesions in patients with virus-related chronic liver disease depicted on dynamic CT. Sixty lesions (mean size, 1.3 cm) exhibiting hypoattenuation or isoattenuation in the arterial and delayed phases of dynamic CT were retrospectively evaluated with additional CT (mean, six examinations) for a mean period of 838 days. The primary end point was emergence of hyperattenuating areas within hypoattenuating lesions, a phenomenon called attenuation conversion. Cumulative attenuation conversion rates suggesting rates of malignant transformation were calculated with the Kaplan-Meier method, and factors affecting attenuation conversion rate were analyzed with the Cox proportional hazard model. Thirty-six (60%) of 60 hypoattenuating lesions developed to hyperattenuating lesions, 21 were unchanged, and three disappeared spontaneously. The 36 lesions that became hyperattenuating were divided into two subgroups according to lesion enhancement pattern: hyper-in-hypoattenuating (n = 25) and entirely hyperattenuating (n = 11). The cumulative attenuation conversion rates for the 60 hypoattenuating lesions were 15.8%, 44.3%, and 58.7% at 1, 2, and 3 years. The hyper-in-hypoattenuating lesions showed more rapid progression to entirely enhanced lesions. Positive results for hepatitis C viral antibody (p = 0.028) and initial lesion size (p = 0.007) showed a positive correlation with attenuation conversion rate. Hypoattenuating hepatic nodular lesions in chronic liver disease depicted on dynamic CT have high malignant potential and should be followed with special attention to conversion from hypoattenuation to hyperattenuation to determine the optimal timing of treatment.

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

PubMed Central

Bonaldo, Myrna C.; Garratt, Richard C.; Marchevsky, Renato S.; Coutinho, Evandro S. F.; Jabor, Alfredo V.; Almeida, Luís F. C.; Yamamura, Anna M. Y.; Duarte, Adriana S.; Oliveira, Prisciliana J.; Lizeu, Jackeline O. P.; Camacho, Luiz A. B.; Freire, Marcos S.; Galler, Ricardo

2005-01-01

The yellow fever (YF) 17D vaccine is a live attenuated virus. Three-dimensional (3D) homology modeling of the E protein structure from YF 17D virus and its comparison with that from tick-borne encephalitis virus revealed that it is possible to accommodate inserts of different sizes and amino acid compositions in the flavivirus E protein fg loop. This is consistent with the 3D structures of both the dimeric and trimeric forms in which the fg loop lies exposed to solvents. We demonstrate here that YF 17D viruses bearing foreign humoral (17D/8) and T-cell (17D/13) epitopes, which vary in sequence and length, displayed growth restriction. It is hypothesized that interference with the dimer-trimer transition and with the formation of a ring of such trimers in order to allow fusion compromises the capability of the E protein to induce fusion of viral and endosomal membranes, and a slower rate of fusion may delay the extent of virus production. This would account for the lower levels of replication in cultured cells and of viremia in monkeys, as well as for the more attenuated phenotype of the recombinant viruses in monkeys. Testing of both recombinant viruses (17D/8 and 17D/13) for monkey neurovirulence also suggests that insertion at the 17D E protein fg loop does not compromise the attenuated phenotype of YF 17D virus, further confirming the potential use of this site for the development of new live attenuated 17D virus-based vaccines. PMID:15956601

Phase-Shifted Based Numerical Method for Modeling Frequency-Dependent Effects on Seismic Reflections

NASA Astrophysics Data System (ADS)

Chen, Xuehua; Qi, Yingkai; He, Xilei; He, Zhenhua; Chen, Hui

2016-08-01

The significant velocity dispersion and attenuation has often been observed when seismic waves propagate in fluid-saturated porous rocks. Both the magnitude and variation features of the velocity dispersion and attenuation are frequency-dependent and related closely to the physical properties of the fluid-saturated porous rocks. To explore the effects of frequency-dependent dispersion and attenuation on the seismic responses, in this work, we present a numerical method for seismic data modeling based on the diffusive and viscous wave equation (DVWE), which introduces the poroelastic theory and takes into account diffusive and viscous attenuation in diffusive-viscous-theory. We derive a phase-shift wave extrapolation algorithm in frequencywavenumber domain for implementing the DVWE-based simulation method that can handle the simultaneous lateral variations in velocity, diffusive coefficient and viscosity. Then, we design a distributary channels model in which a hydrocarbon-saturated sand reservoir is embedded in one of the channels. Next, we calculated the synthetic seismic data to analytically and comparatively illustrate the seismic frequency-dependent behaviors related to the hydrocarbon-saturated reservoir, by employing DVWE-based and conventional acoustic wave equation (AWE) based method, respectively. The results of the synthetic seismic data delineate the intrinsic energy loss, phase delay, lower instantaneous dominant frequency and narrower bandwidth due to the frequency-dependent dispersion and attenuation when seismic wave travels through the hydrocarbon-saturated reservoir. The numerical modeling method is expected to contribute to improve the understanding of the features and mechanism of the seismic frequency-dependent effects resulted from the hydrocarbon-saturated porous rocks.

Composite Robust $$H_\\infty$$ Control for Uncertain Stochastic Nonlinear Systems with State Delay via Disturbance Observer

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

Liu, Yunlong; Wang, Hong; Guo, Lei

Here in this note, the robust stochastic stabilization and robust H_infinity control problems are investigated for uncertain stochastic time-delay systems with nonlinearity and multiple disturbances. By estimating the disturbance, which can be described by an exogenous model, a composite hierarchical control scheme is proposed that integrates the output of the disturbance observer with state feedback control law. Sufficient conditions for the existence of the disturbance observer and composite hierarchical controller are established in terms of linear matrix inequalities, which ensure the mean-square asymptotic stability of the resulting closed-loop system and the disturbance attenuation. It has been shown that the disturbancemore » rejection performance can also be achieved. A numerical example is provided to show the potential of the proposed techniques and encouraging results have been obtained.« less

Frequency hopping due to acousto-electric interaction in ZnO based surface acoustic wave oscillator

NASA Astrophysics Data System (ADS)

Dasgupta, Daipayan; Sreenivas, K.

2011-08-01

A 36 MHz surface acoustic wave delay line based oscillator has been used to study the effect of acousto-electric interaction due to photo generated charge carriers in rf sputtered ZnO film under UV illumination (λ = 365 nm, 20-100 μW/cm2). Design aspects for developing a delay line based SAW oscillator are specified. The observed linear downshift in frequency (2.2 to 19.0 kHz) with varying UV intensity (20-100 μW/cm2) is related to the fractional velocity change due to acousto-electric interaction. UV illumination level of 100 μW/cm2 leads to a characteristic frequency hopping behavior arising due to a change in the oscillation criteria, and is attributed to the complex interplay between the increased attenuation and velocity shift.

Composite Robust $$H_\\infty$$ Control for Uncertain Stochastic Nonlinear Systems with State Delay via Disturbance Observer

DOE PAGES

Liu, Yunlong; Wang, Hong; Guo, Lei

2018-03-26

Here in this note, the robust stochastic stabilization and robust H_infinity control problems are investigated for uncertain stochastic time-delay systems with nonlinearity and multiple disturbances. By estimating the disturbance, which can be described by an exogenous model, a composite hierarchical control scheme is proposed that integrates the output of the disturbance observer with state feedback control law. Sufficient conditions for the existence of the disturbance observer and composite hierarchical controller are established in terms of linear matrix inequalities, which ensure the mean-square asymptotic stability of the resulting closed-loop system and the disturbance attenuation. It has been shown that the disturbancemore » rejection performance can also be achieved. A numerical example is provided to show the potential of the proposed techniques and encouraging results have been obtained.« less

Attention Regulation in Low-Risk Very Low Birth Weight Preschoolers: The Influence of Child Temperament and Parental Sensitivity

ERIC Educational Resources Information Center

Davis, Deborah Winders; Harris, Ruby Carrie; Burns, Barbara M.

2010-01-01

Even in the absence of major disabilities, children born prematurely are at high risk for academic delays and deficits. Research suggests that some differences in outcomes may relate to problems with self-regulation, especially attention regulation. Previous research has demonstrated that individual differences in attention regulation is…

77 FR 13971 - Regulated Navigation Area; MBTA Saugus River Railroad Drawbridge Rehabilitation Project, Saugus...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-08

.... Wright, Program Manager, Docket Operations, telephone 202-366-9826. SUPPLEMENTARY INFORMATION: Public... MBTA has instituted single track operation, a reduction of speed, and prohibited braking on the bridge... the bridge. The delay of necessary repair operations would result in increased costs, delay the date...

48 CFR 252.219-7011 - Notification to delay performance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... begin performance under this purchase order until 2 working days have passed from the date of its... performance. 252.219-7011 Section 252.219-7011 Federal Acquisition Regulations System DEFENSE ACQUISITION... of Provisions And Clauses 252.219-7011 Notification to delay performance. As prescribed in 219.811-3...

17 CFR 230.251 - Scope of exemption.

Code of Federal Regulations, 2010 CFR

2010-04-01

... consideration must be reasonable at the time made. (c) Integration with other offerings. Offers and sales made... dealers with reasonable quantities of the offering circular for this purpose. (3) Continuous or delayed offerings. Continuous or delayed offerings may be made under this Regulation A if permitted by § 230.415. ...

Self-Regulation of Learning and Academic Delay of Gratification: Individual Differences among College Students.

ERIC Educational Resources Information Center

Bembenutty, Hefer

This study examined whether there were gender and ethnic differences in students' willingness to delay gratification, intrinsic and extrinsic motivation, self-efficacy beliefs, use of cognitive strategies (such as rehearsal, organization, elaboration, and metacognition), and use of learning strategies (help seeking, time management, effort…

Identification and In-vivo Characterization of a Novel OhrR Transcriptional Regulator in Burkholderia xenovorans LB400

DOE PAGES

Nguyen, Tinh T.; Martí-Arbona, Ricardo; Hall, Richard S.; ...

2013-05-21

Transcriptional regulators (TRs) are an important and versatile group of proteins, yet very little progress has been achieved towards the discovery and annotation of their biological functions. We have characterized a previously unknown organic hydroperoxide resistance regulator from Burkholderia xenovoransLB400, Bxe_B2842, which is homologous to E. coli’s OhrR. Bxe_B2842 regulates the expression of an organic hydroperoxide resistance protein (OsmC). We utilized frontal affinity chromatography coupled with mass spectrometry (FAC-MS) and electrophoretic mobility gel shift assays (EMSA) to identify and characterize the possible effectors of the regulation by Bxe_B2842. Without an effector, Bxe_B2842 binds a DNA operator sequence (DOS) upstream ofmore » osmC. FAC-MS results suggest that 2-aminophenol binds to the protein and is potentially an effector molecule. EMSA analysis shows that 2-aminophenol also attenuates the Bxe_B2842’s affinity for its DOS. EMSA analysis also shows that organic peroxides attenuate Bxe_B2842/DOS affinity, suggesting that binding of the TR to its DOS is regulated by the two-cysteine mechanism, common to TRs in this family. Bxe_B2842 is the first OhrR TR to have both oxidative and effector-binding mechanisms of regulation. Our paper reveals further mechanistic diversity TR mediated gene regulation and provides insights into methods for function discovery of TRs.« less

Differential Regulation of Multiple Steps in Inositol 1,4,5-Trisphosphate Signaling by Protein Kinase C Shapes Hormone-stimulated Ca2+ Oscillations*

PubMed Central

Bartlett, Paula J.; Metzger, Walson; Gaspers, Lawrence D.; Thomas, Andrew P.

2015-01-01

How Ca2+ oscillations are generated and fine-tuned to yield versatile downstream responses remains to be elucidated. In hepatocytes, G protein-coupled receptor-linked Ca2+ oscillations report signal strength via frequency, whereas Ca2+ spike amplitude and wave velocity remain constant. IP3 uncaging also triggers oscillatory Ca2+ release, but, in contrast to hormones, Ca2+ spike amplitude, width, and wave velocity were dependent on [IP3] and were not perturbed by phospholipase C (PLC) inhibition. These data indicate that oscillations elicited by IP3 uncaging are driven by the biphasic regulation of the IP3 receptor by Ca2+, and, unlike hormone-dependent responses, do not require PLC. Removal of extracellular Ca2+ did not perturb Ca2+ oscillations elicited by IP3 uncaging, indicating that reloading of endoplasmic reticulum stores via plasma membrane Ca2+ influx does not entrain the signal. Activation and inhibition of PKC attenuated hormone-induced Ca2+ oscillations but had no effect on Ca2+ increases induced by uncaging IP3. Importantly, PKC activation and inhibition differentially affected Ca2+ spike frequencies and kinetics. PKC activation amplifies negative feedback loops at the level of G protein-coupled receptor PLC activity and/or IP3 metabolism to attenuate IP3 levels and suppress the generation of Ca2+ oscillations. Inhibition of PKC relieves negative feedback regulation of IP3 accumulation and, thereby, shifts Ca2+ oscillations toward sustained responses or dramatically prolonged spikes. PKC down-regulation attenuates phenylephrine-induced Ca2+ wave velocity, whereas responses to IP3 uncaging are enhanced. The ability to assess Ca2+ responses in the absence of PLC activity indicates that IP3 receptor modulation by PKC regulates Ca2+ release and wave velocity. PMID:26078455

Dynamics and Synchronization of Nonlinear Oscillators with Time Delays: A Study with Fiber Lasers

DTIC Science & Technology

2007-07-19

or coupling lines PC Polarization Controller PD Photodetector VA Variable Attenuator WDM Wavelength Division Multiplexer x Chapter 1 Introduction 1.1...lasers and detectors. Injection locking of lasers is a common practice that can be used to lock the frequency and phase of a laser to an injected signal...finding a basis vector that maximizes the mean squared projection of the data. Succeeding basis vectors are found that max- imize the projection with the

Synthetic Lg Attenuation on Moho Structure and Group Velocity on Source Depth

NASA Astrophysics Data System (ADS)

Hui, H.; Sandvol, E. A.; Ku, W.

2016-12-01

The regional phase Lg has been the subject of many studies due to its ability to reliably estimate source magnitude and to characterize crustal attenuation, however, the relationship between effective Lg Q and the true intrinsic attenuation of the crust is not well understood. We are working to investigate this relationship by conducting a number of numerical experiments to better understand the nature of Lg scattering attenuation for different type of crustal models. We have partitioned our models by 8-nodes hexahedral meshes with SPECFEM3D-Cartesian which is based on the Spectral Element Method. We have used a time step of 0.01 s to make the simulation stable at high frequencies sufficient enough for our study (about 1.0 Hz). It takes about 50 hours for each model running with 324 processors to generate the waveforms. Then we calculate the effective Lg Q with a Two-Station Method. In order to test our method, we have calculated effective Lg Q tomography for a 2-D model with laterally varying intrinsic attenuation and layered velocity. The tomography result matches the input attenuation model very well. We studied effective Lg Q of models with different Moho structures (flat and with a step) and found that Moho step would lead to lower effective Lg Q than that of flat Moho. Furthermore, we have studied the effective Lg Q tomography of model with 3-D Moho structure and found that effective Lg Q is lower at the area of Moho depth changing than that of flat Moho. This is likely caused by scattering attenuation. We have also modeled the group velocity delay of high frequency (1.0 Hz) Lg, which appears to be dependent on source depth (6km, 10km, 15km and 30km). We have found that the Lg energy arrives later for shallow sources than that of deeper sources which is consistent with prior studies. In the future, we plan to conduct more 3-D attenuation models to investigate azimuthally dependent effective Lg Q.

Oscillatory regulation of Hes1: Discrete stochastic delay modelling and simulation.

PubMed

Barrio, Manuel; Burrage, Kevin; Leier, André; Tian, Tianhai

2006-09-08

Discrete stochastic simulations are a powerful tool for understanding the dynamics of chemical kinetics when there are small-to-moderate numbers of certain molecular species. In this paper we introduce delays into the stochastic simulation algorithm, thus mimicking delays associated with transcription and translation. We then show that this process may well explain more faithfully than continuous deterministic models the observed sustained oscillations in expression levels of hes1 mRNA and Hes1 protein.

Erratum: Sources of Image Degradation in Fundamental and Harmonic Ultrasound Imaging: A Nonlinear, Full-Wave, Simulation Study

PubMed Central

Pinton, Gianmarco F.; Trahey, Gregg E.; Dahl, Jeremy J.

2015-01-01

A full-wave equation that describes nonlinear propagation in a heterogeneous attenuating medium is solved numerically with finite differences in the time domain. This numerical method is used to simulate propagation of a diagnostic ultrasound pulse through a measured representation of the human abdomen with heterogeneities in speed of sound, attenuation, density, and nonlinearity. Conventional delay-and-sum beamforming is used to generate point spread functions (PSFs) that display the effects of these heterogeneities. For the particular imaging configuration that is modeled, these PSFs reveal that the primary source of degradation in fundamental imaging is due to reverberation from near-field structures. Compared with fundamental imaging, reverberation clutter in harmonic imaging is 27.1 dB lower. Simulated tissue with uniform velocity but unchanged impedance characteristics indicates that for harmonic imaging, the primary source of degradation is phase aberration. PMID:21693410

Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils.

PubMed

Min, Dongyu; Mao, Xiaoyuan; Wu, Kuncan; Cao, Yonggang; Guo, Feng; Zhu, Shu; Xie, Ni; Wang, Lei; Chen, Tianbao; Shaw, Chris; Cai, Jiqun

2012-02-21

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Information-Efficient Spectral Imaging Sensor With Tdi

DOEpatents

Rienstra, Jeffrey L.; Gentry, Stephen M.; Sweatt, William C.

2004-01-13

A programmable optical filter for use in multispectral and hyperspectral imaging employing variable gain time delay and integrate arrays. A telescope focuses an image of a scene onto at least one TDI array that is covered by a multispectral filter that passes separate bandwidths of light onto the rows in the TDI array. The variable gain feature of the TDI array allows individual rows of pixels to be attenuated individually. The attenuations are functions of the magnitudes of the positive and negative components of a spectral basis vector. The spectral basis vector is constructed so that its positive elements emphasize the presence of a target and its negative elements emphasize the presence of the constituents of the background of the imaged scene. This system provides for a very efficient determination of the presence of the target, as opposed to the very data intensive data manipulations that are required in conventional hyperspectral imaging systems.

Substance Use to Cope with Stigma in Healthcare Among U.S. Female-to-Male Trans Masculine Adults.

PubMed

Reisner, Sari L; Pardo, Seth T; Gamarel, Kristi E; White Hughto, Jaclyn M; Pardee, Dana J; Keo-Meier, Colton L

2015-12-01

Enacted and anticipated stigma exist within healthcare settings for transgender people, but research has yet to examine the effects of these forms of stigma on the substance use behaviors of female-to-male (FTM) trans masculine people. Data were analyzed from the cross-sectional U.S. National Transgender Discrimination Survey, a convenience sample of transgender adults purposively sampled in 2008. Trans masculine respondents (n=2,578) were identified using a two-step method: Step 1, Assigned birth sex; Step 2, Current gender identity. A gender minority stress model of substance use was tested to examine the relation of enacted and anticipated stigma with substance use to cope with mistreatment. Overall, 14.1% of the sample reported having been refused care by a provider (enacted stigma), 32.8% reported delaying needed medical care when sick/injured, and 39.1% delayed routine preventive care (anticipated stigma). Having been refused care was significantly associated with avoidance of healthcare, including delaying needed medical care when sick/injured and delaying routine preventive medical care. Substance use to cope with mistreatment was self-reported by 27.6% of the sample. Enacted stigma by providers was associated with self-reported substance use to cope. Delays in both needed and preventive care (anticipated stigma) were highly associated with substance use, and attenuated the effect of enacted stigma. Gender minority-related stressors, particularly enacted and anticipated stigma in healthcare, should be integrated into substance use and abuse prevention and intervention efforts with this underserved population.

77 FR 46286 - Drawbridge Operation Regulation; Bayou Boeuf, Amelia, LA

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-03

... Operation Regulation; Bayou Boeuf, Amelia, LA AGENCY: Coast Guard, DHS. ACTION: Delay of effective date for temporary deviation from regulations. SUMMARY: The Coast Guard is modifying the effective date of a... (BNSF) Railway Company swing span bridge across Bayou Boeuf, mile 10.2, at Amelia, St. Mary Parish...

Inhibition of transforming growth factor-β attenuates brain injury and neurological deficits in a rat model of germinal matrix hemorrhage.

PubMed

Manaenko, Anatol; Lekic, Tim; Barnhart, Margaret; Hartman, Richard; Zhang, John H

2014-03-01

Transforming growth factor-β (TGF-β) overproduction and activation of the TGF-β pathway are associated with the development of brain injury following germinal matrix hemorrhage (GMH) in premature infants. We examined the effects of GMH on the level of TGF-β1 in a novel rat collagenase-induced GMH model and determined the effect of inhibition of the TGF receptor I. In total, 92 seven-day old (P7) rats were used. Time-dependent effects of GMH on the level of TGF-β1 and TGF receptor I were evaluated by Western blot. A TGF receptor I inhibitor (SD208) was administered daily for 3 days, starting either 1 hour or 3 days after GMH induction. The effects of GMH and SD208 on the TGF-β pathway were evaluated by Western blot at day 3. The effects of GMH and SD208 on cognitive and motor function were also assessed. The effects of TGF receptor I inhibition by SD208 on GMH-induced brain injury and underlying molecular pathways were investigated by Western blot, immunofluorescence, and morphology studies 24 days after GMH. GMH induced significant delay in development, caused impairment in both cognitive and motor functions, and resulted in brain atrophy in rat subjects. GMH also caused deposition of both vitronectin (an extracellular matrix protein) and glial fibrillary acidic protein in perilesion areas, associated with development of hydrocephalus. SD208 ameliorated GMH-induced developmental delay, improved cognitive and motor functions, and attenuated body weight loss. SD208 also decreased vitronectin and glial fibrillary acidic protein deposition and decreased GMH-induced brain injury. Increased level of TGF-β1 and activation of the TGF-β pathway associate with the development of brain injury after GMH. SD208 inhibits GMH-induced activation of the TGF-β pathway and leads to an improved developmental profile, partial recovery of cognitive and motor functions, and attenuation of GMH-induced brain atrophy and hydrocephalus.

Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension.

PubMed

Fowler, Ewan D; Drinkhill, Mark J; Norman, Ruth; Pervolaraki, Eleftheria; Stones, Rachel; Steer, Emma; Benoist, David; Steele, Derek S; Calaghan, Sarah C; White, Ed

2018-07-01

Right heart failure is the major cause of death in Pulmonary Artery Hypertension (PAH) patients but is not a current, specific therapeutic target. Pre-clinical studies have shown that adrenoceptor blockade can improve cardiac function but the mechanisms of action within right ventricular (RV) myocytes are unknown. We tested whether the β 1 -adrenoceptor blocker metoprolol could improve RV myocyte function in an animal model of PAH, by attenuating adverse excitation-contraction coupling remodeling. PAH with RV failure was induced in rats by monocrotaline injection. When PAH was established, animals were given 10 mg/kg/day metoprolol (MCT + BB) or vehicle (MCT). The median time to the onset of heart failure signs was delayed from 23 days (MCT), to 31 days (MCT + BB). At 23 ± 1 days post-injection, MCT + BB showed improved in vivo cardiac function, measured by echocardiography. RV hypertrophy was reduced despite persistent elevated afterload. RV myocyte contractility during field stimulation was improved at higher pacing frequencies in MCT + BB. Preserved t-tubule structure, more uniform evoked Ca 2+ release, increased SERCA2a expression and faster ventricular repolarization (measured in vivo by telemetry) may account for the improved contractile function. Sarcoplasmic reticulum Ca 2+ overload was prevented in MCT + BB myocytes resulting in fewer spontaneous Ca 2+ waves, with a lower pro-arrhythmic potential. Our novel finding of attenuation of defects in excitation contraction coupling by β 1 -adrenoceptor blockade with delays in the onset of HF, identifies the RV as a promising therapeutic target in PAH. Moreover, our data suggest existing therapies for left ventricular failure may also be beneficial in PAH induced RV failure. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity

PubMed Central

Jaikumkao, Krit; Pongchaidecha, Anchalee; Thongnak, La-ongdao; Wanchai, Keerati; Arjinajarn, Phatchawan; Chatsudthipong, Varanuj; Chattipakorn, Nipon; Lungkaphin, Anusorn

2016-01-01

Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment. PMID:27727327

Visual Occlusion Decreases Motion Sickness in a Flight Simulator.

PubMed

Ishak, Shaziela; Bubka, Andrea; Bonato, Frederick

2018-05-01

Sensory conflict theories of motion sickness (MS) assert that symptoms may result when incoming sensory inputs (e.g., visual and vestibular) contradict each other. Logic suggests that attenuating input from one sense may reduce conflict and hence lessen MS symptoms. In the current study, it was hypothesized that attenuating visual input by blocking light entering the eye would reduce MS symptoms in a motion provocative environment. Participants sat inside an aircraft cockpit mounted onto a motion platform that simultaneously pitched, rolled, and heaved in two conditions. In the occluded condition, participants wore "blackout" goggles and closed their eyes to block light. In the control condition, participants opened their eyes and had full view of the cockpit's interior. Participants completed separate Simulator Sickness Questionnaires before and after each condition. The posttreatment total Simulator Sickness Questionnaires and subscores for nausea, oculomotor, and disorientation in the control condition were significantly higher than those in the occluded condition. These results suggest that under some conditions attenuating visual input may delay the onset of MS or weaken the severity of symptoms. Eliminating visual input may reduce visual/nonvisual sensory conflict by weakening the influence of the visual channel, which is consistent with the sensory conflict theory of MS.

The influence of shear-velocity heterogeneity on ScS2/ScS amplitude ratios and estimates of Q in the mantle

NASA Astrophysics Data System (ADS)

Ritsema, J.; Chaves, C. A. M.

2016-12-01

Regional waveforms of deep-focus Tonga-Fiji earthquakes indicate anomalous traveltime differences (ScS2-ScS) and amplitude ratios (ScS2/ScS) of the phases ScS and ScS2. The correlation between the ScS2-ScS delay time and the ScS2/ScS amplitude ratio suggests that shear-wave apparent Q in the mantle below the Tonga-Fiji region is highest when shear-wave velocities are lowest. This observation is unexpected if temperature variations were responsible for the seismic anomalies. Using spectral-element-method waveform simulations for four tomographic models we demonstrate that focusing and scattering of shear waves by long-wavelength 3D heterogeneity in the mantle may overwhelm the signal from intrinsic attenuation in long-period ScS2/ScS amplitude ratios. The tomographic models reproduce the variability in recorded ScS2-ScS difference times and ScS2/ScS amplitude ratios. Variations in shear-wave attenuation (i.e., the quality factor Q) are not necessary to explain the data. An explanation for slow shear wave propagation without intrinsic attenuation does not require a creative solution from mineral physics.

Identification of High-Z Materials With Photoneutrons Driven by a Low-Energy Electron Linear Accelerator

NASA Astrophysics Data System (ADS)

Yang, Yigang; Zhang, Zhi; Chen, Huaibi; Li, Yulan; Li, Yuanjing

2017-07-01

Contraband-detection systems can use X-rays and photoneutrons delivered from the same 7-MeV electron linear accelerator (e-LINAC) to stimulate and extract information from inspected materials. The X-ray attenuation information is used to measure the mass thickness, which is combined with the photoneutron attenuation information to categorize inspected materials as common organic materials, metals, and heavy metals. Once a heavy metal is found, the beta-delayed neutrons stimulated by the (γ,fission) reaction are measured by a polyethylene-moderated 3He counter to clarify if the material is fissile. The presence of neutron events 2000 μs after the X-ray pulse confirms the existence of the fissile material. The isotopes in the material are then identified using the time-of-flight method to analyze the resonant attenuation of the fissile material to the 10-1-102 eV photoneutrons emitted from and thermalized by the D2O photonto-neutron convertor, which converts X-rays to photoneutrons. Eight high-Z simulants are tested to confirm the feasibility of identifying the isotopes from the photoneutron resonance. The underlying principles and experimental results are discussed.

Attenuation of heavy metals by geosynthetics in the coal gangue-filled columns.

PubMed

Wang, Ping; Hu, Zhenqi; Wang, Peijun

2013-01-01

In the subsided areas backfilled with coal gangue, an issue of continuing environmental concern is the migration of hazardous metals to the subsurface soil and groundwater. As an effective isolation material, geosynthetics have been scarcely applied into mining areas reclamation of China. This paper describes research aimed at characterizing the behaviours of different geosynthetics in the leaching columns filled with coal gangues. Four types of geosynthetics were selected: fibres needle-punched nonwoven geotextiles, high-density polyethylene, needle-punched Na-bentonite geosynthetic clay liner (GCL-NP) and Na-bentonite geosynthetic-overbited film. Heavy metals were significantly attenuated and by monitoring aqueous solutions in the whole percolation period, negative correlation was found between pH value and concentration of heavy metals. Generally, GCL-NP showed comparatively better effects on attenuating the migration of heavy metals. According to the meta-analysis of heavy metals present in the leachates and retained in the columns, geosynthetics have good capabilities of sorption and retardation, which can delay the breakthrough time of heavy metals and retard the accumulation in the subsurface. Future research will use X-ray diffraction and micro-imaging (electron microprobe and scanning electron microscopy) to further explain retention mechanisms.

Molecular recognition of pyr mRNA by the Bacillus subtilis attenuation regulatory protein PyrR

PubMed Central

Bonner, Eric R.; D’Elia, John N.; Billips, Benjamin K.; Switzer, Robert L.

2001-01-01

The pyrimidine nucleotide biosynthesis (pyr) operon in Bacillus subtilis is regulated by transcriptional attenuation. The PyrR protein binds in a uridine nucleotide-dependent manner to three attenuation sites at the 5′-end of pyr mRNA. PyrR binds an RNA-binding loop, allowing a terminator hairpin to form and repressing the downstream genes. The binding of PyrR to defined RNA molecules was characterized by a gel mobility shift assay. Titration indicated that PyrR binds RNA in an equimolar ratio. PyrR bound more tightly to the binding loops from the second (BL2 RNA) and third (BL3 RNA) attenuation sites than to the binding loop from the first (BL1 RNA) attenuation site. PyrR bound BL2 RNA 4–5-fold tighter in the presence of saturating UMP or UDP and 150- fold tighter with saturating UTP, suggesting that UTP is the more important co-regulator. The minimal RNA that bound tightly to PyrR was 28 nt long. Thirty-one structural variants of BL2 RNA were tested for PyrR binding affinity. Two highly conserved regions of the RNA, the terminal loop and top of the upper stem and a purine-rich internal bulge and the base pairs below it, were crucial for tight binding. Conserved elements of RNA secondary structure were also required for tight binding. PyrR protected conserved areas of the binding loop in hydroxyl radical footprinting experiments. PyrR likely recognizes conserved RNA sequences, but only if they are properly positioned in the correct secondary structure. PMID:11726695

Correlations between radiation-induced double strand breaks, cell division delay, and cyclin-dependent signaling in x-irradiated NIH3T3 fibroblasts

NASA Astrophysics Data System (ADS)

Cariveau, Mickael J.

2005-07-01

Molecular responses to radiation-induced DNA double strand breaks (DSB) are mediated by the phosphorylation of the histone variant H2AX which forms identifiable gamma-H2AX foci at the site of the DSB. This event is thought to be linked with the down-regulation of signaling proteins contributing to the checkpoints regulating cell cycle progression and, vis-a-vis , the induction of cell division delay. However, it is unclear whether this division delay is directly related to the number of DSB (gamma-H2AX foci) sustained by an irradiated cell and, if so, whether this number drives cells into cell cycle delay or apoptosis. For this reason, studies were conducted in the immortalized NIH/3T3 fibroblast cell in order to establish correlations between the temporal appearance of the gamma-H2AX foci (a DSB) and the expression of the cell cycle regulatory proteins, cyclin E, A, B1, and their cyclin kinase inhibitor, p21. Cell cycle kinetics and flow cytometry were used to establish radiation-induced division delay over a dose range of 1--6 Gy where a mitotic delay of 2.65 min/cGy was established. Correlations between the expression of cyclin E, A, B1, p21, and the generation of DSB were established in NIH/3T3 cells exposed to 2 or 4 Gy x-irradiation. The data suggest that the G1/S and S phase delay (cyclin E and cyclin A protein levels) are dependent on the dose of radiation while the G2/M (cyclin B1 protein levels) delay is dependent on the quantity of DSB sustained by the irradiated cell.

Characterization and Monitoring of Natural Attenuation of Chlorinated Solvents in Ground Water: A Systems Approach

NASA Astrophysics Data System (ADS)

Cutshall, N. H.; Gilmore, T.; Looney, B. B.; Vangelas, K. M.; Adams, K. M.; Sink, C. H.

2006-05-01

Like many US industries and businesses, the Department of Energy (DOE) is responsible for remediation and restoration of soils and ground water contaminated with chlorinated ethenes. Monitored Natural Attenuation (MNA) is an attractive remediation approach and is probably the universal end-stage technology for removing such contamination. Since 2003 we have carried out a multifaceted program at the Savannah River Site designed to advance the state of the art for MNA of chlorinated ethenes in soils and groundwater. Three lines of effort were originally planned: 1) Improving the fundamental science for MNA, 2) Promoting better characterization and monitoring (CM) techniques, and 3) Advancing the regulatory aspects of MNA management. A fourth line, developing enhanced attenuation methods based on sustainable natural processes, was added in order to deal with sites where the initial natural attenuation capacity cannot offset contaminant loading rates. These four lines have been pursued in an integrated and mutually supportive fashion. Many DOE site-cleanup program managers view CM as major expenses, especially for natural attenuation where measuring attenuation is complex and the most critical attenuation mechanisms cannot be determined directly. We have reviewed new and developing approaches to CM for potential application in support of natural attenuation of chlorinated hydrocarbons in ground water at DOE sites (Gilmore, Tyler, et al., 2006 WSRC-TR- 2005-00199). Although our project is focused on chlorinated ethenes, many of the concepts and strategies are also applicable to a wider range of contaminants including radionuclides and metals. The greatest savings in CM are likely to come from new management approaches. New approaches can be based, for example, on conceptual models of attenuation capacity, the ability of a formation to reduce risks caused by contaminants. Using the mass balance concept as a guide, the integrated mass flux of contaminant is compared to the attenuation capacity. The mass balance approach is controlled by a combination of boundary conditions (e.g., water inputs and outputs), flow dynamics, and contaminant concentrations. As a result, long term monitoring might be improved while reducing costs by measuring fewer point concentrations and simultaneously adding large-scale measurements of boundary conditions, using weather data, remote sensing of evapotranspiration, stream-flow monitoring, etc. Because there are no specific regulatory drivers for performance-monitoring, regulators are not accustomed to participating in monitoring system design. A partnership with the Interstate Technology Regulatory Council (ITRC) has been formed to promote communication and develop advanced guidance for MNA. Early and continued communication among technology developers, end users, regulators and the public has been essential to this progress.

Associations between respiratory sinus arrhythmia (RSA) reactivity and effortful control in preschool-age children.

PubMed

Sulik, Michael J; Eisenberg, Nancy; Spinrad, Tracy L; Silva, Kassondra M

2015-07-01

We tested whether respiratory sinus arrhythmia (RSA) reactivity in response to each of three self-regulation tasks (bird and dragon; knock-tap; and gift wrap) would predict self-regulation performance in a sample of 101 preschool-age children (M age = 4.49, SD = .64). While controlling for baseline RSA, decreases in RSA from bird and dragon to knock-tap (but not from baseline to bird and dragon) predicted a latent variable measuring self-regulation. Furthermore, increases in RSA from the knock-tap to gift wrap-the only task involving delay of gratification-were related to concurrent task performance while controlling for the relation between RSA reactivity and the latent self-regulation variable. Results suggest that the relations between RSA reactivity and self-regulatory ability are influenced by task-specific demands and possibly by task order. Furthermore, RSA reactivity appears to relate differently to performance on motivationally salient self-regulation tasks such as delay of gratification relative to cool executive function tasks. © 2015 Wiley Periodicals, Inc.

Oscillatory Regulation of Hes1: Discrete Stochastic Delay Modelling and Simulation

PubMed Central

Barrio, Manuel; Burrage, Kevin; Leier, André; Tian, Tianhai

2006-01-01

Discrete stochastic simulations are a powerful tool for understanding the dynamics of chemical kinetics when there are small-to-moderate numbers of certain molecular species. In this paper we introduce delays into the stochastic simulation algorithm, thus mimicking delays associated with transcription and translation. We then show that this process may well explain more faithfully than continuous deterministic models the observed sustained oscillations in expression levels of hes1 mRNA and Hes1 protein. PMID:16965175

Associations between Toddler-Age Communication and Kindergarten-Age Self-Regulatory Skills

ERIC Educational Resources Information Center

Aro, Tuija; Laakso, Marja-Leena; Määttä, Sira; Tolvanen, Asko; Poikkeus, Anna-Maija

2014-01-01

Purpose: In this study, the authors aimed at gaining understanding on the associations of different types of early language and communication profiles with later self-regulation skills by using longitudinal data from toddler age to kindergarten age. Method: Children with early language profiles representing expressive delay, broad delay (i.e.,…

ABNORMAL FERTILIZATION IS RESPONSIBLE FOR REDUCED FECUNDITY FOLLOWING THIRAM-INDUCED OVULATORY DELAY IN THE RAT

EPA Science Inventory

Brief exposure to some pesticides, applied during a sensitive window for the neural regulation of ovulation, will block the preovulatory surge of LH, and thus delay ovulation. Previously, we have shown that a single i.p. injection of 50 mg/kg of thiram, a dithiocarbamate fungici...

Utilizing a Rat Delayed Implantation Model to Teach Integrative Endocrinology and Reproductive Biology

ERIC Educational Resources Information Center

Geisert, Rodney D.; Smith, Michael F.; Schmelzle, Amanda L.; Green, Jonathan A.

2018-01-01

In this teaching laboratory, the students are directed in an exercise that involves designing and performing an experiment to determine estrogen's role in regulating delayed implantation (diapause) in female rats. To encourage active participation by the students, a discussion question is provided before the laboratory exercise in which each…

48 CFR 1352.219-71 - Notification to delay performance (Deviation).

Code of Federal Regulations, 2010 CFR

2010-10-01

... not begin performance under this purchase order until 2 working days have passed from the date of its... performance (Deviation). 1352.219-71 Section 1352.219-71 Federal Acquisition Regulations System DEPARTMENT OF....219-71 Notification to delay performance (Deviation). As prescribed in 48 CFR 1319.811-3(b), insert...

Sustaining Learning through Academic Delay of Gratification: Choice and Strategy.

ERIC Educational Resources Information Center

Bembenutty, Hefer; Karabenick, Stuart A.

Academic delay of gratification (ADOG) refers to students' postponement of immediately available opportunities to satisfy impulses in favor of pursuing academic goals that are temporally remote but ostensibly more valuable. This important form of self-regulation was studied among college students to determine how it serves to sustain effort over…

Ectopic expression of Capsicum-specific cell wall protein Capsicum annuum senescence-delaying 1 (CaSD1) delays senescence and induces trichome formation in Nicotiana benthamiana.

PubMed

Seo, Eunyoung; Yeom, Seon-In; Jo, Sunghwan; Jeong, Heejin; Kang, Byoung-Cheorl; Choi, Doil

2012-04-01

Secreted proteins are known to have multiple roles in plant development, metabolism, and stress response. In a previous study to understand the roles of secreted proteins, Capsicum annuum secreted proteins (CaS) were isolated by yeast secretion trap. Among the secreted proteins, we further characterized Capsicum annuum senescence-delaying 1 (CaSD1), a gene encoding a novel secreted protein that is present only in the genus Capsicum. The deduced CaSD1 contains multiple repeats of the amino acid sequence KPPIHNHKPTDYDRS. Interestingly, the number of repeats varied among cultivars and species in the Capsicum genus. CaSD1 is constitutively expressed in roots, and Agrobacterium-mediated transient overexpression of CaSD1 in Nicotiana benthamiana leaves resulted in delayed senescence with a dramatically increased number of trichomes and enlarged epidermal cells. Furthermore, senescence- and cell division-related genes were differentially regulated by CaSD1-overexpressing plants. These observations imply that the pepper-specific cell wall protein CaSD1 plays roles in plant growth and development by regulating cell division and differentiation.

Radio Wave Propagation for Communication on and around Mars. Part 1; Highlights: Propagation Through Mars Environment

NASA Technical Reports Server (NTRS)

Ho, Christian; Golshan, Nasser

1999-01-01

We recommend to use the dayside Martian ionosphere as a reflector for global communication, because the dayside ionosphere has stable density peak and usable critic frequency. This is very crucial for the future Mars ground to around communication. The dayside ionosphere has been well modeled as a Chapman layer. We suggest to perform the Martian nightside ionospheric modeling study. Because the nightside ionosphere has very little measurements available, we propose to drop a digital ionosond instrument into the Mars surface for data collection. Even though the Martian tropospheric radio refractivity has small value, it still can cause the ray bending and multipath effects. We recommend to perform an accurate calculation on excess phase and group delays (range and time delays). Other effects, such as range rate errors, appearance angle deviation, defocusing loss on Mars, etc. are also needed to be estimated. Ice depolarization effects due to Martian clouds on radio waves is unknown yet, which is expected to be small, because lower optical depth and thinner layer of cloud: Total Martian atmospheric gaseous attenuation is expected to be less than 1 dB on microwaves band, because the Martian atmosphere has very low concentration in uncondensed H2O and O2. An accurate calculation for zenith opacity requires the information about scale heights of H2O and O2 distribution. An accurate water vapor altitude profile at Mars is not available yet. Under the normal condition, CO2 and N2 gases do not have electric or magnetic dipoles and do not absorb electromagnetic energy from the waves. However, they may generate the dipoles through a collision and interact with waves under a high density condition and absorb electromagnetic waves in the infrared and visible band. Dust storm is most dominant factor to the radio wave attenuation. Large Martian dust storm can cause at least 3 dB or higher loss to Ka band wave. For a normal dust storm, the attenuation is about 1 dB. The attenuation much depends on dust mass loading, dust size distribution, etc. Most large dust storm occur in the southern hemisphere during later spring and early summer when the southern hemisphere become suddenly hot.

Light attenuation characteristics of glacially-fed lakes

NASA Astrophysics Data System (ADS)

Rose, Kevin C.; Hamilton, David P.; Williamson, Craig E.; McBride, Chris G.; Fischer, Janet M.; Olson, Mark H.; Saros, Jasmine E.; Allan, Mathew G.; Cabrol, Nathalie

2014-07-01

Transparency is a fundamental characteristic of aquatic ecosystems and is highly responsive to changes in climate and land use. The transparency of glacially-fed lakes may be a particularly sensitive sentinel characteristic of these changes. However, little is known about the relative contributions of glacial flour versus other factors affecting light attenuation in these lakes. We sampled 18 glacially-fed lakes in Chile, New Zealand, and the U.S. and Canadian Rocky Mountains to characterize how dissolved absorption, algal biomass (approximated by chlorophyll a), water, and glacial flour contributed to attenuation of ultraviolet radiation (UVR) and photosynthetically active radiation (PAR, 400-700 nm). Variation in attenuation across lakes was related to turbidity, which we used as a proxy for the concentration of glacial flour. Turbidity-specific diffuse attenuation coefficients increased with decreasing wavelength and distance from glaciers. Regional differences in turbidity-specific diffuse attenuation coefficients were observed in short UVR wavelengths (305 and 320 nm) but not at longer UVR wavelengths (380 nm) or PAR. Dissolved absorption coefficients, which are closely correlated with diffuse attenuation coefficients in most non-glacially-fed lakes, represented only about one quarter of diffuse attenuation coefficients in study lakes here, whereas glacial flour contributed about two thirds across UVR and PAR. Understanding the optical characteristics of substances that regulate light attenuation in glacially-fed lakes will help elucidate the signals that these systems provide of broader environmental changes and forecast the effects of climate change on these aquatic ecosystems.

Premature terminator analysis sheds light on a hidden world of bacterial transcriptional attenuation.

PubMed

Naville, Magali; Gautheret, Daniel

2010-01-01

Bacterial transcription attenuation occurs through a variety of cis-regulatory elements that control gene expression in response to a wide range of signals. The signal-sensing structures in attenuators are so diverse and rapidly evolving that only a small fraction have been properly annotated and characterized to date. Here we apply a broad-spectrum detection tool in order to achieve a more complete view of the transcriptional attenuation complement of key bacterial species. Our protocol seeks gene families with an unusual frequency of 5' terminators found across multiple species. Many of the detected attenuators are part of annotated elements, such as riboswitches or T-boxes, which often operate through transcriptional attenuation. However, a significant fraction of candidates were not previously characterized in spite of their unmistakable footprint. We further characterized some of these new elements using sequence and secondary structure analysis. We also present elements that may control the expression of several non-homologous genes, suggesting co-transcription and response to common signals. An important class of such elements, which we called mobile attenuators, is provided by 3' terminators of insertion sequences or prophages that may be exapted as 5' regulators when inserted directly upstream of a cellular gene. We show here that attenuators involve a complex landscape of signal-detection structures spanning the entire bacterial domain. We discuss possible scenarios through which these diverse 5' regulatory structures may arise or evolve.

ACUTE ETHANOL DISRUPTS PHOTIC AND SEROTONERGIC CIRCADIAN CLOCK PHASE-RESETTING IN THE MOUSE

PubMed Central

Brager, Allison J.; Ruby, Christina L.; Prosser, Rebecca A.; Glass, J. David

2011-01-01

Background Alcohol abuse is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: 1) characterize the SCN pharmacokinetics of acute systemic ethanol administration; 2) explore the effects of acute ethanol on photic and non-photic phase-resetting; and 2) determine if the SCN is a direct target for photic effects. Methods First, microdialysis was used to characterize the pharmacokinetics of acute i.p. injections of 3 doses of ethanol (0.5, 1.0 and 2.0 g/kg) in the mouse suprachiasmatic (SCN) circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase-delays and serotonergic ([+]8-OH-DPAT-induced) phase-advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized. Results Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20–40 min post-injection with half-lives for clearance ranging from 0.6–1.8 hr. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase-delays. Conclusions These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and non-photic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism. PMID:21463340

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial.

PubMed

Kubica, Jacek; Adamski, Piotr; Ostrowska, Małgorzata; Sikora, Joanna; Kubica, Julia Maria; Sroka, Wiktor Dariusz; Stankowska, Katarzyna; Buszko, Katarzyna; Navarese, Eliano Pio; Jilma, Bernd; Siller-Matula, Jolanta Maria; Marszałł, Michał Piotr; Rość, Danuta; Koziński, Marek

2016-01-14

The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0-12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

In vivo characterization of 3D skull and brain motion during dynamic head vibration using magnetic resonance elastography.

PubMed

Yin, Ziying; Sui, Yi; Trzasko, Joshua D; Rossman, Phillip J; Manduca, Armando; Ehman, Richard L; Huston, John

2018-05-17

To introduce newly developed MR elastography (MRE)-based dual-saturation imaging and dual-sensitivity motion encoding schemes to directly measure in vivo skull-brain motion, and to study the skull-brain coupling in volunteers with these approaches. Six volunteers were scanned with a high-performance compact 3T-MRI scanner. The skull-brain MRE images were obtained with a dual-saturation imaging where the skull and brain motion were acquired with fat- and water-suppression scans, respectively. A dual-sensitivity motion encoding scheme was applied to estimate the heavily wrapped phase in skull by the simultaneous acquisition of both low- and high-sensitivity phase during a single MRE exam. The low-sensitivity phase was used to guide unwrapping of the high-sensitivity phase. The amplitude and temporal phase delay of the rigid-body motion between the skull and brain was measured, and the skull-brain interface was visualized by slip interface imaging (SII). Both skull and brain motion can be successfully acquired and unwrapped. The skull-brain motion analysis demonstrated the motion transmission from the skull to the brain is attenuated in amplitude and delayed. However, this attenuation (%) and delay (rad) were considerably greater with rotation (59 ± 7%, 0.68 ± 0.14 rad) than with translation (92 ± 5%, 0.04 ± 0.02 rad). With SII the skull-brain slip interface was not completely evident, and the slip pattern was spatially heterogeneous. This study provides a framework for acquiring in vivo voxel-based skull and brain displacement using MRE that can be used to characterize the skull-brain coupling system for understanding of mechanical brain protection mechanisms, which has potential to facilitate risk management for future injury. © 2018 International Society for Magnetic Resonance in Medicine.

The delayed rectifier potassium conductance in the sarcolemma and the transverse tubular system membranes of mammalian skeletal muscle fibers

PubMed Central

DiFranco, Marino; Quinonez, Marbella

2012-01-01

A two-microelectrode voltage clamp and optical measurements of membrane potential changes at the transverse tubular system (TTS) were used to characterize delayed rectifier K currents (IKV) in murine muscle fibers stained with the potentiometric dye di-8-ANEPPS. In intact fibers, IKV displays the canonical hallmarks of KV channels: voltage-dependent delayed activation and decay in time. The voltage dependence of the peak conductance (gKV) was only accounted for by double Boltzmann fits, suggesting at least two channel contributions to IKV. Osmotically treated fibers showed significant disconnection of the TTS and displayed smaller IKV, but with similar voltage dependence and time decays to intact fibers. This suggests that inactivation may be responsible for most of the decay in IKV records. A two-channel model that faithfully simulates IKV records in osmotically treated fibers comprises a low threshold and steeply voltage-dependent channel (channel A), which contributes ∼31% of gKV, and a more abundant high threshold channel (channel B), with shallower voltage dependence. Significant expression of the IKV1.4 and IKV3.4 channels was demonstrated by immunoblotting. Rectangular depolarizing pulses elicited step-like di-8-ANEPPS transients in intact fibers rendered electrically passive. In contrast, activation of IKV resulted in time- and voltage-dependent attenuations in optical transients that coincided in time with the peaks of IKV records. Normalized peak attenuations showed the same voltage dependence as peak IKV plots. A radial cable model including channels A and B and K diffusion in the TTS was used to simulate IKV and average TTS voltage changes. Model predictions and experimental data were compared to determine what fraction of gKV in the TTS accounted simultaneously for the electrical and optical data. Best predictions suggest that KV channels are approximately equally distributed in the sarcolemma and TTS membranes; under these conditions, >70% of IKV arises from the TTS. PMID:22851675

Leptin attenuates BACE1 expression and Amyloid-β genesis via the activation of SIRT1 signaling pathway

PubMed Central

Marwarha, Gurdeep; Raza, Shaneabbas; Meiers, Craig; Ghribi, Othman

2014-01-01

The aspartyl protease β-site AβPP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in Aβ production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Aβ production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Aβ levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor – kappa B (NF-κB) positively regulates BACE1 transcription. NF-κB activity is tightly regulated by the mammalian sirtuin SIRT1. Multiple studies have cogently evinced that leptin activates the metabolic master regulator SIRT1. In this study, we determined the extent to which SIRT1 expression and activity regulate the leptin-induced attenuation in BACE1 expression and Aβ levels in cultured human neuroblastoma SH-SY5Y cells. This study also elucidated and delineated the signal transduction pathways involved in the leptin induced mitigation in BACE1 expression. Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-κB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-κB – mediated transcription of BACE1 and consequently reduces Amyloid-β genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-β production and may help design potential therapeutic interventions. PMID:24874077

miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression.

PubMed

Zheng, Liduan; Jiao, Wanju; Song, Huajie; Qu, Hongxia; Li, Dan; Mei, Hong; Chen, Yajun; Yang, Feng; Li, Huanhuan; Huang, Kai; Tong, Qiangsong

2016-09-29

Previous studies have indicated that as the only mammalian endo-β-D-glucuronidase, heparanase (HPSE) is up-regulated and associated with poor prognosis in gastric cancer, while the underlying mechanisms still remain to be determined. Herein, through integrative analysis of public datasets, we found microRNA-558 (miR-558) and SMAD family member 4 (Smad4) as the crucial transcription regulators of HPSE expression in gastric cancer, with their adjacent target sites within the promoter of HPSE. We identified that endogenous miR-558 activated the transcription and expression of HPSE in gastric cancer cell lines. In contrast, Smad4 suppressed the nascent transcription and expression of HPSE via directly binding to its promoter. Mechanistically, miR-558 recognized its complementary site within HPSE promoter to decrease the binding of Smad4 in an Argonaute 1-dependent manner. Ectopic expression or knockdown experiments indicated that miR-558 promoted the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cell lines via attenuating Smad4-mediated repression of HPSE expression. In clinical gastric cancer specimens, up-regulation of miR-558 and down-regulation of Smad4 were positively correlated with HPSE expression. Kaplan-Meier survival analysis revealed that miR-558 and Smad4 were associated with unfavourable and favourable outcome of gastric cancer patients, respectively. Therefore, these findings demonstrate that miR-558 facilitates the progression of gastric cancer through directly targeting the HPSE promoter to attenuate Smad4-mediated repression of HPSE expression.

miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression

PubMed Central

Zheng, Liduan; Jiao, Wanju; Song, Huajie; Qu, Hongxia; Li, Dan; Mei, Hong; Chen, Yajun; Yang, Feng; Li, Huanhuan; Huang, Kai; Tong, Qiangsong

2016-01-01

Previous studies have indicated that as the only mammalian endo-β-D-glucuronidase, heparanase (HPSE) is up-regulated and associated with poor prognosis in gastric cancer, while the underlying mechanisms still remain to be determined. Herein, through integrative analysis of public datasets, we found microRNA-558 (miR-558) and SMAD family member 4 (Smad4) as the crucial transcription regulators of HPSE expression in gastric cancer, with their adjacent target sites within the promoter of HPSE. We identified that endogenous miR-558 activated the transcription and expression of HPSE in gastric cancer cell lines. In contrast, Smad4 suppressed the nascent transcription and expression of HPSE via directly binding to its promoter. Mechanistically, miR-558 recognized its complementary site within HPSE promoter to decrease the binding of Smad4 in an Argonaute 1-dependent manner. Ectopic expression or knockdown experiments indicated that miR-558 promoted the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cell lines via attenuating Smad4-mediated repression of HPSE expression. In clinical gastric cancer specimens, up-regulation of miR-558 and down-regulation of Smad4 were positively correlated with HPSE expression. Kaplan–Meier survival analysis revealed that miR-558 and Smad4 were associated with unfavourable and favourable outcome of gastric cancer patients, respectively. Therefore, these findings demonstrate that miR-558 facilitates the progression of gastric cancer through directly targeting the HPSE promoter to attenuate Smad4-mediated repression of HPSE expression. PMID:27685626

Methylation of an intragenic alternative promoter regulates transcription of GARP.

PubMed

Haupt, Sonja; Söntgerath, Viktoria Sophie Apollonia; Leipe, Jan; Schulze-Koops, Hendrik; Skapenko, Alla

2016-02-01

Alternative promoter usage has been proposed as a mechanism regulating transcriptional and translational diversity in highly elaborated systems like the immune system in humans. Here, we report that transcription of human glycoprotein A repetitions predominant (GARP) in regulatory CD4 T cells (Tregs) is tightly regulated by two alternative promoters. An intragenic promoter contains several CpGs and acts as a weak promoter that is demethylated and initiates transcription Treg-specifically. The strong up-stream promoter containing a CpG-island is, in contrast, fully demethylated throughout tissues. Transcriptional activity of the strong promoter was surprisingly down-regulated upon demethylation of the weak promoter. This demethylation-induced transcriptional attenuation regulated the magnitude of GARP expression and correlated with disease activity in rheumatoid arthritis. Treg-specific GARP transcription was initiated by synergistic interaction of forkhead box protein 3 (Foxp3) with nuclear factor of activated T cells (NFAT) and was underpinned by permissive chromatin remodeling caused by release of the H3K4 demethylase, PLU-1. Our findings describe a novel function of alternative promoters in regulating the extent of transcription. Moreover, since GARP functions as a transporter of transforming growth factor β (TGFβ), a cytokine with broad pleiotropic traits, GARP transcriptional attenuation by alternative promoters might provide a mechanism regulating peripheral TGFβ to avoid unwanted harmful effects. Copyright © 2015 Elsevier B.V. All rights reserved.

Human microRNA-1245 down-regulates the NKG2D receptor in natural killer cells and impairs NKG2D-mediated functions

PubMed Central

Espinoza, J. Luis; Takami, Akiyoshi; Yoshioka, Katsuji; Nakata, Katsuya; Sato, Tokiharu; Kasahara, Yoshihito; Nakao, Shinji

2012-01-01

Background NKG2D is an activating receptor expressed by natural killer and T cells, which have crucial functions in tumor and microbial immunosurveillance. Several cytokines have been identified as modulators of NKG2D receptor expression. However, little is known about NKG2D gene regulation. In this study, we found that microRNA 1245 attenuated the expression of NKG2D in natural killer cells. Design and Methods We investigated the potential interactions between the 3′-untranslated region of the NKG2D gene and microRNA as well as their functional roles in the regulation of NKG2D expression and cytotoxicity in natural killer cells. Results Transforming growth factor-β1, a major negative regulator of NKG2D expression, post-transcriptionally up-regulated mature microRNA-1245 expression, thus down-regulating NKG2D expression and impairing NKG2D-mediated immune responses in natural killer cells. Conversely, microRNA-1245 down-regulation significantly increased the expression of NKG2D expression in natural killer cells, resulting in more efficient NKG2D-mediated cytotoxicity. Conclusions These results reveal a novel NKG2D regulatory pathway mediated by microRNA-1245, which may represent one of the mechanisms used by transforming growth factor-β1 to attenuate NKG2D expression in natural killer cells. PMID:22491735

CDKL5 and Shootin1 Interact and Concur in Regulating Neuronal Polarization.

PubMed

Nawaz, Mohammad Sarfaraz; Giarda, Elisa; Bedogni, Francesco; La Montanara, Paolo; Ricciardi, Sara; Ciceri, Dalila; Alberio, Tiziana; Landsberger, Nicoletta; Rusconi, Laura; Kilstrup-Nielsen, Charlotte

2016-01-01

In the last years, the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with epileptic encephalopathies characterized by the early onset of intractable epilepsy, severe developmental delay, autistic features, and often the development of Rett syndrome-like features. Still, the role of CDKL5 in neuronal functions is not fully understood. By way of a yeast two hybrid screening we identified the interaction of CDKL5 with shootin1, a brain specific protein acting as a determinant of axon formation during neuronal polarization. We found evidence that CDKL5 is involved, at least in part, in regulating neuronal polarization through its interaction with shootin1. Indeed, the two proteins interact in vivo and both are localized in the distal tip of outgrowing axons. By using primary hippocampal neurons as model system we find that adequate CDKL5 levels are required for axon specification. In fact, a significant number of neurons overexpressing CDKL5 is characterized by supernumerary axons, while the silencing of CDKL5 disrupts neuronal polarization. Interestingly, shootin1 phosphorylation is reduced in neurons silenced for CDKL5 suggesting that the kinase affects, directly or indirectly, the post-translational modification of shootin1. Finally, we find that the capacity of CDKL5 to generate surplus axons is attenuated in neurons with reduced shootin1 levels, in agreement with the notion that two proteins act in a common pathway. Altogether, these results point to a role of CDKL5 in the early steps of neuronal differentiation that can be explained, at least in part, by its association with shootin1.

CDKL5 and Shootin1 Interact and Concur in Regulating Neuronal Polarization

PubMed Central

Nawaz, Mohammad Sarfaraz; Giarda, Elisa; Bedogni, Francesco; La Montanara, Paolo; Ricciardi, Sara; Ciceri, Dalila; Alberio, Tiziana; Landsberger, Nicoletta; Rusconi, Laura; Kilstrup-Nielsen, Charlotte

2016-01-01

In the last years, the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with epileptic encephalopathies characterized by the early onset of intractable epilepsy, severe developmental delay, autistic features, and often the development of Rett syndrome-like features. Still, the role of CDKL5 in neuronal functions is not fully understood. By way of a yeast two hybrid screening we identified the interaction of CDKL5 with shootin1, a brain specific protein acting as a determinant of axon formation during neuronal polarization. We found evidence that CDKL5 is involved, at least in part, in regulating neuronal polarization through its interaction with shootin1. Indeed, the two proteins interact in vivo and both are localized in the distal tip of outgrowing axons. By using primary hippocampal neurons as model system we find that adequate CDKL5 levels are required for axon specification. In fact, a significant number of neurons overexpressing CDKL5 is characterized by supernumerary axons, while the silencing of CDKL5 disrupts neuronal polarization. Interestingly, shootin1 phosphorylation is reduced in neurons silenced for CDKL5 suggesting that the kinase affects, directly or indirectly, the post-translational modification of shootin1. Finally, we find that the capacity of CDKL5 to generate surplus axons is attenuated in neurons with reduced shootin1 levels, in agreement with the notion that two proteins act in a common pathway. Altogether, these results point to a role of CDKL5 in the early steps of neuronal differentiation that can be explained, at least in part, by its association with shootin1. PMID:26849555

Anti-inflammatory effects of sargachromenol-rich ethanolic extract of Myagropsis myagroides on lipopolysaccharide-stimulated BV-2 cells

PubMed Central

2014-01-01

Background Excessive pro-inflammatory cytokine production from activated microglia contributes to neurodegenerative diseases, thus, microglial inactivation may delay the progress of neurodegeneration by attenuating the neuroinflammation. Among 5 selected brown algae, we found the highest antioxidant and anti-neuroinflammatory activities from Myagropsis myagroides ethanolic extract (MME) in lipopolysaccharide (LPS)-stimulated BV-2 cells. Methods The levels of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines were measured by Griess assay and enzyme linked immunesorbent assay. The levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blot. Nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) were determined by immunefluorescence and reporter gene assay, respectively. Results MME inhibited the expression of iNOS and COX-2 at mRNA and protein levels, resulting in reduction of NO and PGE2 production. As a result, pro-inflammatory cytokines were reduced by MME. MME also inhibited the activation and translocation of NF-κB by preventing inhibitor κB-α (IκB-α) degradation. Moreover, MME inhibited the phosphorylation of extracellular signal regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs). Main anti-inflammatory compound in MME was identified as sargachromenol by NMR spectroscopy. Conclusions These results indicate that the anti-inflammatory effect of sargachromenol-rich MME on LPS-stimulated microglia is mainly regulated by the inhibition of IκB-α/NF-κB and ERK/JNK pathways. PMID:25005778

Surfactant protein D delays Fas- and TRAIL-mediated extrinsic pathway of apoptosis in T cells.

PubMed

Djiadeu, Pascal; Kotra, Lakshmi P; Sweezey, Neil; Palaniyar, Nades

2017-05-01

Only a few extracellular soluble proteins are known to modulate apoptosis. We considered that surfactant-associated protein D (SP-D), an innate immune collectin present on many mucosal surfaces, could regulate apoptosis. Although SP-D is known to be important for immune cell homeostasis, whether SP-D affects apoptosis is unknown. In this study we aimed to determine the effects of SP-D on Jurkat T cells and human T cells dying by apoptosis. Here we show that SP-D binds to Jurkat T cells and delays the progression of Fas (CD95)-Fas ligand and TRAIL-TRAIL receptor induced, but not TNF-TNF receptor-mediated apoptosis. SP-D exerts its effects by reducing the activation of initiator caspase-8 and executioner caspase-3. SP-D also delays the surface exposure of phosphatidylserine. The effect of SP-D was ablated by the presence of caspase-8 inhibitor, but not by intrinsic pathway inhibitors. The binding ability of SP-D to dying cells decreases during the early stages of apoptosis, suggesting the release of apoptotic cell surface targets during apoptosis. SP-D also delays FasL-induced death of primary human T cells. SP-D delaying the progression of the extrinsic pathway of apoptosis could have important implications in regulating immune cell homeostasis at mucosal surfaces.

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PubMed Central

Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

2016-01-01

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

PubMed Central

Reyes-Gordillo, Karina; Shah, Ruchi; Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C.

2016-01-01

Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA) that primarily regulates PGC1α and soy protein (SP) that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1) and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c) and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK). Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways. PMID:28074114

Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD).

PubMed

Ni, Xunjun; Wang, Haiyan

2016-01-01

Silymarin, which derived from the milk thistle plant (silybum marianum), has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Considering the therapeutic potential to liver disease, we tested efficacy of silymarin on hepatic steatosis with a high fat diet (HFD)-induced mouse model of non-alcoholic fatty liver disease (NAFLD), and investigated possible effects on lipid metabolic pathways. In our study, silymarin could attenuate the hepatic steatosis, which was proved by both Oil Red O staining and hepatic triglyceride (TG) level determination. Furthermore, compared with INT-747, a potent and selective FXR agonist, silymarin could preserve plasmatic high-density lipoprotein cholesterol (HDL-C) to a higher level and low-density lipoprotein cholesterol (LDL-C) to a lower level, which benefited more to the circulation system. Through real-time PCR analysis, we clarified a vital protective role of silymarin in mRNA regulation of genes involved in lipid metabolism and oxidative stress. It was also shown that silymarin had no effects on body weight, food intake, and liver transaminase. Taken together, silymarin could attenuate hepatic steatosis in a mouse model of NAFLD through regulation of lipid metabolism and oxidative stress, and benefit to the circulation system. All these findings shed new light on NAFLD treatment.

Acetylcholine Attenuates Hydrogen Peroxide-Induced Intracellular Calcium Dyshomeostasis Through Both Muscarinic and Nicotinic Receptors in Cardiomyocytes.

PubMed

Palee, Siripong; Apaijai, Nattayaporn; Shinlapawittayatorn, Krekwit; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2016-01-01

Oxidative stress induced intracellular Ca2+ overload plays an important role in the pathophysiology of several heart diseases. Acetylcholine (ACh) has been shown to suppress reactive oxygen species generation during oxidative stress. However, there is little information regarding the effects of ACh on the intracellular Ca2+ regulation in the presence of oxidative stress. Therefore, we investigated the effects of ACh applied before or after hydrogen peroxide (H2O2) treatment on the intracellular Ca2+ regulation in isolated cardiomyocytes. Single ventricular myocytes were isolated from the male Wistar rats for the intracellular Ca2+ transient study by a fluorimetric ratio technique. H2O2 significantly decreased both of intracellular Ca2+ transient amplitude and decay rate. ACh applied before, but not after, H2O2 treatment attenuated the reduction of intracellular Ca2+ transient amplitude and decay rate. Both atropine (a muscarinic acetylcholine receptor blocker) and mecamylamine (a nicotinic acetylcholine receptor blocker) significantly decreased the protective effects of acetylcholine on the intracellular Ca2+ regulation. Moreover, the combination of atropine and mecamylamine completely abolished the protective effects of acetylcholine on intracellular Ca2+ transient amplitude and decay rate. ACh pretreatment attenuates H2O2-induced intracellular Ca2+ dyshomeostasis through both muscarinic and nicotinic receptors. © 2016 The Author(s) Published by S. Karger AG, Basel.

Crataegus oxycantha extract attenuates apoptotic incidence in myocardial ischemia-reperfusion injury by regulating Akt and HIF-1 signaling pathways.

PubMed

Jayachandran, Kesavan S; Khan, Mahmood; Selvendiran, Karuppaiyah; Devaraj, S Niranjali; Kuppusamy, Periannan

2010-11-01

The objective of the present study was to evaluate the efficacy and mechanism of Crataegus oxycantha (COC) extract in preventing ischemia-reperfusion (IR) injury in an in vivo rat model of acute myocardial infarction induced by a 30-minute regional ischemia followed by 72 hours of reperfusion. The COC extract [100 mg/(kg body weight)] was administered 12 hours after the surgical procedure and then at 24-hour intervals for 3 days. Animals treated with COC extract showed a significant decrease in creatine kinase activity and infarct size. At the molecular level, COC administration resulted in a significant attenuation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) and upregulation of phospho-Akt and c-Raf levels in the heart. As a consequence, cleaved caspase-9 and cleaved caspase-7 levels were significantly downregulated, indicating negative regulation of apoptosis by COC extract. In part with the hypoxia-inducible factor (HIF) signaling pathway, COC extract administration significantly upregulated the prolyl hydroxylase-2 level. In contrast, other proapoptotic proteins such as nuclear factor-κB, cytochrome c, apoptosis-inducing factor, and cleaved poly(adenosine diphosphate-ribose) polymerase levels were significantly downregulated in the COC-treated group when compared with the untreated control group. The results suggested that COC extract attenuated apoptotic incidence in the experimental myocardial ischemia-reperfusion model by regulating Akt and HIF-1 signaling pathways.

Total Glucosides of Danggui Buxue Tang Attenuate BLM-Induced Pulmonary Fibrosis via Regulating Oxidative Stress by Inhibiting NOX4

PubMed Central

Zhao, Ping; Zhou, Wen-Cheng; Li, De-Lin; Mo, Xiao-Ting; Xu, Liang; Li, Liu-Cheng; Cui, Wen-Hui; Gao, Jian

2015-01-01

Pulmonary fibrosis (PF) is a serious chronic lung disease with unknown pathogenesis. Researches have confirmed that oxidative stress which is regulated by NADPH oxidase-4 (NOX4), a main source of reactive oxygen species (ROS), is an important molecular mechanism underlying PF. Previous studies showed that total glucosides of Danggui Buxue Tang (DBTG), an extract from a classical traditional Chinese herbal formula, Danggui Buxue Tang (DBT), attenuated bleomycin-induced PF in rats. However, the mechanisms of DBTG are still not clear. We hypothesize that DBTG attenuates PF through regulating the level of oxidative stress by inhibiting NOX4. And we found that fibrosis indexes hydroxyproline (HYP) and type I collagen (Col-I) were lower in DBTG groups compared with the model group. In addition, the expression of transforming growth factor-β1 (TGF-β1) and expression of alpha smooth muscle actin (α-SMA) were also much more decreased than the model group. For oxidative stress indicators, DBTG blunted the decrease of superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC), and the increase in malondialdehyde (MDA), 8-iso-prostaglandin in lung homogenates. Treatment with DBTG restrained the expression of NOX4 compared to the model group. Present study confirms that DBTG inhibits BLM-induced PF by modulating the level of oxidative stress via suppressing NOX4. PMID:26347805

Scatterometer-Calibrated Stability Verification Method

NASA Technical Reports Server (NTRS)

McWatters, Dalia A.; Cheetham, Craig M.; Huang, Shouhua; Fischman, Mark A.; CHu, Anhua J.; Freedman, Adam P.

2011-01-01

The requirement for scatterometer-combined transmit-receive gain variation knowledge is typically addressed by sampling a portion of the transmit signal, attenuating it with a known-stable attenuation, and coupling it into the receiver chain. This way, the gain variations of the transmit and receive chains are represented by this loop-back calibration signal, and can be subtracted from the received remote radar echo. Certain challenges are presented by this process, such as transmit and receive components that are outside of this loop-back path and are not included in this calibration, as well as the impracticality for measuring the transmit and receive chains stability and post fabrication separately, without the resulting measurement errors from the test set up exceeding the requirement for the flight instrument. To cover the RF stability design challenge, the portions of the scatterometer that are not calibrated by the loop-back, (e.g., attenuators, switches, diplexers, couplers, and coaxial cables) are tightly thermally controlled, and have been characterized over temperature to contribute less than 0.05 dB of calibration error over worst-case thermal variation. To address the verification challenge, including the components that are not calibrated by the loop-back, a stable fiber optic delay line (FODL) was used to delay the transmitted pulse, and to route it into the receiver. In this way, the internal loopback signal amplitude variations can be compared to the full transmit/receive external path, while the flight hardware is in the worst-case thermal environment. The practical delay for implementing the FODL is 100 s. The scatterometer pulse width is 1 ms so a test mode was incorporated early in the design phase to scale the 1 ms pulse at 100-Hz pulse repetition interval (PRI), by a factor of 18, to be a 55 s pulse with 556 s PRI. This scaling maintains the duty cycle, thus maintaining a representative thermal state for the RF components. The FODL consists of an RF-modulated fiber-optic transmitter, 20 km SMF- 28 standard single-mode fiber, and a photodetector. Thermoelectric cooling and insulating packaging are used to achieve high thermal stability of the FODL components. The chassis was insulated with 1-in. (.2.5-cm) thermal isolation foam. Nylon rods support the Micarta plate, onto which are mounted four 5-km fiber spool boxes. A copper plate heat sink was mounted on top of the fiber boxes (with thermal grease layer) and screwed onto the thermoelectric cooler plate. Another thermal isolation layer in the middle separates the fiberoptics chamber from the RF electronics components, which are also mounted on a copper plate that is screwed onto another thermoelectric cooler. The scatterometer subsystem fs overall stability was successfully verified to be calibratable to within 0.1 dB error in thermal vacuum (TVAC) testing with the fiber-optic delay line, while the scatterometer temperature was ramped from 10 to 30 C, which is a much larger temperature range than the worst-case expected seasonal variations.

Meaningful and Maladaptive Homework Practices: The Role of Self-Efficacy and Self-Regulation

ERIC Educational Resources Information Center

Bembenutty, Hefer

2011-01-01

This article examines the role of self-regulation of learning on assigned homework. The findings reveal positive relationships between homework activities and self-efficacy, responsibility for learning, and delay of gratification. This review shows a positive relationship between homework and a range of self-regulation skills that facilitates…

Investigating the Longer-Term Impact of the CREST Inquiry-Based Learning Programme on Student Self-regulated Processes and Related Motivations: Views of Students and Teachers

NASA Astrophysics Data System (ADS)

Moote, Julie

2017-07-01

This study investigates the impact of participation in the CREativity in Science and Technology (CREST) programme on student self-regulated processes and related motivations. The CREST scheme, a student-run science project managed by the British Science Association, is currently being implemented in schools across the UK to increase student engagement and motivation in science. Through implementing a rigorous quasi-experimental research design using two intervention conditions and one control group with immediate as well as 3-month delayed post-test data, the results documented both the immediate and longer-term positive impact of CREST participation on students' self-reported levels of self-regulation. The present study also investigates changes in teachers' perceptions of students' self-regulated learning through CREST programme participation. Group differences regarding changes in student self-reported self-regulation were not matched when looking at the teacher-reported self-regulated learning results at both immediate post-test and delayed post-test. These discrepancies are discussed in relation to analyses conducted on the other motivational constructs measured.

Identification of Location Specific Feature Points in a Cardiac Cycle Using a Novel Seismocardiogram Spectrum System.

PubMed

Lin, Wen-Yen; Chou, Wen-Cheng; Chang, Po-Cheng; Chou, Chung-Chuan; Wen, Ming-Shien; Ho, Ming-Yun; Lee, Wen-Chen; Hsieh, Ming-Jer; Lin, Chung-Chih; Tsai, Tsai-Hsuan; Lee, Ming-Yih

2018-03-01

Seismocardiogram (SCG) or mechanocardiography is a noninvasive cardiac diagnostic method; however, previous studies used only a single sensor to detect cardiac mechanical activities that will not be able to identify location-specific feature points in a cardiac cycle corresponding to the four valvular auscultation locations. In this study, a multichannel SCG spectrum measurement system was proposed and examined for cardiac activity monitoring to overcome problems like, position dependency, time delay, and signal attenuation, occurring in traditional single-channel SCG systems. ECG and multichannel SCG signals were simultaneously recorded in 25 healthy subjects. Cardiac echocardiography was conducted at the same time. SCG traces were analyzed and compared with echocardiographic images for feature point identification. Fifteen feature points were identified in the corresponding SCG traces. Among them, six feature points, including left ventricular lateral wall contraction peak velocity, septal wall contraction peak velocity, transaortic peak flow, transpulmonary peak flow, transmitral ventricular relaxation flow, and transmitral atrial contraction flow were identified. These new feature points were not observed in previous studies because the single-channel SCG could not detect the location-specific signals from other locations due to time delay and signal attenuation. As the results, the multichannel SCG spectrum measurement system can record the corresponding cardiac mechanical activities with location-specific SCG signals and six new feature points were identified with the system. This new modality may help clinical diagnoses of valvular heart diseases and heart failure in the future.

Hypo-responsiveness of interleukin-8 production in human embryonic epithelial intestine 407 cells independent of NF-{kappa}B pathway: New lessons from endotoxin and ribotoxic deoxynivalenol

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

Moon, Yuseok; Yang, Hyun; Park, Seung-Hwan

Mucosal epithelium senses external toxic insults and transmits the danger signals into the epithelial cells in order to activate a broad range of inflammatory responses. However, pre-exposure to the commensal endotoxins can induce inflammatory tolerance and maintain the homeostasis without excessive immune responses. We recently reported that ribotoxin deoxynivalenol (DON) and its derivatives elicited the pro-inflammatory response as the mucosal insults in human epithelial cells. Taking the knowledge into consideration, we tested the hypothesis that endotoxin pre-exposure can attenuate ribotoxin-induced epithelial interleukin-8 (IL-8) production via a tolerance mechanism. Pre-exposure to endotoxin repressed IL-8 release and its gene expression. However, inflammatorymore » tolerance was not mediated by the attenuated NF-{kappa}B activation which has been generally recognized as the major mediator of LPS-mediated toll-like receptor (TLR) signaling pathway. Instead, pre-exposure to endotoxin was observed to trigger the delayed induction of peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) which contributed to the diminished IL-8 production in the human epithelial cells. Moreover, endogenous PPAR-{gamma} agonist suppressed toxicant-mediated interleukin-8 production and IL-8 mRNA stability. Taken together, endotoxin induced hypo-production of pro-inflammatory cytokine IL-8 in the human epithelial cells, which was associated with the delayed activation of PPAR-{gamma} expression by pre-existing endotoxin.« less

A two-hop based adaptive routing protocol for real-time wireless sensor networks.

PubMed

Rachamalla, Sandhya; Kancherla, Anitha Sheela

2016-01-01

One of the most important and challenging issues in wireless sensor networks (WSNs) is to optimally manage the limited energy of nodes without degrading the routing efficiency. In this paper, we propose an energy-efficient adaptive routing mechanism for WSNs, which saves energy of nodes by removing the much delayed packets without degrading the real-time performance of the used routing protocol. It uses the adaptive transmission power algorithm which is based on the attenuation of the wireless link to improve the energy efficiency. The proposed routing mechanism can be associated with any geographic routing protocol and its performance is evaluated by integrating with the well known two-hop based real-time routing protocol, PATH and the resulting protocol is energy-efficient adaptive routing protocol (EE-ARP). The EE-ARP performs well in terms of energy consumption, deadline miss ratio, packet drop and end-to-end delay.

Background Noise Reduction Using Adaptive Noise Cancellation Determined by the Cross-Correlation

NASA Technical Reports Server (NTRS)

Spalt, Taylor B.; Brooks, Thomas F.; Fuller, Christopher R.

2012-01-01

Background noise due to flow in wind tunnels contaminates desired data by decreasing the Signal-to-Noise Ratio. The use of Adaptive Noise Cancellation to remove background noise at measurement microphones is compromised when the reference sensor measures both background and desired noise. The technique proposed modifies the classical processing configuration based on the cross-correlation between the reference and primary microphone. Background noise attenuation is achieved using a cross-correlation sample width that encompasses only the background noise and a matched delay for the adaptive processing. A present limitation of the method is that a minimum time delay between the background noise and desired signal must exist in order for the correlated parts of the desired signal to be separated from the background noise in the crosscorrelation. A simulation yields primary signal recovery which can be predicted from the coherence of the background noise between the channels. Results are compared with two existing methods.

Physico-chemical characterization of products from vacuum oil under delayed coking process by infrared spectroscopy and chemometrics methods

NASA Astrophysics Data System (ADS)

Meléndez, L. V.; Cabanzo, R.; Mejía-Ospino, E.; Guzmán, A.

2016-02-01

Eight vacuum residues and their delayed coking liquids products from Colombian crude were study by infrared spectroscopy with attenuated total reflectance (FTIR-ATR) and principal component analysis (PCA). For the samples the structural parameters of aromaticity factor (fa), alifaticity (A2500-3100cm-1), aromatic condensation degree (GCA), length of aliphatic chains (LCA) and aliphatic chain length associated with aromatic (LACAR) were determined through the development of a methodology, which includes the previous processing of spectroscopy data, identifying the regions in the IR spectra of greatest variance using PCA and molecules patterns. The parameters were compared with the results obtained from proton magnetic resonance (1H-NMR) and 13C-NMR. The results showed the influence and correlation of structural parameters with some physicochemical properties such as API gravity, weight percent sulphur (% S) and Conradson carbon content (% CCR)

Arabidopsis florigen FT binds to diurnally oscillating phospholipids that accelerate flowering.

PubMed

Nakamura, Yuki; Andrés, Fernando; Kanehara, Kazue; Liu, Yu-chi; Dörmann, Peter; Coupland, George

2014-04-04

Arabidopsis FT protein is a component of florigen, which transmits photoperiodic flowering signals from leaf companion cells to the shoot apex. Here, we show that FT specifically binds phosphatidylcholine (PC) in vitro. A transgenic approach to increase PC levels in vivo in the shoot meristem accelerates flowering whereas reduced PC levels delay flowering, demonstrating that PC levels are correlated with flowering time. The early flowering is related to FT activity, because expression of FT-effector genes is increased in these plants. Simultaneous increase of FT and PC in the shoot apical meristem further stimulates flowering, whereas a loss of FT function leads to an attenuation of the effect of increased PC. Specific molecular species of PC oscillate diurnally, and night-dominant species are not the preferred ligands of FT. Elevating night-dominant species during the day delays flowering. We suggest that FT binds to diurnally changing molecular species of PC to promote flowering.

Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone

PubMed Central

Cui, Zhuang; Crane, Janet; Xie, Hui; Jin, Xin; Zhen, Gehua; Li, Changjun; Xie, Liang; Wang, Long; Bian, Qin; Qiu, Tao; Wan, Mei; Xie, Min; Ding, Sheng; Yu, Bin; Cao, Xu

2016-01-01

Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA. PMID:26470720

Real-Time Rain Rate Evaluation via Satellite Downlink Signal Attenuation Measurement

PubMed Central

Reggiannini, Ruggero; Moretti, Marco; Adirosi, Elisa; Baldini, Luca; Facheris, Luca; Melani, Samantha; Bacci, Giacomo; Petrolino, Antonio; Vaccaro, Attilio

2017-01-01

We present the NEFOCAST project (named by the contraction of “Nefele”, which is the Italian spelling for the mythological cloud nymph Nephele, and “forecast”), funded by the Tuscany Region, about the feasibility of a system for the detection and monitoring of precipitation fields over the regional territory based on the use of a widespread network of new-generation Eutelsat “SmartLNB” (smart low-noise block converter) domestic terminals. Though primarily intended for interactive satellite services, these devices can also be used as weather sensors, as they have the capability of measuring the rain-induced attenuation incurred by the downlink signal and relaying it on an auxiliary return channel. We illustrate the NEFOCAST system architecture, consisting of the network of ground sensor terminals, the space segment, and the service center, which has the task of processing the information relayed by the terminals for generating rain field maps. We discuss a few methods that allow the conversion of a rain attenuation measurement into an instantaneous rainfall rate. Specifically, we discuss an exponential model relating the specific rain attenuation to the rainfall rate, whose coefficients were obtained from extensive experimental data. The above model permits the inferring of the rainfall rate from the total signal attenuation provided by the SmartLNB and from the link geometry knowledge. Some preliminary results obtained from a SmartLNB installed in Pisa are presented and compared with the output of a conventional tipping bucket rain gauge. It is shown that the NEFOCAST sensor is able to track the fast-varying rainfall rate accurately with no delay, as opposed to a conventional gauge. PMID:28805692

Active Control of Wind Tunnel Noise

NASA Technical Reports Server (NTRS)

Hollis, Patrick (Principal Investigator)

1991-01-01

The need for an adaptive active control system was realized, since a wind tunnel is subjected to variations in air velocity, temperature, air turbulence, and some other factors such as nonlinearity. Among many adaptive algorithms, the Least Mean Squares (LMS) algorithm, which is the simplest one, has been used in an Active Noise Control (ANC) system by some researchers. However, Eriksson's results, Eriksson (1985), showed instability in the ANC system with an ER filter for random noise input. The Restricted Least Squares (RLS) algorithm, although computationally more complex than the LMS algorithm, has better convergence and stability properties. The ANC system in the present work was simulated by using an FIR filter with an RLS algorithm for different inputs and for a number of plant models. Simulation results for the ANC system with acoustic feedback showed better robustness when used with the RLS algorithm than with the LMS algorithm for all types of inputs. Overall attenuation in the frequency domain was better in the case of the RLS adaptive algorithm. Simulation results with a more realistic plant model and an RLS adaptive algorithm showed a slower convergence rate than the case with an acoustic plant as a delay plant. However, the attenuation properties were satisfactory for the simulated system with the modified plant. The effect of filter length on the rate of convergence and attenuation was studied. It was found that the rate of convergence decreases with increase in filter length, whereas the attenuation increases with increase in filter length. The final design of the ANC system was simulated and found to have a reasonable convergence rate and good attenuation properties for an input containing discrete frequencies and random noise.

Passive Heating Attenuates Post-exercise Cardiac Autonomic Recovery in Healthy Young Males.

PubMed

Peçanha, Tiago; Forjaz, Cláudia L de Moraes; Low, David A

2017-01-01

Post-exercise heart rate (HR) recovery (HRR) presents a biphasic pattern, which is mediated by parasympathetic reactivation and sympathetic withdrawal. Several mechanisms regulate these post-exercise autonomic responses and thermoregulation has been proposed to play an important role. The aim of this study was to test the effects of heat stress on HRR and HR variability (HRV) after aerobic exercise in healthy subjects. Twelve healthy males (25 ± 1 years, 23.8 ± 0.5 kg/m 2 ) performed 14 min of moderate-intensity cycling exercise (40-60% HR reserve ) followed by 5 min of loadless active recovery in two conditions: heat stress (HS) and normothermia (NT). In HS, subjects dressed in a whole-body water-perfused tube-lined suit to increase internal temperature (T c ) by ~1°C. In NT, subjects did not wear the suit. HR, core and skin temperatures (T c and T sk ), mean arterial pressure (MAP) skin blood flow (SKBF), and cutaneous vascular conductance (CVC) were measured throughout and analyzed during post-exercise recovery. HRR was assessed through calculations of HR decay after 60 and 300 s of recovery (HRR60s and HRR300s), and the short- and long-term time constants of HRR (T30 and HRRt). Post-exercise HRV was examined via calculations of RMSSD (root mean square of successive RR intervals) and RMS (root mean square residual of RR intervals). The HS protocol promoted significant thermal stress and hemodynamic adjustments during the recovery (HS-NT differences: T c = +0.7 ± 0.3°C; T sk = +3.2 ± 1.5°C; MAP = -12 ± 14 mmHg; SKBF = +90 ± 80 a.u; CVC = +1.5 ± 1.3 a.u./mmHg). HRR and post-exercise HRV were significantly delayed in HS (e.g., HRR60s = 27 ± 9 vs. 44 ± 12 bpm, P < 0.01; HRR300s = 39 ± 12 vs. 59 ± 16 bpm, P < 0.01). The effects of heat stress (e.g., the HS-NT differences) on HRR were associated with its effects on thermal and hemodynamic responses. In conclusion, heat stress delays HRR, and this effect seems to be mediated by an attenuated parasympathetic reactivation and sympathetic withdrawal after exercise. In addition, the impact of heat stress on HRR is related to the magnitude of the heat stress-induced thermal stress and hemodynamic changes.

Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake.

PubMed

Ryan, Philip J; Ross, Silvano I; Campos, Carlos A; Derkach, Victor A; Palmiter, Richard D

2017-12-01

Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (Oxtr PBN neurons) are key regulators of fluid satiation. Chemogenetic activation of Oxtr PBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, Oxtr PBN neurons were activated by fluid satiation and hypertonic saline injection. Oxtr PBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (Oxt PVH  neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated Oxtr PBN neurons. Our results suggest that Oxtr PBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia.

Plastids Are Major Regulators of Light Signaling in Arabidopsis1[W][OA

PubMed Central

Ruckle, Michael E.; Burgoon, Lyle D.; Lawrence, Lauren A.; Sinkler, Christopher A.; Larkin, Robert M.

2012-01-01

We previously provided evidence that plastid signaling regulates the downstream components of a light signaling network and that this signal integration coordinates chloroplast biogenesis with both the light environment and development by regulating gene expression. We tested these ideas by analyzing light- and plastid-regulated transcriptomes in Arabidopsis (Arabidopsis thaliana). We found that the enrichment of Gene Ontology terms in these transcriptomes is consistent with the integration of light and plastid signaling (1) down-regulating photosynthesis and inducing both repair and stress tolerance in dysfunctional chloroplasts and (2) helping coordinate processes such as growth, the circadian rhythm, and stress responses with the degree of chloroplast function. We then tested whether factors that contribute to this signal integration are also regulated by light and plastid signals by characterizing T-DNA insertion alleles of genes that are regulated by light and plastid signaling and that encode proteins that are annotated as contributing to signaling, transcription, or no known function. We found that a high proportion of these mutant alleles induce chloroplast biogenesis during deetiolation. We quantified the expression of four photosynthesis-related genes in seven of these enhanced deetiolation (end) mutants and found that photosynthesis-related gene expression is attenuated. This attenuation is particularly striking for Photosystem II subunit S expression. We conclude that the integration of light and plastid signaling regulates a number of END genes that help optimize chloroplast function and that at least some END genes affect photosynthesis-related gene expression. PMID:22383539

KinD is a checkpoint protein linking spore formation to extracellular-matrix production in Bacillus subtilis biofilms.

PubMed

Aguilar, Claudio; Vlamakis, Hera; Guzman, Alejandra; Losick, Richard; Kolter, Roberto

2010-05-18

Bacillus subtilis cells form multicellular biofilm communities in which spatiotemporal regulation of gene expression occurs, leading to differentiation of multiple coexisting cell types. These cell types include matrix-producing and sporulating cells. Extracellular matrix production and sporulation are linked in that a mutant unable to produce matrix is delayed for sporulation. Here, we show that the delay in sporulation is not due to a growth advantage of the matrix-deficient mutant under these conditions. Instead, we show that the link between matrix production and sporulation is through the Spo0A signaling pathway. Both processes are regulated by the phosphorylated form of the master transcriptional regulator Spo0A. When cells have low levels of phosphorylated Spo0A (Spo0A~P), matrix genes are expressed; however, at higher levels of Spo0A~P, sporulation commences. We have found that Spo0A~P levels are maintained at low levels in the matrix-deficient mutant, thereby delaying expression of sporulation-specific genes. This is due to the activity of one of the components of the Spo0A phosphotransfer network, KinD. A deletion of kinD suppresses the sporulation defect of matrix mutants, while its overproduction delays sporulation. Our data indicate that KinD displays a dual role as a phosphatase or a kinase and that its activity is linked to the presence of extracellular matrix in the biofilms. We propose a novel role for KinD in biofilms as a checkpoint protein that regulates the onset of sporulation by inhibiting the activity of Spo0A until matrix, or a component therein, is sensed.

KinD Is a Checkpoint Protein Linking Spore Formation to Extracellular-Matrix Production in Bacillus subtilis Biofilms

PubMed Central

Aguilar, Claudio; Vlamakis, Hera; Guzman, Alejandra; Losick, Richard; Kolter, Roberto

2010-01-01

ABSTRACT Bacillus subtilis cells form multicellular biofilm communities in which spatiotemporal regulation of gene expression occurs, leading to differentiation of multiple coexisting cell types. These cell types include matrix-producing and sporulating cells. Extracellular matrix production and sporulation are linked in that a mutant unable to produce matrix is delayed for sporulation. Here, we show that the delay in sporulation is not due to a growth advantage of the matrix-deficient mutant under these conditions. Instead, we show that the link between matrix production and sporulation is through the Spo0A signaling pathway. Both processes are regulated by the phosphorylated form of the master transcriptional regulator Spo0A. When cells have low levels of phosphorylated Spo0A (Spo0A~P), matrix genes are expressed; however, at higher levels of Spo0A~P, sporulation commences. We have found that Spo0A~P levels are maintained at low levels in the matrix-deficient mutant, thereby delaying expression of sporulation-specific genes. This is due to the activity of one of the components of the Spo0A phosphotransfer network, KinD. A deletion of kinD suppresses the sporulation defect of matrix mutants, while its overproduction delays sporulation. Our data indicate that KinD displays a dual role as a phosphatase or a kinase and that its activity is linked to the presence of extracellular matrix in the biofilms. We propose a novel role for KinD in biofilms as a checkpoint protein that regulates the onset of sporulation by inhibiting the activity of Spo0A until matrix, or a component therein, is sensed. PMID:20689749

Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

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

Deng, Yu; Cao, Hong; Cu, Fenglong

Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotinemore » exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes.« less

Vestibular activation of sympathetic nerve activity

NASA Technical Reports Server (NTRS)

Ray, C. A.; Carter, J. R.

2003-01-01

AIM: The vestibulosympathetic reflex refers to sympathetic nerve activation by the vestibular system. Animal studies indicate that the vestibular system assists in blood pressure regulation during orthostasis. Although human studies clearly demonstrate activation of muscle sympathetic nerve activity (MSNA) during engagement of the otolith organs, the role of the vestibulosympathetic reflex in maintaining blood pressure during orthostasis is not well-established. Examination of the vestibulosympathetic reflex with other cardiovascular reflexes indicates that it is a powerful and independent reflex. Ageing, which is associated with an increased risk for orthostatic hypotension, attenuates the vestibulosympathetic reflex. The attenuated reflex is associated with a reduction in arterial pressure. CONCLUSION: These findings suggest that the vestibulosympathetic reflex assists in blood pressure regulation in humans, but future studies examining this reflex in other orthostatically intolerant populations are necessary to address this hypothesis.

Palmitate-induced ER stress and subsequent C 1 HOP activation attenuates leptin and IGF1expression in the brain

USDA-ARS?s Scientific Manuscript database

Background: The peptide hormones insulin-like growth factor-1 (IGF1) and leptin mediate a myriad of biological effects both in the peripheral and central nervous systems. The transcription of these two hormones is regulated by the transcription factor C/EBPa, which in turn is negatively regulated by...

Attenuation of Frontostriatal Connectivity During Reward Processing Predicts Response to Psychotherapy in Major Depressive Disorder.

PubMed

Walsh, Erin; Carl, Hannah; Eisenlohr-Moul, Tory; Minkel, Jared; Crowther, Andrew; Moore, Tyler; Gibbs, Devin; Petty, Chris; Bizzell, Josh; Smoski, Moria J; Dichter, Gabriel S

2017-03-01

There are few reliable predictors of response to antidepressant treatments. In the present investigation, we examined pretreatment functional brain connectivity during reward processing as a potential predictor of response to Behavioral Activation Treatment for Depression (BATD), a validated psychotherapy that promotes engagement with rewarding stimuli and reduces avoidance behaviors. Thirty-three outpatients with major depressive disorder (MDD) and 20 matched controls completed two runs of the monetary incentive delay task during functional magnetic resonance imaging after which participants with MDD received up to 15 sessions of BATD. Seed-based generalized psychophysiological interaction analyses focused on task-based connectivity across task runs, as well as the attenuation of connectivity from the first to the second run of the task. The average change in Beck Depression Inventory-II scores due to treatment was 10.54 points, a clinically meaningful response. Groups differed in seed-based functional connectivity among multiple frontostriatal regions. Hierarchical linear modeling revealed that improved treatment response to BATD was predicted by greater connectivity between the left putamen and paracingulate gyrus during reward anticipation. In addition, MDD participants with greater attenuation of connectivity between several frontostriatal seeds, and midline subcallosal cortex and left paracingulate gyrus demonstrated improved response to BATD. These findings indicate that pretreatment frontostriatal functional connectivity during reward processing is predictive of response to a psychotherapy modality that promotes improving approach-related behaviors in MDD. Furthermore, connectivity attenuation among reward-processing regions may be a particularly powerful endophenotypic predictor of response to BATD in MDD.

High seismic attenuation at a mid-ocean ridge reveals the distribution of deep melt.

PubMed

Eilon, Zachary C; Abers, Geoffrey A

2017-05-01

At most mid-ocean ridges, a wide region of decompression melting must be reconciled with a narrow neovolcanic zone and the establishment of full oceanic crustal thickness close to the rift axis. Two competing paradigms have been proposed to explain melt focusing: narrow mantle upwelling due to dynamic effects related to in situ melt or wide mantle upwelling with lateral melt transport in inclined channels. Measurements of seismic attenuation provide a tool for identifying and characterizing the presence of melt and thermal heterogeneity in the upper mantle. We use a unique data set of teleseismic body waves recorded on the Cascadia Initiative's Amphibious Array to simultaneously measure seismic attenuation and velocity across an entire oceanic microplate. We observe maximal differential attenuation and the largest delays ([Formula: see text] s and δ T S ~ 2 s) in a narrow zone <50 km from the Juan de Fuca and Gorda ridge axes, with values that are not consistent with laboratory estimates of temperature or water effects. The implied seismic quality factor ( Q s ≤ 25) is among the lowest observed worldwide. Models harnessing experimentally derived anelastic scaling relationships require a 150-km-deep subridge region containing up to 2% in situ melt. The low viscosity and low density associated with this deep, narrow melt column provide the conditions for dynamic mantle upwelling, explaining a suite of geophysical observations at ridges, including electrical conductivity and shear velocity anomalies.

Heterologous expression of wheat VERNALIZATION 2 (TaVRN2) gene in Arabidopsis delays flowering and enhances freezing tolerance.

PubMed

Diallo, Amadou; Kane, Ndjido; Agharbaoui, Zahra; Badawi, Mohamed; Sarhan, Fathey

2010-01-13

The vernalization gene 2 (VRN2), is a major flowering repressor in temperate cereals that is regulated by low temperature and photoperiod. Here we show that the gene from Triticum aestivum (TaVRN2) is also regulated by salt, heat shock, dehydration, wounding and abscissic acid. Promoter analysis indicates that TaVRN2 regulatory region possesses all the specific responsive elements to these stresses. This suggests pleiotropic effects of TaVRN2 in wheat development and adaptability to the environment. To test if TaVRN2 can act as a flowering repressor in species different from the temperate cereals, the gene was ectopically expressed in the model plant Arabidopsis. Transgenic plants showed no alteration in morphology, but their flowering time was significantly delayed compared to controls plants, indicating that TaVRN2, although having no ortholog in Brassicaceae, can act as a flowering repressor in these species. To identify the possible mechanism by which TaVRN2 gene delays flowering in Arabidopsis, the expression level of several genes involved in flowering time regulation was determined. The analysis indicates that the late flowering of the 35S::TaVRN2 plants was associated with a complex pattern of expression of the major flowering control genes, FCA, FLC, FT, FVE and SOC1. This suggests that heterologous expression of TaVRN2 in Arabidopsis can delay flowering by modulating several floral inductive pathways. Furthermore, transgenic plants showed higher freezing tolerance, likely due to the accumulation of CBF2, CBF3 and the COR genes. Overall, our data suggests that TaVRN2 gene could modulate a common regulator of the two interacting pathways that regulate flowering time and the induction of cold tolerance. The results also demonstrate that TaVRN2 could be used to manipulate flowering time and improve cold tolerance in other species.

Simulating high frequency water quality monitoring data using a catchment runoff attenuation flux tool (CRAFT).

PubMed

Adams, Russell; Quinn, Paul F; Perks, Matthew; Barber, Nicholas J; Jonczyk, Jennine; Owen, Gareth J

2016-12-01

High resolution water quality data has recently become widely available from numerous catchment based monitoring schemes. However, the models that can reproduce time series of concentrations or fluxes have not kept pace with the advances in monitoring data. Model performance at predicting phosphorus (P) and sediment concentrations has frequently been poor with models not fit for purpose except for predicting annual losses. Here, the data from the Eden Demonstration Test Catchments (DTC) project have been used to calibrate the Catchment Runoff Attenuation Flux Tool (CRAFT), a new, parsimonious model developed with the aim of modelling both the generation and attenuation of nutrients and sediments in small to medium sized catchments. The CRAFT has the ability to run on an hourly timestep and can calculate the mass of sediments and nutrients transported by three flow pathways representing rapid surface runoff, fast subsurface drainage and slow groundwater flow (baseflow). The attenuation feature of the model is introduced here; this enables surface runoff and contaminants transported via this pathway to be delayed in reaching the catchment outlet. It was used to investigate some hypotheses of nutrient and sediment transport in the Newby Beck Catchment (NBC) Model performance was assessed using a suite of metrics including visual best fit and the Nash-Sutcliffe efficiency. It was found that this approach for water quality models may be the best assessment method as opposed to using a single metric. Furthermore, it was found that, when the aim of the simulations was to reproduce the time series of total P (TP) or total reactive P (TRP) to get the best visual fit, that attenuation was required. The model will be used in the future to explore the impacts on water quality of different mitigation options in the catchment; these will include attenuation of surface runoff. Copyright © 2016 Elsevier B.V. All rights reserved.

Intravenous Levetiracetam in the Rat Pilocarpine-Induced Status Epilepticus Model: Behavioral, Physiological and Histological Studies

PubMed Central

Zheng, Yi; Moussally, Jon; Cash, Sydney S.; Karnam, Havisha B.; Cole, Andrew J.

2010-01-01

Purpose Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an antiepileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. Methods We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 minutes after the onset of behavioral status epilepticus, animals were treated with LEV (200–1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. Results When administered 30 minutes after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4 minutes to 23.6 minutes. When administered 10 minutes after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Conclusions Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG. PMID:20026136

Intravenous levetiracetam in the rat pilocarpine-induced status epilepticus model: behavioral, physiological and histological studies.

PubMed

Zheng, Yi; Moussally, Jon; Cash, Sydney S; Karnam, Havisha B; Cole, Andrew J

2010-01-01

Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an anti-epileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 min after the onset of behavioral status epilepticus, animals were treated with LEV (200-1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. When administered 30 min after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4-23.6 min. When administered 10 min after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG. Copyright 2009 Elsevier Ltd. All rights reserved.

Breastfeeding and developmental delay: findings from the millennium cohort study.

PubMed

Sacker, Amanda; Quigley, Maria A; Kelly, Yvonne J

2006-09-01

We investigated whether the duration and exclusivity of breastfeeding affects the likelihood of gross and fine motor delay in infants and examined the effect of factors that might explain any observed differences. The study sample included all term singleton infants who weighed > 2500 g at birth and were not placed in a special care infant unit and whose mothers participated in the first survey of the Millennium Cohort Study. Missing data reduced the sample to 14660 (94%) with complete data. Almost half (47%) of the infants initially were exclusively breastfed, but only 3.5% of these infants were still being fed exclusively on breast milk after 4 months of age, and 34% of infants were not breastfed at all; 9% of the infants were identified with delays in gross motor coordination and 6% with fine motor coordination delays at age 9 months. The proportion of infants who mastered the developmental milestones increased with duration and exclusivity of breastfeeding. Infants who had never been breastfed were 50% more likely to have gross motor coordination delays than infants who had been breastfed exclusively for at least 4 months (10.7% vs 7.3%). Any breast milk also was positively related to development: infants who had never been breastfed were 30% more likely to have gross motor delays than infants who were given some breast milk for up to 2 months (10.7% vs 8.4%). The odds ratios for gross motor delay were not attenuated after adjustment for biological, socioeconomic, or psychosocial factors. Infants who were never breastfed had at least a 40% greater likelihood of fine motor delay than infants who were given breast milk for a prolonged period. Our results suggest that the protective effect of breastfeeding on the attainment of gross motor milestones is attributable to some component(s) of breast milk or feature of breastfeeding and is not simply a product of advantaged social position, education, or parenting style, because control for these factors did not explain any of the observed association. In contrast, the association between breastfeeding and fine motor delay was explained by biological, socioeconomic, and psychosocial factors.

Adenosine kinase regulation of cardiomyocyte hypertrophy

PubMed Central

Fassett, John T.; Hu, Xinli; Xu, Xin; Lu, Zhongbing; Zhang, Ping; Chen, Yingjie

2011-01-01

There is evidence that extracellular adenosine can attenuate cardiac hypertrophy, but the mechanism by which this occurs is not clear. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy. Phenylephrine (PE) caused hypertrophy of neonatal rat cardiomyocytes with increases of cell surface area, protein synthesis, and atrial natriuretic peptide (ANP) expression. These responses were attenuated by 5 μM 2-chloroadenosine (CADO; adenosine deaminase resistant adenosine analog) or 10 μM adenosine. While antagonism of adenosine receptors partially blocked the reduction of ANP expression produced by CADO, it did not restore cell size or protein synthesis. In support of a role for intracellular adenosine metabolism in regulating hypertrophy, the adenosine kinase (AK) inhibitors iodotubercidin and ABT-702 completely reversed the attenuation of cell size, protein synthesis, and expression of ANP by CADO or ADO. Examination of PE-induced phosphosignaling pathways revealed that CADO treatment did not reduce AKTSer473 phosphorylation but did attenuate sustained phosphorylation of RafSer338 (24–48 h), mTORSer2448 (24–48 h), p70S6kThr389 (2.5–48 h), and ERKThr202/Tyr204 (48 h). Inhibition of AK restored activation of these enzymes in the presence of CADO. Using dominant negative and constitutively active Raf adenoviruses, we found that Raf activation is necessary and sufficient for PE-induced mTORC1 signaling and cardiomyocyte hypertrophy. CADO treatment still blocked p70S6kThr389 phosphorylation and hypertrophy downstream of constitutively active Raf, however, despite a high level phosphorylation of ERKThr202/Tyr204 and AKTSer473. Reduction of Raf-induced p70S6kThr389 phosphorylation and hypertrophy by CADO was reversed by inhibiting AK. Together, these results identify AK as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy, which acts, at least in part, through inhibition of Raf signaling to mTOR/p70S6k. PMID:21335462

MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis

PubMed Central

Lippai, Dora; Kodys, Karen; Catalano, Donna; Iracheta-Vellve, Arvin; Szabo, Gyongyi

2015-01-01

Background & Aim MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis. Methods Wild type (WT) and miR-155-deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed. Results MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor κ beta (NF-κB) activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and monocyte chemoattractant protein-1 (MCP1) in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3) and reduction in collagen and α smooth muscle actin (αSMA) levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF), a pro-fibrotic cytokine; SMAD family member 3 (Smad3), a protein involved in transforming growth factor-β (TGFβ) signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT) in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein β (C/EBPβ) a miR-155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice. Conclusions Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis. PMID:26042593

The estimation of the propagation delay through the troposphere from microwave radiometer data. [very long base interferometry

NASA Technical Reports Server (NTRS)

Moran, J. M.; Rosen, B. R.

1980-01-01

The uncertainity in propagation delay estimates is due primarily to tropospheric water, the total amount and vertical distribution of which is variable. Because water vapor both delays and attenuates microwave signals, the propagation delay, or wet path length, can be estimated from the microwave brightness temperature near the 22.235 GHz transition of water vapor. The data from a total of 240 radiosonde launches taken simultaneously were analyzed. Estimates of brightness temperature at 19 and 22 GHz and wet path length were made from these data. The wet path length in the zenith direction could be estimated from the surface water vapor density to an accuracy of 5 cm for the summer data and 2 cm for winter data. Using the brightness temperatures, the wet path could be estimated to an accuracy of 0.3 cm. Two dual frequency radiometers were refurbished in order to test these techniques. These radiometers were capable of measuring the difference in the brightness temperature at 30 deg elevation angle and at the zenith to an accuracy of about 1 K. In August 1975, 45 radiosondes were launched over an 11 day period. Brightness temperature measurements were made simultaneously at 19 and 22 GHz with the radiometers. The rms error for the estimation of wet path length from surface meteorological parameters was 3.2 cm, and from the radiometer brightness temperatures, 1.5 cm.

An Inequality Constrained Least-Squares Approach as an Alternative Estimation Procedure for Atmospheric Parameters from VLBI Observations

NASA Astrophysics Data System (ADS)

Halsig, Sebastian; Artz, Thomas; Iddink, Andreas; Nothnagel, Axel

2016-12-01

On its way through the atmosphere, radio signals are delayed and affected by bending and attenuation effects relative to a theoretical path in vacuum. In particular, the neutral part of the atmosphere contributes considerably to the error budget of space-geodetic observations. At the same time, space-geodetic techniques become more and more important in the understanding of the Earth's atmosphere, because atmospheric parameters can be linked to the water vapor content in the atmosphere. The tropospheric delay is usually taken into account by applying an adequate model for the hydrostatic component and by additionally estimating zenith wet delays for the highly variable wet component. Sometimes, the Ordinary Least Squares (OLS) approach leads to negative estimates, which would be equivalent to negative water vapor in the atmosphere and does, of course, not reflect meteorological and physical conditions in a plausible way. To cope with this phenomenon, we introduce an Inequality Constrained Least Squares (ICLS) method from the field of convex optimization and use inequality constraints to force the tropospheric parameters to be non-negative allowing for a more realistic tropospheric parameter estimation in a meteorological sense. Because deficiencies in the a priori hydrostatic modeling are almost fully compensated by the tropospheric estimates, the ICLS approach urgently requires suitable a priori hydrostatic delays. In this paper, we briefly describe the ICLS method and validate its impact with regard to station positions.

Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

PubMed

De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

2016-01-01

While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (<24 h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Immediate and Delayed Effects of Meta-Cognitive Instruction on Regulation of Cognition and Mathematics Achievement

ERIC Educational Resources Information Center

Mevarech, Zemira R.; Amrany, Chagit

2008-01-01

The present study addressed two research questions: (a) the extent to which students who were exposed to meta-cognitive instruction are able to implement meta-cognitive processes in a delayed, stressful situation, in our case--being examined on the matriculation exam; and (b) whether students preparing themselves for the matriculation exam in…