Reactive oxygen species derived from NAD(P)H oxidase play a role on ethanol-induced hypertension and endothelial dysfunction in rat resistance arteries.

PubMed

Simplicio, Janaina A; do Vale, Gabriel T; Gonzaga, Natália A; Leite, Letícia N; Hipólito, Ulisses V; Pereira, Camila A; Tostes, Rita C; Tirapelli, Carlos R

2017-02-01

Chronic ethanol consumption is a risk factor for cardiovascular diseases. We studied whether NAD(P)H oxidase-derived reactive oxygen species (ROS) play a role in ethanol-induced hypertension, vascular dysfunction, and protein expression in resistance arteries. Male Wistar rats were treated with ethanol (20 % v/v) for 6 weeks. Ethanol treatment increased blood pressure and decreased acetylcholine-induced relaxation in the rat mesenteric arterial bed (MAB). These responses were attenuated by apocynin (30 mg/kg/day; p.o. gavage). Ethanol consumption increased superoxide anion (O 2 - ) generation and decreased nitrate/nitrite (NO x ) concentration in the rat MAB and apocynin prevented these responses. Conversely, ethanol did not affect the concentration of hydrogen peroxide (H 2 O 2 ) and reduced glutathione (GSH) or the activity of superoxide dismutase (SOD) and catalase (CAT) in the rat MAB. Ethanol increased interleukin (IL)-10 levels in the rat MAB but did not affect the levels of tumor necrosis factor (TNF)-α, IL-6, or IL-1β. Ethanol increased the expression of Nox2 and the phosphorylation of SAPK/JNK, but reduced eNOS expression in the rat MAB. Apocynin prevented these responses. However, ethanol treatment did not affect the expression of Nox1, Nox4, p38MAPK, ERK1/2, or SAPK/JNK in the rat MAB. Ethanol increased plasma levels of TBARS, TNF-α, IL-6, IL-1β, and IL-10, whereas it decreased NO x levels. The major finding of our study is that NAD(P)H oxidase-derived ROS play a role on ethanol-induced hypertension and endothelial dysfunction in resistance arteries. Moreover, ethanol consumption affects the expression and phosphorylation of proteins that regulate vascular function and NAD(P)H oxidase-derived ROS play a role in such responses.

Derivation of an occupational exposure limit (OEL) for methylene chloride based on acute CNS effects and relative potency analysis.

PubMed

Storm, J E; Rozman, K K

1998-06-01

The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.

Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma

PubMed Central

Johnson, Martin; Nikolos, Christina; Jester, William; Klanderman, Barbara; Litonjua, Augusto A.; Tantisira, Kelan G.; Truskowski, Kevin; MacDonald, Kevin; Panettieri, Reynold A.; Weiss, Scott T.

2015-01-01

Globally, asthma is a chronic inflammatory respiratory disease affecting over 300 million people. Some asthma patients remain poorly controlled by conventional therapies and experience more life-threatening exacerbations. Vitamin D, as an adjunct therapy, may improve disease control in severe asthma patients since vitamin D enhances glucocorticoid responsiveness and mitigates airway smooth muscle (ASM) hyperplasia. We sought to characterize differences in transcriptome responsiveness to vitamin D between fatal asthma- and non-asthma-derived ASM by using RNA-Seq to measure ASM transcript expression in five donors with fatal asthma and ten non-asthma-derived donors at baseline and with vitamin D treatment. Based on a Benjamini-Hochberg corrected p-value <0.05, 838 genes were differentially expressed in fatal asthma vs. non-asthma-derived ASM at baseline, and vitamin D treatment compared to baseline conditions induced differential expression of 711 and 867 genes in fatal asthma- and non-asthma-derived ASM, respectively. Functional gene categories that were highly represented in all groups included extracellular matrix, and responses to steroid hormone stimuli and wounding. Genes differentially expressed by vitamin D also included cytokine and chemokine activity categories. Follow-up qPCR and individual analyte ELISA experiments were conducted for four cytokines (i.e. CCL2, CCL13, CXCL12, IL8) to measure TNFα-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNFα-induced IL8 protein secretion levels to a comparable degree in fatal asthma- and non-asthma-derived ASM even though IL8 had significantly higher baseline levels in fatal asthma-derived ASM. Our findings identify vitamin D-specific gene targets and provide transcriptomic data to explore differences in the ASM of fatal asthma- and non-asthma-derived donors. PMID:26207385

Health Systems' Responsiveness and Its Characteristics: A Cross-Country Comparative Analysis

PubMed Central

Robone, Silvana; Rice, Nigel; Smith, Peter C

2011-01-01

Objectives Responsiveness has been identified as one of the intrinsic goals of health care systems. Little is known, however, about its determinants. Our objective is to investigate the potential country-level drivers of health system responsiveness. Data Source Data on responsiveness are taken from the World Health Survey. Information on country-level characteristics is obtained from a variety of sources including the United Nations Development Program (UNDP). Study Design A two-step procedure. First, using survey data we derive a country-level measure of system responsiveness purged of differences in individual reporting behavior. Secondly, we run cross-sectional country-level regressions of responsiveness on potential drivers. Principal Findings Health care expenditures per capita are positively associated with responsiveness, after controlling for the influence of potential confounding factors. Aspects of responsiveness are also associated with public sector spending (negatively) and educational development (positively). Conclusions From a policy perspective, improvements in responsiveness may require higher spending levels. The expansion of nonpublic sector provision, perhaps in the form of increased patient choice, may also serve to improve responsiveness. However, these inferences are tentative and require further study. PMID:21762144

Phylogenetic and structural response of heterotrophic bacteria to dissolved organic matter of different chemical composition in a continuous culture study.

PubMed

Landa, M; Cottrell, M T; Kirchman, D L; Kaiser, K; Medeiros, P M; Tremblay, L; Batailler, N; Caparros, J; Catala, P; Escoubeyrou, K; Oriol, L; Blain, S; Obernosterer, I

2014-06-01

Dissolved organic matter (DOM) and heterotrophic bacteria are highly diverse components of the ocean system, and their interactions are key in regulating the biogeochemical cycles of major elements. How chemical and phylogenetic diversity are linked remains largely unexplored to date. To investigate interactions between bacterial diversity and DOM, we followed the response of natural bacterial communities to two sources of phytoplankton-derived DOM over six bacterial generation times in continuous cultures. Analyses of total hydrolysable neutral sugars and amino acids, and ultrahigh resolution mass spectrometry revealed large differences in the chemical composition of the two DOM sources. According to 454 pyrosequences of 16S ribosomal ribonucleic acid genes, diatom-derived DOM sustained higher levels of bacterial richness, evenness and phylogenetic diversity than cyanobacteria-derived DOM. These distinct community structures were, however, not associated with specific taxa. Grazing pressure affected bacterial community composition without changing the overall pattern of bacterial diversity levels set by DOM. Our results demonstrate that resource composition can shape several facets of bacterial diversity without influencing the phylogenetic composition of bacterial communities, suggesting functional redundancy at different taxonomic levels for the degradation of phytoplankton-derived DOM. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Response of puppies to canine-origin parvovirus vaccines.

PubMed

Carmichael, L E; Pollock, R V; Joubert, J C

1984-02-01

Pups 9-18 1/2 weeks old were given a single dose of 1 of 4 commercial, live, canine-origin parvovirus vaccines. All 4 vaccines evoked high levels of antibody in seronegative pups, but variable response in those with low levels of maternally derived antibodies. Vaccinal virus spread to unvaccinated contact controls and elicited essentially equivalent titers. No clinical signs of parvovirus infection were observed in vaccinates or controls.

Increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long-chain omega-3 PUFA.

PubMed

Schuchardt, Jan Philipp; Schneider, Inga; Willenberg, Ina; Yang, Jun; Hammock, Bruce D; Hahn, Andreas; Schebb, Nils Helge

2014-06-01

Several supplementation studies with long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) describe an increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acids in blood, while changes in levels of other LC n-3 and n-6 PUFA-derived oxylipins were minor. In order to investigate the kinetics of changes in oxylipin levels in response to LC n-3 PUFA ingestion, we conducted a single dose treatment study with healthy subjects. In the present kinetic study, we compared patterns of hydroxy, epoxy and dihydroxy fatty acids in plasma of 6 healthy men before and after 6, 8, 24, and 48h of fish oil (1008mg EPA and 672mg DHA) ingestion. Levels of EPA- as well as other LC PUFA-derived hydroxy, epoxy and dihydroxy fatty acids were analyzed in plasma by LC-MS. Additionally, levels of these oxylipins were compared with their parent PUFA levels in plasma phospholipids. All EPA-derived oxylipin levels were significantly increased 6h after LC n-3 PUFA ingestion and gradually drop thereafter reaching the baseline levels about 48h after treatment. The relative increase in EPA plasma phospholipid levels highly correlated with the increase of plasma EPA-derived oxylipin levels at different time points. In contrast, plasma levels of arachidonic acid- and DHA-derived oxylipins as well as parent PUFA levels in plasma phospholipids were hardly changed. Our findings demonstrate that a single dose of LC n-3 PUFAs can rapidly induce a shift in the EPA oxylipin profile of healthy subjects within a few hours. Taking the high biological activity of the EPA-derived epoxy fatty acids into account, even short-term treatment with LC n-3 PUFAs may cause systemic effects, which warrant further investigation. Copyright © 2014 Elsevier Inc. All rights reserved.

Relations among pure-tone sound stimuli, neural activity, and the loudness sensation

NASA Technical Reports Server (NTRS)

Howes, W. L.

1972-01-01

Both the physiological and psychological responses to pure-tone sound stimuli are used to derive formulas which: (1) relate the loudness, loudness level, and sound-pressure level of pure tones; (2) apply continuously over most of the acoustic regime, including the loudness threshold; and (3) contain no undetermined coefficients. Some of the formulas are fundamental for calculating the loudness of any sound. Power-law formulas relating the pure-tone sound stimulus, neural activity, and loudness are derived from published data.

Estimating of aquifer parameters from the single-well water-level measurements in response to advancing longwall mine by using particle swarm optimization

NASA Astrophysics Data System (ADS)

Buyuk, Ersin; Karaman, Abdullah

2017-04-01

We estimated transmissivity and storage coefficient values from the single well water-level measurements positioned ahead of the mining face by using particle swarm optimization (PSO) technique. The water-level response to the advancing mining face contains an semi-analytical function that is not suitable for conventional inversion shemes because the partial derivative is difficult to calculate . Morever, the logaritmic behaviour of the model create difficulty for obtaining an initial model that may lead to a stable convergence. The PSO appears to obtain a reliable solution that produce a reasonable fit between water-level data and model function response. Optimization methods have been used to find optimum conditions consisting either minimum or maximum of a given objective function with regard to some criteria. Unlike PSO, traditional non-linear optimization methods have been used for many hydrogeologic and geophysical engineering problems. These methods indicate some difficulties such as dependencies to initial model, evolution of the partial derivatives that is required while linearizing the model and trapping at local optimum. Recently, Particle swarm optimization (PSO) became the focus of modern global optimization method that is inspired from the social behaviour of birds of swarms, and appears to be a reliable and powerful algorithms for complex engineering applications. PSO that is not dependent on an initial model, and non-derivative stochastic process appears to be capable of searching all possible solutions in the model space either around local or global optimum points.

Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women

PubMed Central

Milivojevic, Verica; Fox, Helen C.; Sofuoglu, Mehmet; Covault, Jonathan; Sinha, Rajita

2015-01-01

Objectives Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. Methods Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M / 8F) (400mg/day) or placebo (14M / 9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5–7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. Results Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. Conclusions As expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence. PMID:26716877

Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women.

PubMed

Milivojevic, Verica; Fox, Helen C; Sofuoglu, Mehmet; Covault, Jonathan; Sinha, Rajita

2016-03-01

Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5-7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. As expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence. Copyright © 2015 Elsevier Ltd. All rights reserved.

Assessment of stress tolerance acquisition in the heat-tolerant derivative strains of Bifidobacterium animalis subsp. lactis BB-12 and Lactobacillus rhamnosus GG.

PubMed

Aakko, J; Sánchez, B; Gueimonde, M; Salminen, S

2014-07-01

The purpose of this study was to investigate the heat-shock response at molecular level in Lactobacillus rhamnosus GG, Bifidobacterium animalis subsp. lactis BB-12 and their heat-tolerant derivatives and to characterize the changes that make the derivatives more robust in terms of heat stress. The study strains were exposed for 2 h to a heat-shock treatment, Bif. animalis subsp. lactis BB-12 and its derivative at 50°C and the Lact. rhamnosus GG and its derivative at 60°C. Protein synthesis before and after heat shock was examined using proteomics and RT-qPCR. The analysis revealed that the regulation of seven proteins in both strain pairs was modified as a response to heat or between the original and the derivative strain. The comparison of wild-type strains and the heat-tolerant derivatives suggests that the acquisition of heat tolerance in the Bif. animalis subsp. lactis BB-12 derivative is due to a slightly increased constitutive level of chaperones, while in Lact. rhamnosus GG derivative, the main reason seems to be a higher ability to induce the production of chaperones. This study revealed possible markers of heat tolerance in B. lactis and Lact. rhamnosus strains. This study increases our knowledge on how Lactobacillus and Bifidobacterium strains may acquire heat tolerance. These findings may be useful for improving the heat tolerance of existing probiotic strains as well as screening new heat-tolerant strains. © 2014 The Society for Applied Microbiology.

A Potential Function Derivation of a Constitutive Equation for Inelastic Material Response

NASA Technical Reports Server (NTRS)

Stouffer, D. C.; Elfoutouh, N. A.

1983-01-01

Physical and thermodynamic concepts are used to develop a potential function for application to high temperature polycrystalline material response. Inherent in the formulation is a differential relationship between the potential function and constitutive equation in terms of the state variables. Integration of the differential relationship produces a state variable evolution equation that requires specification of the initial value of the state variable and its time derivative. It is shown that the initial loading rate, which is directly related to the initial hardening rate, can significantly influence subsequent material response. This effect is consistent with observed material behavior on the macroscopic and microscopic levels, and may explain the wide scatter in response often found in creep testing.

Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease.

PubMed

Smith, R E; Reyes, N J; Khandelwal, P; Schlereth, S L; Lee, H S; Masli, S; Saban, D R

2016-08-01

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. © Society for Leukocyte Biology.

Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease

PubMed Central

Smith, R. E.; Reyes, N. J.; Khandelwal, P.; Schlereth, S. L.; Lee, H. S.; Masli, S.; Saban, D. R.

2016-01-01

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. PMID:26856994

Peer Review for EPA’s Biologically Based Dose-Response (BBDR) Model for Perchlorate

EPA Science Inventory

EPA is developing a regulation for perchlorate in drinking water. As part the regulatory process EPA must develop a Maximum Contaminant Level Goal (MCLG). FDA and EPA scientists developed a biologically based dose-response (BBDR) model to assist in deriving the MCLG. This mode...

Essays in Information Economics

ERIC Educational Resources Information Center

Chiao, Hak Fung

2010-01-01

I study two economic responses to the challenges of copyright infringements and spam brought about by the birth of the Internet. These responses are anti-spam mechanisms and open contents. I derive conditions under which distribution and care level taken to avoid damages in open contents are socially efficient or inefficient. Then I report…

Dissociation of POMC Peptides after Self-Injury Predicts Responses To Centrally Acting Opiate Blockers.

ERIC Educational Resources Information Center

Sandman, Curt A.; Hetrick, William; Taylor, Derek V.; Chicz-DeMet, Aleksandra

1997-01-01

This study investigated whether blood plasma levels of pro-opiomelanocortin-derived (POMC) peptides, beta-endorphin-like activity, adrenocorticotrophic hormone, and adrenal cortisol immediately after self injurious behavior (SIB) episodes predicted subsequent response to an opiate blocker in 10 patients with mental retardation. Results suggest…

Development of chitosan-pullulan composite nanoparticles for nasal delivery of vaccines: in vivo studies.

PubMed

Cevher, Erdal; Salomon, Stefan K; Somavarapu, Satyanarayana; Brocchini, Steve; Alpar, H Oya

2015-01-01

Here, we aimed at developing chitosan/pullulan composite nanoparticles and testing their potential as novel systems for the nasal delivery of diphtheria toxoid (DT). All the chitosan derivatives [N-trimethyl (TMC), chloride and glutamate] and carboxymethyl pullulan (CMP) were synthesised and antigen-loaded composites were prepared by polyion complexation of chitosan and pullulan derivatives (particle size: 239-405 nm; surface charge: +18 and +27 mV). Their immunological effects after intranasal administration to mice were compared to intramuscular route. Composite nanoparticles induced higher levels of IgG responses than particles formed with chitosan derivative and antigen. Nasally administered TMC-pullulan composites showed higher DT serum IgG titre when compared with the other composites. Co-encapsulation of CpG ODN within TMC-CMP-DT nanoparticles resulted in a balanced Th1/Th2 response. TMC/pullulan composite nanoparticles also induced highest cytokine levels compared to those of chitosan salts. These findings demonstrated that TMC-CMP-DT composite nanoparticles are promising delivery system for nasal vaccination.

Dynamic release and clearance of circulating microparticles during cardiac stress.

PubMed

Augustine, Daniel; Ayers, Lisa V; Lima, Eduardo; Newton, Laura; Lewandowski, Adam J; Davis, Esther F; Ferry, Berne; Leeson, Paul

2014-01-03

Microparticles are cell-derived membrane vesicles, relevant to a range of biological responses and known to be elevated in cardiovascular disease. To investigate microparticle release during cardiac stress and how this response differs in those with vascular disease. We measured a comprehensive panel of circulating cell-derived microparticles by a standardized flow cytometric protocol in 119 patients referred for stress echocardiography. Procoagulant, platelet, erythrocyte, and endothelial but not leukocyte, granulocyte, or monocyte-derived microparticles were elevated immediately after a standardized dobutamine stress echocardiogram and decreased after 1 hour. Twenty-five patients developed stress-induced wall motion abnormalities suggestive of myocardial ischemia. They had similar baseline microparticle levels to those who did not develop ischemia, but, interestingly, their microparticle levels did not change during stress. Furthermore, no stress-induced increase was observed in those without inducible ischemia but with a history of vascular disease. Fourteen patients subsequently underwent coronary angiography. A microparticle rise during stress echocardiography had occurred only in those with normal coronary arteries. Procoagulant, platelet, erythrocyte, and endothelial microparticles are released during cardiac stress and then clear from the circulation during the next hour. This stress-induced rise seems to be a normal physiological response that is diminished in those with vascular disease.

Key cytokines of adaptive immunity are differentially induced in rainbow trout kidney by a group of structurally related geranyl aromatic derivatives.

PubMed

Valenzuela, Beatriz; Obreque, Javiera; Soto-Aguilera, Sarita; Maisey, Kevin; Imarai, Mónica; Modak, Brenda

2016-02-01

Filifolinone is a semi-synthetic terpenoid derivative obtained from Heliotropium filifolium that increases the expression level of pro-inflammatory and anti-inflammatory cytokines in kidney cells of salmon. Because cytokines are produced in response to a foreign organism and by distinct other signals modulating immune responses, we further studied the potential immunomodulatory effects of a group of structural related terpenoid derivatives from H. filifolium on salmonids to determine the relationship between the chemical structure of the derivatives and their ability to modify cytokine expression and the lymphoid content. The resin and four 3H-spiro 1-benzofuran-2,1'-cyclohexane derivatives were tested in vivo in rainbow trout (Oncorhynchus mykiss) by quantifying the transcript levels of antiviral and T helper-type cytokines and T and B cells in the kidney. Three of the four terpenoids differ only in the C-7'substituent of the cyclohexane and the presence of the ketone group at this position in Filifolinone appeared responsible of an important up-regulation of IFN-α1, IFN-γ, IL-4/13A and IL-17D in the kidney of the treated trout. In addition, the absence of a methoxy group in carbon 7 of the benzene ring, found in all compounds but not in Folifolinoic acid, produced a significant reduction of IFN-γ, IL-12 and IL-4/13A transcripts. B cells were not affected by the compound treatment but Filifolinoic acid and the resin induced a significant reduction of T cells. Altogether, results showed that immunomodulating responses observed in the trout by effect of 3H-spiro 1-benzofuran-2,1'-cyclohexane derivatives is related to the presence of the ketone group in the carbon 7' and the methoxy group in carbon 7 of the benzene ring, being Filifolinone the most active immunostimulatory compound identified. Copyright © 2015 Elsevier Ltd. All rights reserved.

Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

PubMed Central

Markworth, James F.; Vella, Luke; Lingard, Benjamin S.; Tull, Dedreia L.; Rupasinghe, Thusitha W.; Sinclair, Andrew J.; Maddipati, Krishna Rao

2013-01-01

Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0–3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery. PMID:24089379

Cadmium (Cd(2+)) exposure differentially elicits both cell proliferation and cell death related responses in SK-RC-45.

PubMed

Sinha, Krishnendu; Pal, Pabitra Bikash; Sil, Parames C

2014-03-01

Cadmium (Cd(2+)) is a major nephrotoxic environmental pollutant, affecting mostly proximal convoluted tubule (PCT) cells of the mammalian kidney, while conditionally Cd(2+) could also elicit protective responses with great variety and variability in different systems. The present study was designed to evaluate the molecular mechanism of Cd(2+) toxicity on human PCT derived Renal Cell Carcinoma (RCC), SK-RC-45 and compare its responses with normal human PCT derived cell line, NKE. Exposure of SK-RC-45 cells with different concentrations of CdCl2 (e.g. 0, 10 and 20μM) in serum free medium for 24h generate considerable amount of ROS, accompanied with decreased cell viability and alternations in the cellular and nuclear morphologies, heat shock responses and GCLC mediated protective responses. Also phosphatidylserine externalization, augmentation in the level of caspase-3, PARP, BAD, Apaf1 and cleaved caspase-9 along with decreased expression of Bcl2 and release of cytochrome c confirmed that, Cd(2+) dose dependently induces solely intrinsic pathway of apoptosis in SK-RC-45, independent of JNK. Furthermore, the non-toxic concentration (10μM) of Cd(2+) induced nuclear translocation of Nrf2 and increased expression in the level of HO-1 enzyme suggesting that at the milder concentration, Cd(2+) induces protective signaling pathways. On the other hand, exposure of NKE to different concentrations of CdCl2 (e.g. 0, 10, 20, 30 and 50μM) under the same conditions elevate stronger heat shock and SOD2 mediated protective responses. In contrary to the RCC PCT, the normal PCT derived cell follows JNK dependent and extrinsic pathways of apoptosis. Cumulatively, these results suggest that Cd(2+) exposure dose dependently elicit both cell proliferative and cell death related responses in SK-RC-45 cells and is differentially regulated with respect to normal kidney epithelia derived NKE cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Body Mass Changes Associated With Hyper-Gravity are Independent of Adrenal Derived Hormones

NASA Technical Reports Server (NTRS)

Wade, Charles E.; Moran, Megan M.; Wang, Tommy J.; Baer, Lisa A.; Yuan, Fang; Fung, Cyra K.; Stein, T. Peter; Dalton, Bonnie P. (Technical Monitor)

2001-01-01

Exposure to hyper-gravity results in a number of metabolic changes associated with increases in catecholamines and corticosterone. These changes result in a loss of body and fat mass. To assess the role of hormones derived from the adrenal gland in the changes we studied sham operated (SO) and adrenalectomized (ADX) male rats exposed to hyper-gravity of 2 G for 14 days. Control groups at 1 G were also studied. Urinary epinephrine (EPI) and corticosterone (CORT) were reduced in ADX animals. In response to 2 G there was an increase in urinary EPI and CORT in SO rats, while levels were unchanged in ADX animals. Both groups of animals had similar increases in urinary norepinephrine levels. The reductions of body mass gain in response to 2 G were the same in both groups. The decrease in relative fat mass was greater in ADX. Energy intake and expenditure were not different between groups. In response of returning to 1 G for 24 hours and reexposure to hyper-gravity there were no differences between SO and ADX in the changes of food and water intake, body mass or activity. The changes in metabolism with exposure to hyper-gravity do not appear to require hormones derived from the adrenal gland. The increase in lypolysis and alterations body and fat mass appear to be modulated by sympathetically derived norepinehrine.

Seaweed Polysaccharides and Derived Oligosaccharides Stimulate Defense Responses and Protection Against Pathogens in Plants

PubMed Central

Vera, Jeannette; Castro, Jorge; Gonzalez, Alberto; Moenne, Alejandra

2011-01-01

Plants interact with the environment by sensing “non-self” molecules called elicitors derived from pathogens or other sources. These molecules bind to specific receptors located in the plasma membrane and trigger defense responses leading to protection against pathogens. In particular, it has been shown that cell wall and storage polysaccharides from green, brown and red seaweeds (marine macroalgae) corresponding to ulvans, alginates, fucans, laminarin and carrageenans can trigger defense responses in plants enhancing protection against pathogens. In addition, oligosaccharides obtained by depolymerization of seaweed polysaccharides also induce protection against viral, fungal and bacterial infections in plants. In particular, most seaweed polysaccharides and derived oligosaccharides trigger an initial oxidative burst at local level and the activation of salicylic (SA), jasmonic acid (JA) and/or ethylene signaling pathways at systemic level. The activation of these signaling pathways leads to an increased expression of genes encoding: (i) Pathogenesis-Related (PR) proteins with antifungal and antibacterial activities; (ii) defense enzymes such as pheylalanine ammonia lyase (PAL) and lipoxygenase (LOX) which determine accumulation of phenylpropanoid compounds (PPCs) and oxylipins with antiviral, antifugal and antibacterial activities and iii) enzymes involved in synthesis of terpenes, terpenoids and/or alkaloids having antimicrobial activities. Thus, seaweed polysaccharides and their derived oligosaccharides induced the accumulation of proteins and compounds with antimicrobial activities that determine, at least in part, the enhanced protection against pathogens in plants. PMID:22363237

Seaweed polysaccharides and derived oligosaccharides stimulate defense responses and protection against pathogens in plants.

PubMed

Vera, Jeannette; Castro, Jorge; Gonzalez, Alberto; Moenne, Alejandra

2011-12-01

Plants interact with the environment by sensing "non-self" molecules called elicitors derived from pathogens or other sources. These molecules bind to specific receptors located in the plasma membrane and trigger defense responses leading to protection against pathogens. In particular, it has been shown that cell wall and storage polysaccharides from green, brown and red seaweeds (marine macroalgae) corresponding to ulvans, alginates, fucans, laminarin and carrageenans can trigger defense responses in plants enhancing protection against pathogens. In addition, oligosaccharides obtained by depolymerization of seaweed polysaccharides also induce protection against viral, fungal and bacterial infections in plants. In particular, most seaweed polysaccharides and derived oligosaccharides trigger an initial oxidative burst at local level and the activation of salicylic (SA), jasmonic acid (JA) and/or ethylene signaling pathways at systemic level. The activation of these signaling pathways leads to an increased expression of genes encoding: (i) Pathogenesis-Related (PR) proteins with antifungal and antibacterial activities; (ii) defense enzymes such as pheylalanine ammonia lyase (PAL) and lipoxygenase (LOX) which determine accumulation of phenylpropanoid compounds (PPCs) and oxylipins with antiviral, antifugal and antibacterial activities and iii) enzymes involved in synthesis of terpenes, terpenoids and/or alkaloids having antimicrobial activities. Thus, seaweed polysaccharides and their derived oligosaccharides induced the accumulation of proteins and compounds with antimicrobial activities that determine, at least in part, the enhanced protection against pathogens in plants.

Digital phase-locked loop

NASA Technical Reports Server (NTRS)

Cliff, R. A. (Inventor)

1975-01-01

An digital phase-locked loop is provided for deriving a loop output signal from an accumulator output terminal. A phase detecting exclusive OR gate is fed by the loop digital input and output signals. The output of the phase detector is a bi-level digital signal having a duty cycle indicative of the relative phase of the input and output signals. The accumulator is incremented at a first rate in response to a first output level of the phase detector and at a second rate in response to a second output level of the phase detector.

Pre-pubertal stress exposure affects adult behavioral response in association with changes in circulating corticosterone and brain-derived neurotrophic factor.

PubMed

Bazak, Noam; Kozlovsky, Nitsan; Kaplan, Zeev; Matar, Michael; Golan, Hava; Zohar, Joseph; Richter-Levin, Gal; Cohen, Hagit

2009-07-01

Early-life stress produces a cascade of neurobiological events that cause enduring changes in neural plasticity and synaptic efficacy that appear to play pivotal roles in the pathophysiology of post-traumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) has been implicated in the neurobiological mechanisms of these changes, in interaction with components of the stress response, such as corticosterone. This study examined the consequences of juvenile stress for behavior during adulthood in association with circulating corticosterone levels and BDNF expression. The experiments examined single exposure to predator scent stress (soiled cat litter for 10 min) as compared to repeated exposure, early in life and later on. Behavioral responses were assessed in the elevated plus maze and the acoustic startle response paradigms at 28, 60 and 90 days of age. Plasma corticosterone was measured and brain areas analyzed for BDNF levels. The results show that juvenile stress exposure increased anxiety-like behavior and startle amplitude and decreased plasma corticosterone. This response was seen immediately after exposure and also long term. Adult stress exposure increased anxiety-like behavior, startle amplitude and plasma corticosterone. Exposure to both early and later life trauma elicited reduced levels of corticosterone following the initial exposure, which were not raised by re-exposure, and elicited significant downregulation of BDNF mRNA and protein levels in the hippocampus CA1 subregion. The consequences of adult stress exposure were more severe in rats were exposed to the same stressor as juveniles, indicated increased vulnerability. The results suggest that juvenile stress has resounding effects in adulthood reflected in behavioral responses. The concomitant changes in BDNF and corticosterone levels may mediate the changes in neural plasticity and synaptic functioning underlying clinical manifestations of PTSD.

Health systems' responsiveness and its characteristics: a cross-country comparative analysis.

PubMed

Robone, Silvana; Rice, Nigel; Smith, Peter C

2011-12-01

OBJECTIVES. Responsiveness has been identified as one of the intrinsic goals of health care systems. Little is known, however, about its determinants. Our objective is to investigate the potential country-level drivers of health system responsiveness. DATA SOURCE. Data on responsiveness are taken from the World Health Survey. Information on country-level characteristics is obtained from a variety of sources including the United Nations Development Program (UNDP). STUDY DESIGN. A two-step procedure. First, using survey data we derive a country-level measure of system responsiveness purged of differences in individual reporting behavior. Secondly, we run cross-sectional country-level regressions of responsiveness on potential drivers. PRINCIPAL FINDINGS. Health care expenditures per capita are positively associated with responsiveness, after controlling for the influence of potential confounding factors. Aspects of responsiveness are also associated with public sector spending (negatively) and educational development (positively). CONCLUSIONS. From a policy perspective, improvements in responsiveness may require higher spending levels. The expansion of nonpublic sector provision, perhaps in the form of increased patient choice, may also serve to improve responsiveness. However, these inferences are tentative and require further study. © Health Research and Educational Trust.

A comparison of scoring weights for the EuroQol derived from patients and the general public.

PubMed

Polsky, D; Willke, R J; Scott, K; Schulman, K A; Glick, H A

2001-01-01

General health state classification systems, such as the EuroQol instrument, have been developed to improve the systematic measurement and comparability of health state preferences. In this paper we generate valuations for EuroQol health states using responses to this instrument's visual analogue scale made by patients enrolled in a randomized clinical trial evaluating tirilazad mesylate, a new drug used to treat subarachnoid haemorrhage. We then compare these valuations derived from patients with published valuations derived from responses made by a sample from the general public. The data were derived from two sources: (1) responses to the EuroQol instrument from 649 patients 3 months after enrollment in the clinical trial, and (2) from a published study reporting a scoring rule for the EuroQol instrument that was based upon responses made by the general public. We used a linear regression model to develop an additive scoring rule. This rule enables direct valuation of all 243 EuroQol health states using patients' scores for their own health states elicited using a visual analogue scale. We then compared predicted scores generated using our scoring rule with predicted scores derived from a sample from the general public. The predicted scores derived using the additive scoring rules met convergent validity criteria and explained a substantial amount of the variation in visual analogue scale scores (R(2)=0.57). In the pairwise comparison of the predicted scores derived from the study sample with those derived from the general public, we found that the former set of scores were higher for 223 of the 243 states. Despite the low level of correspondence in the pairwise comparison, the overall correlation between the two sets of scores was 87%. The model presented in this paper demonstrated that scoring weights for the EuroQol instrument can be derived directly from patient responses from a clinical trial and that these weights can explain a substantial amount of variation in health valuations. Scoring weights based on patient responses are significantly higher than those derived from the general public. Further research is required to understand the source of these differences. Copyright 2001 John Wiley & Sons, Ltd.

Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me–induced apoptosis in breast cancer cells

PubMed Central

Lee, A Reum; Yoon, Mi Jin; Cho, Hyeseong; Lee, Jong-Soo; Choi, Kyeong Sook

2015-01-01

The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me–induced increases in intracellular Ca2+ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca2+ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIPL (cellular FLICE-inhibitory protein) and overexpression of c-FLIPL blocked CDDO-Me–induced cell death, but not vacuolation. These results suggest that c-FLIPL downregulation is a key contributor to CDDO-Me–induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca2+ influx and ROS generation as well as caspase activation via c-FLIPL downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells. PMID:26053096

Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me-induced apoptosis in breast cancer cells.

PubMed

Jeong, Soo Ah; Kim, In Young; Lee, A Reum; Yoon, Mi Jin; Cho, Hyeseong; Lee, Jong-Soo; Choi, Kyeong Sook

2015-08-28

The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me-induced increases in intracellular Ca2+ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca2+ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIPL (cellular FLICE-inhibitory protein) and overexpression of c-FLIPL blocked CDDO-Me-induced cell death, but not vacuolation. These results suggest that c-FLIPL downregulation is a key contributor to CDDO-Me-induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca2+ influx and ROS generation as well as caspase activation via c-FLIPL downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells.

Brain-Derived Neurotrophic Factor Gene Expression in Pediatric Bipolar Disorder: Effects of Treatment and Clinical Response

ERIC Educational Resources Information Center

Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Dwivedi, Yogesh; Pavuluri, Mani N.

2008-01-01

The study determines the gene expression of brain-derived neurotrophic factor (BDNF) in the lymphocytes of subjects with pediatric bipolar disorder (PBD) before and during treatment with mood stabilizers and in drug-free normal control subjects. Results indicate the potential of BDNF levels as a biomarker for PBD and as a treatment predictor and…

Do Resting Plasma β-Endorphin Levels Predict Responses to Opioid Analgesics?

PubMed

Bruehl, Stephen; Burns, John W; Gupta, Rajnish; Buvanendran, Asokumar; Chont, Melissa; Orlowska, Daria; Schuster, Erik; France, Christopher R

2017-01-01

Clinically feasible predictors of opioid analgesic responses for use in precision pain medicine protocols are needed. This study evaluated whether resting plasma β-endorphin (BE) levels predicted responses to an opioid analgesic, and whether chronic pain status or sex moderated these effects. Participants included 73 individuals with chronic low back pain (CLBP) and 88 pain-free controls, all using no daily opioid analgesics. Participants attended 2 identical laboratory sessions during which they received either intravenous morphine (0.08 mg/kg) or saline placebo, with blood samples obtained before drug administration to assay resting plasma BE levels. Once peak drug activity was achieved in each session, participants engaged in an ischemic forearm pain task (ISC) and a heat pain task. Morphine analgesic effects were derived reflecting the difference in pain outcomes between placebo and morphine conditions. In hierarchical regressions, significant Type (CLBP vs. control)×BE interactions (Ps<0.05) were noted for morphine effects on ISC tolerance, ISC intratask pain ratings, and thermal VAS unpleasantness ratings. These interactions derived primarily from associations between higher BE levels and smaller morphine effects restricted to the CLBP subgroup. All other BE-related effects, including sex interactions, for predicting morphine analgesia failed to reach statistical significance. BE was a predictor of morphine analgesia for only 3 out of 9 outcomes examined, with these effects moderated by chronic pain status but not sex. On the whole, results do not suggest that resting plasma BE levels are likely to be a clinically useful predictor of opioid analgesic responses.

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

PubMed Central

Kode, Aruna; Mosialou, Ioanna; Silva, Barbara C.; Rached, Marie-Therese; Zhou, Bin; Wang, Ji; Townes, Tim M.; Hen, Rene; DePinho, Ronald A.; Guo, X. Edward; Kousteni, Stavroula

2012-01-01

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element–binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID:22945629

Moral valuation: a third domain of conscience functioning.

PubMed

Stilwell, B M; Galvin, M; Kopta, S M; Padgett, R J

1996-02-01

To assess development of moral valuation in normal children and adolescents, that is, how moral rules for living are derived and justified, and to examine the relationship of this progression with previously identified stages of conceptualization of conscience. Using three semistructured questions from the Stilwell Conscience Interview, 132 normal volunteers between the ages of 5 and 17 years were assessed. All moral valuation responses were examined within three aspects of social reference: authority-derived, self-derived, and peer-derived. Each aspect was scaled for complexity into six anchored levels. The levels of all three aspects correlated positively with conceptualization stages as well as with each other. When the covariate, age, was taken into consideration, peer-derived valuation was significantly correlated with both age and stage. Moral valuation is a domain of conscience functioning in which moral rules and their justifications are socially referenced in relationship to authority, self, and peers. Anchored levels of these three aspects of moral valuation provide developmental guidelines for mental status examinations in patients between 5 and 17 years of age as well as providing criteria for future comparative studies in various diagnostic categories of psychopathology.

Low oleic acid-derived repression of jasmonic acid-inducible defense responses requires the WRKY50 and WRKY51 proteins

USDA-ARS?s Scientific Manuscript database

Signaling induced upon a reduction in oleic acid (18:1) levels simultaneously up-regulates salicylic acid (SA)-mediated responses and inhibits jasmonic acid (JA)-inducible defenses, resulting in enhanced resistance to biotrophs but increased susceptibility to necrotrophs. SA and the signaling compon...

Differential carrier lifetime and transport effects in electrically injected III-nitride light-emitting diodes

NASA Astrophysics Data System (ADS)

Rashidi, A.; Nami, M.; Monavarian, M.; Aragon, A.; DaVico, K.; Ayoub, F.; Mishkat-Ul-Masabih, S.; Rishinaramangalam, A.; Feezell, D.

2017-07-01

This work describes a small-signal microwave method for determining the differential carrier lifetime and transport effects in electrically injected InGaN/GaN light-emitting diodes (LEDs). By considering the carrier diffusion, capture, thermionic escape, and recombination, the rate equations are used to derive an equivalent small-signal electrical circuit for the LEDs, from which expressions for the input impedance and modulation response are obtained. The expressions are simultaneously fit to the experimental data for the input impedance and modulation response for nonpolar InGaN/GaN micro-LEDs on free-standing GaN substrates. The fittings are used to extract the transport related circuit parameters and differential carrier lifetimes. The dependence of the parameters on the device diameter and current density is reported. We also derive approximations for the modulation response under low and high injection levels and show that the transport of carriers affects the modulation response of the device, especially at low injection levels. The methods presented are relevant to the design of high-speed LEDs for visible-light communication.

Selection of inbred maize (Zea mays L.) progenies by topcrosses conducted in contrasting environments.

PubMed

Rodrigues, C S; Pacheco, C A P; Guedes, M L; Pinho, R G V; Castro, C R

2016-09-23

The aim of this study was to identify inbred progenies of S 0:1 maize (Zea mays L.) plants that were efficient at a low level of technology and responsive at a high level of technology through the use of topcrosses. Two contrasting environments were created using two levels of base fertilization and topdressing, so that the levels of nitrogen, phosphorus, and potassium were applied four times higher in one environment than in the other. We used S 0:1 progenies derived from commercial hybrids in topcrosses with two testers (an elite line from the flint heterotic group and an elite line from the dent heterotic group). The progenies and three controls were evaluated in an augmented block design in Nossa Senhora das Dores, SE, Brazil in the 2010 crop season. The average grain yield in the high-technological level was 21.44% greater than that in the low-technological level. There were no changes in progeny behavior in the two technological levels for grain yield. The testers did not differ in the average grain yield of the progenies at the two technological levels. Therefore, it is possible to select progenies derived from commercial hybrids that have an efficient response to fertilization.

Immune-responsiveness of CD4+ T cells during Streptococcus suis serotype 2 infection

PubMed Central

Lecours, Marie-Pier; Letendre, Corinne; Clarke, Damian; Lemire, Paul; Galbas, Tristan; Benoit-Biancamano, Marie-Odile; Thibodeau, Jacques; Gottschalk, Marcelo; Segura, Mariela

2016-01-01

The pathogenesis of Streptococcus suis infection, a major swine and human pathogen, is only partially understood and knowledge on the host adaptive immune response is critically scarce. Yet, S. suis virulence factors, particularly its capsular polysaccharide (CPS), enable this bacterium to modulate dendritic cell (DC) functions and potentially impair the immune response. This study aimed to evaluate modulation of T cell activation during S. suis infection and the role of DCs in this response. S. suis-stimulated total mouse splenocytes readily produced TNF-α, IL-6, IFN-γ, CCL3, CXCL9, and IL-10. Ex vivo and in vivo analyses revealed the involvement of CD4+ T cells and a Th1 response. Nevertheless, during S. suis infection, levels of the Th1-derived cytokines TNF-α and IFN-γ were very low. A transient splenic depletion of CD4+ T cells and a poor memory response were also observed. Moreover, CD4+ T cells secreted IL-10 and failed to up-regulate optimal levels of CD40L and CD69 in coculture with DCs. The CPS hampered release of several T cell-derived cytokines in vitro. Finally, a correlation was established between severe clinical signs of S. suis disease and impaired antibody responses. Altogether, these results suggest S. suis interferes with the adaptive immune response. PMID:27905502

GC-Rich Extracellular DNA Induces Oxidative Stress, Double-Strand DNA Breaks, and DNA Damage Response in Human Adipose-Derived Mesenchymal Stem Cells.

PubMed

Kostyuk, Svetlana; Smirnova, Tatiana; Kameneva, Larisa; Porokhovnik, Lev; Speranskij, Anatolij; Ershova, Elizaveta; Stukalov, Sergey; Izevskaya, Vera; Veiko, Natalia

2015-01-01

Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases. CfDNA is substantially enriched in its GC-content as compared with human genomic DNA. Exposure of haMSCs to GC-DNA induces short-term oxidative stress (determined with H2DCFH-DA) and results in both single- and double-strand DNA breaks (comet assay and γH2AX, foci). As a result in the cells significantly increases the expression of repair genes (BRCA1 (RT-PCR), PCNA (FACS)) and antiapoptotic genes (BCL2 (RT-PCR and FACS), BCL2A1, BCL2L1, BIRC3, and BIRC2 (RT-PCR)). Under the action of GC-DNA the potential of mitochondria was increased. Here we show that GC-rich extracellular DNA stimulates adipocyte differentiation of human adipose-derived mesenchymal stem cells (haMSCs). Exposure to GC-DNA leads to an increase in the level of RNAPPARG2 and LPL (RT-PCR), in the level of fatty acid binding protein FABP4 (FACS analysis) and in the level of fat (Oil Red O). GC-rich fragments in the pool of cfDNA can potentially induce oxidative stress and DNA damage response and affect the direction of mesenchymal stem cells differentiation in human adipose-derived mesenchymal stem cells. Such a response may be one of the causes of obesity or osteoporosis.

GC-Rich Extracellular DNA Induces Oxidative Stress, Double-Strand DNA Breaks, and DNA Damage Response in Human Adipose-Derived Mesenchymal Stem Cells

PubMed Central

Smirnova, Tatiana; Kameneva, Larisa; Porokhovnik, Lev; Speranskij, Anatolij; Ershova, Elizaveta; Stukalov, Sergey; Izevskaya, Vera; Veiko, Natalia

2015-01-01

Background. Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases. CfDNA is substantially enriched in its GC-content as compared with human genomic DNA. Principal Findings. Exposure of haMSCs to GC-DNA induces short-term oxidative stress (determined with H2DCFH-DA) and results in both single- and double-strand DNA breaks (comet assay and γH2AX, foci). As a result in the cells significantly increases the expression of repair genes (BRCA1 (RT-PCR), PCNA (FACS)) and antiapoptotic genes (BCL2 (RT-PCR and FACS), BCL2A1, BCL2L1, BIRC3, and BIRC2 (RT-PCR)). Under the action of GC-DNA the potential of mitochondria was increased. Here we show that GC-rich extracellular DNA stimulates adipocyte differentiation of human adipose-derived mesenchymal stem cells (haMSCs). Exposure to GC-DNA leads to an increase in the level of RNAPPARG2 and LPL (RT-PCR), in the level of fatty acid binding protein FABP4 (FACS analysis) and in the level of fat (Oil Red O). Conclusions. GC-rich fragments in the pool of cfDNA can potentially induce oxidative stress and DNA damage response and affect the direction of mesenchymal stem cells differentiation in human adipose—derived mesenchymal stem cells. Such a response may be one of the causes of obesity or osteoporosis. PMID:26273425

New evidence for "far-field" Holocene sea level oscillations and links to global climate records

NASA Astrophysics Data System (ADS)

Leonard, N. D.; Welsh, K. J.; Clark, T. R.; Feng, Y.-x.; Pandolfi, J. M.; Zhao, J.-x.

2018-04-01

Rising sea level in the coming century is of significant concern, yet predicting relative sea level change in response to eustatic sea level variability is complex. Potential analogues are provided by the recent geological past but, until recently, many sea level reconstructions have been limited to millennial scale interpretations due to age uncertainties and paucity in proxy derived records. Here we present a sea level history for the tectonically stable "far-field" Great Barrier Reef, Australia, derived from 94 high precision uranium-thorium dates of sub-fossil coral microatolls. Our results provide evidence for at least two periods of relative sea level instability during the Holocene. These sea level oscillations are broadly synchronous with Indo-Pacific negative sea surface temperature anomalies, rapid global cooling events and glacial advances. We propose that the pace and magnitude of these oscillations are suggestive of eustatic/thermosteric processes operating in conjunction with regional climatic controls.

Network Analysis of Epidermal Growth Factor Signaling Using Integrated Genomic, Proteomic and Phosphorylation Data

PubMed Central

Waters, Katrina M.; Liu, Tao; Quesenberry, Ryan D.; Willse, Alan R.; Bandyopadhyay, Somnath; Kathmann, Loel E.; Weber, Thomas J.; Smith, Richard D.; Wiley, H. Steven; Thrall, Brian D.

2012-01-01

To understand how integration of multiple data types can help decipher cellular responses at the systems level, we analyzed the mitogenic response of human mammary epithelial cells to epidermal growth factor (EGF) using whole genome microarrays, mass spectrometry-based proteomics and large-scale western blots with over 1000 antibodies. A time course analysis revealed significant differences in the expression of 3172 genes and 596 proteins, including protein phosphorylation changes measured by western blot. Integration of these disparate data types showed that each contributed qualitatively different components to the observed cell response to EGF and that varying degrees of concordance in gene expression and protein abundance measurements could be linked to specific biological processes. Networks inferred from individual data types were relatively limited, whereas networks derived from the integrated data recapitulated the known major cellular responses to EGF and exhibited more highly connected signaling nodes than networks derived from any individual dataset. While cell cycle regulatory pathways were altered as anticipated, we found the most robust response to mitogenic concentrations of EGF was induction of matrix metalloprotease cascades, highlighting the importance of the EGFR system as a regulator of the extracellular environment. These results demonstrate the value of integrating multiple levels of biological information to more accurately reconstruct networks of cellular response. PMID:22479638

Dual Mode NOx Sensor: Measuring Both the Accumulated Amount and Instantaneous Level at Low Concentrations

PubMed Central

Groß, Andrea; Beulertz, Gregor; Marr, Isabella; Kubinski, David J.; Visser, Jaco H.; Moos, Ralf

2012-01-01

The accumulating-type (or integrating-type) NOx sensor principle offers two operation modes to measure low levels of NOx: The direct signal gives the total amount dosed over a time interval and its derivative the instantaneous concentration. With a linear sensor response, no baseline drift, and both response times and recovery times in the range of the gas exchange time of the test bench (5 to 7 s), the integrating sensor is well suited to reliably detect low levels of NOx. Experimental results are presented demonstrating the sensor’s integrating properties for the total amount detection and its sensitivity to both NO and to NO2. We also show the correlation between the derivative of the sensor signal and the known gas concentration. The long-term detection of NOx in the sub-ppm range (e.g., for air quality measurements) is discussed. Additionally, a self-adaption of the measurement range taking advantage of the temperature dependency of the sensitivity is addressed. PMID:22736980

A Sensor-Independent Gust Hazard Metric

NASA Technical Reports Server (NTRS)

Stewart, Eric C.

2001-01-01

A procedure for calculating an intuitive hazard metric for gust effects on airplanes is described. The hazard metric is for use by pilots and is intended to replace subjective pilot reports (PIREPs) of the turbulence level. The hazard metric is composed of three numbers: the first describes the average airplane response to the turbulence, the second describes the positive peak airplane response to the gusts, and the third describes the negative peak airplane response to the gusts. The hazard metric is derived from any time history of vertical gust measurements and is thus independent of the sensor making the gust measurements. The metric is demonstrated for one simulated airplane encountering different types of gusts including those derived from flight data recorder measurements of actual accidents. The simulated airplane responses to the gusts compare favorably with the hazard metric.

Cortisol and Anti-social Behavior in Early Adolescence: The Role of Gender in an Economically Disadvantaged Sample

PubMed Central

Kobak, Roger; Zajac, Kristyn; Levine, Seymour

2014-01-01

This study examines the relation between adolescents’ anti-social behaviors and adrenocortical activity during a laboratory visit in a sample of economically disadvantaged families (N = 116, ages 12 – 14, 51% female). Pre-task cortisol levels indexed adolescents’ pre-challenge response to the lab visit, while adolescents’ response to a conflict discussion with their caregivers was indexed with residualized change in pre- to post- conflict cortisol levels. A trait measure of anti-social behavior (derived from parent, teacher, and self-reports) was associated with lower pre-task cortisol levels but greater cortisol response to the conflict discussion. Gender moderated anti-social adolescents’ cortisol response to the conflict discussion with girls who reported more covert risky problem behaviors showing an increased cortisol response. The findings suggest that, while anti-social adolescents had lower pre-task cortisol levels, conflict discussions with caregivers present a unique challenge to anti-social girls compared with anti-social boys. PMID:19338699

Microdose-induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

PubMed Central

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W.; Cimino, George D.; Tepper, Clifford G.; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-xian; Henderson, Paul T.

2017-01-01

We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry (AMS) in blood and tumor samples collected within 24 hours, and compared to subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [14C]carboplatin or [14C]gemcitabine and the resulting drug-DNA adduct levels were compared to tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. PMID:27903751

Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts

PubMed Central

Guffanti, Federica; Fratelli, Maddalena; Ganzinelli, Monica; Bolis, Marco; Ricci, Francesca; Bizzaro, Francesca; Chilà, Rosaria; Sina, Federica Paola; Fruscio, Robert; Lupia, Michela; Cavallaro, Ugo; Cappelletti, Maria Rosa; Generali, Daniele; Giavazzi, Raffaella; Damia, Giovanna

2018-01-01

A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanconi anemia, homologous recombination, base excision repair, mismatch repair and translesion repair pathways and the methylation patterns of some of these genes. We also investigated the correlation with the response to platinum-based therapy. The mRNA levels of the selected genes were evaluated by Real Time-PCR (RT-PCR) with ad hoc validated primers and gene promoter methylation by pyrosequencing. All the DNA repair genes were variably expressed in all 42 PDX samples analyzed, with no particular histotype-specific pattern of expression. In high-grade serous/endometrioid PDXs, the CDK12 mRNA expression levels positively correlated with the expression of TP53BP1, PALB2, XPF and POLB. High-grade serous/endometrioid PDXs with TP53 mutations had significantly higher levels of POLQ, FANCD2, RAD51 and POLB than high-grade TP53 wild type PDXs. The mRNA levels of CDK12, PALB2 and XPF inversely associated with the in vivo DDP antitumor activity; higher CDK12 mRNA levels were associated with a higher recurrence rate in ovarian patients with low residual tumor. These data support the important role of CDK12 in the response to a platinum based therapy in ovarian patients. PMID:29872499

Analysis of immune response in young and aged mice vaccinated with corn-derived antigen against Escherichia coli heat-labile enterotoxin.

PubMed

Karaman, Sule; Cunnick, Joan; Wang, Kan

2006-01-01

Enterotoxigenic strains of Escherichia coli produce a heat-labile holotoxin (LT), which causes diarrhea. We engineered corn seeds to produce LT-B, the nontoxic subunit of LT, to serve as a plant-derived vaccine to traveler's diarrhea and as an adjuvant for co-administered proteins. We previously demonstrated that a strong mucosal and systemic antibody response is elicited in young mice with oral administration of corn-derived LT-B. The present study examined systemic and mucosal antibody responses to LT-B in young and aged mice, and recall responses to oral administration and injection of LT-B in aged mice. Specific IgA and IgG antibodies were detectable during an 11-mo period, although the concentration of antigen-specific antibodies declined gradually. Booster by feeding or injection dramatically increased the concentration of specific IgA from that seen in young mice. Specific IgG levels were boosted to concentrations similar to those in young mice. This effect may be age-dependent and related to prior immunization exposure. Analysis of the antibody response of naïve aged mice against corn-derived LT-B demonstrated an age-related suppression in specific IgG production, but not specific IgA. These results may provide important information for edible vaccine strategies for young and aged individuals.

New stomatal flux-based critical levels for ozone effects on vegetation

NASA Astrophysics Data System (ADS)

Mills, Gina; Pleijel, Håkan; Braun, Sabine; Büker, Patrick; Bermejo, Victoria; Calvo, Esperanza; Danielsson, Helena; Emberson, Lisa; Fernández, Ignacio González; Grünhage, Ludger; Harmens, Harry; Hayes, Felicity; Karlsson, Per-Erik; Simpson, David

2011-09-01

The critical levels for ozone effects on vegetation have been reviewed and revised by the LRTAP Convention. Eight new or revised critical levels based on the accumulated stomatal flux of ozone (POD Y, the Phytotoxic Ozone Dose above a threshold flux of Y nmol m -2 PLA s -1, where PLA is the projected leaf area) have been agreed. For each receptor, data were combined from experiments conducted under naturally fluctuating environmental conditions in 2-4 countries, resulting in linear dose-response relationships with response variables specific to each receptor ( r2 = 0.49-0.87, p < 0.001 for all). For crops, critical levels were derived for effects on wheat (grain yield, grain mass, and protein yield), potato (tuber yield) and tomato (fruit yield). For forest trees, critical levels were derived for effects on changes in annual increment in whole tree biomass for beech and birch, and Norway spruce. For (semi-)natural vegetation, the critical level for effects on productive and high conservation value perennial grasslands was based on effects on important component species of the genus Trifolium (clover species). These critical levels can be used to assess protection against the damaging effects of ozone on food security, important ecosystem services provided by forest trees (roundwood production, C sequestration, soil stability and flood prevention) and the vitality of pasture.

Uridine Affects Liver Protein Glycosylation, Insulin Signaling, and Heme Biosynthesis

PubMed Central

Urasaki, Yasuyo; Pizzorno, Giuseppe; Le, Thuc T.

2014-01-01

Purines and pyrimidines are complementary bases of the genetic code. The roles of purines and their derivatives in cellular signal transduction and energy metabolism are well-known. In contrast, the roles of pyrimidines and their derivatives in cellular function remain poorly understood. In this study, the roles of uridine, a pyrimidine nucleoside, in liver metabolism are examined in mice. We report that short-term uridine administration in C57BL/6J mice increases liver protein glycosylation profiles, reduces phosphorylation level of insulin signaling proteins, and activates the HRI-eIF-2α-ATF4 heme-deficiency stress response pathway. Short-term uridine administration is also associated with reduced liver hemin level and reduced ability for insulin-stimulated blood glucose removal during an insulin tolerance test. Some of the short-term effects of exogenous uridine in C57BL/6J mice are conserved in transgenic UPase1 −/− mice with long-term elevation of endogenous uridine level. UPase1 −/− mice exhibit activation of the liver HRI-eIF-2α-ATF4 heme-deficiency stress response pathway. UPase1 −/− mice also exhibit impaired ability for insulin-stimulated blood glucose removal. However, other short-term effects of exogenous uridine in C57BL/6J mice are not conserved in UPase1 −/− mice. UPase1 −/− mice exhibit normal phosphorylation level of liver insulin signaling proteins and increased liver hemin concentration compared to untreated control C57BL/6J mice. Contrasting short-term and long-term consequences of uridine on liver metabolism suggest that uridine exerts transient effects and elicits adaptive responses. Taken together, our data support potential roles of pyrimidines and their derivatives in the regulation of liver metabolism. PMID:24918436

Evaluation of the Immunogenicity of a Potyvirus-Like Particle as an Adjuvant of a Synthetic Peptide.

PubMed

Cárdenas-Vargas, Albertina; Elizondo-Quiroga, Darwin; Gutierrez-Ortega, Abel; Charles-Niño, Claudia; Pedroza-Roldán, César

2016-12-01

Improvement of current vaccines is highly necessary to increase immunogenicity levels and protection against several pathogens. Virus-like particles (VLPs) are promising approaches for vaccines because they emulate infectious virus structure, but lack any genetic material needed for replication. Plant viruses have emerged as a potential framework for VLP design, mainly because there is no preexisting immunity in mammals. In this study, we evaluated the scaffold of the papaya ringspot virus (PRSV) as a VLP adjuvant for a short synthetic peptide derived from the Hemagglutinin protein of AH1 N1 influenza virus-hemagglutinin (VLP-HA). Our results demonstrated that the adjuvant property of this VLP is highly similar to the trivalent influenza vaccine, showing comparable levels of IgG- and IgA-specific antibodies to HA-derived peptide in serum and feces of vaccinated mice, respectively. Furthermore, VLP-HA-immunized mice showed Th1-biased immune response as suggested by measuring IgG subclasses in comparison with the predominance of Th2-biased immune response in trivalent influenza vaccine dose-vaccinated mice. VLP-HA administration in mice induced comparable levels of activated CD4 + - and CD8 + -specific T lymphocytes for the HA-derived peptide. These results suggest the potential adjuvant capacity of the PRSV-VLP as a carrier for short synthetic peptides.

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

Investigations of student understanding of entropy and of mixed second-order partial derivatives in upper-level thermodynamics

NASA Astrophysics Data System (ADS)

Bucy, Brandon R.

While much of physics education research (PER) has traditionally been conducted in introductory undergraduate courses, researchers have begun to study student understanding of physics concepts at the upper-level. In this dissertation, we describe investigations conducted in advanced undergraduate thermodynamics courses. We present and discuss results pertaining to student understanding of two topics: entropy and the role of mixed second-order partial derivatives in thermodynamics. Our investigations into student understanding of entropy consisted of an analysis of written student responses to researcher-designed diagnostic questions. Data gathered in clinical interviews is employed to illustrate and extend results gathered from written responses. The question sets provided students with several ideal gas processes, and asked students to determine and compare the entropy changes of these processes. We administered the question sets to students from six distinct populations, including students enrolled in classical thermodynamics, statistical mechanics, thermal physics, physical chemistry, and chemical engineering courses, as well as a sample of physics graduate students. Data was gathered both before and after instruction in several samples. Several noteworthy features of student reasoning are identified and discussed. These features include student ideas about entropy prior to instruction, as well as specific difficulties and other aspects of student reasoning evident after instruction. As an example, students from various populations tended to emphasize either the thermodynamic or the statistical definition of entropy. Both approaches present students with a unique set of benefits as well as challenges. We additionally studied student understanding of partial derivatives in a thermodynamics context. We identified specific difficulties related to the mixed second partial derivatives of a thermodynamic state function, based on an analysis of student responses to homework and exam problems. Students tended to set these partial derivatives identically equal to zero. Students also displayed difficulties in relating the physical description of a material property to a corresponding mathematical statement involving partial derivatives. We describe the development of a guided-inquiry tutorial activity designed to address these specific difficulties. This tutorial focused on the graphical interpretation of partial derivatives. Preliminary results suggest that the tutorial was effective in addressing several student difficulties related to partial derivatives.

The presence of food-derived collagen peptides in human body-structure and biological activity.

PubMed

Sato, Kenji

2017-12-13

It has been demonstrated that the ingestion of some protein hydrolysates exerts health-promoting effects. For understanding the underlying mechanisms responsible for these effects, the identification of bioactive peptides in the target organ is crucial. For this purpose, in vitro activity-guided fractionation for peptides in the protein hydrolysate has been performed. However, the peptides in the hydrolysate may be further degraded during digestion. The concentration of the active peptides, which were identified by in vitro activity-guided fractionation, in human blood is frequently very low (nanomolar levels). In contrast, micromolar levels of food-derived collagen peptides are present in human blood. Pro-Hyp, one of the major food-derived collagen peptides, enhances the growth of fibroblasts and synthesis of hyaluronic acid. These observations partially explain the beneficial effects of collagen hydrolysate ingestion on the enhancement of wound healing and improvement in the skin condition. The recent advancement involving liquid chromatography and mass spectrometry coupled with a pre-column derivatization technique has enabled the identification of food-derived peptides at nanomolar levels in the body post-ingestion of protein hydrolysates. Thus, this technique can be used for the identification of bioactive food-derived peptides in the body.

In vitro fermentation of alginate and its derivatives by human gut microbiota.

PubMed

Li, Miaomiao; Li, Guangsheng; Shang, Qingsen; Chen, Xiuxia; Liu, Wei; Pi, Xiong'e; Zhu, Liying; Yin, Yeshi; Yu, Guangli; Wang, Xin

2016-06-01

Alginate (Alg) has a long history as a food ingredient in East Asia. However, the human gut microbes responsible for the degradation of alginate and its derivatives have not been fully understood yet. Here, we report that alginate and the low molecular polymer derivatives of mannuronic acid oligosaccharides (MO) and guluronic acid oligosaccharides (GO) can be completely degraded and utilized at various rates by fecal microbiota obtained from six Chinese individuals. However, the derivative of propylene glycol alginate sodium sulfate (PSS) was not hydrolyzed. The bacteria having a pronounced ability to degrade Alg, MO and GO were isolated from human fecal samples and were identified as Bacteroides ovatus, Bacteroides xylanisolvens, and Bacteroides thetaiotaomicron. Alg, MO and GO can increase the production level of short chain fatty acids (SCFA), but GO generates the highest level of SCFA. Our data suggest that alginate and its derivatives could be degraded by specific bacteria in the human gut, providing the basis for the impacts of alginate and its derivates as special food additives on human health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Equilibrium finite-frequency noise of an interacting mesoscopic capacitor studied in time-dependent density functional theory

NASA Astrophysics Data System (ADS)

Dittmann, Niklas; Splettstoesser, Janine; Helbig, Nicole

2018-03-01

We calculate the frequency-dependent equilibrium noise of a mesoscopic capacitor in time-dependent density functional theory (TDDFT). The capacitor is modeled as a single-level quantum dot with on-site Coulomb interaction and tunnel coupling to a nearby reservoir. The noise spectra are derived from linear-response conductances via the fluctuation-dissipation theorem. Thereby, we analyze the performance of a recently derived exchange-correlation potential with time-nonlocal density dependence in the finite-frequency linear-response regime. We compare our TDDFT noise spectra with real-time perturbation theory and find excellent agreement for noise frequencies below the reservoir temperature.

Effect of different anesthesia techniques on the serum brain-derived neurotrophic factor (BDNF) levels.

PubMed

Ozer, A B; Demirel, I; Erhan, O L; Firdolas, F; Ustundag, B

2015-10-01

Serum Brain-Derived Neurotrophic Factor (BDNF) levels are associated with neurotransmission and cognitive functions. The goal of this study was to examine the effect of general anesthesia on BDNF levels. It was also to reveal whether this effect had a relationship with the surgical stress response or not. The study included 50 male patients, age 20-40, who were scheduled to have inguinoscrotal surgery, and who were in the ASA I-II risk group. The patients were divided into two groups according to the anesthesia techniques used: general (GA) and spinal (SA). In order to measure serum BDNF, cortisol, insulin and glucose levels, blood samples were taken at four different times: before and after anesthesia, end of the surgery, and before transferal from the recovery room. Serum BDNF levels were significantly low (p < 0.01), cortisol and glucose levels were higher (p < 0.05 and p < 0.01) in Group GA compared with Group SA. No significant difference was detected between the groups in terms of serum insulin levels. There was no correlation between serum BDNF and the stress hormones. Our findings suggested that general anesthetics had an effect on serum BDNF levels independent of the stress response. In future, BDNF could be used as biochemical parameters of anesthesia levels, but studies with a greater scope should be carried out to present the relationship between anesthesia and neurotrophins.

Copper sulphate (CuSO4) toxicity on tissue phosphatases activity and carbohydrates turnover in Achatina fulica.

PubMed

Ramalingam, K; Indra, D

2002-04-01

A time course study on the sublethal toxicity of CuSO4 on tissue carbohydrate metabolites level and their phosphatases activity in Achatina fulica revealed differential response. The levels of total carbohydrates and glycogen in the body mass muscle, foot muscle and hemolymph revealed their involvement in the endogenous derivation of energy during stress. The same metabolites in digestive gland revealed its importance to reproduction and development. The lactate accumulated in all the tissues implied the mechanism of CuSO4 toxicosis in the metabolic acidosis. The decrease of pyruvate in foot muscle, body mass muscle and hemolymph inferred the preponderance of glycolysis in energy derivation. In contrast, the pyruvate concentration in digestive gland revealed its differential response in the stress metabolic sequence of changes, as a unique tissue. The lactate/pyruvate ratio and the calcium content in tissues constitute direct evidences for the snails adaptation to toxic stress.

Effect of baseline corrections on response spectra for two recordings of the 1999 Chi-Chi, Taiwan, earthquake

USGS Publications Warehouse

Boore, David M.

1999-01-01

Displacements derived from the accelerogram recordings of the 1999 Chi-Chi, Taiwan earthquake at stations TCU078 and TCU129 show drifts when only a simple baseline derived from the pre-event portion of the record is removed from the records. The appearance of the velocity and displacement records suggests that changes in the zero-level of the acceleration are responsible for these drifts. The source of the shifts in zero-level are unknown, but might include tilts in the instruments or the response of the instruments to strong shaking. This note illustrates the effect on the velocity, displacement, and response spectra of several schemes for accounting for these baseline shifts. The most important conclusion for earthquake engineering purposes is that the response spectra for periods less than about 20 sec are unaffected by the baseline correction. The results suggest, however, that staticdisplac ements estimated from the instruments should be used with caution. Although limited to the analysis of only two recordings, the results may have more general significance both for the many other recordings of this earthquake and for data that will be obtained in the future from similar high-quality accelerograph networks now being installed or soon to be installed in many parts of the world.

RNA:DNA Ratio and Other Nucleic Acid Derived Indices in Marine Ecology

PubMed Central

Chícharo, Maria Alexandra; Chícharo, Luis

2008-01-01

Some of most used indicators in marine ecology are nucleic acid-derived indices. They can be divided by target levels in three groups: 1) at the organism level as ecophysiologic indicators, indicators such as RNA:DNA ratios, DNA:dry weight and RNA:protein, 2) at the population level, indicators such as growth rate, starvation incidence or fisheries impact indicators, and 3) at the community level, indicators such as trophic interactions, exergy indices and prey identification. The nucleic acids derived indices, especially RNA:DNA ratio, have been applied with success as indicators of nutritional condition, well been and growth in marine organisms. They are also useful as indicators of natural or anthropogenic impacts in marine population and communities, such as upwelling or dredge fisheries, respectively. They can help in understanding important issues of marine ecology such as trophic interactions in marine environment, fish and invertebrate recruitment failure and biodiversity changes, without laborious work of counting, measuring and identification of small marine organisms. Besides the objective of integrate nucleic acid derived indices across levels of organization, the paper will also include a general characterization of most used nucleic acid derived indices in marine ecology and also advantages and limitations of them. We can conclude that using indicators, such RNA:DNA ratios and other nucleic acids derived indices concomitantly with organism and ecosystems measures of responses to climate change (distribution, abundance, activity, metabolic rate, survival) will allow for the development of more rigorous and realistic predictions of the effects of anthropogenic climate change on marine systems. PMID:19325815

Validation of ozone response functions for annual Mediterranean pasture species using close-to-field-conditions experiments.

PubMed

González-Fernández, Ignacio; Sanz, Javier; Calvete-Sogo, Héctor; Elvira, Susana; Alonso, Rocío; Bermejo-Bermejo, Victoria

2017-12-01

Ozone (O 3 ) critical levels have been established under the Long-Range Transboundary Air Pollution Convention to assess the risk of O 3 effects in European vegetation. A recent review study has led to the development of O 3 critical levels for annual Mediterranean pasture species using plants growing in well-watered pots at a coastal site and under low levels of competition. However, uncertainties remain in the extrapolation of the O 3 sensitivity of these species under natural conditions. The response of two O 3 -sensitive annual Mediterranean pasture Trifolium species at the coastal site was compared with the response of the same species growing at a continental site, in natural soil and subject to water-stress and inter-specific competition, representing more closely their natural habitat. The slopes of exposure- and dose-response relationships derived for the two sites showed differences in the response to O 3 between sites attributed to differences in environmental growing conditions, growing medium and the level of inter-specific competition, but the effect of the individual factors could not be assessed separately. Dose-based O 3 indices partially explained differences due to environmental growing conditions between sites. The slopes showed that plants were more sensitive to O 3 at the continental site, but homogeneity of slopes tests revealed that results from both experimental sites may be combined. Although more experimental data considering complex inter-specific competition situations and the effect of important interactive factors such as nitrogen would be needed, these results confirm the validity of applying the current flux-based O 3 critical level under close to natural growing conditions. The AOT40-based O 3 critical level derived at the coastal site was also considered a suitable risk indicator in close to natural growing conditions in the absence of soil moisture limitations on plant growth.

Ozone response to enhanced heterogeneous processing after the eruption of Mt. Pinatubo

NASA Technical Reports Server (NTRS)

Rodriguez, Jose M.; Ko, M. K. W.; Sze, N. D.; Heisey, C. W.; Yue, G. K.; Mccormick, M. P.

1994-01-01

Increases in aerosol loading after the Pinatubo eruption are expected to cause additional ozone depletion. Even though aerosol loadings were highest in the winter of 1991-1992, recent analyses of satellite and ground-based ozone measurements indicate that ozone levels in the winter of 1992-1993 are the lowest recorded in recent years, raising the question of the mechanisms responsible for such behavior. We have incorporated aerosol surface areas derived from the Stratospheric Aerosol and Gas Experiment II (SAGE-II) measurements into our two-dimensional model. Inclusion of heterogeneous chemsitry on these enhanced aerosol surfaces yields maximum ozone reductions during the winter of 1992-1993 in the Northern Hemisphere, consistent with those derived from observations. This delayed behavior is due to the combination of the non-linear nature of the impact of heterogeneous reactions as a function of aerosol surface area, and the long time constants for ozone in the lower stratosphere. If heterogeneous mechanisms are primarily responsible for the low 1992-1993 ozone levels, we expect ozone concentrations to start recovering in 1994.

Serum levels of hematoporphyrin derivatives in the photodynamic therapy of malignant tumors

NASA Astrophysics Data System (ADS)

Chan, H. K.; Low, K. S.; Haji Baba, A. S.; Arimbalam, S.; Yip, C. H.; Chang, K. W.; Baskaran, G.; Lo, Y. L.; Jayalakshmi, P.; Looi, L. M.; Tan, N. H.

1995-03-01

In photodynamic therapy (PDT), red light is administered 24 - 72 hours post intravenous (i.v.) injection of hematoporphyrin derivatives (HpD). In an earlier animal model study, more effective therapeutic response was obtained when red light irradiation was carried out 15 mins after the injection of HpD. The effectiveness of this immediate PDT protocol has been correlated to the high serum level of HpD immediately after administration and the destruction of the microcirculation system as the dominant tumor destruction mechanism. This study examines the pharmacokinetics and the serum levels of HpD in rats and also in human patients. Such data can assist in defining the optimum time delay for light irradiation in the PDT of cancer.

Dynamics of Heat Shock Protein 70 Serum Levels As a Predictor of Clinical Response in Non-Small-Cell Lung Cancer and Correlation with the Hypoxia-Related Marker Osteopontin

PubMed Central

Ostheimer, Christian; Gunther, Sophie; Bache, Matthias; Vordermark, Dirk; Multhoff, Gabriele

2017-01-01

Hypoxia mediates resistance to radio(chemo)therapy (RT) by stimulating the synthesis of hypoxia-related genes, such as osteopontin (OPN) and stress proteins, including the major stress-inducible heat shock protein 70 (Hsp70). Apart from its intracellular localization, Hsp70 is also present on the plasma membrane of viable tumor cells that actively release it in lipid vesicles with biophysical characteristics of exosomes. Exosomal Hsp70 contributes to radioresistance while Hsp70 derived from dying tumor cells can serve as a stimulator of immune cells. Given these opposing traits of extracellular Hsp70 and the unsatisfactory outcome of locally advanced lung tumors, we investigated the role of Hsp70 in the plasma of patients with advanced, non-metastasized non-small-cell lung cancer (NSCLC) before (T1) and 4–6 weeks after RT (T2) in relation to OPN as potential biomarkers for clinical response. Plasma levels of Hsp70 correlate with those of OPN at T1, and high OPN levels are significantly associated with a decreased overall survival (OS). Due to a therapy-induced reduction in viable tumor mass after RT Hsp70 plasma levels dropped significantly at T2 (p = 0.016). However, with respect to the immunostimulatory capacity of Hsp70 derived from dying tumor cells, patients with higher post-therapeutic Hsp70 levels showed a significantly better response to RT (p = 0.034) than those with lower levels at T2. In summary, high OPN plasma levels at T1 are indicative for poor OS, whereas elevated post-therapeutic Hsp70 plasma levels together with a drop of Hsp70 between T1 and T2, successfully predict favorable responses to RT. Monitoring the dynamics of Hsp70 in NSCLC patients before and after RT can provide additional predictive information for clinical outcome and therefore might allow a more rapid therapy adaptation. PMID:29093708

A comprehensive evaluation of the toxicology of cigarette ingredients: cocoa-derived ingredients.

PubMed

Coggins, Christopher R E; Fisher, Michael T; Smith, Donna C; Oldham, Michael J

2011-06-01

Cocoa-derived ingredients are used in cigarette tobacco. A battery of tests was used to compare toxicity of mainstream smoke from experimental cigarettes containing different added levels of cocoa-derived ingredients. Five cocoa-derived ingredients chocolate (CH), cocoa (COC), cocoa-grand prix black (CGPB), cocoa nibs tincture (CNT) and cocoa shells extract (CSE) were added individually to experimental cigarettes at three different levels. Smoke from each of the experimental cigarette types was evaluated using analytical chemistry; in vitro cytotoxicity and mutagenicity testing were performed for four of the five compounds. For CH, COC and CNT, 90-day smoke inhalation studies were performed with 6-week recovery periods. No consistent changes were found in the analytical chemistry results. Results of the cytotoxicity and mutagenicity were unaffected by any of the ingredients. Two of the three inhalation studies showed very few differences between the groups. The inhalation study with COC showed several increases in mean histopathology severity scores in groups exposed to different levels of COC, compared with the controls. These apparent effects of COC on histopathology lesion severity scores were only present in a single sex and none were dose-related, which is not consistent with a true increase in biological activity. Also there were effectively no differences in the patterns of recovery for any of the compounds. Even at high inclusion levels there was a lack of toxicological response in these COC derived ingredients.

Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3.

PubMed

Zhang, Yuefeng; Huang, Shifei; Li, Pengping; Chen, Qing; Li, Yongzhou; Zhou, Yizhao; Wang, Lantian; Kang, Muxing; Zhang, Bo; Yang, Bin; Wu, Yulian

2018-05-22

One hallmark of pancreatic cancer (PC) is the high prevalence of pancreatic cancer-associated diabetes mellitus (PC-DM), but the mechanisms remain to be elucidated. Patients with PC who are diagnosed with new-onset diabetes/prediabetes have recently been shown to display significantly lower levels of glucose-dependent insulinotropic peptide (GIP) secreted mainly by enteroendocrine cells. We hypothesized that PC-derived exosomes are responsible for the decreased levels of incretins in patients with PC-DM. In this study, exosomes were successfully isolated from PANC-1, MIA PaCa-2 and SW620 cells and characterized. Only the exosomes from MIA PaCa-2 cells (Exo-Mia) reduce the production of GIP and glucagon-like peptide-1 (GLP-1) from STC-1 cells in vitro in a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of the Gip and proglucagon mRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing of Gip and proglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p, miR-6763-5p, miR-4750-3p and miR-197-3p) were identified and considered to be responsible for the inhibitory effects on GIP and GLP-1 production. To further determine the approach of cancer-derived exosomes reaching enteroendocrine cells, we analyzed the uptake and distribution of exosomes in animal model. It was observed that exosomes infused into the intestinal cavity were more easily internalized by the intestinal epithelium than exosomes injected into blood. In conclusion, pancreatic cancer-derived exosomes (Exo-Mia) suppress the synthesis of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3. Moreover, it may be the pancreatic juice that transport cancer-derived exosomes to target cells (K and L cells) in the gut. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of subchronic inhalation exposure of rats to emissions from a diesel engine burning soybean oil-derived biodiesel fuel.

PubMed

Finch, G L; Hobbs, C H; Blair, L F; Barr, E B; Hahn, F F; Jaramillo, R J; Kubatko, J E; March, T H; White, R K; Krone, J R; Ménache, M G; Nikula, K J; Mauderly, J L; Van Gerpen, J; Merceica, M D; Zielinska, B; Stankowski, L; Burling, K; Howell, S

2002-10-01

There is increasing interest in diesel fuels derived from plant oils or animal fats ("biodiesel"), but little information on the toxicity of biodiesel emissions other than bacterial mutagenicity. F344 rats were exposed by inhalation 6 h/day, 5 days/wk for 13 wk to 1 of 3 dilutions of emissions from a diesel engine burning 100% soybean oil-derived fuel, or to clean air as controls. Whole emissions were diluted to nominal NO(x) concentrations of 5, 25, or 50 ppm, corresponding to approximately 0.04, 0.2, and 0.5 mg particles/m(3), respectively. Biologically significant, exposure-related effects were limited to the lung, were greater in females than in males, and were observed primarily at the highest exposure level. There was a dose-related increase in the numbers of alveolar macrophages and the numbers of particles in the macrophages, as expected from repeated exposure, but no neutrophil response even at the highest exposure level. The macrophage response was reduced 28 days after cessation of the exposure. Among the high-level females, the group mean lung weight/body weight ratio was increased, and minimal, multifocal bronchiolar metaplasia of alveolar ducts was observed in 4 of 30 rats. Lung weights were not significantly increased, and metaplasia of the alveolar ducts was not observed in males. An increase in particle-laden macrophages was the only exposure-related finding in lungs at the intermediate and low levels, with fewer macrophages and fewer particles per macrophage at the low level. Alveolar histiocytosis was observed in a few rats in both exposed and control groups. There were statistically significant, but minor and not consistently exposure-related, differences in body weight, nonpulmonary organ weights, serum chemistry, and glial fibrillary acidic protein in the brain. There were no significant exposure-related effects on survival, clinical signs, feed consumption, ocular toxicity, hematology, neurohistology, micronuclei in bone marrow, sister chromatid exchanges in peripheral blood lymphocytes, fertility, reproductive toxicity, or teratology. This study demonstrated modest adverse effects at the highest exposure level, and none other than the expected physiological macrophage response to repeated particle exposure at the intermediate level.

Characterization of immune response to Eimeria tenella antigens in a natural immunity model with hosts which differ serologically at the B locus of the major histocompatibility complex.

PubMed Central

Brake, D A; Fedor, C H; Werner, B W; Miller, T J; Taylor, R L; Clare, R A

1997-01-01

A model to simulate natural immunity to Eimeria tenella was developed in three chicken lines which differ at the B locus of the major histocompatibility complex. Homozygous, 1-day-old chicks of the B19B19, B24B24, or B30B30 genotype were trickle immunized by being orally fed a small infectious dose of E. tenella oocysts for 5 consecutive days. These naturally exposed birds were then challenged at different times between 5 and 24 days after the final dose, and the level of protection was assessed 6 days after challenge, using body weight gain and intestinal lesion scores. The duration of immunity in naturally exposed birds differed among the major histocompatibility complex lines. Trickle immunization of the B19B19 haplotype afforded the longest and strongest level of protection compared to the other two haplotypes tested. In addition, in vitro splenic and peripheral blood lymphocyte proliferative responses in trickle-immunized birds were measured against sporozoite, merozoite, and tissue culture-derived E. tenella parasite antigens isolated from the recently described SB-CEV-1/F7 established cell line. The lymphocytes obtained from B19B19 birds trickle immunized responded in vitro to the E. tenella-infected SB-CEV-1/F7 tissue culture-derived parasite antigen. Furthermore, antigen-specific immune responses appeared earlier in immune, challenged B19B19 birds than in their naive, challenged counterparts. The development of a model simulating natural immunization will serve as a foundation to further characterize both humoral and cell-mediated responses to E. tenella tissue culture-derived parasite antigens and to better understand host protective immune responses to avian coccidiosis. PMID:9119452

Comparing Vertical Scales Derived from Dichotomous and Polytomous IRT Models for a Test Composed of Testlets.

ERIC Educational Resources Information Center

Bishop, N. Scott; Omar, Md Hafidz

Previous research has shown that testlet structures often violate important assumptions of dichotomous item response theory (D-IRT) models, applied to item-level scores, that can in turn affect the results of many measurement applications. In this situation, polytomous IRT (P-IRT) models, applied to testlet-level scores, have been used as an…

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases

PubMed Central

Alvarez, Irene; Iglesias, Olalla; Crespo, Ignacio; Figueroa, Jesus; Aleixandre, Manuel; Linares, Carlos; Granizo, Elias; Garcia-Fantini, Manuel; Marey, Jose; Masliah, Eliezer; Winter, Stefan; Muresanu, Dafin; Moessler, Herbert

2016-01-01

Background: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer’s disease. Methods: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer’s disease patients. Results: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. Conclusion: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer’s disease cases with apolipoprotein E epsilon-4 allele. PMID:27207906

Elucidation of a novel phenformin derivative on glucose-deprived stress responses in HT-29 cells.

PubMed

Oh-Hashi, Kentaro; Irie, Nao; Sakai, Takayuki; Okuda, Kensuke; Nagasawa, Hideko; Hirata, Yoko; Kiuchi, Kazutoshi

2016-08-01

Recently, we developed a variety of phenformin derivatives as selective antitumor agents. Based on previous findings, this study evaluated a promising compound, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on the basis of stress responses in the human colon cancer cell line HT-29 under a serum- and glucose-deprived condition. 2-Cl-Phen triggered morphological changes such as shrinkage and plasma membrane disintegration, as well as a decrease in mitochondrial activity and an increase in LDH leakage. To understand intracellular issues relating to 2-Cl-Phen, this study focused on the expression levels of ER stress-inducible genes and several oncogenic genes. Serum and glucose deprivation significantly induced a variety of ER stress-inducible genes, but a 12-h treatment of 2-Cl-Phen down-regulated expression of several ER stress-related genes, with the exception of GADD153. Interestingly, the expression levels of ATF6α, GRP78, MANF, and CRELD2 mRNA were almost completely decreased by 2-Cl-Phen. This study also observed that a 24-h treatment of 2-Cl-Phen attenuated the expression levels of GRP78, GADD153, and c-Myc protein. The decrease in c-Myc protein occurred before the fluctuation of GRP78 protein, while the expression of c-Myc mRNA showed little change with cotreatment of serum and glucose deprivation with 2-Cl-Phen. To further understand the 2-Cl-Phen-induced down-regulation of ATF6-related genes, this study investigated the stability of ATF6α and GRP78 proteins using NanoLuc-tagged constructs. The expression levels of NanoLuc-tagged ATF6α and GRP78 were significantly down-regulated by 2-Cl-Phen in the presence or absence of the translation inhibitor cycloheximide. Taken together, our novel phenformin derivative 2-Cl-Phen has the unique characteristic of diminishing tumor adaptive responses, especially the expression of ATF6-related genes, as well as that of c-Myc protein, in a transcriptional and posttranscriptional manner under a serum- and glucose-deprived condition. Further characterization of cytotoxic mechanisms related to phenformin derivatives may give new insights into developing additional promising anticancer agents.

Oral immunogenicity of tomato-derived sDPT polypeptide containing Corynebacterium diphtheriae, Bordetella pertussis and Clostridium tetani exotoxin epitopes.

PubMed

Soria-Guerra, Ruth E; Rosales-Mendoza, Sergio; Moreno-Fierros, Leticia; López-Revilla, Rubén; Alpuche-Solís, Angel G

2011-03-01

DPT vaccine, designed to immunize against diphtheria, pertussis, and tetanus, has been shown to be effective in humans. Nevertheless, dissatisfaction with the whole-cell preparations is due to the reactogenicity, which has to lead to the development of new safer formulations. Previously, we described the expression in tomato of a plant-optimized synthetic gene encoding the recombinant polypeptide sDPT, containing mainly immunoprotective epitopes of the diphtheria, pertussis and tetanus exotoxins and two adjuvants. In this study, we examined whether the ingestion of tomato-derived sDPT protein induces specific antibodies in mice after three weekly doses scheme. A positive group immunized with DPT toxoids was included. Specific antibody levels were assessed in serum, gut and lung. Sera tested for IgG antibody response to pertussis, tetanus and diphtheria toxin showed responses to the foreign antigens; interestingly, the response to diphtheria epitope was similar to those observed in the positive group. We found higher IgG1 than IgG2a responses in serum. A modest IgG response was observed in the tracheopulmonary fluid. High response of IgA against tetanus toxin was evident in gut, which was statistically comparable to that obtained in the positive group. The levels of response in these groups were higher than those in mice that received wild-type tomato. These findings support the concept of using transgenic tomatoes expressing sDPT polypeptide as model for edible vaccine against diphtheria, pertussis, and tetanus.

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

DOE PAGES

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; ...

2016-11-30

Here, we report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice weremore » dosed with [ 14C]carboplatin or [ 14C]gemcitabine and the resulting drug–DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug–DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug–DNA adducts as predictive biomarkers.« less

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

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

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong

Here, we report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice weremore » dosed with [ 14C]carboplatin or [ 14C]gemcitabine and the resulting drug–DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug–DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug–DNA adducts as predictive biomarkers.« less

Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice.

PubMed

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-Yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W; Cimino, George D; Tepper, Clifford G; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-Xian; Henderson, Paul T

2017-02-01

We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14 C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [ 14 C]carboplatin or [ 14 C]gemcitabine and the resulting drug-DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. Mol Cancer Ther; 16(2); 376-87. ©2016 AACR. ©2016 American Association for Cancer Research.

Equine colostral carbohydrates reduce lipopolysaccharide-induced inflammatory responses in equine peripheral blood mononuclear cells.

PubMed

Vendrig, J C; Coffeng, L E; Fink-Gremmels, J

2012-12-01

Increasing evidence suggests that reactions to lipopolysaccharide (LPS), particularly in the gut, can be partly or completely mitigated by colostrum- and milk-derived oligosaccharides. Confirmation of this hypothesis could lead to the development of new therapeutic concepts. To demonstrate the influence of equine colostral carbohydrates on the inflammatory response in an in vitro model with equine peripheral blood mononuclear cells (PBMCs). Carbohydrates were extracted from mare colostrum, and then evaluated for their influence on LPS-induced inflammatory responses in PBMCs isolated from the same mares, mRNA expression of tumour necrosis factor-alpha, interleukin-6 and interleukin-10 was measured as well as the protein levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10). Equine colostral carbohydrates significantly reduced LPS-induced TNF-alpha protein at both times measured and significantly reduced LPS-induced TNF-alpha, IL-6 and IL-10 mRNA expression by PBMCs. Moreover, cell viability significantly increased in the presence of high concentrations of colostral carbohydrates. Carbohydrates derived from equine colostrum reduce LPS-induced inflammatory responses of equine PBMCs. Colostrum and milk-derived carbohydrates are promising candidates for new concepts in preventive and regenerative medicine.

Efficacy of Human Adipose Tissue-Derived Stem Cells on Neonatal Bilirubin Encephalopathy in Rats.

PubMed

Amini, Naser; Vousooghi, Nasim; Hadjighassem, Mahmoudreza; Bakhtiyari, Mehrdad; Mousavi, Neda; Safakheil, Hosein; Jafari, Leila; Sarveazad, Arash; Yari, Abazar; Ramezani, Sara; Faghihi, Faezeh; Joghataei, Mohammad Taghi

2016-05-01

Kernicterus is a neurological syndrome associated with indirect bilirubin accumulation and damages to the basal ganglia, cerebellum and brain stem nuclei particularly the cochlear nucleus. To mimic haemolysis in a rat model such that it was similar to what is observed in a preterm human, we injected phenylhydrazine in 7-day-old rats to induce haemolysis and then infused sulfisoxazole into the same rats at day 9 to block bilirubin binding sites in the albumin. We have investigated the effectiveness of human adiposity-derived stem cells as a therapeutic paradigm for perinatal neuronal repair in a kernicterus animal model. The level of total bilirubin, indirect bilirubin, brain bilirubin and brain iron was significantly increased in the modelling group. There was a significant decreased in all severity levels of the auditory brainstem response test in the two modelling group. Akinesia, bradykinesia and slip were significantly declined in the experience group. Apoptosis in basal ganglia and cerebellum were significantly decreased in the stem cell-treated group in comparison to the vehicle group. All severity levels of the auditory brainstem response tests were significantly decreased in 2-month-old rats. Transplantation results in the substantial alleviation of walking impairment, apoptosis and auditory dysfunction. This study provides important information for the development of therapeutic strategies using human adiposity-derived stem cells in prenatal brain damage to reduce potential sensori motor deficit.

[Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor].

PubMed

Toscano-Garibay, Julia Dolores; Quiroz-Mercado, Hugo; Espitia-Pinzón, Clara; Gil-Carrasco, Félix; Flores-Estrada, José Javier

2014-01-01

Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium-derived factor. Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days).

Mycobacterium leprae upregulates IRGM expression in monocytes and monocyte-derived macrophages.

PubMed

Yang, Degang; Chen, Jia; Zhang, Linglin; Cha, Zhanshan; Han, Song; Shi, Weiwei; Ding, Ru; Ma, Lan; Xiao, Hong; Shi, Chao; Jing, Zhichun; Song, Ningjing

2014-08-01

Leprosy is caused by the infection of Mycobacterium leprae, which evokes a strong inflammatory response and leads to nerve damage. Immunity-related GTPase family M protein (IRGM) plays critical roles in controlling inflammation. The objective of the study was to investigate whether IRGM is involved in the infection of M. leprae. Levels of IRGM were assessed in M. leprae-infected CD4(+) T cells, monocytes, and monocyte-derived macrophages. Data revealed that both protein and mRNA levels of IRGM were increased in monocytes after M. leprae infection. Interestingly, monocyte-derived macrophages showed more prominent IRGM expression with M. leprae infection, whereas the bacteria did not affect IRGM in CD4(+) T cells. Furthermore, we assessed levels of IRGM in CD4(+) T cells and monocytes from 78 leprosy patients and 40 healthy controls, and observed upregulated protein level of IRGM in the monocytes from leprosy patients. Also, IRGM expression was inversely correlated with the severity of the disease. These findings suggested a close involvement of IRGM in M. leprae infection and indicated a potential mechanism of defending M. leprae infection.

Incorporating biologically based models into assessments of risk from chemical contaminants

NASA Technical Reports Server (NTRS)

Bull, R. J.; Conolly, R. B.; De Marini, D. M.; MacPhail, R. C.; Ohanian, E. V.; Swenberg, J. A.

1993-01-01

The general approach to assessment of risk from chemical contaminants in drinking water involves three steps: hazard identification, exposure assessment, and dose-response assessment. Traditionally, the risks to humans associated with different levels of a chemical have been derived from the toxic responses observed in animals. It is becoming increasingly clear, however, that further information is needed if risks to humans are to be assessed accurately. Biologically based models help clarify the dose-response relationship and reduce uncertainty.

Commensal bacterial–derived signals regulate basophil hematopoiesis and allergic inflammation

PubMed Central

Hill, David A.; Siracusa, Mark C.; Abt, Michael C.; Kim, Brian S.; Kobuley, Dmytro; Kubo, Masato; Kambayashi, Taku; LaRosa, David F.; Renner, Ellen D.; Orange, Jordan S.; Bushman, Frederic D.; Artis, David

2012-01-01

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (TH2) cytokine–dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we identify that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum immunoglobulin E (IgE) levels, increased steady–state circulating basophil populations, and exaggerated basophil–mediated TH2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of MyD88 was required to limit serum IgE levels and circulating basophil populations in mice. Commensal–derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal–derived signals influence basophil hematopoiesis and susceptibility to TH2 cytokine–dependent inflammation and allergic disease. PMID:22447074

A Unified Probabilistic Framework for Dose–Response Assessment of Human Health Effects

PubMed Central

Slob, Wout

2015-01-01

Background When chemical health hazards have been identified, probabilistic dose–response assessment (“hazard characterization”) quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. Objectives We developed a unified framework for probabilistic dose–response assessment. Methods We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose–response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, “effect metrics” can be specified to define “toxicologically equivalent” sizes for this underlying individual response; and d) dose–response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose–response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Results Probabilistically derived exposure limits are based on estimating a “target human dose” (HDMI), which requires risk management–informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%–10% effect sizes. Conclusions Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions. Citation Chiu WA, Slob W. 2015. A unified probabilistic framework for dose–response assessment of human health effects. Environ Health Perspect 123:1241–1254; http://dx.doi.org/10.1289/ehp.1409385 PMID:26006063

Dose-dependent bioavailability indicators for curcumin and two of its novel derivatives.

PubMed

Abd el Aziz, Mohamed; El-Asmer, Mohamed; Rezq, Ameen; Al-Malki, Abdulrahman; Kumosani, Taha; Fouad, Hanan; Ahmed, Hanan; Taha, Fatma; Hassouna, Amira; Hafez, Hafez

2014-01-01

Novel water-soluble curcumin derivatives have been developed to overcome low in vivo bioavailability of curcumin. The aim of this work is to assess the potential utility of certain downstream targets as bioavailability indicators of systemic activity of pure curcumin and two novel water-soluble curcumin derivatives (NCD) by constructing dose-dependent response curves and to prove whether this novel curcumin derivatives retained, improved, or abolished biological activity of pure curcumin when applied in vivo. Pure curcumin (CUR), curcumin-carboxy derivative (NCD-1), and curcumin protein conjugate (NCD-2) were administered orally to rats at escalating doses: 37, 74, 148, and 296 μM/kg body weight, respectively. Plasma levels of GST activity, cavernous tissue levels of cGMP, and enzymatic activity of both HO-1 and GST were assessed one and half and 24 hours after oral administration of curcumin formulae. This study showed that there was a progressive elevation of cavernous tissue levels of cGMP and enzymatic activity of both HO-1 and GST in a dose-dependent manner that was maintained for 24 h with CUR, NCD-1, and NCD-2. Plasma GST activity was decreased by the lowest doses on the curve. The three dose-dependent bioavailability indicators as surrogates of curcumin and two of its novel derivatives are valid in the studied range of concentration and extended time. The novel curcumin derivatives still conserve with improvement the biological activity of natural curcumin when applied in vivo. © 2013 International Union of Biochemistry and Molecular Biology.

The effects of urbanization on the biological, physical, and chemical characteristics of coastal New England streams

USGS Publications Warehouse

Coles, J.F.; Cuffney, T.F.; McMahon, G.; Beaulieu, K.M.

2004-01-01

During August 2000, responses of biological communities (invertebrates, fish, and algae), physical habitat, and water chemistry to urban intensity were compared among 30 streams within 80 miles of Boston, Massachusetts. Sites chosen for sampling represented a gradient of the intensity of urban development (urban intensity) among drainage basins that had minimal natural variability. In this study, spatial differences were used as surrogates for temporal changes to represent the effects of urbanization over time. The degree of urban intensity for each drainage basin was characterized with a standardized urban index (0?100, lowest to highest) derived from land cover, infrastructure, and socioeconomic variables. Multivariate and multimetric analyses were used to compare urban index values with biological, physical, and chemical data to determine how the data indicated responses to urbanization. Multivariate ordinations were derived for the invertebrate-, fish-, and algaecommunity data by use of correspondence analysis, and ordinations were derived for the chemical and physical data by use of principal-component analysis. Site scores from each of the ordinations were plotted in relation to the urban index to test for a response. In all cases, the primary axis scores showed the strongest response to the urban index, indicating that urbanization was a primary factor affecting the data ordination. For the multimetric analyses, each of the biological data sets was used to calculate a series of community metrics. For the sets of chemical and physical data, the individual variables and various combinations of individual variables were used as measured and derived metrics, respectively. Metrics that were generally most responsive to the urban index for each data set included: EPT (Ephemeroptera, Plecoptera, Trichoptera) taxa for invertebrates; cyprinid taxa for fish; diatom taxa for algae; bicarbonate, conductivity, and nitrogen for chemistry; and water depth and temperature for physical habitat. The slopes of the responses generally were higher between the urban index values of 0 to 35, indicating that the greatest change in aquatic health may occur between low and moderate levels of urban intensity. Additionally, many of the responses showed that at urban index values greater than 35, there was a threshold effect where the response variable no longer changed with respect to urban intensity. Recognizing and understanding this type of response is important in management and monitoring programs that rely on decisive interpretations of variable responses. Any biological, physical, or chemical variable that is used to haracterize stream health over a gradient of disturbance would not be a reliable indicator when a level of disturbance is reached where the variable does not respond in a predictable manner.

Plants mediate soil organic matter decomposition in response to sea level rise.

PubMed

Mueller, Peter; Jensen, Kai; Megonigal, James Patrick

2016-01-01

Tidal marshes have a large capacity for producing and storing organic matter, making their role in the global carbon budget disproportionate to land area. Most of the organic matter stored in these systems is in soils where it contributes 2-5 times more to surface accretion than an equal mass of minerals. Soil organic matter (SOM) sequestration is the primary process by which tidal marshes become perched high in the tidal frame, decreasing their vulnerability to accelerated relative sea level rise (RSLR). Plant growth responses to RSLR are well understood and represented in century-scale forecast models of soil surface elevation change. We understand far less about the response of SOM decomposition to accelerated RSLR. Here we quantified the effects of flooding depth and duration on SOM decomposition by exposing planted and unplanted field-based mesocosms to experimentally manipulated relative sea level over two consecutive growing seasons. SOM decomposition was quantified as CO2 efflux, with plant- and SOM-derived CO2 separated via δ(13) CO2 . Despite the dominant paradigm that decomposition rates are inversely related to flooding, SOM decomposition in the absence of plants was not sensitive to flooding depth and duration. The presence of plants had a dramatic effect on SOM decomposition, increasing SOM-derived CO2 flux by up to 267% and 125% (in 2012 and 2013, respectively) compared to unplanted controls in the two growing seasons. Furthermore, plant stimulation of SOM decomposition was strongly and positively related to plant biomass and in particular aboveground biomass. We conclude that SOM decomposition rates are not directly driven by relative sea level and its effect on oxygen diffusion through soil, but indirectly by plant responses to relative sea level. If this result applies more generally to tidal wetlands, it has important implications for models of SOM accumulation and surface elevation change in response to accelerated RSLR. © 2015 John Wiley & Sons Ltd.

Modulation of the allergen-induced human IgE response in Hu-SCID mice: inhibitory effect of human recombinant IFN-gamma and allergen-derived lipopeptide.

PubMed

Duez, C; Gras-Masse, H; Hammad, H; Akoum, H; Didierlaurent, A; André, C; Tonnel, A B; Pestel, J

2001-01-01

We have previously established a model to study the in vivo human IgE response using humanized SCID mice. Allergic SCID mice were obtained following intraperitoneal injection with mononuclear cells from Dermatophagoides pteronyssinus (Dpt)-sensitive patients, and sensitization by Dpt allergen intraperitoneal injection (immunization) or Dpt aerosol (inhalation). Human serum IgE was measured in allergic SCID mice after administration of human recombinant IFN-gamma or the lipopeptide LP 52-71 (derived from peptide p52-71 from Der p 1, Dpt major allergen, coupled to a lipophilic moiety), during the immunization or the inhalation phase. IFN-gamma inhibited human IgE production when given at the time of immunization, but not during inhalation. This effect was long-lasting as Dpt aerosol, given one month after immunization and IFN-gamma administration, failed to increase IgE levels. Unlike Dpt or p52-71, LP 52-71 failed to induce human IgE production at day 14 and 21 after its injection, but did inhibit the development of the IgE response after a secondary Dpt-challenge. Moreover, LP 52-71 administration 14 days after Dpt inhalation decreased IgE levels, in contrast to peptide 52-71, which increased IgE levels. Thus, taken together these results indicate that the development of the human IgE response in allergic SCID mice can be modulated by modified allergen and a Th1 cytokine.

Starvation and recovery in the deep-sea methanotroph Methyloprofundus sedimenti.

PubMed

Tavormina, Patricia L; Kellermann, Matthias Y; Antony, Chakkiath Paul; Tocheva, Elitza I; Dalleska, Nathan F; Jensen, Ashley J; Valentine, David L; Hinrichs, Kai-Uwe; Jensen, Grant J; Dubilier, Nicole; Orphan, Victoria J

2017-01-01

In the deep ocean, the conversion of methane into derived carbon and energy drives the establishment of diverse faunal communities. Yet specific biological mechanisms underlying the introduction of methane-derived carbon into the food web remain poorly described, due to a lack of cultured representative deep-sea methanotrophic prokaryotes. Here, the response of the deep-sea aerobic methanotroph Methyloprofundus sedimenti to methane starvation and recovery was characterized. By combining lipid analysis, RNA analysis, and electron cryotomography, it was shown that M. sedimenti undergoes discrete cellular shifts in response to methane starvation, including changes in headgroup-specific fatty acid saturation levels, and reductions in cytoplasmic storage granules. Methane starvation is associated with a significant increase in the abundance of gene transcripts pertinent to methane oxidation. Methane reintroduction to starved cells stimulates a rapid, transient extracellular accumulation of methanol, revealing a way in which methane-derived carbon may be routed to community members. This study provides new understanding of methanotrophic responses to methane starvation and recovery, and lays the initial groundwork to develop Methyloprofundus as a model chemosynthesizing bacterium from the deep sea. © 2016 John Wiley & Sons Ltd.

Response of salt marsh and mangrove wetlands to changes in atmospheric CO2, climate, and sea-level

USGS Publications Warehouse

Mckee, Karen L.; Rogers, Kerrylee; Saintilan, Neil; Middleton, Beth A.

2012-01-01

Coastal salt marsh and mangrove ecosystems are particularly vulnerable to changes in atmospheric CO2 concentrations and associated climate and climate-induced changes. We provide a review of the literature detailing theoretical predictions and observed responses of coastal wetlands to a range of climate change stressors, including CO2, temperature, rainfall, and sea-level rise. This review incorporates a discussion of key processes controlling responses in different settings and thresholds of resilience derived from experimental and observational studies. We specifically consider the potential and observed effects on salt marsh and mangrove vegetation of changes in (1) elevated [CO2] on physiology, growth, and distribution; (2) temperature on distribution and diversity; (3) rainfall and salinity regimes on growth and competitive interactions; and (4) sea level on geomorphological, hydrological, and biological processes.

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

PubMed

Haile, C N; Murrough, J W; Iosifescu, D V; Chang, L C; Al Jurdi, R K; Foulkes, A; Iqbal, S; Mahoney, J J; De La Garza, R; Charney, D S; Newton, T F; Mathew, S J

2014-02-01

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

Strategies for memory-based decision making: Modeling behavioral and neural signatures within a cognitive architecture.

PubMed

Fechner, Hanna B; Pachur, Thorsten; Schooler, Lael J; Mehlhorn, Katja; Battal, Ceren; Volz, Kirsten G; Borst, Jelmer P

2016-12-01

How do people use memories to make inferences about real-world objects? We tested three strategies based on predicted patterns of response times and blood-oxygen-level-dependent (BOLD) responses: one strategy that relies solely on recognition memory, a second that retrieves additional knowledge, and a third, lexicographic (i.e., sequential) strategy, that considers knowledge conditionally on the evidence obtained from recognition memory. We implemented the strategies as computational models within the Adaptive Control of Thought-Rational (ACT-R) cognitive architecture, which allowed us to derive behavioral and neural predictions that we then compared to the results of a functional magnetic resonance imaging (fMRI) study in which participants inferred which of two cities is larger. Overall, versions of the lexicographic strategy, according to which knowledge about many but not all alternatives is searched, provided the best account of the joint patterns of response times and BOLD responses. These results provide insights into the interplay between recognition and additional knowledge in memory, hinting at an adaptive use of these two sources of information in decision making. The results highlight the usefulness of implementing models of decision making within a cognitive architecture to derive predictions on the behavioral and neural level. Copyright © 2016 Elsevier B.V. All rights reserved.

Different protein of Echinococcus granulosus stimulates dendritic induced immune response.

PubMed

Wang, Yana; Wang, Qiang; Lv, Shiyu; Zhang, Shengxiang

2015-06-01

Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear.

Self-monitoring of plasma triglyceride levels to evaluate postprandial response to different nutrients.

PubMed

Iovine, C; Gentile, A; Hattemer, A; Pacioni, D; Riccardi, G; Rivellese, A A

2004-05-01

Self-monitoring of plasma triglycerides (TG) may be a very useful tool to monitor, on a daily basis, the TG responses to different nutrients, particularly carbohydrates (CHO) and fat, whose influence on postprandial TG levels is not very well known. Therefore, the aim of the present study was to evaluate the TG response of hypertriglyceridemic patients to a similar amount of calories deriving from different sources of CHO and fat. Thirty-nine hypertriglyceridemic patients were randomly assigned to 1 of 2 experimental groups. In 1 group (the fat group), patients were given a standard meal plus a fat supplement of 300 kcal derived from different types of fat (butter, sunflower margarine, olive oil) for dinner, once a week for 3 weeks. In the other group (the CHO group), patients consumed the same standard meal plus a supplement of 300 kcal derived from different types of CHO (bread, coke, fruit). In both groups, patients measured their plasma TG before and 3 hours after each meal by Accutrend GCT (ROCHE, Mannheim, Germany). A subgroup of patients (n = 18) also performed TG determinations 2 hours after the test meals. The 3-hour TG increments were not significantly different between the different test meals (f = 0.671; P =.52); instead, the TG increments induced by fat supplements were significantly higher than those induced by the CHO supplements (f = 14.31; P =.0001). Similar results were also obtained 2 hours after the test meals. In conclusion, this study shows that the 2- and 3-hour TG responses to fat are higher compared with that induced by carbohydrate. This point, especially if confirmed by experiments with more frequent after meal measurements and of longer duration, should be taken into account in defining the best dietary approach to lower plasma TG levels throughout the whole day.

EphA2 is a biomarker of hMSCs derived from human placenta and umbilical cord.

PubMed

Shen, Shih-Pei; Liu, Wei-Ting; Lin, Yun; Li, Yuan-Tsung; Chang, Chih-Hao; Chang, Fung-Wei; Wang, Le-Ming; Teng, Sen-Wen; Hsuan, Yogi

2015-12-01

The heterogeneous nature of mesenchymal stem cells (MSCs) and the absence of known MSC-specific biomarkers make it challenging to define MSC phenotypes and characteristics. In this study, we compared the phenotypic and functional features of human placenta-derived MSCs with those of human dermal fibroblasts in vitro in order to identify a biomarker that can be used to increase the purity of MSCs in a primary culture of placenta-derived cells. Liquid chromatography-tandem mass spectrometry analysis was used to analyze and compare the proteome of human placenta-derived MSCs with that of fibroblasts. Quantitative real-time polymerase chain reaction, immunofluorescence, and flow cytometry were used to determine expression levels of EphA2 in placenta-derived MSCs. EphA2-positive cells were enriched by magnetic-activated cell sorting or with a cell sorter. An shRNA-mediated EphA2 knockdown was used to assess the role of EphA2 in MSC response to Tumor necrosis factor (TNF)-α stimulation. Analysis of proteomics data from MSCs and fibroblasts resulted in the identification of the EphA2 surface protein biomarker, which could reliably distinguish MSCs from fibroblasts. EphA2 was significantly upregulated in placenta-derived MSCs when compared to fibroblasts. EphA2 played an important role in MSC migration in response to inflammatory stimuli, such as TNF-α. EphA2-enriched MSCs were also more responsive to inflammatory stimuli in vitro when compared to unsorted MSCs, indicating a role for EphA2 in the immunomodulatory functionality of MSCs. EphA2 can be used to distinguish and isolate MSCs from a primary culture of placenta-derived cells. EphA2-sorted MSCs exhibited superior responsiveness to TNF-α signaling in an inflammatory environment compared with unsorted MSCs or MSC-like cells. Copyright © 2015. Published by Elsevier B.V.

Low and moderate photosynthetically active radiation affects the flavonol glycosides and hydroxycinnamic acid derivatives in kale (Brassica oleracea var. sabellica) dependent on two low temperatures.

PubMed

Neugart, Susanne; Fiol, Michaela; Schreiner, Monika; Rohn, Sascha; Zrenner, Rita; Kroh, Lothar W; Krumbein, Angelika

2013-11-01

Kale (Brassica oleracea var. sabellica) contains a large number of naturally occurring structurally different non-acylated and acylated flavonol glycosides as well as hydroxycinnamic acid derivatives. The objective of this study was to determine the effect of low and moderate photosynthetic active radiation (PAR) and how these levels interact with low temperature in these phenolic compounds. Juvenile kale plants were treated with PAR levels from 200 to 800 μmol m(-2) s(-1) at 5 and 10 °C under defined conditions in climate chambers. Of the investigated 20 compounds, 11 and 17 compounds were influenced by PAR and temperature, respectively. In addition, an interaction between PAR and temperature was found for eight compounds. The response of the phenolic compounds to PAR was structure-dependent. While quercetin triglycosides increased with higher PAR at 5 and 10 °C, the kaempferol triglycosides exhibited the highest concentrations at 400 μmol m(-2) s(-1). In contrast, kaempferol diglycosides exhibited the highest concentrations at increased PAR levels of 600 and 800 μmol m(-2) s(-1) at 10 °C. However, key genes of flavonol biosynthesis were influenced by temperature but remained unaffected by PAR. Furthermore, there was no interaction between the PAR level and the low temperature in the response of hydroxycinnamic acid derivatives in kale with the exception of caffeoylquinic acid, which decreased with higher PAR levels of 600 and 800 μmol m(-2) s(-1) and at a lower temperature. In conclusion, PAR and its interaction with temperature could be a suitable tool for modifying the profile of phenolic compounds. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Endothelial- and Platelet-Derived Microparticles Are Generated During Liver Resection in Humans.

PubMed

Banz, Yara; Item, Gian-Marco; Vogt, Andreas; Rieben, Robert; Candinas, Daniel; Beldi, Guido

2016-01-01

Cell-derived plasma microparticles (<1.5 μm) originating from various cell types have the potential to regulate thrombogenesis and inflammatory responses. The aim of this study was to test the hypothesis that microparticles generated during hepatic surgery co-regulate postoperative procoagulant and proinflammatory events. In 30 patients undergoing liver resection, plasma microparticles were isolated, quantitated, and characterized as endothelial (CD31+, CD41-), platelet (CD41+), or leukocyte (CD11b+) origin by flow cytometry and their procoagulant and proinflammatory activity was measured by immunoassays. During liver resection, the total numbers of microparticles increased with significantly more Annexin V-positive, endothelial and platelet-derived microparticles following extended hepatectomy compared to standard and minor liver resections. After liver resection, microparticle tissue factor and procoagulant activity increased along with overall coagulation as assessed by thrombelastography. Levels of leukocyte-derived microparticles specifically increased in patients with systemic inflammation as assessed by C-reactive protein but are independent of the extent of liver resection. Endothelial and platelet-derived microparticles are specifically elevated during liver resection, accompanied by increased procoagulant activity. Leukocyte-derived microparticles are a potential marker for systemic inflammation. Plasma microparticles may represent a specific response to surgical stress and may be an important mediator of postoperative coagulation and inflammation.

Macroscopic response in active nonlinear photonic crystals.

PubMed

Alagappan, Gandhi; John, Sajeev; Li, Er Ping

2013-09-15

We derive macroscopic equations of motion for the slowly varying electric field amplitude in three-dimensional active nonlinear optical nanostructures. We show that the microscopic Maxwell equations and polarization dynamics can be simplified to a macroscopic one-dimensional problem in the direction of group velocity. For a three-level active material, we derive the steady-state equations for normal mode frequency, threshold pumping, nonlinear Bloch mode amplitude, and lasing in photonic crystals. Our analytical results accurately recapture the results of exact numerical methods.

Synthesis of Two Coumarin-Derived Schiff Bases and Investigation of theirs Selectivity for Zn2.

PubMed

Fan, Long

2017-07-01

In this study, the coumarin-derived schiff bases (HL 1 and HL 2 ) have been designed and synthesized. Upon the addition of Zn 2+ , both of them show significant fluorescence enhancement owing to inhibits PET and ESIPT process respectively. However, the receptor HL 2 response toward Cd 2+ , Mg 2+ , Ba 2+ , Ca 2+ besides Zn 2+ and exhibits fluorescence enhancement but not enough to detection of the concentration levels of Zn 2+ .

A Simple Approach to the Landau-Zener Formula

ERIC Educational Resources Information Center

Vutha, Amar C.

2010-01-01

The Landau-Zener formula provides the probability of non-adiabatic transitions occurring when two energy levels are swept through an avoided crossing. The formula is derived here in a simple calculation that emphasizes the physics responsible for non-adiabatic population transfer. (Contains 2 figures.)

EFFECTS OF INSTILLED COMBUSTION-DERIVED ENVIRONMENTAL PARTICLES IN SPONTANEOUSLY HYPERTENSIVE RATS. PART 1: CARDIOVASCULAR RESPONSES

EPA Science Inventory

Epidemiological studies have reported a robust correlation between levels of ambient particulate matter (PM) and the incidence of morbidity and mortality, particularly among persons with cardiopulmonary disease. While similar effects have been demonstrated in animals, the mechan...

An Updated Comprehensive Risk Analysis for Radioisotopes Identified of High Risk to National Security in the Event of a Radiological Dispersion Device Scenario

NASA Astrophysics Data System (ADS)

Robinson, Alexandra R.

An updated global survey of radioisotope production and distribution was completed and subjected to a revised "down-selection methodology" to determine those radioisotopes that should be classified as potential national security risks based on availability and key physical characteristics that could be exploited in a hypothetical radiological dispersion device. The potential at-risk radioisotopes then were used in a modeling software suite known as Turbo FRMAC, developed by Sandia National Laboratories, to characterize plausible contamination maps known as Protective Action Guideline Zone Maps. This software also was used to calculate the whole body dose equivalent for exposed individuals based on various dispersion parameters and scenarios. Derived Response Levels then were determined for each radioisotope using: 1) target doses to members of the public provided by the U.S. EPA, and 2) occupational dose limits provided by the U.S. Nuclear Regulatory Commission. The limiting Derived Response Level for each radioisotope also was determined.

Proposed method to calculate FRMAC intervention levels for the assessment of radiologically contaminated food and comparison of the proposed method to the U.S. FDA's method to calculate derived intervention levels

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

Kraus, Terrence D.; Hunt, Brian D.

This report reviews the method recommended by the U.S. Food and Drug Administration for calculating Derived Intervention Levels (DILs) and identifies potential improvements to the DIL calculation method to support more accurate ingestion pathway analyses and protective action decisions. Further, this report proposes an alternate method for use by the Federal Emergency Radiological Assessment Center (FRMAC) to calculate FRMAC Intervention Levels (FILs). The default approach of the FRMAC during an emergency response is to use the FDA recommended methods. However, FRMAC recommends implementing the FIL method because we believe it to be more technically accurate. FRMAC will only implement themore » FIL method when approved by the FDA representative on the Federal Advisory Team for Environment, Food, and Health.« less

Glutathione and growth inhibition of Mycobacterium tuberculosis in healthy and HIV infected subjects

PubMed Central

Venketaraman, Vishwanath; Rodgers, Tatanisha; Linares, Rafael; Reilly, Nancy; Swaminathan, Shobha; Hom, David; Millman, Ariel C; Wallis, Robert; Connell, Nancy D

2006-01-01

Intracellular levels of glutathione are depleted in patients with acquired immunodeficiency syndrome in whom the risk of tuberculosis, particularly disseminated disease is many times that of healthy individuals. In this study, we examined the role of glutathione in immunity against tuberculosis infection in samples derived from healthy and human immunodeficiency virus infected subjects. Our studies confirm that glutathione levels are reduced in peripheral blood mononuclear cells and in red blood cells isolated from human immunodeficiency virus-infected subjects (CD4>400/cumm). Furthermore, treatment of blood cultures from human immunodeficiency virus infected subjects with N-acetyl cysteine, a glutathione precursor, caused improved control of intracellular M. tuberculosis infection. N-acetyl cysteine treatment decreased the levels of IL-1, TNF-α, and IL-6, and increased the levels of IFN-γ in blood cultures derived from human immunodeficiency virus-infected subjects, promoting the host immune responses to contain M. tuberculosis infection successfully. PMID:16504020

Expression of DNA translesion synthesis polymerase η in head and neck squamous cell cancer predicts resistance to gemcitabine and cisplatin-based chemotherapy.

PubMed

Zhou, Wendi; Chen, Yih-wen; Liu, Xiyong; Chu, Peiguo; Loria, Sofia; Wang, Yafan; Yen, Yun; Chou, Kai-Ming

2013-01-01

The development of resistance against anticancer drugs has been a persistent clinical problem for the treatment of locally advanced malignancies in the head and neck mucosal derived squamous cell carcinoma (HNSCC). Recent evidence indicates that the DNA translesion synthesis (TLS) polymerase η (Pol η; hRad30a gene) reduces the effectiveness of gemcitabine/cisplatin. The goal of this study is to examine the relationship between the expression level of Pol η and the observed resistance against these chemotherapeutic agents in HNSCC, which is currently unknown. Sixty-four mucosal derived squamous cell carcinomas of head and neck (HNSCC) from 1989 and 2007 at the City of Hope National Medical Center (Duarte, CA) were retrospectively analyzed. Pretreatment samples were immunostained with anti-Pol η antibody and the correlation between the expression level of Pol η and clinical outcomes were evaluated. Forty-nine cases treated with platinum (n=40) or gemcitabine (n=9) based chemotherapy were further examined for Pol η expression level for comparison with patient response to chemotherapy. The expression of Pol η was elevated in 67% of the head and neck tumor samples. Pol η expression level was significantly higher in grade 1 to grade 2 tumors (well to moderately differentiated). The overall benefit rate (complete response+ partial response) in patients treated with platinum and gemcitabine based chemotherapy was 79.5%, where low Pol η level was significantly associated with high complete response rate (p=0.03), although not associated with overall survival. Furthermore, no significant correlation was observed between Pol η expression level with gender, age, tobacco/alcohol history, tumor stage and metastatic status. Our data suggest that Pol η expression may be a useful prediction marker for the effectiveness of platinum or gemcitabine based therapy for HNSCC.

Expression of DNA Translesion Synthesis Polymerase η in Head and Neck Squamous Cell Cancer Predicts Resistance to Gemcitabine and Cisplatin-Based Chemotherapy

PubMed Central

Zhou, Wendi; Chen, Yih-wen; Liu, Xiyong; Chu, Peiguo; Loria, Sofia; Wang, Yafan; Yen, Yun; Chou, Kai-Ming

2013-01-01

Purpose The development of resistance against anticancer drugs has been a persistent clinical problem for the treatment of locally advanced malignancies in the head and neck mucosal derived squamous cell carcinoma (HNSCC). Recent evidence indicates that the DNA translesion synthesis (TLS) polymerase η (Pol η; hRad30a gene) reduces the effectiveness of gemcitabine/cisplatin. The goal of this study is to examine the relationship between the expression level of Pol η and the observed resistance against these chemotherapeutic agents in HNSCC, which is currently unknown. Methods Sixty-four mucosal derived squamous cell carcinomas of head and neck (HNSCC) from 1989 and 2007 at the City of Hope National Medical Center (Duarte, CA) were retrospectively analyzed. Pretreatment samples were immunostained with anti-Pol η antibody and the correlation between the expression level of Pol η and clinical outcomes were evaluated. Forty-nine cases treated with platinum (n=40) or gemcitabine (n=9) based chemotherapy were further examined for Pol η expression level for comparison with patient response to chemotherapy. Results The expression of Pol η was elevated in 67% of the head and neck tumor samples. Pol η expression level was significantly higher in grade 1 to grade 2 tumors (well to moderately differentiated). The overall benefit rate (complete response+ partial response) in patients treated with platinum and gemcitabine based chemotherapy was 79.5%, where low Pol η level was significantly associated with high complete response rate (p=0.03), although not associated with overall survival. Furthermore, no significant correlation was observed between Pol η expression level with gender, age, tobacco/alcohol history, tumor stage and metastatic status. Conclusions Our data suggest that Pol η expression may be a useful prediction marker for the effectiveness of platinum or gemcitabine based therapy for HNSCC. PMID:24376779

Estimation of dynamic stability parameters from drop model flight tests

NASA Technical Reports Server (NTRS)

Chambers, J. R.; Iliff, K. W.

1981-01-01

A recent NASA application of a remotely-piloted drop model to studies of the high angle-of-attack and spinning characteristics of a fighter configuration has provided an opportunity to evaluate and develop parameter estimation methods for the complex aerodynamic environment associated with high angles of attack. The paper discusses the overall drop model operation including descriptions of the model, instrumentation, launch and recovery operations, piloting concept, and parameter identification methods used. Static and dynamic stability derivatives were obtained for an angle-of-attack range from -20 deg to 53 deg. The results of the study indicated that the variations of the estimates with angle of attack were consistent for most of the static derivatives, and the effects of configuration modifications to the model (such as nose strakes) were apparent in the static derivative estimates. The dynamic derivatives exhibited greater uncertainty levels than the static derivatives, possibly due to nonlinear aerodynamics, model response characteristics, or additional derivatives.

A dynamic multi-level optimal design method with embedded finite-element modeling for power transformers

NASA Astrophysics Data System (ADS)

Zhang, Yunpeng; Ho, Siu-lau; Fu, Weinong

2018-05-01

This paper proposes a dynamic multi-level optimal design method for power transformer design optimization (TDO) problems. A response surface generated by second-order polynomial regression analysis is updated dynamically by adding more design points, which are selected by Shifted Hammersley Method (SHM) and calculated by finite-element method (FEM). The updating stops when the accuracy requirement is satisfied, and optimized solutions of the preliminary design are derived simultaneously. The optimal design level is modulated through changing the level of error tolerance. Based on the response surface of the preliminary design, a refined optimal design is added using multi-objective genetic algorithm (MOGA). The effectiveness of the proposed optimal design method is validated through a classic three-phase power TDO problem.

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection

PubMed Central

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD) and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity) optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments. PMID:28928987

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection.

PubMed

Phillips, Cristy

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD) and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity) optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments.

Cardiac Nerve Growth Factor Overexpression Induces Bone Marrow-derived Progenitor Cells Mobilization and Homing to the Infarcted Heart.

PubMed

Meloni, Marco; Cesselli, Daniela; Caporali, Andrea; Mangialardi, Giuseppe; Avolio, Elisa; Reni, Carlotta; Fortunato, Orazio; Martini, Stefania; Madeddu, Paolo; Valgimigli, Marco; Nikolaev, Evgeni; Kaczmarek, Leszek; Angelini, Gianni D; Beltrami, Antonio P; Emanueli, Costanza

2015-12-01

Reparative response by bone marrow (BM)-derived progenitor cells (PCs) to ischemia is a multistep process that comprises the detachment from the BM endosteal niche through activation of osteoclasts and proteolytic enzymes (such as matrix metalloproteinases (MMPs)), mobilization to the circulation, and homing to the injured tissue. We previously showed that intramyocardial nerve growth factor gene transfer (NGF-GT) promotes cardiac repair following myocardial infarction (MI) in mice. Here, we investigate the impact of cardiac NGF-GT on postinfarction BM-derived PCs mobilization and homing at different time points after adenovirus-mediated NGF-GT in mice. Immunohistochemistry and flow cytometry newly illustrate the temporal profile of osteoclast and activation of MMP9, PCs expansion in the BM, and liberation/homing to the injured myocardium. NGF-GT amplified these responses and increased the BM levels of active osteoclasts and MMP9, which were not observed in MMP9-deficient mice. Taken together, our results suggest a novel role for NGF in BM-derived PCs mobilization/homing following MI.

Computational Studies on Optoelectronic and Nonlinear Properties of Octaphyrin Derivatives

PubMed Central

Islam, Nasarul; Lone, Irfan H.

2017-01-01

The electronic and nonlinear optical (NLO) properties of octaphyrin derivatives were studied by employing the DFT/TDFT at CAM-B3LYP/6-311++G (2d, 2p) level of the theory. Thiophene, phenyl, methyl and cyano moieties were substituted on the molecular framework of octaphyrin core, in order to observe the change in optoelectronic and nonlinear response of these systems. The frontier molecular orbital studies and values of electron affinity reveals that the studied compounds are stable against the oxygen and moisture present in air. The calculated ionization energies, adiabatic electron affinity and reorganization energy values indicate that octaphyrin derivatives can be employed as effective n-type material for Organic Light Emitting Diodes (OLEDs). This character shows an enhancement with the introduction of an electron withdrawing group in the octaphyrin framework. The polarizability and hyperpolarizability values of octaphyrin derivatives demonstrate that they are good candidates for NLO devices. The nonlinear response of these systems shows enhancement on the introduction of electron donating groups on octaphyrin moiety. However, these claims needs further experimental verification. PMID:28321394

Accumulation and suppressive function of regulatory T cells in malignant ascites: Reducing their suppressive function using arsenic trioxide in vitro.

PubMed

Hu, Zilong; Hu, Shidong; Wu, Youjun; Li, Songyan; He, Changzheng; Xing, Xiaowei; Wang, Yufeng; Du, Xiaohui

2018-04-01

Although adoptive cell therapy (ACT) has demonstrated effective and remarkable clinical responses in several studies, this approach does not lead to objective clinical responses in all cases. The function of ACT is often compromised by various tumor escape mechanisms, including the accumulation of immunoregulatory cells. As a result of peritoneal metastasis in the terminal stage, malignant ascites fluid lacks effectiveness and is a poor prognostic factor for gastric cancer. The present study assessed T-cell subsets in lymphocytes derived from malignant ascites, and investigated the effects of arsenic trioxide (As 2 O 3 ) on regulatory T cells (Tregs) and ascites-derived tumor-infiltrating lymphocytes (TILs) in vitro . In this study, lymphocytes were separated from malignant ascites and T-cell subsets were detected via flow cytometry. Forkhead box P3 (FoxP3) expression was assessed by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. In addition, cytokines, including interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and interferon-γ (IFN-γ), were measured by enzyme-linked immunosorbent assay (ELISA). Abundant Tregs were observed in ascites lymphocytes, which and exhibited a significantly increased frequency compared with that in the peripheral blood of patients. Furthermore, As 2 O 3 treatment significantly reduced Treg numbers and Foxp3 mRNA levels in vitro (P<0.05). IFN-γ levels in the supernatant of ascites-derived TILs were increased by As 2 O 3 , whereas IL-10 and TGF-β levels were significantly reduced (P<0.05). As 2 O 3 may induce selective depletion and inhibit immunosuppressive function of Tregs, and may enhance the cytotoxic activity of ascites-derived TILs.

In vivo response of Mesocestoides vogae to human insulin.

PubMed

Canclini, L; Esteves, A

2009-02-01

Successful host invasion by parasitic helminths involves detection and appropriate response to a range of host-derived signals. Insulin signal response pathways are ancient and highly-conserved throughout the metazoans. However, very little is known about helminth insulin signalling and the potential role it may play in host-parasite interactions. The response of Mesocestoides vogae (Cestoda: Cyclophyllidea) larvae to human insulin was investigated, focusing on tyrosine-phosphorylation status, glucose content, survival and asexual reproduction rate. Parasite larvae were challenged with different levels of insulin for variable periods. The parameters tested were influenced by human insulin, and suggested a host-parasite molecular dialogue.

Simultaneous detection and functional response of testosterone and estradiol receptors in osteoblast plasma membranes.

PubMed

Armen, T A; Gay, C V

2000-09-14

Osteoblasts derived from the periosteal surfaces of two-three-week-old male broiler chicken tibias were cultured for eight days. The cells were then loaded with fura-2/AM ester to detect surges in intracellular Ca(2+). Treatment with 10(-7) M testosterone (T) or 17beta-estradiol (E) elicited a rapid (within seconds) response that was substantially reduced by introducing the calcium chelating agent EGTA or the calcium-channel blocker verapamil. The hormones were equally effective when covalently linked to bovine serum albumin (BSA), a procedure that ensures the hormone does not enter the cells. The rapid response to surface-bound steroids indicates that the responses were invoked through plasma-membrane receptors. The source of Ca(2+) was shown to be through entry from external sources, as well as from intracellular stores. Flow cytometry of fluorescein-tagged T-BSA and E-BSA revealed that osteoblasts derived from male chickens had similar and substantial levels of both receptors. Copyright 2000 Wiley-Liss, Inc.

Effects of maternally-derived antibodies on serologic responses to vaccination in kittens.

PubMed

Digangi, Brian A; Levy, Julie K; Griffin, Brenda; Reese, Michael J; Dingman, Patricia A; Tucker, Sylvia J; Dubovi, Edward J

2012-02-01

The optimal vaccination protocol to induce immunity in kittens with maternal antibodies is unknown. The objective of this study was to determine the effects of maternally-derived antibody (MDA) on serologic responses to vaccination in kittens. Vaccination with a modified live virus (MLV) product was more effective than an inactivated (IA) product at inducing protective antibody titers (PAT) against feline panleukopenia virus (FPV). IA vaccination against feline herpesvirus-1 (FHV) and feline calicivirus (FCV) was more effective in the presence of low MDA than high MDA. Among kittens with low MDA, MLV vaccination against FCV was more effective than IA vaccination. A total of 15%, 44% and 4% of kittens had insufficient titers against FPV, FHV and FCV, respectively, at 17 weeks of age. Serologic response to vaccination of kittens varies based on vaccination type and MDA level. In most situations, MLV vaccination should be utilized and protocols continued beyond 14 weeks of age to optimize response by all kittens.

The Chinese-Western Intercultural Couple Standards Scale.

PubMed

Hiew, Danika N; Halford, W Kim; van de Vijver, Fons J R; Liu, Shuang

2015-09-01

We developed the Chinese-Western Intercultural Couple Standards Scale (CWICSS) to assess relationship standards that may differ between Chinese and Western partners and may challenge intercultural couples. The scale assesses 4 Western-derived relationship standards (demonstrations of love, demonstrations of caring, intimacy expression, and intimacy responsiveness) and 4 Chinese-derived relationship standards (relations with the extended family, relational harmony, face, and gender roles). We administered the CWICSS to 983 Chinese and Western participants living in Australia to assess the psychometric properties of the scores as measures of respondents' relationship standards. The CWICSS has a 2-level factor structure with the items reflecting the 8 predicted standards. The 4 Western derived standards loaded onto a higher order factor of couple bond, and the 4 Chinese derived standards loaded onto a higher order factor of family responsibility. The scale scores were structurally equivalent across cultures, genders, and 2 independent samples, and good convergent and discriminant validity was found for the interpretation of scale scores as respondents' endorsement of the predicted standards. Scores on the 8 scales and 2 superordinate scales showed high internal consistency and test-retest coefficients. Chinese endorsed all 4 family responsibility standards more strongly than did Westerners, but Chinese and Western participants were similar in endorsement of couple bond standards. Across both cultures, couple bond standards were endorsed more highly than were family responsibility standards. The CWICSS assesses potential areas of conflict in Chinese-Western relationships. (c) 2015 APA, all rights reserved.

Chlorophyll derivatives enhance invertebrate red-light and ultraviolet phototaxis.

PubMed

Degl'Innocenti, Andrea; Rossi, Leonardo; Salvetti, Alessandra; Marino, Attilio; Meloni, Gabriella; Mazzolai, Barbara; Ciofani, Gianni

2017-06-13

Chlorophyll derivatives are known to enhance vision in vertebrates. They are thought to bind visual pigments (i.e., opsins apoproteins bound to retinal chromophores) directly within the retina. Consistent with previous findings in vertebrates, here we show that chlorin e 6 - a chlorophyll derivative - enhances photophobicity in a flatworm (Dugesia japonica), specifically when exposed to UV radiation (λ = 405 nm) or red light (λ = 660 nm). This is the first report of chlorophyll derivatives acting as modulators of invertebrate phototaxis, and in general the first account demonstrating that they can artificially alter animal response to light at a behavioral level. Our findings show that the interaction between chlorophyll derivatives and opsins virtually concerns the vast majority of bilaterian animals, and also occurs in visual systems based on rhabdomeric (rather than ciliary) opsins.

Professionalism Among Criminal Justice Educators.

ERIC Educational Resources Information Center

Regoli, Robert M.; Miracle, Andrew W., Jr.

Professionalism and its relationship to scholarly productivity was studied. Specific areas of analysis were the degree of professionalism of criminal justice educators, rankings of a series of selected publications, and the relationship between professionalism level and journal productivity. Data were derived from responses by 1,028 of 1,274…

RESPIRATORY TOXICOLOGCAL EFFECTS OF WORLD TRADE CENTER FINE PARTICULATE MATTER IN MICE

EPA Science Inventory

ABSTRACT BODY:
The destruction of the World Trade Center (WTC) caused the release of high levels of airborne pollutants which were reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate mat...

Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

PubMed

Cui, Guo-Hong; Wu, Jing; Mou, Fang-Fang; Xie, Wei-Hua; Wang, Fu-Bo; Wang, Qiang-Li; Fang, Jie; Xu, Yan-Wu; Dong, You-Rong; Liu, Jian-Ren; Guo, Hai-Dong

2018-02-01

Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1β); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1β, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Particulate matter triggers depressive-like response associated with modulation of inflammatory cytokine homeostasis and brain-derived neurotrophic factor signaling pathway in mice.

PubMed

Liu, Xuemei; Qian, Xin; Xing, Jing; Wang, Jinhua; Sun, Yixuan; Wang, Qin'geng; Li, Huiming

2018-04-23

Particulate matter (PM) exposure may contribute to depressive-like response in mice. However, few studies have evaluated the adaptive impacts of long-term PM exposure on depressive-like response associated with systemic inflammation and brain-derived neurotrophic factor (BDNF) signaling pathway. We studied the association among depressive-like behaviors, mRNA levels of pro- and anti-inflammatory cytokines, and the expression of BDNF signaling pathway in mice by long-term PM exposure. C57BL/6 male mice were exposed to ambient air alongside control mice breathing air filtered through a high-efficiency air PM (HEPA) filter. Depressive-like behaviors were assessed together with pro-inflammatory, anti-inflammatory cytokine mRNA levels and the modulation of BDNF pathway in hippocampus and olfactory-bulb of mice exposed to PM for 4, 8, and 12 weeks. Exposure to HEPA filtered air for 4 weeks may exert antidepressant like effects in mice. Pro-inflammatory cytokines were up-regulated while the expression of BDNF, its high-affinity receptor tropomyosin-related kinase B (TrkB), and the transcription factor cAMP-response-element binding protein (CREB) were down-regulated in ambient air mice. However, after 8 weeks, there was no significant difference in the rate of depressive-like behaviors between the two groups. After 12 weeks, mice exposed to ambient air again had a higher rate of depressive-like behaviors, significant up-regulation of pro-inflammatory cytokines, down-regulation of interleukin-10 (IL-10), BDNF, TrkB, and CREB than HEPA mice. Ultrafine PM in brain tissues of mice exposed to ambient air was observed. Our results suggest continuous high-level PM exposure alters the depressive-like response in mice and induces a damage-repair-imbalance reaction.

Oral supplementation with areca-derived polyphenols attenuates food allergic responses in ovalbumin-sensitized mice

PubMed Central

2013-01-01

Background Arecae semen, the dried slice of areca nuts, is a traditional Chinese medicine used to treat intestinal parasitosis, rectal tenesmus and diarrhea. Areca nuts contain a rich amount of polyphenols that have been shown to modulate the functionality of mast cells and T cells. The objective of this study is to investigate the effect of polyphenol-enriched areca nut extracts (PANE) against food allergy, a T cell-mediated immune disorder. Methods BALB/c mice were left untreated or administered with PANE (0.05% and 0.1%) via drinking water throughout the entire experiment. The mice were sensitized with ovalbumin (OVA) twice by intraperitoneal injection, and then repeatedly challenged with OVA by gavage to induce food allergic responses. Results PANE administration attenuated OVA-induced allergic responses, including the occurrence of diarrhea and the infiltration and degranulation of mast cells in the duodenum. The serum level of OVA-specific IgE and the expression of interleukin-4 in the duodenum were suppressed by PANE treatment. In addition, PANE administration induced Gr-1+, IL-10+ and Gr-1+IL-10+ cells in the duodenum. Conclusion These results demonstrate that oral intake of areca-derived polyphenols attenuates food allergic responses accompanied with a decreased Th2 immunity and an enhanced induction of functional myeloid-derived suppressor cells. PMID:23816049

Endothelium-dependent Hyperpolarization-mediated Vasodilatation Compensates Nitric Oxide-mediated Endothelial Dysfunction during Ischemia in Diabetes-induced Canine Coronary Collateral Microcirculation in Vivo.

PubMed

Yada, Toyotaka; Shimokawa, Hiroaki; Tachibana, Hiroyuki

2018-04-17

It has been previously demonstrated that endothelial caveolin-1 plays crucial roles to produce an endothelium-derived hyperpolarizing factor in mouse mesenteric arteries. We examined whether this mechanism is involved in the endothelium-derived hyperpolarizing-mediated responses to compensate reduced NO-mediated responses in diabetes mellitus during coronary occlusion in dogs in vivo. Canine subepicardial collateral coronary small arteries (≥100 μm) and arterioles (<100 μm) were observed by an intravital microscope. Experiments were performed during occlusion of the left anterior descending coronary artery (90 min) under the following conditions (n=6 each); (i) control, (ii) diabetes mellitus, and (iii) diabetes mellitus+L-NMMA+K C a channel blockade. Vascular and myocardial levels of caveolin-1, eNOS and caspase-3 were measured by ELISA. Caveolin-1 levels in the ischemic area were greater in coronary microvessels than in conduit arteries in the control group. NO-mediated coronary vasodilatations of small arteries to bradykinin did not increase in diabetes mellitus associated with decreased eNOS phosphorylation at Ser1177 compared with baseline of controls, and were restored by compensation of endothelium-derived hyperpolarizing, and were suppressed by K C a channel blockade. NO-mediated vasodilatations of small coronary arteries during coronary occlusion are impaired in diabetes mellitus and are compensated by endothelium-derived hyperpolarizing of arterioles in dogs in vivo. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Lecithin derived from ω-3 PUFA fortified eggs decreases blood pressure in spontaneously hypertensive rats.

PubMed

Nowacki, Dorian; Martynowicz, Helena; Skoczyńska, Anna; Wojakowska, Anna; Turczyn, Barbara; Bobak, Łukasz; Trziszka, Tadeusz; Szuba, Andrzej

2017-09-28

Hypertension is the most common risk factor for stroke, coronary heart disease and heart failure, which are the leading causes of death worldwide. Dietary patterns and supplements intakes are becoming important factors in the hypertension. The aim of this study was to estimate the effects of new generation egg yolk phospholipids rich in lecithin (SL) esterified with omega-3 and omega-6 fatty acids on blood pressure in hypertensive rats (SHR). Here we have reported that lecithin (SL) derived from egg yolk lowers blood pressure in pathology of hypertension. The SHR rats treated with SL had significantly lower blood pressure than control group (157/104 vs. 178/121 mmHg; P < 0.05) and down-regulated mesenteric artery over-response to norepinephrine and potassium chloride, giving similar arterial response as for normotensive Wistar Kyoto rats (WKY). Hypertensive rats treated by SL demonstrated significantly lower serum level of inflammatory factors. This work also indicates that SL treatment lowers heart rate and reduces the serum level of oxidative stress marker - nitrotyrosine - by 30-34% in both hypertensive and normotensive animals. Phospholipids with lecithin derived from PUFA fortified eggs may be a valuable dietary supplement in prophylaxis of hypertension and in patients with hypertension, however, this requires further studies on humans.

Dynamic fuzzy modeling of storm water infiltration in urban fractured aquifers

USGS Publications Warehouse

Hong, Y.-S.; Rosen, Michael R.; Reeves, R.R.

2002-01-01

In an urban fractured-rock aquifer in the Mt. Eden area of Auckland, New Zealand, disposal of storm water is via "soakholes" drilled directly into the top of the fractured basalt rock. The dynamic response of the groundwater level due to the storm water infiltration shows characteristics of a strongly time-varying system. A dynamic fuzzy modeling approach, which is based on multiple local models that are weighted using fuzzy membership functions, has been developed to identify and predict groundwater level fluctuations caused by storm water infiltration. The dynamic fuzzy model is initialized by the fuzzy clustering algorithm and optimized by the gradient-descent algorithm in order to effectively derive the multiple local models-each of which is associated with a locally valid model that represents the groundwater level state as a response to different intensities of rainfall events. The results have shown that even if the number of fuzzy local models derived is small, the fuzzy modeling approach developed provides good prediction results despite the highly time-varying nature of this urban fractured-rock aquifer system. Further, it allows interpretable representations of the dynamic behavior of the groundwater system due to storm water infiltration.

Unrepaired DNA damage in macrophages causes elevation of particulate matter- induced airway inflammatory response.

PubMed

Luo, Man; Bao, Zhengqiang; Xu, Feng; Wang, Xiaohui; Li, Fei; Li, Wen; Chen, Zhihua; Ying, Songmin; Shen, Huahao

2018-04-14

The inflammatory cascade can be initiated with the recognition of damaged DNA. Macrophages play an essential role in particulate matter (PM)-induced airway inflammation. In this study, we aim to explore the PM induced DNA damage response of macrophages and its function in airway inflammation. The DNA damage response and inflammatory response were assessed using bone marrow-derived macrophages following PM treatment and mouse model instilled intratracheally with PM. We found that PM induced significant DNA damage both in vitro and in vivo and simultaneously triggered a rapid DNA damage response, represented by nuclear RPA, 53BP1 and γH2AX foci formation. Genetic ablation or chemical inhibition of the DNA damage response sensor amplified the production of cytokines including Cxcl1, Cxcl2 and Ifn-γ after PM stimulation in bone marrow-derived macrophages. Similar to that seen in vitro , mice with myeloid-specific deletion of RAD50 showed higher levels of airway inflammation in response to the PM challenge, suggesting a protective role of DNA damage sensor during inflammation. These data demonstrate that PM exposure induces DNA damage and activation of DNA damage response sensor MRN complex in macrophages. Disruption of MRN complex lead to persistent, unrepaired DNA damage that causes elevated inflammatory response.

Shoot-derived abscisic acid promotes root growth.

PubMed

McAdam, Scott A M; Brodribb, Timothy J; Ross, John J

2016-03-01

The phytohormone abscisic acid (ABA) plays a major role in regulating root growth. Most work to date has investigated the influence of root-sourced ABA on root growth during water stress. Here, we tested whether foliage-derived ABA could be transported to the roots, and whether this foliage-derived ABA had an influence on root growth under well-watered conditions. Using both application studies of deuterium-labelled ABA and reciprocal grafting between wild-type and ABA-biosynthetic mutant plants, we show that both ABA levels in the roots and root growth in representative angiosperms are controlled by ABA synthesized in the leaves rather than sourced from the roots. Foliage-derived ABA was found to promote root growth relative to shoot growth but to inhibit the development of lateral roots. Increased root auxin (IAA) levels in plants with ABA-deficient scions suggest that foliage-derived ABA inhibits root growth through the root growth-inhibitor IAA. These results highlight the physiological and morphological importance, beyond the control of stomata, of foliage-derived ABA. The use of foliar ABA as a signal for root growth has important implications for regulating root to shoot growth under normal conditions and suggests that leaf rather than root hydration is the main signal for regulating plant responses to moisture. © 2015 John Wiley & Sons Ltd.

Defining the baseline for inhibition concentration calculations for hormetic hazards.

PubMed

Bailer, A J; Oris, J T

2000-01-01

The use of endpoint estimates based on modeling inhibition of test organism response relative to a baseline response is an important tool in the testing and evaluation of aquatic hazards. In the presence of a hormetic hazard, the definition of the baseline response is not clear because non-zero levels of the hazard stimulate an enhanced response prior to inhibition. In the present study, the methodology and implications of how one defines a baseline response for inhibition concentration estimation in aquatic toxicity tests was evaluated. Three possible baselines were considered: the control response level; the pooling of responses, including controls and all concentration conditions with responses enhanced relative to controls; and, finally, the maximal response. The statistical methods associated with estimating inhibition relative to the first two baseline definitions were described and a method for estimating inhibition relative to the third baseline definition was derived. These methods were illustrated with data from a standard aquatic zooplankton reproductive toxicity test in which the number of young produced in three broods of a cladoceran exposed to effluent was modeled as a function of effluent concentration. Copyright 2000 John Wiley & Sons, Ltd.

Biology Based Lung Cancer Model for Chronic Low Radon Exposures

NASA Astrophysics Data System (ADS)

TruÅ£ǎ-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

2008-08-01

Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival. To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.

An Aggregate IRT Procedure for Exploratory Factor Analysis

ERIC Educational Resources Information Center

Camilli, Gregory; Fox, Jean-Paul

2015-01-01

An aggregation strategy is proposed to potentially address practical limitation related to computing resources for two-level multidimensional item response theory (MIRT) models with large data sets. The aggregate model is derived by integration of the normal ogive model, and an adaptation of the stochastic approximation expectation maximization…

Diversity in Literary Response: Revisiting Gender Expectations

ERIC Educational Resources Information Center

Brendler, Beth M.

2014-01-01

Drawing on and reexamining theories on gender and literacy, derived from research performed between 1974 and 2002, this qualitative study explored the gender assumptions and expectations of Language Arts teachers in a graduate level adolescent literature course at a university in the Midwestern United States. The theoretical framework was…

Deriving a dosage-response relationship for community response to high-energy impulsive noise

NASA Technical Reports Server (NTRS)

Fidell, Sanford; Pearsons, Karl S.

1994-01-01

The inability to systematically predict community response to exposure to sonic booms (and other high energy impulsive sounds) is a major impediment to credible analyses of the environmental effects of supersonic flight operations. Efforts to assess community response to high energy impulsive sounds are limited in at least two important ways. First, a paucity of appropriate empirical data makes it difficult to infer a dosage-response relationship by means similar to those used in the case of general transportation noise. Second, it is unclear how well the 'equal energy hypothesis' (the notion that duration, number, and level of individual events are directly interchangeable determinants of annoyance) applies to some forms of impulsive noise exposure. Some of the issues currently under consideration by a CHABA working group addressing these problems are discussed. These include means for applying information gained in controlled exposure studies about different rates of growth of annoyance with impulsive and non-impulsive sound exposure levels, and strategies for developing a dosage-response relationship in a data-poor area.

The effects of urbanization on the biological, physical, and chemical characteristics of coastal New England streams

USGS Publications Warehouse

Coles, James F.; Cuffney, Thomas F.; McMahon, Gerard; Beaulieu, Karen M.

2004-01-01

During August 2000, responses of biological communities (invertebrates, fish, and algae), physical habitat, and water chemistry to urban intensity were compared among 30 streams within 80 miles of Boston, Massachusetts. Sites chosen for sampling represented a gradient of the intensity of urban development (urban intensity) among drainage basins that had minimal natural variability. In this study, spatial differences were used as surrogates for temporal changes to represent the effects of urbanization over time. The degree of urban intensity for each drainage basin was characterized with a standardized urban index (0-100, lowest to highest) derived from land cover, infrastructure, and socioeconomic variables. Multivariate and multimetric analyses were used to compare urban index values with biological, physical, and chemical data to determine how the data indicated responses to urbanization. Multivariate ordinations were derived for the invertebrate-, fish-, and algae-community data by use of correspondence analysis, and ordinations were derived for the chemical and physical data by use of principal-component analysis. Site scores from each of the ordinations were plotted in relation to the urban index to test for a response. In all cases, the primary axis scores showed the strongest response to the urban index, indicating that urbanization was a primary factor affecting the data ordination. For the multimetric analyses, each of the biological data sets was used to calculate a series of community metrics. For the sets of chemical and physical data, the individual variables and various combinations of individual variables were used as measured and derived metrics, respectively. Metrics that were generally most responsive to the urban index for each data set included: EPT (Ephemeroptera, Plecoptera, Trichoptera) taxa for invertebrates; cyprinid taxa for fish; diatom taxa for algae; bicarbonate, conductivity, and nitrogen for chemistry; and water depth and temperature for physical habitat. The slopes of the responses generally were higher between the urban index values of 0 to 35, indicating that the greatest change in aquatic health may occur between low and moderate levels of urban intensity. Additionally, many of the responses showed that at urban index values greater than 35, there was a threshold effect where the response variable no longer changed with respect to urban intensity. Recognizing and understanding this type of response is important in management and monitoring programs that rely on decisive interpretations of variable responses. Any biological, physical, or chemical variable that is used to characterize stream health over a gradient of disturbance would not be a reliable indicator when a level of disturbance is reached where the variable does not respond in a predictable manner.

Pancreatic Endoderm-Derived From Diabetic Patient-Specific Induced Pluripotent Stem Cell Generates Glucose-Responsive Insulin-Secreting Cells.

PubMed

Rajaei, Bahareh; Shamsara, Mehdi; Amirabad, Leila Mohammadi; Massumi, Mohammad; Sanati, Mohammad Hossein

2017-10-01

Human-induced pluripotent stem cells (hiPSCs) can potentially serve as an invaluable source for cell replacement therapy and allow the creation of patient- and disease-specific stem cells without the controversial use of embryos and avoids any immunological incompatibility. The generation of insulin-producing pancreatic β-cells from pluripotent stem cells in vitro provides an unprecedented cell source for personal drug discovery and cell transplantation therapy in diabetes. A new five-step protocol was introduced in this study, effectively induced hiPSCs to differentiate into glucose-responsive insulin-producing cells. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, primitive gut-tube endoderm, posterior foregut, pancreatic endoderm, and endocrine precursor. Each stage of differentiation were characterized by stage-specific markers. The produced cells exhibited many properties of functional β-cells, including expression of critical β-cells transcription factors, the potency to secrete C-peptide in response to high levels of glucose and the presence of mature endocrine secretory granules. This high efficient differentiation protocol, established in this study, yielded 79.18% insulin-secreting cells which were responsive to glucose five times higher than the basal level. These hiPSCs-derived glucose-responsive insulin-secreting cells might provide a promising approach for the treatment of type I diabetes mellitus. J. Cell. Physiol. 232: 2616-2625, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Response of melanoma tumor phospholipid metabolism to chloroethyle nitrosourea: a high resolution proton NMR spectroscopy study.

PubMed

Morvan, Daniel; Demidem, Aïcha; Madelmont, Jean-Claude

2003-07-01

Phospholipid metabolism is tightly involved in tumor growth regulation and tumor cell survival. The response of phospholipid metabolism to chloroethyle nitrosourea treatment is investigated in a murine B16 melanoma model. Measurements of phospholipid derivatives are performed on intact tumor tissue samples using one- and two-dimensional proton NMR spectroscopy. During the tumor growth inhibition phase under treatment, tumors overexpress phosphocholine, phosphoethanolamine, glycerophosphocholine and glycerophosphoethanolamine, whereas phosphatidylcholine and phosphatidylethanolamine levels are maintained to control levels. During re-growth, which remained quantitatively much below control growth, chloroethyle nitrosourea-treated melanoma tumors overexpress phosphocholine and phosphoethanolamine only. In treated melanoma, phosphatidylcholine levels show an inverse relationship with tumor growth rates. In conclusion, chloroethyle nitrosourea-treated melanoma tumors maintain their phosphatidylcholine levels and exhibit transformed phospholipid metabolism phenotype, by mechanisms that could participate in tumor cell survival.

Peripheral Blood Mononuclear Cells Derived from Grand Multigravidae Display a Distinct Cytokine Profile in Response to P. falciparum Infected Erythrocytes

PubMed Central

Ludlow, Louise E.; Hasang, Wina; Umbers, Alexandra J.; Forbes, Emily K.; Ome, Maria; Unger, Holger W.; Mueller, Ivo; Siba, Peter M.; Jaworowski, Anthony; Rogerson, Stephen J.

2014-01-01

Immunopathology of placental malaria is most significant in women in their first pregnancy especially in endemic areas, due to a lack of protective immunity to Plasmodium falciparum, which is acquired in successive pregnancies. In some studies (but not all), grand multigravidae (defined as 5 or more pregnancies, G5–7) are more susceptible to poor birth outcomes associated with malaria compared to earlier gravidities. By comparing peripheral cellular responses in primigravidae (G1), women in their second to fourth pregnancy (G2–4) and grand multigravidae we sought to identify key components of the dysregulated immune response. PBMC were exposed to CS2-infected erythrocytes (IE) opsonised with autologous plasma or unopsonised IE, and cytokine and chemokine secretion was measured. Higher levels of opsonising antibody were present in plasma derived from multigravid compared to primigravid women. Significant differences in the levels of cytokines and chemokines secreted in response to IE were observed. Less IL-10, IL-1β, IL-6 and TNF but more CXCL8, CCL8, IFNγ and CXCL10 were detected in G5–7 compared to G2–4 women. Our study provides fresh insight into the modulation of peripheral blood cell function and effects on the balance between host protection and immunopathology during placental malaria infection. PMID:24465935

Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes

PubMed Central

Tang, Chun-Lian; Liu, Zhi-Ming; Gao, Yan Ru; Xiong, Fei

2018-01-01

Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed—Schistosoma infection and Schistosoma-derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma-derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D. PMID:29387059

Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes.

PubMed

Tang, Chun-Lian; Liu, Zhi-Ming; Gao, Yan Ru; Xiong, Fei

2017-01-01

Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed- Schistosoma infection and Schistosoma -derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma -derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D.

Generation of a transplantable erythropoietin-producer derived from human mesenchymal stem cells.

PubMed

Yokoo, Takashi; Fukui, Akira; Matsumoto, Kei; Ohashi, Toya; Sado, Yoshikazu; Suzuki, Hideaki; Kawamura, Tetsuya; Okabe, Masataka; Hosoya, Tatsuo; Kobayashi, Eiji

2008-06-15

Differentiation of autologous stem cells into functional transplantable tissue for organ regeneration is a promising regenerative therapeutic approach for cancer, diabetes, and many human diseases. Yet to be established, however, is differentiation into tissue capable of producing erythropoietin (EPO), which has a critical function in anemia. We report a novel EPO-producing organ-like structure (organoid) derived from human mesenchymal stem cells. Using our previously established relay culture system, a human mesenchymal stem cell-derived, human EPO-competent organoid was established in rat omentum. The organoid-derived levels of human EPO increased in response to anemia induced by rapid blood withdrawal. In addition, the presence of an organoid in rats suppressed for native (rat) EPO production enhanced recovery from anemia when compared with control animals lacking the organoid. Together these results confirmed the generation of a stem cell-derived organoid that is capable of producing EPO and sensitive to physiological regulation.

Intrapericardial denervation - Radial artery blood flow and heart rate responses to LBNP

NASA Technical Reports Server (NTRS)

Mckeever, Kenneth H.; Skidmore, Michael G.; Keil, Lanny C.; Sandler, Harold

1990-01-01

The effects of intrapericardial denervation on the radial artery blood flow velocity (RABFV) and heart rate (HR) responses to LBNP in rhesus monkeys were investigated by measuring the RABFV transcutaneously by a continuous-wave Doppler ultrasonic flowmeter in order to derive an index of forearm blood flow response to low (0 to -20 mm Hg) and high (0 to -60 mm Hg) ramp exposures during supine LBNP. Four of the eight subjects were subjected to efferent and afferent cardiac denervation. It was found that, during low levels of LBNP, monkeys with cardiac denervation exhibited no cardiopulmonary baroreceptor-mediated change in the RABFV or HR, unlike the intact animals, which showed steady decreases in RABFV during both high- and low-pressure protocols. It is suggested that forearm blood flow and HR responses to low-level LBNP, along with pharmacological challenge, are viable physiological tests for verifying the completeness of atrial and cardiopulmonary baroreceptor denervation.

Is Social Anhedonia related to Emotional Responsivity and Expressivity? A laboratory study in Women

PubMed Central

Leung, Winnie W.; Couture, Shannon M.; Blanchard, Jack J.; Lin, Stephanie; Llerena, Katiah

2010-01-01

Social anhedonia is an important feature of schizophrenia and it is a promising indicator of schizotypy. Although social anhedonia is defined as an affective construct (less pleasure derived from social encounters), little is known about the emotional responsivity and expressivity of individuals with high levels of social anhedonia. After screening a large sample of female undergraduate students (N = 1 085), a cohort of psychometrically identified individuals with high levels of social anhedonia (n = 34) and normally hedonic controls (n = 45) participated in laboratory assessments involving trait affectivity, self-reported dispositional emotional expressiveness, and the expression and experience of emotion in response to neutral, nonaffiliative (i.e., comedy) and affiliative film clips. Results revealed that individuals with high levels of social anhedonia are characterized by lower positive affect, both as a trait and in response to emotionally evocative stimuli, and are less facially expressive, both by their own self-report and in response to film clips. Attenuated positive affect was observed across film stimuli, indicating a general reduction in affective response rather than a specific decrease in responsivity for affiliative stimuli. Future work should continue to investigate whether there is a unique role for social stimuli in the emotional lives of individuals with high levels of social anhedonia or whether these individuals tend to experience anhedonia more broadly regardless of social context. PMID:20620020

Developmental changes in the hypothalamic mRNA expression levels of brain-derived neurotrophic factor and serum leptin levels: Their responses to fasting in male and female rats.

PubMed

Iwasa, Takeshi; Matsuzaki, Toshiya; Yano, Kiyohito; Munkhzaya, Munkhsaikhan; Tungalagsuvd, Altankhuu; Yiliyasi, Maira; Kuwahara, Akira; Irahara, Minoru

2016-11-01

The actions and responses of hypothalamic appetite regulatory factors change markedly during the neonatal to pre-pubertal period in order to maintain appropriate metabolic and nutritional conditions. In this study, we examined the developmental changes in the hypothalamic mRNA levels of brain-derived neurotrophic factor (BDNF), which is a potent anorectic factor and the changes in the sensitivity of the hypothalamic expression of this factor to fasting during the neonatal to pre-pubertal period. Under fed conditions, hypothalamic BDNF mRNA expression decreased during development in both male and female rats. Similarly, the serum levels of leptin, which is a positive regulator of hypothalamic BDNF expression, also tended to fall during the developmental period. The serum leptin level and the hypothalamic BDNF mRNA level were found to be positively correlated in both sexes under the fed conditions. Hypothalamic BDNF mRNA expression was decreased by 24h fasting (separating the rats from their mothers) in the early neonatal period (postnatal day 10) in both males and females, but no such changes were seen at postnatal day 20. Twenty-four hours' fasting (food deprivation) did not affect hypothalamic BDNF mRNA expression in the pre-pubertal period (postnatal day 30). On the other hand, the rats' serum leptin levels were decreased by 24h fasting (separating the rats from their mothers at postnatal day 10 and 20, and food deprivation at postnatal day 30) throughout the early neonatal to pre-pubertal period. The correlation between serum leptin and hypothalamic BDNF mRNA levels was not significant under the fasted conditions. It can be speculated that leptin partially regulates hypothalamic BDNF mRNA levels, but only in fed conditions. Such changes in hypothalamic BDNF expression might play a role in maintaining appropriate metabolic and nutritional conditions and promoting normal physical development. In addition, because maternal separation induces a negative energy balance and short- and long-term stress responses, it is also possible that reductions in hypothalamic BDNF mRNA levels in the early neonatal period (postnatal day 10) may be partially induced by stress responses of the maternal deprivation. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Soil organic matter decomposition follows plant productivity response to sea-level rise

NASA Astrophysics Data System (ADS)

Mueller, Peter; Jensen, Kai; Megonigal, James Patrick

2015-04-01

The accumulation of soil organic matter (SOM) is an important mechanism for many tidal wetlands to keep pace with sea-level rise. SOM accumulation is governed by the rates of production and decomposition of organic matter. While plant productivity responses to sea-level rise are well understood, far less is known about the response of SOM decomposition to accelerated sea-level rise. Here we quantified the effects of sea-level rise on SOM decomposition by exposing planted and unplanted tidal marsh monoliths to experimentally manipulated flood duration. The study was performed in a field-based mesocosm facility at the Smithsonian Global Change Research Wetland, a micro tidal brackish marsh in Maryland, US. SOM decomposition was quantified as CO2 efflux, with plant- and SOM-derived CO2 separated using a stable carbon isotope approach. Despite the dogma that decomposition rates are inversely related to flooding, SOM mineralization was not sensitive to varying flood duration over a 35 cm range in surface elevation in unplanted mesocoms. In the presence of plants, decomposition rates were strongly and positively related to aboveground biomass (p≤0.01, R2≥0.59). We conclude that rates of soil carbon loss through decomposition are driven by plant responses to sea level in this intensively studied tidal marsh. If our result applies more generally to tidal wetlands, it has important implications for modeling carbon sequestration and marsh accretion in response to accelerated sea-level rise.

The Rapamycin-Binding Domain of the Protein Kinase mTOR is a Destabilizing Domain*

PubMed Central

Edwards, Sarah R.; Wandless, Thomas J.

2013-01-01

Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding domain (FRB) of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization. We synthesized two rapamycin derivatives that possess large substituents at the C16 position within the FRB-binding interface, and these derivatives were screened against a library of FRB mutants using a three-hybrid assay in Saccharomyces cerevisiae. Several FRB mutants responded to one of the rapamycin derivatives, and twenty of these mutants were further characterized in mammalian cells. The mutants most responsive to the ligand were fused to yellow fluorescent protein, and fluorescence levels in the presence and absence of the ligand were measured to determine stability of the fusion proteins. Wild-type and mutant FRB domains were expressed at low levels in the absence of the rapamycin derivative, and expression levels rose up to ten-fold upon treatment with ligand. The synthetic rapamycin derivatives were further analyzed using quantitative mass spectrometry, and one of the compounds was found to contain contaminating rapamycin. Furthermore, uncontaminated analogs retain the ability to inhibit mTOR, albeit with diminished potency relative to rapamycin. The ligand-dependent stability displayed by wildtype FRB and FRB mutants as well as the inhibitory potential and purity of the rapamycin derivatives should be considered as potentially confounding experimental variables when using these systems. PMID:17350953

The rapamycin-binding domain of the protein kinase mammalian target of rapamycin is a destabilizing domain.

PubMed

Edwards, Sarah R; Wandless, Thomas J

2007-05-04

Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization. We synthesized two rapamycin derivatives that possess large substituents at the C-16 position within the FRB-binding interface, and these derivatives were screened against a library of FRB mutants using a three-hybrid assay in Saccharomyces cerevisiae. Several FRB mutants responded to one of the rapamycin derivatives, and twenty of these mutants were further characterized in mammalian cells. The mutants most responsive to the ligand were fused to yellow fluorescent protein, and fluorescence levels in the presence and absence of the ligand were measured to determine stability of the fusion proteins. Wild-type and mutant FRB domains were expressed at low levels in the absence of the rapamycin derivative, and expression levels rose up to 10-fold upon treatment with ligand. The synthetic rapamycin derivatives were further analyzed using quantitative mass spectrometry, and one of the compounds was found to contain contaminating rapamycin. Furthermore, uncontaminated analogs retained the ability to inhibit mTOR, although with diminished potency relative to rapamycin. The ligand-dependent stability displayed by wild-type FRB and FRB mutants as well as the inhibitory potential and purity of the rapamycin derivatives should be considered as potentially confounding experimental variables when using these systems.

Postthymic maturation influences the CD8 T cell response to antigen.

PubMed

Makaroff, Lydia E; Hendricks, Deborah W; Niec, Rachel E; Fink, Pamela J

2009-03-24

Complete T cell development requires postthymic maturation, and we investigated the influence of this ontological period on the CD8 T cell response to infection by comparing responses of mature CD8 T cells with those of recent thymic emigrants (RTEs). When activated with a noninflammatory stimulus or a bacterial or viral pathogen, CD8 RTEs generated a lower proportion of cytokine-producing effector cells and long-lived memory precursors compared with their mature counterparts. Although peripheral T cell maturation is complete within several weeks after thymic egress, RTE-derived memory cells continued to express inappropriate levels of memory cell markers and display an altered pattern of cytokine production, even 8 weeks after infection. When rechallenged, RTE-derived memory cells generated secondary effector cells that were phenotypically and functionally equivalent to those generated by their mature counterparts. The defects at the effector and memory stages were not associated with differences in the expression of T cell receptor-, costimulation-, or activation-associated cell surface markers yet were associated with lower Ly6C expression levels at the effector stage. This work demonstrates that the stage of postthymic maturation influences cell fate decisions and cytokine profiles of stimulated CD8 T cells, with repercussions that are apparent long after cells have progressed from the RTE compartment.

Investigating Graphical Representations of Slope and Derivative without a Physics Context

ERIC Educational Resources Information Center

Christensen, Warren M.; Thompson, John R.

2012-01-01

By analysis of student use of mathematics in responses to conceptual physics questions, as well as analogous math questions stripped of physical meaning, we have previously found evidence that students often enter upper-level physics courses lacking the assumed prerequisite mathematics knowledge and/or the ability to apply it productively in a…

No effect of escitalopram versus placebo on brain-derived neurotrophic factor in healthy individuals: a randomised trial.

PubMed

Knorr, Ulla; Koefoed, Pernille; Soendergaard, Mia H Greisen; Vinberg, Maj; Gether, Ulrik; Gluud, Christian; Wetterslev, Jørn; Winkel, Per; Kessing, Lars V

2016-04-01

Brain-derived neurotrophic factor (BDNF) seems to play an important role in the course of depression including the response to antidepressants in patients with depression. We aimed to study the effect of an antidepressant intervention on peripheral BDNF in healthy individuals with a family history of depression. We measured changes in BDNF messenger RNA (mRNA) expression and whole-blood BDNF levels in 80 healthy first-degree relatives of patients with depression randomly allocated to receive daily tablets of escitalopram 10 mg versus placebo for 4 weeks. We found no statistically significant difference between the escitalopram and the placebo group in the change in BDNF mRNA expression and whole-blood BDNF levels. Post hoc analyses showed a statistically significant negative correlation between plasma escitalopram concentration and change in whole-blood BDNF levels in the escitalopram-treated group. The results of this randomised trial suggest that escitalopram 10 mg has no effect on peripheral BDNF levels in healthy individuals.

Dissecting innate immune responses with the tools of systems biology.

PubMed

Smith, Kelly D; Bolouri, Hamid

2005-02-01

Systems biology strives to derive accurate predictive descriptions of complex systems such as innate immunity. The innate immune system is essential for host defense, yet the resulting inflammatory response must be tightly regulated. Current understanding indicates that this system is controlled by complex regulatory networks, which maintain homoeostasis while accurately distinguishing pathogenic infections from harmless exposures. Recent studies have used high throughput technologies and computational techniques that presage predictive models and will be the foundation of a systems level understanding of innate immunity.

The stringent response regulates adaptation to darkness in the cyanobacterium Synechococcus elongatus.

PubMed

Hood, Rachel D; Higgins, Sean A; Flamholz, Avi; Nichols, Robert J; Savage, David F

2016-08-16

The cyanobacterium Synechococcus elongatus relies upon photosynthesis to drive metabolism and growth. During darkness, Synechococcus stops growing, derives energy from its glycogen stores, and greatly decreases rates of macromolecular synthesis via unknown mechanisms. Here, we show that the stringent response, a stress response pathway whose genes are conserved across bacteria and plant plastids, contributes to this dark adaptation. Levels of the stringent response alarmone guanosine 3'-diphosphate 5'-diphosphate (ppGpp) rise after a shift from light to dark, indicating that darkness triggers the same response in cyanobacteria as starvation in heterotrophic bacteria. High levels of ppGpp are sufficient to stop growth and dramatically alter many aspects of cellular physiology, including levels of photosynthetic pigments and polyphosphate, DNA content, and the rate of translation. Cells unable to synthesize ppGpp display pronounced growth defects after exposure to darkness. The stringent response regulates expression of a number of genes in Synechococcus, including ribosomal hibernation promoting factor (hpf), which causes ribosomes to dimerize in the dark and may contribute to decreased translation. Although the metabolism of Synechococcus differentiates it from other model bacterial systems, the logic of the stringent response remains remarkably conserved, while at the same time having adapted to the unique stresses of the photosynthetic lifestyle.

The stringent response regulates adaptation to darkness in the cyanobacterium Synechococcus elongatus

PubMed Central

Hood, Rachel D.; Higgins, Sean A.; Flamholz, Avi; Nichols, Robert J.

2016-01-01

The cyanobacterium Synechococcus elongatus relies upon photosynthesis to drive metabolism and growth. During darkness, Synechococcus stops growing, derives energy from its glycogen stores, and greatly decreases rates of macromolecular synthesis via unknown mechanisms. Here, we show that the stringent response, a stress response pathway whose genes are conserved across bacteria and plant plastids, contributes to this dark adaptation. Levels of the stringent response alarmone guanosine 3′-diphosphate 5′-diphosphate (ppGpp) rise after a shift from light to dark, indicating that darkness triggers the same response in cyanobacteria as starvation in heterotrophic bacteria. High levels of ppGpp are sufficient to stop growth and dramatically alter many aspects of cellular physiology, including levels of photosynthetic pigments and polyphosphate, DNA content, and the rate of translation. Cells unable to synthesize ppGpp display pronounced growth defects after exposure to darkness. The stringent response regulates expression of a number of genes in Synechococcus, including ribosomal hibernation promoting factor (hpf), which causes ribosomes to dimerize in the dark and may contribute to decreased translation. Although the metabolism of Synechococcus differentiates it from other model bacterial systems, the logic of the stringent response remains remarkably conserved, while at the same time having adapted to the unique stresses of the photosynthetic lifestyle. PMID:27486247

Cellular Levels of Oxidative Stress Affect the Response of Cervical Cancer Cells to Chemotherapeutic Agents

PubMed Central

Williams, Vonetta M.; Kokoza, Anatolii; Bashkirova, Svetlana; Duerksen-Hughes, Penelope

2014-01-01

Treatment of advanced and relapsed cervical cancer is frequently ineffective, due in large part to chemoresistance. To examine the pathways responsible, we employed the cervical carcinoma-derived SiHa and CaSki cells as cellular models of resistance and sensitivity, respectively, to treatment with chemotherapeutic agents, doxorubicin, and cisplatin. We compared the proteomic profiles of SiHa and CaSki cells and identified pathways with the potential to contribute to the differential response. We then extended these findings by comparing the expression level of genes involved in reactive oxygen species (ROS) metabolism through the use of a RT-PCR array. The analyses demonstrated that the resistant SiHa cells expressed higher levels of antioxidant enzymes. Decreasing or increasing oxidative stress led to protection or sensitization, respectively, in both cell lines, supporting the idea that cellular levels of oxidative stress affect responsiveness to treatment. Interestingly, doxorubicin and cisplatin induced different profiles of ROS, and these differences appear to contribute to the sensitivity to treatment displayed by cervical cancer cells. Overall, our findings demonstrate that cervical cancer cells display variable profiles with respect to their redox-generating and -adaptive systems, and that these different profiles have the potential to contribute to their responses to treatments with chemotherapy. PMID:25478571

On the importance of excited state dynamic response electron correlation in polarizable embedding methods.

PubMed

Eriksen, Janus J; Sauer, Stephan P A; Mikkelsen, Kurt V; Jensen, Hans J Aa; Kongsted, Jacob

2012-09-30

We investigate the effect of including a dynamic reaction field at the lowest possible ab inito wave function level of theory, namely the Hartree-Fock (HF) self-consistent field level within the polarizable embedding (PE) formalism. We formulate HF based PE within the linear response theory picture leading to the PE-random-phase approximation (PE-RPA) and bridge the expressions to a second-order polarization propagator approximation (SOPPA) frame such that dynamic reaction field contributions are included at the RPA level in addition to the static response described at the SOPPA level but with HF induced dipole moments. We conduct calculations on para-nitro-aniline and para-nitro-phenolate using said model in addition to dynamic PE-RPA and PE-CAM-B3LYP. We compare the results to recently published PE-CCSD data and demonstrate how the cost effective SOPPA-based model successfully recovers a great portion of the inherent PE-RPA error when the observable is the solvatochromic shift. We furthermore demonstrate that whenever the change in density resulting from the ground state-excited state electronic transition in the solute is not associated with a significant change in the electric field, dynamic response contributions formulated at the HF level of theory manage to capture the majority of the system response originating from derivative densities. Copyright © 2012 Wiley Periodicals, Inc.

Modeling panel detection frequencies by queuing system theory: an application in gas chromatography olfactometry.

PubMed

Bult, Johannes H F; van Putten, Bram; Schifferstein, Hendrik N J; Roozen, Jacques P; Voragen, Alphons G J; Kroeze, Jan H A

2004-10-01

In continuous vigilance tasks, the number of coincident panel responses to stimuli provides an index of stimulus detectability. To determine whether this number is due to chance, panel noise levels have been approximated by the maximum coincidence level obtained in stimulus-free conditions. This study proposes an alternative method by which to assess noise levels, derived from queuing system theory (QST). Instead of critical coincidence levels, QST modeling estimates the duration of coinciding responses in the absence of stimuli. The proposed method has the advantage over previous approaches that it yields more reliable noise estimates and allows for statistical testing. The method was applied in an olfactory detection experiment using 16 panelists in stimulus-present and stimulus-free conditions. We propose that QST may be used as an alternative to signal detection theory for analyzing data from continuous vigilance tasks.

Elucidation of molecular kinetic schemes from macroscopic traces using system identification

PubMed Central

González-Maeso, Javier; Sealfon, Stuart C.; Galocha-Iragüen, Belén; Brezina, Vladimir

2017-01-01

Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE). SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology can be successfully applied to accurately derive molecular kinetic schemes from experimental macroscopic traces, and we anticipate that it may be useful in the study of a wide variety of biological systems. PMID:28192423

Anxiety response and restraint-induced stress differentially affect ethanol intake in female adolescent rats.

PubMed

Acevedo, María Belén; Fabio, Maria Carolina; Fernández, Macarena Soledad; Pautassi, Ricardo Marcos

2016-10-15

Anxiety disorders are more likely to occur in women than in men, usually emerge during adolescence and exhibit high comorbidity with alcohol use disorders (AUD). Adolescents with high levels of anxiety or heightened reactivity to stress may be at-risk for developing AUD. An approach to analyze if high levels of inborn anxiety predict greater ethanol drinking is to assess the latter variable in subjects classified as high- or low-anxiety responders. The present study assessed ethanol drinking in adolescent, female Wistar, rats classified as high-, low- or average-anxiety responders and exposed or not to restraint stress (RS, Exp. 1). Classification was made through a multivariate index derived from testing anxiety responses in an elevated plus maze and a light-dark box tests. RS was applied after animals had been initiated to ethanol drinking. Intake of sweetened ethanol was unaffected by level of anxiety response. Adolescents with high levels of inborn anxiety exhibited significantly higher intake of unsweetened ethanol than counterparts with standard levels of anxiety, yet this effect was inhibited by RS exposure. Experiment 2 assessed FOS immunoreactivity after RS. Stress induced a significant increase in FOS immunoreactivity at the paraventricular nucleus, yet this effect was unaffected by level of anxiety response. Female adolescents with high levels of basal anxiety may be at-risk for exhibiting increased predisposition for ethanol intake and preference. The study also indicates that stress may exert differential effects on adolescent ethanol intake as a function of the level of anxiety response. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Characterization of Microparticles after Hepatic Ischemia-Reperfusion Injury

PubMed Central

Freeman, Christopher M.; Quillin, Ralph C.; Wilson, Gregory C.; Nojima, Hiroyuki; Johnson, Bobby L.; Sutton, Jeffrey M.; Schuster, Rebecca M.; Blanchard, John; Edwards, Michael J.; Caldwell, Charles C.; Lentsch, Alex B.

2014-01-01

Background Hepatic ischemia-reperfusion (I/R) is a well-studied model of liver injury and has demonstrated a biphasic injury followed by recovery and regeneration. Microparticles (MPs) are a developing field of study and these small membrane bound vesicles have been shown to have effector function in other physiologic and pathologic states. This study was designed to quantify the levels of MPs from various cell origins–platelets, neutrophils, and endolethial cells–following hepatic ischemia-reperfusion injury. Methods A murine model was used with mice undergoing 90 minutes of partial hepatic ischemia followed by various times of reperfusion. Following reperfusion, plasma samples were taken and MPs of various cell origins were labeled and levels were measured using flow cytometry. Additionally, cell specific MPs were further assessed by Annexin V, which stains for the presence of phosphatidylserine, a cell surface marker linked to apoptosis. Statistical analysis was performed using one-way analysis of variance with subsequent Student-Newman-Keuls test with data presented as the mean and standard error of the mean. Results MPs from varying sources show an increase in circulating levels following hepatic I/R injury. However, the timing of the appearance of different MP subtypes differs for each cell type. Platelet and neutrophil-derived MP levels demonstrated an acute elevation following injury whereas endothelial-derived MP levels demonstrated a delayed elevation. Conclusion This is the first study to characterize circulating levels of cell-specific MPs after hepatic I/R injury and suggests that MPs derived from platelets and neutrophils serve as markers of inflammatory injury and may be active participants in this process. In contrast, MPs derived from endothelial cells increase after the injury response during the reparative phase and may be important in angiogenesis that occurs in the regenerating liver. PMID:24879335

Cannabidiol (CBD) Induces Functional Tregs in Response to Low-Level T Cell Activation

PubMed Central

Dhital, Saphala; Stokes, John V.; Park, Nogi; Seo, Keun-Seok; Kaplan, Barbara L.F.

2016-01-01

Many effects of the non-psychoactive cannabinoid, cannabidiol (CBD), have been described in immune responses induced by strong immunological stimuli. It has also been shown that CBD enhances IL-2 production in response to low-level T cell stimulation. Since IL-2, in combination with TGF-β1, are critical for Treg induction, we hypothesized that CBD would induce CD4+CD25+FOXP3+ Tregs in response to low-level stimulation. Low-level T cell stimulation conditions were established based on minimal CD25 expression in CD4+ cells using suboptimal PMA/Io (4 nM/0.05 μM, S/o), ultrasuboptimal PMA/Io (1 nM/0.0125 μM, Us/o) or soluble anti-CD3/28 (400-800 ng each, s3/28). CBD increased CD25+FOXP3+ cells from CD4+, CD4+CD25+, and CD4+CD25− T cells, as well as in CD4+ T cells derived from FOXP3-GFP mice. Most importantly, the Us/o + CBD-induced CD4+CD25+ Tregs robustly suppressed responder T cell proliferation, demonstrating that the mechanism by which CBD is immunosuppressive under low-level T cell stimulation involves induction of functional Tregs. PMID:27865421

Cannabidiol (CBD) induces functional Tregs in response to low-level T cell activation.

PubMed

Dhital, Saphala; Stokes, John V; Park, Nogi; Seo, Keun Seok; Kaplan, Barbara L F

2017-02-01

Many effects of the non-psychoactive cannabinoid, cannabidiol (CBD), have been described in immune responses induced by strong immunological stimuli. It has also been shown that CBD enhances IL-2 production in response to low-level T cell stimulation. Since IL-2, in combination with TGF-β1, are critical for Treg induction, we hypothesized that CBD would induce CD4 + CD25 + FOXP3 + Tregs in response to low-level stimulation. Low-level T cell stimulation conditions were established based on minimal CD25 expression in CD4 + cells using suboptimal PMA/Io (4nM/0.05μM, S/o), ultrasuboptimal PMA/Io (1nM/0.0125μM, Us/o) or soluble anti-CD3/28 (400-800ng each, s3/28). CBD increased CD25 + FOXP3 + cells from CD4 + , CD4 + CD25 + , and CD4 + CD25 - T cells, as well as in CD4 + T cells derived from FOXP3-GFP mice. Most importantly, the Us/o+CBD-induced CD4 + CD25 + Tregs robustly suppressed responder T cell proliferation, demonstrating that the mechanism by which CBD is immunosuppressive under low-level T cell stimulation involves induction of functional Tregs. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunopathologic effects of scorpion venom on hepato-renal tissues: Involvement of lipid derived inflammatory mediators.

PubMed

Lamraoui, Amal; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

2015-10-01

Scorpion venoms are known to cause different inflammatory disorders through complex mechanisms in various tissues. In the study here, the involvement of phospholipase A2 (PLA2) and cyclo-oxygenase (COX)-derived metabolites in hepatic and renal inflammation responses were examined. Mice were envenomed with Androctonus australis hector scorpion venom in the absence or presence of inhibitors that can interfere with lipid inflammatory mediator synthesis, i.e., dexamethasone (PLA2 inhibitor), indomethacin (non-selective COX-1/COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor). The inflammatory response was assessed by evaluating vascular permeability changes, inflammatory cell infiltration, oxidative/nitrosative stress marker levels, and by histologic and functional analyses of the liver and kidney. Results revealed that the venom alone induced an inflammatory response in this tissues marked by increased microvascular permeability and inflammatory cell infiltration, increases in levels of nitric oxide and lipid peroxidation, and decreases in antioxidant defense. Moreover, significant alterations in the histological architecture of these organs were associated with increased serum levels of some metabolic enzymes, as well as urea and uric acid. Pre-treatment of mice with dexamethasone led to significant decreases of the inflammatory disorders in the hepatic parenchyma; celecoxib pre-treatment seemed to be more effective against renal inflammation. Indomethacin pre-treatment only slightly reduced the inflammatory disorders in the tissues. These results suggest that the induced inflammation response in liver was mediated mainly by PLA2 activation, while the renal inflammatory process was mediated by prostaglandin formation by COX-2. These findings provide additional insight toward the understanding of activated pathways and related mechanisms involved in scorpion envenoming syndrome.

Immunological and cytotoxicological characterization of tuberculin purified protein derivative (PPD) conjugated to single-walled carbon nanotubes.

PubMed

Zeinali, Majid; Jammalan, Mostafa; Ardestani, Sussan K; Mosaveri, Nader

2009-09-22

Tuberculosis (TB) represents one of the leading killers among all infectious disease. Protection against TB depends on the activation of T-helper type I (Th1) immune response. Carbon nanotubes (CNTs) have attracted considerable attention because of their potential applications as new nanovehicle. In the current study, tuberculin purified protein derivative (PPD) was conjugated to carboxylated single-walled carbon nanotubes (SWCNTs). Cytotoxicity of the carboxylated SWCNT and SWCNT-PPD conjugate was analyzed with MTT assay and by reactive oxygen species (ROS) and nitric oxide (NO) generation. Male BALB/c mice were immunized with BCG, PPD, SWCNT-PPD conjugate and PPD in complete Freund's adjuvant (CFA). Induction of cellular immune response was analyzed by measuring the levels of Th1 cytokines (IFN-gamma and IL-12) and Th2 cytokines (IL-10 and IL-5). Immunization with non-conjugated PPD or PPD in Freund's adjuvant induced a Th2 cytokine response while immunization with BCG resulted to a mixed Th1/Th2 cytokine response. In contrast, PPD in conjugation with SWCNT generated preferentially a Th1-type cytokine response in the absence of potential cytotoxic effects.

Tobacco derived cancer vaccines for non-Hodgkin's lymphoma: perspectives and progress.

PubMed

McCormick, Alison A

2011-03-01

Everyone appreciates the irony of using tobacco plants to cure cancer. (1) Recently featured in a populist Wall Street Journal article, (2) the use of plants to produce medicinal products was presented as novel, even though we are decades into development of numerous products for specific medical applications (reviewed extensively in (3, 4)). Though the tobacco plant and its relatives offer a qualified set of advantages for producing complex biologicals, and in many cases overcome problems that plague traditional expression systems, FDA licensed products derived from bioengineered plants have yet to appear in the marketplace. Despite a difficult beginning, recent advances in plant biotechnology have been as cutting edge as those in the fields of molecular biology and chemical engineering, which now position the field for a new level of commercial relevance. The basis for this review is a description of the first FDA qualified parenterally administered vaccine clinical trial using a plant derived product. We have confirmed in this trial that plant proteins can be qualified to the same level as biologicals from other sources, and are safe when given as injected vaccines. Most importantly though, immune responses to plant proteins were seen in 66% of cancer patients, and these responses were to the desired antigenic determinants, not to xenogenic plant antigens. Problems and solutions that arose during the development of a safe and effective human vaccine are discussed.

Cell behavior of human mesenchymal stromal cells in response to silica/collagen based xerogels and calcium deficient culture conditions.

PubMed

Wagner, Alena-Svenja; Glenske, Kristina; Henß, Anja; Kruppke, Benjamin; Rößler, Sina; Hanke, Thomas; Moritz, Andreas; Rohnke, Marcus; Kressin, Monika; Arnhold, Stefan; Schnettler, Reinhard; Wenisch, Sabine

2017-07-04

Herein, we aim to elucidate osteogenic effects of two silica-based xerogels with different degrees of bioactivity on human bone-derived mesenchymal stromal cells by means of scanning electron microscopy, quantitative PCR enhanced osteogenic effects and the formation of an extracellular matrix which could be ascribed to the sample with lower bioactivity. Given the high levels of bioactivity, the cells revealed remarkable sensitivity to extremely low calcium levels of the media. Therefore, additional experiments were performed to elucidate cell behavior under calcium deficient conditions. The results refer to capacity of the bone-derived stromal cells to overcome calcium deficiency even though proliferation, migration and osteogenic differentiation capabilities were diminished. One reason for the differences of the cellular response (on tissue culture plates versus xerogels) to calcium deficiency seems to be the positive effect of silica. The silica could be detected intracellularly as shown by time of flight-secondary ion mass spectrometry after cultivation of primary cells for 21 days on the surfaces of the xerogels. Thus, the present findings refer to different osteogenic differentiation potentials of the xerogels according to the different degrees of bioactivity, and to the role of silica as a stimulator of osteogenesis. Finally, the observed pattern of connexin-based hemichannel gating supports the assumption that connexin 43 is a key factor for calcium-mediated osteogenesis in bone-derived mesenchymal stromal cells.

First Insights into Human Fingertip Regeneration by Echo-Doppler Imaging and Wound Microenvironment Assessment.

PubMed

Jafari, Paris; Muller, Camillo; Grognuz, Anthony; Applegate, Lee Ann; Raffoul, Wassim; di Summa, Pietro G; Durand, Sébastien

2017-05-13

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome.

First Insights into Human Fingertip Regeneration by Echo-Doppler Imaging and Wound Microenvironment Assessment

PubMed Central

Jafari, Paris; Muller, Camillo; Grognuz, Anthony; Applegate, Lee Ann; Raffoul, Wassim; di Summa, Pietro G.; Durand, Sébastien

2017-01-01

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome. PMID:28505080

Impact of maternally derived immunity on piglets' immune response and protection against porcine circovirus type 2 (PCV2) after vaccination against PCV2 at different age.

PubMed

Martelli, Paolo; Saleri, Roberta; Ferrarini, Giulia; De Angelis, Elena; Cavalli, Valeria; Benetti, Michele; Ferrari, Luca; Canelli, Elena; Bonilauri, Paolo; Arioli, Elena; Caleffi, Antonio; Nathues, Heiko; Borghetti, Paolo

2016-05-11

This study was aimed at evaluating the clinical protection, the level of Porcine circovirus type 2 (PCV2) viremia and the immune response (antibodies and IFN-γ secreting cells (SC)) in piglets derived from PCV2 vaccinated sows and themselves vaccinated against PCV2 at different age, namely at 4, 6 and 8 weeks. The cohort study has been carried out over three subsequent production cycles (replicates). At the start/enrolment, 46 gilts were considered at first mating, bled and vaccinated. At the first, second and third farrowing, dams were bled and re-vaccinated at the subsequent mating after weaning piglets. Overall 400 piglets at each farrowing (first, second and third) were randomly allocated in three different groups (100 piglets/group) based on the timing of vaccination (4, 6 or 8 weeks of age). A fourth group was kept non-vaccinated (controls). Piglets were vaccinated intramuscularly with one dose (2 mL) of a commercial PCV2a-based subunit vaccine (Porcilis® PCV). Twenty animals per group were bled at weaning and from vaccination to slaughter every 4 weeks for the detection of PCV2 viremia, humoral and cell-mediated immune responses. Clinical signs and individual treatments (morbidity), mortality, and body weight of all piglets were recorded. All vaccination schemes (4, 6 and 8 weeks of age) were able to induce an antibody response and IFN-γ SC. The highest clinical and virological protection sustained by immune reactivity was observed in pigs vaccinated at 6 weeks of age. Overall, repeated PCV2 vaccination in sows at mating and the subsequent higher levels of maternally derived antibodies did not significantly interfere with the induction of both humoral and cell-mediated immunity in their piglets after vaccination. The combination of vaccination in sows at mating and in piglets at 6 weeks of age was more effective for controlling PCV2 natural infection, than other vaccination schemas, thus sustaining that some interference of MDA with the induction of an efficient immune response could be considered. In conclusion, optimal vaccination strategy needs to balance the levels of passive immunity, the management practices and timing of infection.

Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells-derived and fetal hepatocytes.

PubMed

Avior, Yishai; Levy, Gahl; Zimerman, Michal; Kitsberg, Daniel; Schwartz, Robert; Sadeh, Ronen; Moussaieff, Arieh; Cohen, Merav; Itskovitz-Eldor, Joseph; Nahmias, Yaakov

2015-07-01

The liver is the main organ responsible for the modification, clearance, and transformational toxicity of most xenobiotics owing to its abundance in cytochrome P450 (CYP450) enzymes. However, the scarcity and variability of primary hepatocytes currently limits their utility. Human pluripotent stem cells (hPSCs) represent an excellent source of differentiated hepatocytes; however, current protocols still produce fetal-like hepatocytes with limited mature function. Interestingly, fetal hepatocytes acquire mature CYP450 expression only postpartum, suggesting that nutritional cues may drive hepatic maturation. We show that vitamin K2 and lithocholic acid, a by-product of intestinal flora, activate pregnane X receptor (PXR) and subsequent CYP3A4 and CYP2C9 expression in hPSC-derived and isolated fetal hepatocytes. Differentiated cells produce albumin and apolipoprotein B100 at levels equivalent to primary human hepatocytes, while demonstrating an 8-fold induction of CYP450 activity in response to aryl hydrocarbon receptor (AhR) agonist omeprazole and a 10-fold induction in response to PXR agonist rifampicin. Flow cytometry showed that over 83% of cells were albumin and hepatocyte nuclear factor 4 alpha (HNF4α) positive, permitting high-content screening in a 96-well plate format. Analysis of 12 compounds showed an R(2) correlation of 0.94 between TC50 values obtained in stem cell-derived hepatocytes and primary cells, compared to 0.62 for HepG2 cells. Finally, stem cell-derived hepatocytes demonstrate all toxicological endpoints examined, including steatosis, apoptosis, and cholestasis, when exposed to nine known hepatotoxins. Our work provides fresh insights into liver development, suggesting that microbial-derived cues may drive the maturation of CYP450 enzymes postpartum. Addition of these cues results in the first functional, inducible, hPSC-derived hepatocyte for predictive toxicology. © 2015 by the American Association for the Study of Liver Diseases.

From public to private and back again: sustaining a high service-delivery level during transition of management authority: a Cambodia case study.

PubMed

Jacobs, Bart; Thomé, Jean-Marc; Overtoom, Rob; Sam, Sam Oeun; Indermühle, Lorenz; Price, Neil

2010-05-01

Contracting non-governmental organizations (NGOs) has been shown to increase health service delivery output considerably over relatively short time frames in low-income countries, especially when applying performance-related pay as a stimulus. A key concern is how to manage the transition back to government-operated systems while maintaining health service delivery output levels. In this paper we describe and analyse the transition from NGO-managed to government-managed health services over a 3-year period in a health district in Cambodia with a focus on the level of health service delivery. Data are derived from four sources, including cross-sectional surveys and health management and financial information systems. The transition was achieved by focusing on all the building blocks of the health care system and ensuring an acceptable financial remuneration for the staff members of contracted health facilities. The latter was attained through performance subsidies derived from financial commitment by the central government, and revenue from user fees. Performance management had a crucial role in the gradual handover of responsibilities. Not all responsibilities were handed back to government over the case study period-notably the development of performance indicators and targets and the performance monitoring.

The legume miR1514a modulates a NAC transcription factor transcript to trigger phasiRNA formation in response to drought

PubMed Central

Sosa-Valencia, Guadalupe; Palomar, Miguel; Covarrubias, Alejandra A.

2017-01-01

Abstract Recent studies have identified microRNAs as post-transcriptional regulators involved in stress responses. miR1514a is a legume microRNA that is induced in response to drought stress in Phaseolus vulgaris (common bean) and shows differential accumulation levels in roots during water deficit in two cultivars with different drought tolerance phenotypes. A recent degradome analysis revealed that miR1514a targets the transcripts of two NAC transcription factors (TFs), Phvul.010g121000 and Phvul.010g120700. Furthermore, expression studies and small RNA-seq data indicate that only Phvul.010g120700 generates phasiRNAs, which also accumulate under water deficit conditions. To confirm these results, we over-expressed miR1514a in transgenic hairy roots, and observed a reduced accumulation of Phvul.010g120700 and an increase in NAC-derived phasiRNAs; inhibition of miR1514a activity resulted in the opposite effect. Moreover, we determined that a NAC-derived phasiRNA associates with ARGONAUTE 1 (AGO1), suggesting that it is functional. In addition, a transcriptome analysis of transgenic hairy roots with reduced miR1514a levels revealed several differentially expressed transcripts, mainly involved in metabolism and stress responses, suggesting they are regulated by the NAC TF and/or by phasiRNAs. This work therefore demonstrates the participation of miR1514 in the regulation of a NAC transcription factor transcript through phasiRNA production during the plant response to water deficit. PMID:28338719

[Complete hormonal and metabolic response after iodine-131 metaiodobenzylguanidine treatment in a patient diagnosed of malignant pheochromocytoma].

PubMed

García Alonso, M P; Balsa Bretón, M A; Paniagua Correa, C; Castillejos Rodríguez, L; Rodríguez Pelayo, E; Mendoza Paulini, A; Ortega Valle, A; Penín González, J

2013-01-01

Radiolabeled metaiodobenzylguanidine is an analogue of norepinephrine used to localize tumors that express the neurohormone transporters, specifically those derived from the neural crest having a neuroendocrine origin. It is also used to treat non-surgical metastases derived from them. A review of the literature revealed symptomatic improvements associated to a decrease in hormone levels in a significant percentage of patients after (131)I-MIBG treatment. However, complete tumor remission has been described only in very few cases and hardly ever when bone metastases exist. We present a case of a patient diagnosed of malignant pheochromocytoma who achieved complete hormonal and metabolic response after (131)I-MIBG treatment (600 mCi) in spite of the presence of bone metastases. Copyright © 2012 Elsevier España, S.L. and SEMNIM. All rights reserved.

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

PubMed

Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

1999-01-01

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Mitochondria Are Critical for BDNF-Mediated Synaptic and Vascular Plasticity of Hippocampus following Repeated Electroconvulsive Seizures.

PubMed

Chen, Fenghua; Ardalan, Maryam; Elfving, Betina; Wegener, Gregers; Madsen, Torsten M; Nyengaard, Jens R

2018-03-01

Electroconvulsive therapy is a fast-acting and efficient treatment of depression used in the clinic. The underlying mechanism of its therapeutic effect is still unclear. However, recovery of synaptic connections and synaptic remodeling is thought to play a critical role for the clinical efficacy obtained from a rapid antidepressant response. Here, we investigated the relationship between synaptic changes and concomitant nonneuronal changes in microvasculature and mitochondria and its relationship to brain-derived neurotrophic factor level changes after repeated electroconvulsive seizures, an animal model of electroconvulsive therapy. Electroconvulsive seizures or sham treatment was given daily for 10 days to rats displaying a genetically driven phenotype modelling clinical depression: the Flinders Sensitive and Resistant Line rats. Stereological principles were employed to quantify numbers of synapses and mitochondria, and the length of microvessels in the hippocampus. The brain-derived neurotrophic factor protein levels were quantified with immunohistochemistry. In untreated controls, a lower number of synapses and mitochondria was accompanied by shorter microvessels of the hippocampus in "depressive" phenotype (Flinders Sensitive Line) compared with the "nondepressed" phenotype (Flinders Resistant Line). Electroconvulsive seizure administration significantly increased the number of synapses and mitochondria, and length of microvessels both in Flinders Sensitive Line-electroconvulsive seizures and Flinders Resistant Line-electroconvulsive seizures rats. In addition, the amount of brain-derived neurotrophic factor protein was significantly increased in Flinders Sensitive Line and Flinders Resistant Line rats after electroconvulsive seizures. Furthermore, there was a significant positive correlation between brain-derived neurotrophic factor level and mitochondria/synapses. Our results indicate that rapid and efficient therapeutic effect of electroconvulsive seizures may be related to synaptic plasticity, accompanied by brain-derived neurotrophic factor protein level elevation and mitochondrial and vascular support. © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells dose-dependently attenuates hyperoxia-induced lung injury in neonatal rats.

PubMed

Chang, Yun Sil; Choi, Soo Jin; Sung, Dong Kyung; Kim, Soo Yoon; Oh, Wonil; Yang, Yoon Sun; Park, Won Soon

2011-01-01

Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this preclinical translation study was to optimize the dose of human UCB-derived MSCs in attenuating hyperoxia-induced lung injury in newborn rats. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (95% oxygen) or normoxia after birth for 14 days. Three different doses of human UCB-derived MSCs, 5 × 10(3) (HT1), 5 × 10(4) (HT2), and 5 × 10(5) (HT3), were delivered intratracheally at postnatal day (P) 5. At P14, lungs were harvested for analyses including morphometry for alveolarization, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, myeoloperoxidase activity, mRNA level of tumor necross factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and transforming growth factor-β (TGF-β), human glyceradehyde-3-phosphate dehydrogenase (GAPDH), and p47(phox), and collagen levels. Increases in TUNEL-positive cells were attenuated in all transplantation groups. However, hyperoxia-induced lung injuries, such as reduced alveolarization, as evidenced by increased mean linear intercept and mean alveolar volume, and increased collagen levels were significantly attenuated in both HT2 and HT3, but not in HT1, with better attenuation in HT3 than in HT2. Dose-dependent human GAPDH expression, indicative of the presence of human RNA in lung tissue, was observed only in the transplantation groups, with higher expression in HT3 than in HT2, and higher expression in HT2 than in HT1. Hyperoxia-induced inflammatory responses such as increased myeloperoxidase acitivity, mRNA levels of TNF-α, IL-1β, IL-6, and TGF-β of the lung tissue, and upregulation of both cytosolic and membrane p47(phox), indicative of oxidative stress, were significantly attenuated in both HT2 and HT3 but not in HT1. These results demonstrate that intratracheal transplantation of human UCB-derived MSCs with appropriate doses may attenuate hyperoxia-induced lung injury through active involvement of these cells in modulating host inflammatory responses and oxidative stress in neonatal rats.

Item Response Theory to Quantify Longitudinal Placebo and Paliperidone Effects on PANSS Scores in Schizophrenia.

PubMed

Krekels, Ehj; Novakovic, A M; Vermeulen, A M; Friberg, L E; Karlsson, M O

2017-08-01

As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data discards information and violates the numerical nature of the scale. Here a longitudinal analysis based on Item Response Theory is presented using PANSS data from phase III clinical trials. Latent disease severity variables were derived from item-level data on the positive, negative, and general PANSS subscales each. On all subscales, the time course of placebo responses were best described with Weibull models, and dose-independent functions with exponential models to describe the onset of the full effect were used to describe paliperidone's effect. Placebo and drug effect were most pronounced on the positive subscale. The final model successfully describes the time course of treatment effects on the individual PANSS item-levels, on all PANSS subscale levels, and on the total score level. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

A laboratory study of subjective response to sonic booms measured at White Sands Missile Range

NASA Technical Reports Server (NTRS)

Sullivan, Brenda M.; Leatherwood, Jack D.

1993-01-01

The Sonic Boom Simulator of the Langley Research Center was used to quantify subjective loudness response to boom signatures consisting of: (1) simulator reproductions of booms recently recorded at White Sands Missile Range; (2) idealized N-waves; and (3) idealized booms having intermediate shocks. The booms with intermediate shocks represented signatures derived from CFD predictions. The recorded booms represented those generated by F15 and T38 aircraft flyovers and represented a variety of waveforms reflecting the effects of propagation through a turbulent atmosphere. These waveforms included the following shape categories: N-waves, peaked, rounded, and U-shaped. Results showed that Perceived Level and Zwicker Loudness Level were good estimators of the loudness of turbulence modified sonic booms. No significant differences were observed between loudness responses for the several shape categories when expressed in terms of Perceived Level. Thus, Perceived Level effectively accounted for waveform differences due to turbulence. Idealized booms with intermediate shocks, however, were rated as being approximately 2.7 dB(PL) less loud than the recorded signatures. This difference was not accounted for by PL.

Nitric oxide in adaptation to altitude

PubMed Central

Laskowski, Daniel; Erzurum, Serpil C.

2012-01-01

This review summarizes published information on levels of nitric oxide gas (NO) in the lungs and NO-derived liquid phase molecules in the acclimatization of visitors newly arrived at altitudes of 2500m or more and adaptation of populations whose ancestors arrived thousands of years ago. Studies of acutely exposed visitors to high altitude focus on the first 24–48 hours with just a few extending to days or weeks. Among healthy visitors, NO levels in the lung, plasma and/or red blood cells fell within three hours, but then returned toward baseline or slightly higher by 48 hours, and increased above baseline by 5 days. Among visitors ill with high-altitude pulmonary edema at the time of the study or in the past, NO levels were lower than their healthy counterparts. As for highland populations, Tibetans had NO levels in the lung, plasma and red blood cells that were at least double and in some cases orders of magnitude greater than other populations regardless of altitude. Red blood cell associated nitrogen oxides were more than two hundred times higher. Other highland populations had generally higher levels although not to the degree showed by Tibetans. Overall, responses of those acclimatized and those presumed to be adapted are in the same direction although the Tibetans have much larger responses. Missing are long-term data on lowlanders at altitude showing how similar they become to the Tibetan phenotype. Also missing are data on Tibetans at low altitude to see the extent to which their phenotype is a response to the immediate environment or expressed constitutively. The mechanisms causing the visitors’ and the Tibetans’ high levels of NO and NO-derived molecules at altitude remain unknown. Limited data suggest processes including hypoxic upregulation of NO synthase gene expression, hemoglobin-NO reactions and genetic variation. Gains in understanding will require integrating appropriate methods and measurement techniques with indicators of adaptive function under hypoxic stress. PMID:22300645

Greenland uplift and regional sea level changes from ICESat observations and GIA modelling

NASA Astrophysics Data System (ADS)

Spada, G.; Ruggieri, G.; Sørensen, L. S.; Nielsen, K.; Melini, D.; Colleoni, F.

2012-06-01

We study the implications of a recently published mass balance of the Greenland ice sheet (GrIS), derived from repeated surface elevation measurements from NASA's ice cloud and land elevation satellite (ICESat) for the time period between 2003 and 2008. To characterize the effects of this new, high-resolution GrIS mass balance, we study the time-variations of various geophysical quantities in response to the current mass loss. They include vertical uplift and subsidence, geoid height variations, global patterns of sea level change (or fingerprints), and regional sea level variations along the coasts of Greenland. Long-wavelength uplifts and gravity variations in response to current or past ice thickness variations are obtained solving the sea level equation, which accounts for both the elastic and the viscoelastic components of deformation. To capture the short-wavelength components of vertical uplift in response to current ice mass loss, which is not resolved by satellite gravity observations, we have specifically developed a high-resolution regional elastic rebound (ER) model. The elastic component of vertical uplift is combined with estimates of the viscoelastic displacement fields associated with the process of glacial-isostatic adjustment (GIA), according to a set of published ice chronologies and associated mantle rheological profiles. We compare the sensitivity of global positioning system (GPS) observations along the coasts of Greenland to the ongoing ER and GIA. In notable contrast with past reports, we show that vertical velocities obtained by GPS data from five stations with sufficiently long records and from one tide gauge at the GrIS margins can be reconciled with model predictions based on the ICE-5G deglaciation model and the ER associated with the new ICESat-derived mass balance.

Secretion of interferon-tau by bovine embryos in long-term culture: comparison of in vivo derived, in vitro produced, nuclear transfer and demi-embryos.

PubMed

Stojkovic, M; Büttner, M; Zakhartchenko, V; Riedl, J; Reichenbach, H D; Wenigerkind, H; Brem, G; Wolf, E

1999-04-30

Interferon-tau (IFNtau) is the pregnancy recognition signal of bovine embryos, inhibiting luteolysis. We studied trophoblastic growth and IFNtau secretion of embryos with different developmental potential, i.e., in vivo derived and in vitro produced embryos, cloned embryos and demi-embryos, to evaluate if the ability of secreting IFNtau might be responsible for differences in pregnancy rates after transfer of these categories of embryos to recipients. Day 8 embryos of excellent quality were individually placed in microdrops of buffalo rat liver cell-conditioned medium and maintained for up to 23 days. Embryos were observed on Days 11, 15, 19 and 23, the mean diameter (2r) of attached and spherical embryos was measured, and their trophoblastic area was calculated as r2pi or 4r2pi, respectively. Simultaneously, medium was changed and the IFNtau levels of conditioned media were determined using a bioassay of antiviral activity. Trophoblastic area was smaller (P < 0.05) in demi-embryos than in all other groups, which exhibited similar trophoblastic growth until Day 19. However, on Day 23 trophoblastic area of in vivo derived embryos was more than twice (P < 0.05) as large as those of in vitro produced and nuclear transfer (NT) embryos. IFNtau levels increased only slowly with time in culture of demi-embryos. By contrast, the level of IFNtau doubled from Day 11 to Day 15 in conditioned media from all other groups of embryos. The linear increase in IFNtau production of vivo and in vitro derived embryos continued until the end of the culture period, whereas conditioned media from NT embryos contained significantly (P < 0.05) less IFNtau activity on Days 19 and 23 than those of the former two groups. Our results demonstrate different capabilities of secreting IFNtau for in vivo derived and in vitro produced embryos vs. NT and demi-embryos, which may--at least part--be responsible for the differences in pregnancy rates after transfer to recipients.

Short term response of insulin, glucose, growth hormone and corticosterone to acute vibration in rats.

NASA Technical Reports Server (NTRS)

Dolkas, C. B.; Leon, H. A.; Chackerian, M.

1971-01-01

Study carried out to obtain some notion of the initial phasing and interactive effects among some hormones known to be responsive to vibration stress. Sprague-Dawley derived rats were exposed to the acute effects of confinement and confinement with lateral (plus or minus G sub y) vibration. The coincident monitoring of glucose, insulin, growth hormone, and corticosterone plasma levels, during and immediately subsequent to exposure to brief low level vibration, exhibits the effects of inhibition of insulin release by epinephrine. The ability of insulin (IRI) to return rapidly to basal levels, from appreciably depressed levels during vibration, in the face of elevated levels of glucose is also shown. Corticosterone responds with almost equal rapidity, but in opposite phase to the IRI. The immuno-assayable growth hormone (IGH) dropped from a basal level of 32 ng/ml to 7.3 ng/ml immediately subsequent to vibration and remained at essentially that level throughout the experiment (60 min). Whether these levels represent a real fall in the rat or whether they merely follow the immuno-logically deficient form is still in question.

Establishment and characterization of mouse bone marrow-derived mast cell hybridomas

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

Kawahara, Takeshi, E-mail: tkawafb@shinshu-u.ac.jp

2012-11-01

Interleukin (IL)-3-dependent mouse bone marrow-derived mast cells (BMMCs) are an important model for studying the function of mucosal-type mast cells. In the present study, BMMCs were successfully immortalized by cell fusion using a hypoxanthine-aminopterin-thymidine medium-sensitive variant of P815 mouse mastocytoma (P815-6TgR) as a partner cell line. The established mouse mast cell hybridomas (MMCHs) expressed {alpha}, {beta}, and {gamma} subunits of high-affinity immunoglobulin E (IgE) receptor (Fc{epsilon}RI) and possessed cytoplasmic granules devoid of or partially filled with electron-dense material. Four independent MMCH clones continuously proliferated without supplemental exogenous IL-3 and showed a degranulation response on stimulation with IgE+antigen. Furthermore, histamine synthesismore » and release by degranulation were confirmed in MMCH-D5, a MMCH clone that showed the strongest degranulation response. MMCH-D5 exhibited elevated levels of IL-3, IL-4, IL-13, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor (TNF)-{alpha}, and cyclooxygenase 2, and production of prostaglandin D{sub 2} and leukotriene C{sub 4} in response to IgE-induced stimulation. MMCH clones also expressed Toll-like receptors (TLRs) 1, 2, 4, and 6 and showed elevated levels of TNF-{alpha} expression in response to stimulation with TLR2 and TLR4 ligands. The MMCHs established using this method should be suitable for studies on Fc{epsilon}RI- and TLR-mediated effector functions of mast cells.« less

Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability

PubMed Central

Zago, Michela; Sheridan, Jared A.; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H.; Hamid, Qutayba

2017-01-01

Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients. PMID:28749959

Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability.

PubMed

Zago, Michela; Sheridan, Jared A; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H; Hamid, Qutayba; Baglole, Carolyn J

2017-01-01

Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients.

Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine

NASA Technical Reports Server (NTRS)

Rudas, L.; Crossman, A. A.; Morillo, C. A.; Halliwill, J. R.; Tahvanainen, K. U.; Kuusela, T. A.; Eckberg, D. L.

1999-01-01

We evaluated a method of baroreflex testing involving sequential intravenous bolus injections of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside in 18 healthy men and women, and we drew inferences regarding human sympathetic and vagal baroreflex mechanisms. We recorded the electrocardiogram, photoplethysmographic finger arterial pressure, and peroneal nerve muscle sympathetic activity. We then contrasted least squares linear regression slopes derived from the depressor (nitroprusside) and pressor (phenylephrine) phases with 1) slopes derived from spontaneous fluctuations of systolic arterial pressures and R-R intervals, and 2) baroreflex gain derived from cross-spectral analyses of systolic pressures and R-R intervals. We calculated sympathetic baroreflex gain from integrated muscle sympathetic nerve activity and diastolic pressures. We found that vagal baroreflex slopes are less when arterial pressures are falling than when they are rising and that this hysteresis exists over pressure ranges both below and above baseline levels. Although pharmacological and spontaneous vagal baroreflex responses correlate closely, pharmacological baroreflex slopes tend to be lower than those derived from spontaneous fluctuations. Sympathetic baroreflex slopes are similar when arterial pressure is falling and rising; however, small pressure elevations above baseline silence sympathetic motoneurons. Vagal, but not sympathetic baroreflex gains vary inversely with subjects' ages and their baseline arterial pressures. There is no correlation between sympathetic and vagal baroreflex gains. We recommend repeated sequential nitroprusside followed by phenylephrine doses as a simple, efficientmeans to provoke and characterize human vagal and sympathetic baroreflex responses.

Unruh effect for general trajectories

NASA Astrophysics Data System (ADS)

Obadia, N.; Milgrom, M.

2007-03-01

We consider two-level detectors coupled to a scalar field and moving on arbitrary trajectories in Minkowski space-time. We first derive a generic expression for the response function using a (novel) regularization procedure based on the Feynman prescription that is explicitly causal, and we compare it to other expressions used in the literature. We then use this expression to study, analytically and numerically, the time dependence of the response function in various nonstationarity situations. We show that, generically, the response function decreases like a power in the detector’s level spacing, E, for high E. It is only for stationary worldlines that the response function decays faster than any power law, in keeping with the known exponential behavior for some stationary cases. Under some conditions the (time-dependent) response function for a nonstationary worldline is well approximated by the value of the response function for a stationary worldline having the same instantaneous acceleration, torsion, and hypertorsion. While we cannot offer general conditions for this to apply, we discuss special cases; in particular, the low-energy limit for linear space trajectories.

Response to "The Iris Hypothesis: A Negative or Positive Cloud Feedback?"

NASA Technical Reports Server (NTRS)

Chou, Ming-Dah; Lindzen, Richard S.; Hou, Arthur Y.; Lau, William K. M. (Technical Monitor)

2001-01-01

Based on radiance measurements of Japan's Geostationary Meteorological Satellite, Lindzen et al. found that the high-level cloud cover averaged over the tropical western Pacific decreases with increasing sea surface temperature. They further found that the response of high-level clouds to the sea surface temperature had an effect of reducing the magnitude of climate change, which is referred as a negative climate feedback. Lin et al. reassessed the results found by Lindzen et al. by analyzing the radiation and clouds derived from the Tropical Rainfall Measuring Mission Clouds and the Earth's Radiant Energy System measurements. They found a weak positive feedback between high-level clouds and the surface temperature. We have found that the approach taken by Lin et al. to estimating the albedo and the outgoing longwave radiation is incorrect and that the inferred climate sensitivity is unreliable.

Serologic response of roosters to gradient dosage levels of a commercially available live F strain-derived Mycoplasma gallisepticum vaccine over time

USDA-ARS?s Scientific Manuscript database

Spray application is a commonly used time- and labor-efficient means to deliver live Mycoplasma gallisepticum (MG) vaccine to laying hens in commercial production facilities. The dosage of vaccine received by spray vaccinated birds can vary due to variation in the spray plume and vaccine suspension...

Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

EPA Science Inventory

Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be ap...

Development of a Methodology to Guide the Replacement of Agency Default Uncertainty Factors with Those Based on Data

EPA Science Inventory

The Agency's guidance for the derivation of RfD and RfC values call for the downward adjustment of exposure-response levels observed in animals and/or humans to account for the potentially greater sensitivity of humans as compared to test animals (UFA) and the differential sensit...

Linking Physiological Responses, Chlorophyll Fluorescence and Hyperspectral Imagery to Detect Salinity Stress Using the Physiological Reflectance Index in the Coastal Shrub, Myrica cerifera

DTIC Science & Technology

2008-01-01

rainforests under various precipitation and substrate conditions (Asner et al., 2005). AMODIS-derived PRI has also been correlated to ecosystem-level...carbon uptake in an Amazon forest measured with spaceborne imaging spectroscopy. Proceedings of the National Academy of Sciences of the United States of

De-Emphasizing Gender in Talk about Texts: Literature Response, Discussion, and Gender within a Classroom Community of Practice

ERIC Educational Resources Information Center

Brendler, Beth Monica

2012-01-01

Drawing on and reexamining theories on gender and literacy, derived from research performed between 1974 and 2002, this qualitative study explored the gender assumptions and expectations of 19 preservice and practicing secondary language arts teachers in a graduate level adolescent literature course. The theoretical framework was structured around…

In situ diselenide-crosslinked polymeric micelles for ROS-mediated anticancer drug delivery.

PubMed

Deepagan, V G; Kwon, Seunglee; You, Dong Gil; Nguyen, Van Quy; Um, Wooram; Ko, Hyewon; Lee, Hansang; Jo, Dong-Gyu; Kang, Young Mo; Park, Jae Hyung

2016-10-01

Stimuli-responsive micelles have emerged as the drug carrier for cancer therapy since they can exclusively release the drug via their structural changes in response to the specific stimuli of the target site. Herein, we developed the in situ diselenide-crosslinked micelles (DCMs), which are responsive to the abnormal ROS levels of tumoral region, as anticancer drug carriers. The DCMs were spontaneously derived from selenol-bearing triblock copolymers consisting of polyethylene glycol (PEG) and polypeptide derivatives. During micelle formation, doxorubicine (DOX) was effectively encapsulated in the hydrophobic core, and diselenide crosslinks were formed in the shell. The DCMs maintained their structural integrity, at least for 6 days in physiological conditions, even in the presence of destabilizing agents. However, ROS-rich conditions triggered rapid release of DOX from the DOX-encapsulating DCMs (DOX-DCMs) because the hydrophobic diselenide bond was cleaved into hydrophilic selenic acid derivatives. Interestingly, after their systemic administration into the tumor-bearing mice, DOX-DCMs delivered significantly more drug to tumors (1.69-fold and 3.73-fold higher amount compared with their non-crosslinked counterparts and free drug, respectively) and effectively suppressed tumor growth. Overall, our data indicate that DCMs have great potential as drug carriers for anticancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling

PubMed Central

Masuda, Tetsuro; Endo, Motoyoshi; Yamamoto, Yutaka; Odagiri, Haruki; Kadomatsu, Tsuyoshi; Nakamura, Takayuki; Tanoue, Hironori; Ito, Hitoshi; Yugami, Masaki; Miyata, Keishi; Morinaga, Jun; Horiguchi, Haruki; Motokawa, Ikuyo; Terada, Kazutoyo; Morioka, Masaki Suimye; Manabe, Ichiro; Iwase, Hirotaka; Mizuta, Hiroshi; Oike, Yuichi

2015-01-01

Bone metastasis of breast cancer cells is a major concern, as it causes increased morbidity and mortality in patients. Bone tissue-derived CXCL12 preferentially recruits breast cancer cells expressing CXCR4 to bone metastatic sites. Thus, understanding how CXCR4 expression is regulated in breast cancer cells could suggest approaches to decrease bone metastasis of breast tumor cells. Here, we show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) increases responsiveness of breast cancer cells to CXCL12 by promoting up-regulation of CXCR4 in those cells. In addition, we used a xenograft mouse model established by intracardiac injection of tumor cells to show that ANGPTL2 knockdown in breast cancer cells attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression in those cells, thereby decreasing bone metastasis. Finally, we found that ANGPTL2 and CXCR4 expression levels within primary tumor tissues from breast cancer patients are positively correlated. We conclude that tumor cell-derived ANGPTL2 may increase bone metastasis by enhancing breast tumor cell responsiveness to CXCL12 signaling through up-regulation of tumor cell CXCR4 expression. These findings may suggest novel therapeutic approaches to treat metastatic breast cancer. PMID:25773070

Lung-Derived Mediators Induce Cytokine Production in Downstream Organs via an NF-κ B-Dependent Mechanism

PubMed Central

Patterson, E. K.; Yao, L. J.; Ramic, N.; Lewis, J. F.; Cepinskas, G.; McCaig, L.; Veldhuizen, R. A. W.; Yamashita, C. M.

2013-01-01

In the setting of acute lung injury, levels of circulating inflammatory mediators have been correlated with adverse outcomes. Previous studies have demonstrated that injured, mechanically ventilated lungs represent the origin of the host inflammatory response; however, mechanisms which perpetuate systemic inflammation remain uncharacterized. We hypothesized that lung-derived mediators generated by mechanical ventilation (MV) are amplified by peripheral organs in a “feed forward” mechanism of systemic inflammation. Herein, lung-derived mediators were collected from 129X1/SVJ mice after 2 hours of MV while connected to the isolated perfused mouse lung model setup. Exposure of liver endothelial cells to lung-derived mediators resulted in a significant increase in G-CSF, IL-6, CXCL-1, CXCL-2, and MCP-1 production compared to noncirculated control perfusate media (P < 0.05). Furthermore, inhibition of the NF-κB pathway significantly mitigated this response. Changes in gene transcription were confirmed using qPCR for IL-6, CXCL-1, and CXCL-2. Additionally, liver tissue obtained from mice subjected to 2 hours of in vivo MV demonstrated significant increases in hepatic gene transcription of IL-6, CXCL-1, and CXCL-2 compared to nonventilated controls. Collectively, this data demonstrates that lung-derived mediators, generated in the setting of MV, are amplified by downstream organs in a feed forward mechanism of systemic inflammation. PMID:23606793

Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles

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

Oh, Jung-Hwa; Department of human and environmental toxicology, University of Science & Technology, Daejeon 34113; Son, Mi-Young

Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10–200 μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24 h. The results showed that Ag NPs evoked significant toxicity in hESC-derivedmore » NPCs at 24 h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans. - Highlights: • This system served as a suitable model for developmental neurotoxicity testing. • Ag NPs induce the apoptosis in human neural cells by ROS generation. • Genes for development of neurons were dysregulated in response to Ag NPs. • Molecular events during early developmental neurotoxicity were proposed.« less

The potential mechanism of Bursal-derived BPP-II on the antibody production and avian pre-B cell.

PubMed

Feng, Xiuli; Cao, Ruibing; Zhou, Bin; Liu, Qingtao; Liu, Ke; Liu, Xiaodong; Zhang, Yuanpeng; Gu, Jinyan; Miao, Denian; Chen, Puyan

2013-03-01

The bursa of Fabricius is critical for the normal development of the B lymphocytes responsible for antibody production. However, the mechanism of the bursal-derived bioactive factor on B cell development is little reported. In this paper, chicks were immunized with BPP-II and AIV vaccine or AIV antigen, and antibody and IL-4 production were detected. The results showed that BPP-II played strongly inducing roles on the humoral immune responses. To investigate the gene expression at transcriptional level, avian pre-B lymphocyte DT40 cells were treated with BPP-II, and were analyzed with the gene microarray. The results proved that BPP-II treatment regulated 11 pathways, in which homologous recombination is a vital mechanism which is involved in antibody Ig gene conversion and diversification during B cell development. These results suggested Bursal-derived biological active factor BPP-II might be involved in the antibody production processes and B cell development, which is vital to the humoral central immune organ, the bursa of Fabricius. Copyright © 2012 Elsevier Ltd. All rights reserved.

Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed against Prostate Cancer

DTIC Science & Technology

2017-08-01

Award Number: W81XWH-15-1-0328 TITLE: Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed against...1 August 2016 - 31 July 2017 4. TITLE AND SUBTITLE Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed...discovered that a subset of regulatory T cells (Tregs), termed peripheral-derived Tregs (pTregs), impair immune responses directed against tumor

Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone.

PubMed

Yang, Li; Yang, Jin Bo; Chen, Jia; Yu, Guang Yao; Zhou, Pei; Lei, Lei; Wang, Zhen Zhen; Cy Chang, Catherine; Yang, Xin Ying; Chang, Ta Yuan; Li, Bo Liang

2004-08-01

In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.

Gorlin syndrome-derived induced pluripotent stem cells are hypersensitive to hedgehog-mediated osteogenic induction.

PubMed

Hasegawa, Daigo; Ochiai-Shino, Hiromi; Onodera, Shoko; Nakamura, Takashi; Saito, Akiko; Onda, Takeshi; Watanabe, Katsuhito; Nishimura, Ken; Ohtaka, Manami; Nakanishi, Mahito; Kosaki, Kenjiro; Yamaguchi, Akira; Shibahara, Takahiko; Azuma, Toshifumi

2017-01-01

Gorlin syndrome is an autosomal dominant inherited syndrome that predisposes a patient to the formation of basal cell carcinomas, odontogenic keratocysts, and skeletal anomalies. Causative mutations in several genes associated with the sonic hedgehog (SHH) signaling pathway, including PTCH1, have been identified in Gorlin syndrome patients. However, no definitive genotype-phenotype correlations are evident in these patients, and their clinical presentation varies greatly, often leading to delayed diagnosis and treatment. We generated iPSCs from four unrelated Gorlin syndrome patients with loss-of-function mutations in PTCH1 using the Sendai virus vector (SeVdp(KOSM)302). The patient-derived iPSCs exhibited basic iPSC features, including stem cell marker expression, totipotency, and the ability to form teratomas. GLI1 expression levels were greater in fibroblasts and patient-derived iPSCs than in the corresponding control cells. Patient-derived iPSCs expressed lower basal levels than control iPSCs of the genes encoding the Hh ligands Indian Hedgehog (IHH) and SHH, the Hh acetyltransferase HHAT, Wnt proteins, BMP4, and BMP6. Most of these genes were upregulated in patient-derived iPSCs grown in osteoblast differentiation medium (OBM) and downregulated in control iPSCs cultured in OBM. The expression of GLI1 and GLI2 substantially decreased in both control and patient-derived iPSCs cultured in OBM, whereas GLI3, SHH, and IHH were upregulated in patient-derived iPSCs and downregulated in control iPSCs grown in OBM. Activation of Smoothened by SAG in cells grown in OBM significantly enhanced alkaline phosphatase activity in patient-derived iPSCs compared with control iPSC lines. In summary, patient-derived iPSCs expressed lower basal levels than the control iPSCs of the genes encoding Hh, Wnt, and bone morphogenetic proteins, but their expression of these genes strongly increased under osteogenic conditions. These findings indicate that patient-derived iPSCs are hypersensitive to osteogenic induction. We propose that Hh signaling is constituently active in iPSCs from Gorlin syndrome patients, enhancing their response to osteogenic induction and contributing to disease-associated abnormalities.

The small non-coding RNA response to virus infection in the Leishmania vector Lutzomyia longipalpis.

PubMed

Ferreira, Flávia Viana; Aguiar, Eric Roberto Guimarães Rocha; Olmo, Roenick Proveti; de Oliveira, Karla Pollyanna Vieira; Silva, Emanuele Guimarães; Sant'Anna, Maurício Roberto Viana; Gontijo, Nelder de Figueiredo; Kroon, Erna Geessien; Imler, Jean Luc; Marques, João Trindade

2018-06-01

Sandflies are well known vectors for Leishmania but also transmit a number of arthropod-borne viruses (arboviruses). Few studies have addressed the interaction between sandflies and arboviruses. RNA interference (RNAi) mechanisms utilize small non-coding RNAs to regulate different aspects of host-pathogen interactions. The small interfering RNA (siRNA) pathway is a broad antiviral mechanism in insects. In addition, at least in mosquitoes, another RNAi mechanism mediated by PIWI interacting RNAs (piRNAs) is activated by viral infection. Finally, endogenous microRNAs (miRNA) may also regulate host immune responses. Here, we analyzed the small non-coding RNA response to Vesicular stomatitis virus (VSV) infection in the sandfly Lutzoymia longipalpis. We detected abundant production of virus-derived siRNAs after VSV infection in adult sandflies. However, there was no production of virus-derived piRNAs and only mild changes in the expression of vector miRNAs in response to infection. We also observed abundant production of virus-derived siRNAs against two other viruses in Lutzomyia Lulo cells. Together, our results suggest that the siRNA but not the piRNA pathway mediates an antiviral response in sandflies. In agreement with this hypothesis, pre-treatment of cells with dsRNA against VSV was able to inhibit viral replication while knock-down of the central siRNA component, Argonaute-2, led to increased virus levels. Our work begins to elucidate the role of RNAi mechanisms in the interaction between L. longipalpis and viruses and should also open the way for studies with other sandfly-borne pathogens.

Modulating the Levels of Plant Hormone Cytokinins at the Host-Pathogen Interface.

PubMed

Naseem, Muhammad; Shams, Shabana; Roitsch, Thomas

2017-01-01

Cytokinins are adenine and non-adenine derived heterogeneous class of regulatory molecules that participate in almost every aspect of plant biology. They also affect plant defense responses as well as help microbial pathogens to establish pathogenesis. The functional approaches that ensure desired and subtle modulations in the levels of plant cytokinins are highly instrumental in assessing their functions in plant immunity. Here, we describe a detailed working protocol regarding the enhanced production of cytokinins from plants that harbor isopentenyltransferase (IPT) enzyme gene under the control of 4xJERE (jasmonic acid and elicitor-responsive element) pathogen-inducible promoter. Our devised expression system is a context-dependent solution when it comes to investigating host-pathogen interactions under the modulated conditions of plant cytokinins.

Stress (hypothalamic-pituitary-adrenal axis) and pain response in male rats exposed lifelong to high vs. low phytoestrogen diets.

PubMed

Lephart, Edwin D; Galindo, Edwardo; Bu, Li Hong

2003-05-15

Estrogens exhibit complex but beneficial effects on brain structure, function and behavior. Soy-derived dietary phytoestrogens protect against hormone-dependent and age-related diseases, due to their estrogen-like hormonal actions. However, the effects of phytoestrogens on brain and behavior are relatively unknown. This study examined the influence of exposing male Long-Evans rats (lifelong) to either a phytoestrogen-rich (Phyto-600) or a phytoestrogen-free (Phyto-free) diet on body weights, behavioral pain thresholds, the hypothalamic-pituitary-adrenal (HPA) hormonal stress response, hippocampal glucocorticoid receptor and brain neural cell adhesion molecules (NCAM) and synaptophysin levels using standard behavioral and biochemical techniques. Body weights were significantly decreased in Phyto-600 fed animals compared to Phyto-free values. There were no significant changes in behavioral pain thresholds, circulating corticosterone concentrations (after acute immobilization stress) or NCAM and synaptophysin levels in various brain regions by the diet treatments. However, Phyto-600 fed males displayed significantly higher plasma adrenocorticotrophin (ACTH) (post-stress) and hippocampal glucocorticoid receptor levels vs. Phyto-free values. These data suggest that (1) body weights are significantly reduced by soy-derived phytoestrogens, (2) behavioral pain thresholds (via heat stimuli) are not influenced by dietary phytoestrogens, but (3) these estrogenic molecules in the hippocampus enhance glucocorticoid receptor abundance and alter the negative feedback of stress hormones towards a female-like pattern of higher ACTH release after activation of the HPA stress axis. This study is the first to show that lifelong consumption of dietary phytoestrogens alters the HPA stress response in male rats.

Nuclear factor erythroid-derived 2-related factor 2 activates glutathione S-transferase expression in the midgut of Spodoptera litura (Lepidoptera: Noctuidae) in response to phytochemicals and insecticides.

PubMed

Chen, S; Lu, M; Zhang, N; Zou, X; Mo, M; Zheng, S

2018-05-10

Detoxication enzymes play an important role in insect resistance to xenobiotics such as insecticides and phytochemicals. We studied the pathway for activating the expression of glutathione S-transferases (GSTs) in response to selected xenobiotics. An assay of the promoter activity of GST epsilon 1 (Slgste1) of Spodoptera litura led to the discovery of a cis-regulating element. An antioxidant response element was activated in response to indole-3-carbinol (I3C) and chlorpyrifos (CPF) and was able to bind with the xenobiotic sensor protein nuclear factor erythroid-derived 2-related factor 2 (SlNrf2). SlNrf2 and Slgste1 were responsive to reactive oxygen species induced by I3C and CPF in a S. litura cell line, as well as in S. litura midguts. SlNrf2 RNA interference (RNAi) reduced the message RNA levels of Slgste1 and the peroxidase activity of GSTs in response to I3C, xanthotoxin, CPF and deltamethrin. SlNrf2 RNAi and inhibitor treatment of GST activity decreased the viability of I3C-treated cells. These results indicate that SlNrf2 activates the expression of GSTs in response to oxidative stresses caused by exposure to xenobiotics. © 2018 The Royal Entomological Society.

Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner

PubMed Central

Saland, Samantha K.; Schoepfer, Kristin J.; Kabbaj, Mohamed

2016-01-01

We recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex- and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and progesterone on initiation and maintenance of hedonic response to low-dose ketamine (2.5 mg/kg) in intact and gonadectomized male and female rats. Ketamine induced a sustained increase in sucrose preference of female, but not male, rats in an E2P4-dependent manner. Whereas testosterone failed to alter male treatment response, concurrent administration of P4 alone in intact males enhanced hedonic response low-dose ketamine. Treatment responsiveness in female rats only was associated with greater hippocampal BDNF levels, but not activation of key downstream signaling effectors. We provide novel evidence supporting activational roles for ovarian-, but not testicular-, derived hormones in mediating hedonic sensitivity to low-dose ketamine in female and male rats, respectively. Organizational differences may, in part, account for the persistence of sex differences following gonadectomy and selective involvement of BDNF in treatment response. PMID:26888470

Role of adipose tissue-derived stem cells in the progression of renal disease.

PubMed

Donizetti-Oliveira, Cassiano; Semedo, Patricia; Burgos-Silva, Marina; Cenedeze, Marco Antonio; Malheiros, Denise Maria Avancini Costa; Reis, Marlene Antônia Dos; Pacheco-Silva, Alvaro; Câmara, Niels Olsen Saraiva

2011-03-01

To analyze the role of adipose tissue-derived stem cells in reducing the progression of renal fibrosis. adipose tissue-derived stem cells were isolated from C57Bl/6 mice and characterized by cytometry and differentiation. Renal fibrosis was established after unilateral clamping of the renal pedicle for 1 hour. Four hours after reperfusion, 2.105 adipose tissue-derived stem cells were administered intraperitoneally and the animals were followed for 24 hours during 6 weeks. In another experimental group, 2.105adipose tissue-derived stem cells were administered only after 6 weeks of reperfusion, and they were euthanized and studied 4 weeks later. Twenty-four hours after reperfusion, the animals treated with adipose tissue-derived stem cells displayed reduced renal and tubular dysfunction and an increase of the regenerative process. Renal expression of IL-6 and TNF mRNA were decreased in the animals treated with adipose tissue-derived stem cells, while the levels of IL-4, IL-10, and HO-1 were increased, despite the fact that adipose tissue-derived stem cells were not observed in the kidneys via SRY analysis. In 6 weeks, the kidneys of non-treated animals decreased in size, and the kidneys of the animals treated with adipose tissue-derived stem cells remained at normal size and display less deposition of type 1 collagen and FSP-1. The renal protection observed in animals treated with adipose tissue-derived stem cells was followed by a drop in serum levels of TNF-α, KC, RANTES, and IL-1a. Treatment with adipose tissue-derived stem cells after 6 weeks, when the animals already displayed established fibrosis, demonstrated an improvement in functional parameters and less fibrosis analyzed by Picrosirius stain, as well as a reduction of the expression of type 1 collagen and vimentin mRNA. Treatment with adipose tissue-derived stem cells may deter the progression of renal fibrosis by modulation of the early inflammatory response, likely via reduction of the epithelial-mesenchymal transition.

World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice.

PubMed

Gavett, Stephen H; Haykal-Coates, Najwa; Highfill, Jerry W; Ledbetter, Allen D; Chen, Lung Chi; Cohen, Mitchell D; Harkema, Jack R; Wagner, James G; Costa, Daniel L

2003-06-01

Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory protection, individual differences in sensitivity to WTC PM2.5, and species differences in responses must be considered in assessing the risks of exposure to WTC PM2.5.

Can dendritic cells see light?

NASA Astrophysics Data System (ADS)

Chen, Aaron C.-H.; Huang, Ying-Ying; Sharma, Sulbha K.; Hamblin, Michael R.

2010-02-01

There are many reports showing that low-level light/laser therapy (LLLT) can enhance wound healing, upregulate cell proliferation and has anti-apoptotic effects by activating intracellular protective genes. In the field of immune response study, it is not known with any certainty whether light/laser is proinflammatory or anti-inflammatory. Increasingly in recent times dendritic cells have been found to play an important role in inflammation and the immunological response. In this study, we try to look at the impact of low level near infrared light (810-nm) on murine bone-marrow derived dendritic cells. Changes in surface markers, including MHC II, CD80 and CD11c and the secretion of interleukins induced by light may provide additional evidence to reveal the mystery of how light affects the maturation of dendritic cells as well how these light-induced mature dendritic cells would affect the activation of adaptive immune response.

Thermionic gas switch

DOEpatents

Hatch, George L.; Brummond, William A.; Barrus, Donald M.

1986-01-01

A temperature responsive thermionic gas switch having folded electron emitting surfaces. An ionizable gas is located between the emitter and an interior surface of a collector, coaxial with the emitter. In response to the temperature exceeding a predetermined level, sufficient electrons are derived from the emitter to cause the gas in the gap between the emitter and collector to become ionized, whereby a very large increase in current in the gap occurs. Due to the folded emitter surface area of the switch, increasing the "on/off" current ratio and adjusting the "on" current capacity is accomplished.

PLC-beta2 monitors the drug-induced release of differentiation blockade in tumoral myeloid precursors.

PubMed

Brugnoli, Federica; Bovolenta, Matteo; Benedusi, Mascia; Miscia, Sebastianó; Capitani, Silvano; Bertagnolo, Valeria

2006-05-01

The differentiation therapy in treatment of acute promyelocytic leukemia (APL), based on the administration of all-trans retinoic acid (ATRA), is currently flanked with the use of As2O3, a safe and effective agent for patients showing a resistance to ATRA treatment. A synergy between ATRA and As3O3 was also reported in inducing granulocytic differentiation of APL-derived cells. We have demonstrated that phospholipase C-beta2 (PLC-beta2), highly expressed in neutrophils and nearly absent in tumoral promyelocytes, largely increases during ATRA treatment of APL-derived cells and strongly correlates with the responsiveness of APL patients to ATRA-based differentiating therapies. Here we report that, in APL-derived cells, low doses of As3O3 induce a slight increase of PLC-beta2 together with a moderate maturation, and cooperate with ATRA to provoke a significant increase of PLC-beta2 expression. Remarkably, the amounts of PLC-beta2 draw a parallel with the differentiation levels reached by both ATRA-responsive and -resistant cells treated with ATRA/As2O3 combinations. PLC-beta2 is not necessary for the progression of tumoral promyelocytes along the granulocytic lineage and is unable to overcome the differentiation block or to potentiate the agonist-induced maturation. On the other hand, since its expression closely correlates with the differentiation level reached by APL-derived cells induced to maturate by drugs presently employed in APL therapies, PLC-beta2 represents indeed a specific marker to test the ability of differentiation agents to induce the release of the maturation blockade of tumoral myeloid precursors.

Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats.

PubMed

Matveyenko, Aleksey V; Georgia, Senta; Bhushan, Anil; Butler, Peter C

2010-11-01

Embryonic stem cell therapy has been proposed as a therapeutic strategy to restore β-cell mass and function in T1DM. Recently, a group from Novocell (now ViaCyte) reported successful development of glucose-responsive islet-like structures after implantation of pancreatic endoderm (PE) derived from human embryonic stem cells (hESC) into immune-deficient mice. Our objective was to determine whether implantation of hESC-derived pancreatic endoderm from Novocell into athymic nude rats results in development of viable glucose-responsive pancreatic endocrine tissue. Athymic nude rats were implanted with PE derived from hESC either via implantation into the epididymal fat pads or by subcutaneous implantation into TheraCyte encapsulation devices for 20 wk. Blood glucose, weight, and human insulin/C-peptide secretion were monitored by weekly blood draws. Graft β-cell function was assessed by a glucose tolerance test, and graft morphology was assessed by immunohistochemistry and immunofluorescence. At 20 wk postimplantation, epididymal fat-implanted PE progressed to develop islet-like structures in 50% of implants, with a mean β-cell fractional area of 0.8 ± 0.3%. Human C-peptide and insulin were detectable, but at very low levels (C-peptide = 50 ± 26 pmol/l and insulin = 15 ± 7 pmol/l); however, there was no increase in human C-peptide/insulin levels after glucose challenge. There was no development of viable pancreatic tissue or meaningful secretory function when human PE was implanted in the TheraCyte encapsulation devices. These data confirm that islet-like structures develop from hESC differentiated to PE by the protocol developed by NovoCell. However, the extent of endocrine cell formation and secretory function is not yet sufficient to be clinically relevant.

Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats

PubMed Central

Matveyenko, Aleksey V.; Georgia, Senta; Bhushan, Anil

2010-01-01

Embryonic stem cell therapy has been proposed as a therapeutic strategy to restore β-cell mass and function in T1DM. Recently, a group from Novocell (now ViaCyte) reported successful development of glucose-responsive islet-like structures after implantation of pancreatic endoderm (PE) derived from human embryonic stem cells (hESC) into immune-deficient mice. Our objective was to determine whether implantation of hESC-derived pancreatic endoderm from Novocell into athymic nude rats results in development of viable glucose-responsive pancreatic endocrine tissue. Athymic nude rats were implanted with PE derived from hESC either via implantation into the epididymal fat pads or by subcutaneous implantation into TheraCyte encapsulation devices for 20 wk. Blood glucose, weight, and human insulin/C-peptide secretion were monitored by weekly blood draws. Graft β-cell function was assessed by a glucose tolerance test, and graft morphology was assessed by immunohistochemistry and immunofluorescence. At 20 wk postimplantation, epididymal fat-implanted PE progressed to develop islet-like structures in 50% of implants, with a mean β-cell fractional area of 0.8 ± 0.3%. Human C-peptide and insulin were detectable, but at very low levels (C-peptide = 50 ± 26 pmol/l and insulin = 15 ± 7 pmol/l); however, there was no increase in human C-peptide/insulin levels after glucose challenge. There was no development of viable pancreatic tissue or meaningful secretory function when human PE was implanted in the TheraCyte encapsulation devices. These data confirm that islet-like structures develop from hESC differentiated to PE by the protocol developed by NovoCell. However, the extent of endocrine cell formation and secretory function is not yet sufficient to be clinically relevant. PMID:20587750

Maternal sympathetic stress impairs follicular development and puberty of the offspring.

PubMed

Barra, Rafael; Cruz, Gonzalo; Mayerhofer, Artur; Paredes, Alfonso; Lara, Hernán E

2014-08-01

Chronic cold stress applied to adult rats activates ovarian sympathetic innervation and develops polycystic ovary (PCO) phenotype. The PCO syndrome in humans originates during early development and is expressed before or during puberty, which suggests that the condition derived from in utero exposure to neural- or metabolic-derived insults. We studied the effects of maternal sympathetic stress on the ovarian follicular development and on the onset of puberty of female offspring. Timed pregnant rats were exposed to chronic cold stress (4 °C, 3 h/daily from 1000 to 1300 h) during the entire pregnancy. Neonatal rats exposed to sympathetic stress during gestation had a lower number of primary, primordial, and secondary follicles in the ovary and a lower recruitment of primary and secondary follicles derived from the primordial follicular pool. The expression of the FSH receptor and response of the neonatal ovary to FSH were reduced. A decrease in nerve growth factor (NGF) mRNA was found without change in the low-affinity NGF receptor. The FSH-induced development of secondary follicles was decreased. At puberty, estradiol plasma levels decreased without changes in LH plasma levels. Puberty onset (as shown by the vaginal opening) was delayed. Ovarian norepinephrine (NE) was reduced; there was no change in its metabolite, 3-methoxy-4-hydroxyphenylglycol, in stressed rats and no change in NE turnover. The changes in ovarian NE in prepubertal rats stressed during gestation could represent a lower development of sympathetic nerves as a compensatory response to the chronically increased NE levels during gestation and hence participate in delaying reproductive performance in the rat. © 2014 Society for Reproduction and Fertility.

Analysis of neutrophil-derived antimicrobial peptides in gingival crevicular fluid suggests importance of cathelicidin LL-37 in the innate immune response against periodontogenic bacteria

PubMed Central

Puklo, M.; Guentsch, A.; Hiemstra, P. S.; Eick, S.; Potempa, J.

2008-01-01

Introduction During periodontitis, an innate immune response to bacterial challenge is primarily mediated by neutrophils. We compared neutrophilic content and the level of neutrophil-derived antimicrobial peptides in gingival crevicular fluid (GCF) in two clinical forms of severe periodontitis. Methods GCF was collected from 14 patients with aggressive periodontitis, 17 patients with chronic periodontitis, and nine healthy subjects. Samples were analyzed for periodontopathogen load using real-time polymerase chain reactions. The amounts of myeloperoxidase and α-defensins (HNP1–3) were determined by enzyme-linked immunosorbent assay, and the level of cathelicidin (hCAP18/LL-37) was assayed by Western blot. Results Myeloperoxidase concentration was not correlated with levels of LL-37 and HNP1–3 in samples from patients, compared to controls. The amount of HNP1–3 was twofold and fourfold higher in patients with aggressive and chronic periodontitis, respectively. Those with chronic disease had significantly elevated amounts of mature LL-37. The increased concentration of both peptides in chronic periodontitis correlated with the load of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola. Conclusion The lack of a correlation between LL-37, HNP1–3, and myeloperoxidase content suggests that neutrophils are not the sole source of these bactericidal peptides in the GCF of patients with periodontitis; and that other cells contribute to their local production. The bacterial proteases of P. gingivalis, T. forsythia, and T. denticola might degrade hCAP18/LL-37, because the 11-kDa cathelicidin-derived fragment was present in GCF collected from pockets infected with these bacteria. Collectively, it appears that a local deficiency in LL-37 can be considered as a supporting factor in the pathogenesis of severe cases of periodontitis. PMID:18582333

Hydrological response to earthquakes in the Haibara well, central Japan - II. Possible mechanism inferred from time-varying hydraulic properties

USGS Publications Warehouse

Matsumoto, N.; Roeloffs, E.A.

2003-01-01

28 coseismic groundwater level decreases have been observed at the Haibara well, Shizuoka prefecture, central Japan, from 1981 to 1997. These groundwater level changes cannot be explained as the poroelastic response to coseismic static strain. We use the atmospheric pressure and tidal responses of the well, rock properties measured on core samples from the same formation and pumping test results to characterize the hydraulic and mechanical properties of the aquifer. The responses of the Haibara well to the M2 Earth tide constituent and to atmospheric pressure have varied over time. In particular, increasing amplitude and decreasing phase lags were observed after the 1993 pumping test, as well as after earthquakes that caused coseismic water level changes. The tidal response, together with the surface load efficiency derived from the atmospheric pressure response, is used to estimate the mechanical properties of the aquifer. The largest amplitude of the M2 constituent, 2.2 mm, is small enough to imply that pore fluid in this system is approximately twice as compressible as water, possibly due to the presence of a small amount of exsolved gas. Diffusion of a coseismic pressure drop near the well could account for the observed time histories of the water level changes. The time histories of the water level drops are well matched by the decay of a coseismic pressure drop at least 80 m away from the well. Removal of a small amount of gas from the formation in that location might in turn explain the coseismic pressure drops.

Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression

PubMed Central

Damuzzo, Vera; Francescato, Samuela; Pozzuoli, Assunta; Berizzi, Antonio; Mocellin, Simone; Rossi, Carlo Riccardo; Bronte, Vincenzo; Mandruzzato, Susanna

2016-01-01

The expansion of myeloid derived suppressor cells (MDSCs), a suppressive population able to hamper the immune response against cancer, correlates with tumor progression and overall survival in several cancer types. We have previously shown that MDSCs can be induced in vitro from precursors present in the bone marrow and observed that these cells are able to actively proliferate in the presence of activated T cells, whose activation level is critical to drive the suppressive activity of MDSCs. Here we investigated at molecular level the mechanisms involved in the interplay between MDSCs and activated T cells. We found that activated T cells secrete IL-10 following interaction with MDSCs which, in turn, activates STAT3 phosphorylation on MDSCs then leading to B7-H1 expression. We also demonstrated that B7-H1+ MDSCs are responsible for immune suppression through a mechanism involving ARG-1 and IDO expression. Finally, we show that the expression of ligands B7-H1 and MHC class II both on in vitro-induced MDSCs and on MDSCs in the tumor microenvironment of cancer patients is paralleled by an increased expression of their respective receptors PD-1 and LAG-3 on T cells, two inhibitory molecules associated with T cell dysfunction. These findings highlight key molecules and interactions responsible for the extensive cross-talk between MDSCs and activated T cells that are at the basis of immune suppression. PMID:26700461

Akt and ERK/Nrf2 activation by PUFA oxidation-derived aldehydes upregulates FABP4 expression in human macrophages.

PubMed

Lázaro, Iolanda; Ferré, Raimon; Masana, Lluís; Cabré, Anna

2013-10-01

In macrophages, adipocyte fatty acid-binding protein (FABP4) coordinates key events in oxidized LDL-induced foam cell formation, such as cholesterol trafficking and inflammatory responses. Nrf2 is a redox-sensitive transcription factor with antioxidant and anti-inflammatory properties. We investigated the involvement of the Nrf2 signaling pathway in FABP4-upregulation in response to aldehydes that are derived from polyunsaturated fatty acid (PUFA) oxidation. Using RT-PCR and western blotting, we found that the aldehyde 2,4-decadienal (2,4-DDE) produced a marked increase in FABP4 mRNA and protein levels. 2,4-DDE acts at the transcriptional level of FABP4 by promoting mRNA synthesis and prolonging the half-life of the de novo synthesized mRNA. 2,4-DDE consistently enhanced nuclear translocation of phosphorylated Nrf2, which was mediated by the activation of the Akt and ERK signaling pathways. A chromatin immunoprecipitation assay showed the in vivo binding of activated Nrf2 to a newly identified ARE site in the human FABP4 promoter. We propose an Akt and ERK/Nrf2-dependent FABP4 upregulation pathway in response to PUFA oxidation end-products in human macrophages. These results open a new avenue for putative therapeutic targets addressed to control atherogenesis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Using Modified Mercalli Intensities to estimate acceleration response spectra for the 1906 San Francisco earthquake

USGS Publications Warehouse

Boatwright, J.; Bundock, H.; Seekins, L.C.

2006-01-01

We derive and test relations between the Modified Mercalli Intensity (MMI) and the pseudo-acceleration response spectra at 1.0 and 0.3 s - SA(1.0 s) and SA(0.3 s) - in order to map response spectral ordinates for the 1906 San Francisco earthquake. Recent analyses of intensity have shown that MMI ??? 6 correlates both with peak ground velocity and with response spectra for periods from 0.5 to 3.0 s. We use these recent results to derive a linear relation between MMI and log SA(1.0 s), and we refine this relation by comparing the SA(1.0 s) estimated from Boatwright and Bundock's (2005) MMI map for the 1906 earthquake to the SA(1.0 s) calculated from recordings of the 1989 Loma Prieta earthquake. South of San Jose, the intensity distributions for the 1906 and 1989 earthquakes are remarkably similar, despite the difference in magnitude and rupture extent between the two events. We use recent strong motion regressions to derive a relation between SA(1.0 s) and SA(0.3 s) for a M7.8 strike-slip earthquake that depends on soil type, acceleration level, and source distance. We test this relation by comparing SA(0.3 s) estimated for the 1906 earthquake to SA(0.3 s) calculated from recordings of both the 1989 Loma Prieta and 1994 Northridge earthquakes, as functions of distance from the fault. ?? 2006, Earthquake Engineering Research Institute.

Exposure to Nickel, Chromium, or Cadmium Causes Distinct Changes in the Gene Expression Patterns of a Rat Liver Derived Cell Line

PubMed Central

Permenter, Matthew G.; Lewis, John A.; Jackson, David A.

2011-01-01

Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells. PMID:22110744

Indoor noise annoyance due to 3-5 megawatt wind turbines-An exposure-response relationship.

PubMed

Hongisto, Valtteri; Oliva, David; Keränen, Jukka

2017-10-01

The existing exposure-response relationships describing the association between wind turbine sound level and noise annoyance concern turbine sizes of 0.15-3.0 MW. The main purpose of this study was to determine a relationship concerning turbines with nominal power of 3-5 MW. A cross-sectional survey was conducted around three wind power areas in Finland. The survey involved all households within a 2 km distance from the nearest turbine. Altogether, 429 households out of 753 participated. The households were exposed to wind turbine noise having sound levels within 26.7-44.2 dB L Aeq . Standard prediction methods were applied to determine the sound level, L Aeq , in each participant's yard. The measured sound level agreed well with the predicted sound level. The exposure-response relationship was derived between L Aeq outdoors and the indoor noise annoyance. The relationship was in rather good agreement with two previous studies involving much smaller turbines (0.15-1.5 MW) under 40 dB L Aeq . The Community Tolerance Level (CTL), CTL 20  = 50 dB, was 3 dB lower than for two previous studies. Above 40 dB, a small number of participants prevented a reliable comparison to previous studies.

Are children's vitamin D levels and BMI associated with antibody titers produced in response to 2014-2015 influenza vaccine?

PubMed

Lin, Chyongchiou J; Martin, Judith M; Cole, Kelly Stefano; Zimmerman, Richard K; Susick, Michael; Moehling, Krissy K; Levine, Min Z; Spencer, Sarah; Flannery, Brendan; Nowalk, Mary Patricia

2017-07-03

Vitamin D is an immunomodulating hormone, which has been associated with susceptibility to infectious diseases. Serum vitamin D levels in 135 children ages 3-17 y were measured at baseline and hemagglutinin influenza antibody titers were measured pre- and 21 d post influenza vaccination with live attenuated influenza vaccine (LAIV) or inactivated influenza vaccine (IIV). Height and weight were derived from the electronic medical record and were used to calculate body mass index (BMI). Thirty-nine percent of children were ages 3-8 years; 75% were black, 34% were obese (BMI ≥ 95 th percentile); vitamin D levels were >20 ng/ml in 55%. In linear regression analyses, post vaccination antibody titers for LAIV B lineages (B Brisbane and B Massachusetts) were significantly higher among those with lower vitamin D levels and among younger participants (P < 0.05). No associations between vitamin D levels and responses to LAIV A strains (A/H1N1 and A/H3N2) or to any IIV strains or lineages were found. Low vitamin D levels were associated with higher response to LAIV B lineages in the 2014-2015 LAIV, but not related to LAIV A or any IIV strains.

A Longitudinal Hepatitis B Vaccine Cohort Demonstrates Long-lasting Hepatitis B Virus (HBV) Cellular Immunity Despite Loss of Antibody Against HBV Surface Antigen

PubMed Central

Simons, Brenna C.; Spradling, Philip R.; Bruden, Dana J. T.; Zanis, Carolyn; Case, Samantha; Choromanski, Tammy L.; Apodaca, Minjun; Brogdon, Hazel D.; Dwyer, Gaelen; Snowball, Mary; Negus, Susan; Bruce, Michael G.; Morishima, Chihiro; Knall, Cindy; McMahon, Brian J.

2016-01-01

Background. Long-lasting protection resulting from hepatitis B vaccine, despite loss of antibody against hepatitis B virus (HBV) surface antigen (anti-HBs), is undetermined. Methods. We recruited persons from a cohort vaccinated with plasma-derived hepatitis B vaccine in 1981 who have been followed periodically since. We performed serological testing for anti-HBs and microRNA-155 and assessed HBV-specific T-cell responses by enzyme-linked immunospot and cytometric bead array. Study subgroups were defined 32 years after vaccination as having an anti-HBs level of either ≥10 mIU/mL (group 1; n = 13) or <10 mIU/mL (group 2; n = 31). Results. All 44 participants, regardless of anti-HBs level, tested positive for tumor necrosis factor α, interleukin 10, or interleukin 6 production by HBV surface antigen–specific T cells. The frequency of natural killer T cells correlated with the level of anti-HBs (P = .008). The proportion of participants who demonstrated T-cell responses to HBV core antigen varied among the cytokines measured, suggesting some natural exposure to HBV in the study group. No participant had evidence of breakthrough HBV infection. Conclusions. Evidence of long-lasting cellular immunity, regardless of anti-HBs level, suggests that protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 32 years. PMID:27056956

Role of the human cytomegalovirus major immediate-early promoter's 19-base-pair-repeat cyclic AMP-response element in acutely infected cells.

PubMed

Keller, M J; Wheeler, D G; Cooper, E; Meier, J L

2003-06-01

Prior studies have suggested a role of the five copies of the 19-bp-repeat cyclic AMP (cAMP)-response element (CRE) in major immediate-early (MIE) promoter activation, the rate-limiting step in human cytomegalovirus (HCMV) replication. We used two different HCMV genome modification strategies to test this hypothesis in acutely infected cells. We report the following: (i) the CREs do not govern basal levels of MIE promoter activity at a high or low multiplicity of infection (MOI) in human foreskin fibroblast (HFF)- or NTera2-derived neuronal cells; (ii) serum and virion components markedly increase MIE promoter-dependent transcription at a low multiplicity of infection (MOI), but this increase is not mediated by the CREs; (iii) forskolin stimulation of the cAMP signaling pathway induces a two- to threefold increase in MIE RNA levels in a CRE-specific manner at a low MOI in both HFF- and NTera2-derived neuronal cells; and (iv) the CREs do not regulate basal levels of HCMV DNA replication at a high or low MOI in HFF. Their presence does impart a forskolin-induced increase in viral DNA replication at a low MOI but only when basal levels of MIE promoter activity are experimentally diminished. In conclusion, the 19-bp-repeat CREs add to the robust MIE promoter activity that occurs in the acutely infected stimulated cells, although the CREs' greater role may be in other settings.

Inhibition of endogenous pyrogen-induced fever by a muramyl dipeptide derivative.

PubMed

Parant, M; Riveau, G; Parant, F; Chedid, L

1984-09-01

N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP), is a synthetic immunoadjuvant analogue of a bacterial peptidoglycan subunit that has a definite pyrogenic effect in the rabbit. Some adjuvant-active derivatives such as murabutide [MDP(Gln)-OnBu] or murametide [MDP(Gln)-OMe] are not pyrogenic. Murabutide did not stimulate human or rabbit cells to release endogenous pyrogen (EP), but murametide induced EP production at the same dosage levels as MDP. Moreover, plasma from rabbits treated with murametide transferred into untreated recipients elicited a febrile response typical of EP fever and comparable with that induced by plasma from MDP-treated animals. Murametide not only inhibited the central effect of EP that is generated but also the effect of an extra dose of EP administered later by the intravenous route. Moreover, pretreatment of rabbits with murametide decreased fever responses induced by certain high-molecular-weight exogenous pyrogens as mediated through the production of EP.

Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants.

PubMed

Schneider, M L

1992-11-01

This prospective study investigated whether mild maternal stress during pregnancy could alter the behavioral and affective responses in rhesus monkey infants in a complex, novel environment. Twenty-four rhesus monkey infants were tested on three occasions at 6 months of age in a novel environment. Twelve infants were derived from mothers exposed to a daily 10-min mild stressor from Day 90 to Day 145 postconception, while 12 were derived from mothers undisturbed during pregnancy. Prenatally stressed infants demonstrated more disturbance behavior, and lower levels of gross motor/exploratory behavior. Moreover, half of the prenatally stressed infants showed an abnormal response, falling asleep, while none of the control infants displayed this behavior. Males exhibited more clinging to surrogates, while females spent more time in gross motor/exploratory behaviors, with prenatally stressed males tending to spend the least time in gross motor/exploratory activity.

Granulocytic Myeloid Derived Suppressor Cells Expansion during Active Pulmonary Tuberculosis Is Associated with High Nitric Oxide Plasma Level

PubMed Central

El Daker, Sary; Sacchi, Alessandra; Tempestilli, Massimo; Carducci, Claudia; Goletti, Delia; Vanini, Valentina; Colizzi, Vittorio; Lauria, Francesco Nicola; Martini, Federico; Martino, Angelo

2015-01-01

Tuberculosis (TB) is still the principal cause of death caused by a single infectious agent, and the balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. The aim of this work was to study the role of myeloid-derived suppressor cells (MDSCs) during active pulmonary tuberculosis at the site of infection. We observed an expansion of MDSCs in the lung and blood of patients with active TB, which are correlated with an enhanced amount of nitric oxide in the plasma. We also found that these cells have the remarkable ability to suppress T-cell response, suggesting an important role in the modulation of the immune response against TB. Interestingly, a trend in the diminution of MDSCs was found after an efficacious anti-TB therapy, suggesting that these cells may be used as a potential biomarker for monitoring anti-TB therapy efficacy. PMID:25879532

Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury.

PubMed

Griesbach, Grace S; Tio, Delia L; Vincelli, Jennifer; McArthur, David L; Taylor, Anna N

2012-05-01

Voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF) after traumatic brain injury (TBI) when it occurs during a delayed time window. In contrast, acute post-TBI exercise does not increase BDNF. It is well known that increases in glucocorticoids suppress levels of BDNF. Moreover, recent work from our laboratory showed that there is a heightened stress response after fluid percussion injury (FPI). In order to determine if a heightened stress response is also observed with acute exercise, at post-injury days 0-4 and 7-11, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) release were measured in rats running voluntarily or exposed to two daily 20-min periods of forced running wheel exercise. Forced, but not voluntary exercise, continuously elevated CORT. ACTH levels were initially elevated with forced exercise, but decreased by post-injury day 7 in the control, but not the FPI animals. As previously reported, voluntary exercise did not increase BDNF in the FPI group as it did in the control animals. Forced exercise did not increase levels of BDNF in any group. It did, however, decrease hippocampal glucocorticoid receptors in the control group. The results suggest that exercise regimens with strong stress responses may not be beneficial during the early post-injury period.

Subsonic stability and control derivatives for an unpowered, remotely piloted 3/8-scale F-15 airplane model obtained from flight test

NASA Technical Reports Server (NTRS)

Iliff, K. W.; Maine, R. E.; Shafer, M. F.

1976-01-01

In response to the interest in airplane configuration characteristics at high angles of attack, an unpowered remotely piloted 3/8-scale F-15 airplane model was flight tested. The subsonic stability and control characteristics of this airplane model over an angle of attack range of -20 to 53 deg are documented. The remotely piloted technique for obtaining flight test data was found to provide adequate stability and control derivatives. The remotely piloted technique provided an opportunity to test the aircraft mathematical model in an angle of attack regime not previously examined in flight test. The variation of most of the derivative estimates with angle of attack was found to be consistent, particularly when the data were supplemented by uncertainty levels.

Urinary and plasma purine derivatives in fed and fasted llamas (Lama glama and L. guanacoe).

PubMed

Bakker, M L; Chen, X B; Kyle, D J; Orskov, E R; Bourke, D A

1996-02-01

The changes in urinary and plasma purine derivatives in response to fasting and level of feeding in llamas were examines. In one experiment, four llamas were gradually deprived of feed within 3 days and then fasted for 6 days. Daily urinary excretion of purine derivatives decreased with feed intake and leveled on the last 3 days of fasting at 177 +/- 26 mumol/kg W0.75. Allantoin and uric acid comprised 71% and 15% of total purine derivatives, respectively, in both fed and fasted states, but hypoxanthine plus xanthine increased from 9% to 36%. Plasma concentration of allantoin declined with feed intake reduction, but those of uric acid (217 mumol/l) and hypoxanthine plus xanthine (27 mumol/l) remained relatively unchanged. Concentration of uric acid was higher than that of allantoin, probably due to a high reabsorption of uric acid in renal tubules, which was measured as over 90%. In a second experiment, the four llamas were fed at 860 and 1740 g dry matter/d in a crossover design. Urinary total purine derivatives excretion responded to feed intake (10.4 vs 14.4 mmol/d), although the observed differences did not reach significance. Compared with some ruminant species, it appears that the llama resembles sheep regarding the magnitude of urinary purine derivatives excretion but is unique in maintaining a high concentration of uric acid in plasma, which could be part of the llama's adaptation to their environment.

Predicting Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer with Textural Features Derived from Pretreatment 18F-FDG PET/CT Imaging.

PubMed

Beukinga, Roelof J; Hulshoff, Jan B; van Dijk, Lisanne V; Muijs, Christina T; Burgerhof, Johannes G M; Kats-Ugurlu, Gursah; Slart, Riemer H J A; Slump, Cornelis H; Mul, Véronique E M; Plukker, John Th M

2017-05-01

Adequate prediction of tumor response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer (EC) patients is important in a more personalized treatment. The current best clinical method to predict pathologic complete response is SUV max in 18 F-FDG PET/CT imaging. To improve the prediction of response, we constructed a model to predict complete response to nCRT in EC based on pretreatment clinical parameters and 18 F-FDG PET/CT-derived textural features. Methods: From a prospectively maintained single-institution database, we reviewed 97 consecutive patients with locally advanced EC and a pretreatment 18 F-FDG PET/CT scan between 2009 and 2015. All patients were treated with nCRT (carboplatin/paclitaxel/41.4 Gy) followed by esophagectomy. We analyzed clinical, geometric, and pretreatment textural features extracted from both 18 F-FDG PET and CT. The current most accurate prediction model with SUV max as a predictor variable was compared with 6 different response prediction models constructed using least absolute shrinkage and selection operator regularized logistic regression. Internal validation was performed to estimate the model's performances. Pathologic response was defined as complete versus incomplete response (Mandard tumor regression grade system 1 vs. 2-5). Results: Pathologic examination revealed 19 (19.6%) complete and 78 (80.4%) incomplete responders. Least absolute shrinkage and selection operator regularization selected the clinical parameters: histologic type and clinical T stage, the 18 F-FDG PET-derived textural feature long run low gray level emphasis, and the CT-derived textural feature run percentage. Introducing these variables to a logistic regression analysis showed areas under the receiver-operating-characteristic curve (AUCs) of 0.78 compared with 0.58 in the SUV max model. The discrimination slopes were 0.17 compared with 0.01, respectively. After internal validation, the AUCs decreased to 0.74 and 0.54, respectively. Conclusion: The predictive values of the constructed models were superior to the standard method (SUV max ). These results can be considered as an initial step in predicting tumor response to nCRT in locally advanced EC. Further research in refining the predictive value of these models is needed to justify omission of surgery. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: A meta-analysis study.

PubMed

Rocha, Renan Boeira; Dondossola, Eduardo Ronconi; Grande, Antônio José; Colonetti, Tamy; Ceretta, Luciane Bisognin; Passos, Ives C; Quevedo, Joao; da Rosa, Maria Inês

2016-12-01

We performed a systematic review and meta-analysis to estimate brain-derived neurotrophic factor (BDNF) level in patients with major depressive disorder (MDD) after electroconvulsive therapy (ECT). A comprehensive search of the Cochrane Library, MEDLINE, LILACS, Grey literature, and EMBASE was performed for papers published from January 1990 to April 2016. The following key terms were searched: "major depressive disorder", "unipolar depression", "brain-derived neurotrophic factor", and "electroconvulsive therapy". A total of 252 citations were identified by the search strategy, and nine studies met the inclusion criteria of the meta-analysis. BDNF levels were increased among patients with MDD after ECT (P value = 0.006). The standardized mean difference was 0.56 (95% CI: 0.17-0.96). Additionally, we found significant heterogeneity between studies (I 2  = 73%). Our findings suggest a potential role of BDNF as a marker of treatment response after ECT in patients with MDD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Poroelastic properties of the Arbuckle Group in Oklahoma derived from well fluid level response to the 3 September 2016 Mw 5.8 Pawnee and 7 November 2016 Mw 5.0 Cushing earthquakes

USGS Publications Warehouse

Kroll, Kayla A.; Cochran, Elizabeth S.; Murray, Kyle E.

2017-01-01

The Arbuckle Group (Arbuckle) is a basal sedimentary unit that is the primary target for saltwater disposal in Oklahoma. Thus, the reservoir characteristics of the Arbuckle, including how the poroelastic properties change laterally and over time are of significant interest. We report observations of fluid level changes in two monitoring wells in response to the 3 September 2016 Mw 5.8 Pawnee and the 7 November 2016 Mw 5.0 Cushing earthquakes. We investigate the relationship between static strain resulting from these events and the fluid level changes observed in the wells. We model the fluid level response by estimating static strains from a set of earthquake source parameters and spatiotemporal poroelastic properties of the Arbuckle in the neighborhood of the monitoring wells. Results suggest that both the direction of the observed fluid level step and the amplitude can be predicted from the computed volumetric strain change and a reasonable set of poroelastic parameters. Modeling results indicate that poroelastic parameters differ at the time of the Pawnee and Cushing earthquakes, with a moderately higher Skempton’s coefficient required to fit the response to the Cushing earthquake. This may indicate that dynamic shaking resulted in physical alteration of the Arbuckle at distances up to ∼50  km from the Pawnee earthquake.

Adjunctive N-acetylcysteine in depression: exploration of interleukin-6, C-reactive protein and brain-derived neurotrophic factor.

PubMed

Hasebe, Kyoko; Gray, Laura; Bortolasci, Chiara; Panizzutti, Bruna; Mohebbi, Mohammadreza; Kidnapillai, Srisaiyini; Spolding, Briana; Walder, Ken; Berk, Michael; Malhi, Gin; Dodd, Seetal; Dean, Olivia M

2017-12-01

This study aimed to explore effects of adjunctive N-acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression. We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum samples at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment. NAC treatment significantly improved depressive symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment. Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.

Linear response to long wavelength fluctuations using curvature simulations

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

Baldauf, Tobias; Zaldarriaga, Matias; Seljak, Uroš

2016-09-01

We study the local response to long wavelength fluctuations in cosmological N -body simulations, focusing on the matter and halo power spectra, halo abundance and non-linear transformations of the density field. The long wavelength mode is implemented using an effective curved cosmology and a mapping of time and distances. The method provides an alternative, more direct, way to measure the isotropic halo biases. Limiting ourselves to the linear case, we find generally good agreement between the biases obtained from the curvature method and the traditional power spectrum method at the level of a few percent. We also study the responsemore » of halo counts to changes in the variance of the field and find that the slope of the relation between the responses to density and variance differs from the naïve derivation assuming a universal mass function by approximately 8–20%. This has implications for measurements of the amplitude of local non-Gaussianity using scale dependent bias. We also analyze the halo power spectrum and halo-dark matter cross-spectrum response to long wavelength fluctuations and derive second order halo bias from it, as well as the super-sample variance contribution to the galaxy power spectrum covariance matrix.« less

Understanding the hydrologic impacts of wastewater treatment plant discharge to shallow groundwater: Before and after plant shutdown

USGS Publications Warehouse

Hubbard, Laura E.; Keefe, Steffanie H.; Kolpin, Dana W.; Barber, Larry B.; Duris, Joseph W.; Hutchinson, Kasey J.; Bradley, Paul M.

2016-01-01

Effluent-impacted surface water has the potential to transport not only water, but wastewater-derived contaminants to shallow groundwater systems. To better understand the effects of effluent discharge on in-stream and near-stream hydrologic conditions in wastewater-impacted systems, water-level changes were monitored in hyporheic-zone and shallow-groundwater piezometers in a reach of Fourmile Creek adjacent to and downstream of the Ankeny (Iowa, USA) wastewater treatment plant (WWTP). Water-level changes were monitored from approximately 1.5 months before to 0.5 months after WWTP closure. Diurnal patterns in WWTP discharge were closely mirrored in stream and shallow-groundwater levels immediately upstream and up to 3 km downstream of the outfall, indicating that such discharge was the primary control on water levels before shutdown. The hydrologic response to WWTP shutdown was immediately observed throughout the study reach, verifying the far-reaching hydraulic connectivity and associated contaminant transport risk. The movement of WWTP effluent into alluvial aquifers has implications for potential WWTP-derived contamination of shallow groundwater far removed from the WWTP outfall.

Adjoint-based constant-mass partial derivatives

DOE PAGES

Favorite, Jeffrey A.

2017-09-01

In transport theory, adjoint-based partial derivatives with respect to mass density are constant-volume derivatives. Likewise, adjoint-based partial derivatives with respect to surface locations (i.e., internal interface locations and the outer system boundary) are constant-density derivatives. This study derives the constant-mass partial derivative of a response with respect to an internal interface location or the outer system boundary and the constant-mass partial derivative of a response with respect to the mass density of a region. Numerical results are given for a multiregion two-dimensional (r-z) cylinder for three very different responses: the uncollided gamma-ray flux at an external detector point, k effmore » of the system, and the total neutron leakage. Finally, results from the derived formulas compare extremely well with direct perturbation calculations.« less

Using response evaluation criteria in solid tumors in real-world evidence cancer research.

PubMed

Feinberg, Bruce A; Bharmal, Murtuza; Klink, Andrew J; Nabhan, Chadi; Phatak, Hemant

2018-05-31

Real-world evidence of charted treatment responses to cancer drug therapy was compared with medical record derived radiographic measurements of target lesions per Response Evaluation Criteria in Solid Tumors (RECIST). 15 physicians treating 59 metastatic Merkel cell cancer (mMCC) patients contributed patient-level data. A comparison of medical record reported best response with radiographic measurements per RECIST of pre- and post-treatment target lesions. RECIST response rates were significantly lower compared with medical record reported with a concordance of 43.2% (95% CI: 28.0-58.4%). Subjective assessment of tumor response collected via traditional chart abstraction may overestimate benefit and limit the potential role of real-world evidence in value-based care research. The use of target lesion measurements presents an attractive alternative that better aligns with trial results.

Biota Modeling in EPA's Preliminary Remediation Goal and Dose Compliance Concentration Calculators for Use in EPA Superfund Risk Assessment: Explanation of Intake Rate Derivation, Transfer Factor Compilation, and Mass Loading Factor Sources

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

Manning, Karessa L.; Dolislager, Fredrick G.; Bellamy, Michael B.

The Preliminary Remediation Goal (PRG) and Dose Compliance Concentration (DCC) calculators are screening level tools that set forth Environmental Protection Agency's (EPA) recommended approaches, based upon currently available information with respect to risk assessment, for response actions at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) sites, commonly known as Superfund. The screening levels derived by the PRG and DCC calculators are used to identify isotopes contributing the highest risk and dose as well as establish preliminary remediation goals. Each calculator has a residential gardening scenario and subsistence farmer exposure scenarios that require modeling of the transfer of contaminants frommore » soil and water into various types of biota (crops and animal products). New publications of human intake rates of biota; farm animal intakes of water, soil, and fodder; and soil to plant interactions require updates be implemented into the PRG and DCC exposure scenarios. Recent improvements have been made in the biota modeling for these calculators, including newly derived biota intake rates, more comprehensive soil mass loading factors (MLFs), and more comprehensive soil to tissue transfer factors (TFs) for animals and soil to plant transfer factors (BV's). New biota have been added in both the produce and animal products categories that greatly improve the accuracy and utility of the PRG and DCC calculators and encompass greater geographic diversity on a national and international scale.« less

Bacterium-Induced CXCL10 Secretion by Osteoblasts Can Be Mediated in Part through Toll-Like Receptor 4

PubMed Central

Gasper, Nancy A.; Petty, Cynthia C.; Schrum, Laura W.; Marriott, Ian; Bost, Kenneth L.

2002-01-01

Two common pathogens known to cause bone infection, Salmonella and Staphylococcus aureus, were investigated to determine their abilities to induce chemokine expression in cultured mouse and human osteoblasts. While these cells are responsible for bone formation, we were surprised to find that they could respond to bacterial infection by upregulating expression of the chemokine CXCL10 (IP-10). However, there were significant differences in the abilities of the gram-negative bacterium Salmonella and the gram-positive bacterium S. aureus to induce expression of CXCL10. Reverse transcription-PCR and enzyme-linked immunosorbent assay analyses showed high levels of Salmonella-induced CXCL10 mRNA and protein expression, respectively, whereas the osteoblast response to S. aureus was significantly less. Consistent with these findings, Salmonella-derived lipopolysaccharide (LPS), but not S. aureus-derived peptidoglycan, could induce expression of CXCL10. An antibody against toll-like receptor 4 (TLR4) could block the LPS-induced CXCL10 production, demonstrating the functional expression of TLR4 by osteoblasts. Despite the inducible nature of TLR2 mRNA expression by bacterium-infected osteoblasts, peptidoglycan failed to stimulate CXCL10 secretion. Immunofluorescent staining of bacterium-infected calvaria (i.e., skull bone) demonstrated the presence of CXCL10 in osteoblasts. The fact that osteoblasts did not express CXCR3 mRNA, whereas T lymphocytes can express high levels of this receptor, suggests that osteoblast-derived CXCL10 may recruit T lymphocytes to the sites of bone infections. PMID:12117914

Patient-derived ovarian cancer xenografts re-growing after a cisplatinum treatment are less responsive to a second drug re-challenge: a new experimental setting to study response to therapy.

PubMed

Ricci, Francesca; Fratelli, Maddalena; Guffanti, Federica; Porcu, Luca; Spriano, Filippo; Dell'Anna, Tiziana; Fruscio, Robert; Damia, Giovanna

2017-01-31

Even if ovarian cancer patients are very responsive to a cisplatinum-based therapy, most will relapse with a resistant disease. New experimental animal models are needed to explore the mechanisms of resistance, to better tailor treatment and improve patient prognosis. To address these aims, seven patient-derived high-grade serous/endometrioid ovarian cancer xenografts were characterized for the antitumor response after one and two cycles of cisplatinum and classified as Very Responsive, Responsive, and Low Responsive to drug treatment. Xenografts re-growing after the first drug cycle were much less responsive to the second one. The expression of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) genes was investigated in cisplatinum-treated and not-treated tumors. We found that different EMT (TCF3, CAMK2N1, EGFR, and IGFBP4) and CSCs (SMO, DLL1, STAT3, and ITGA6) genes were expressed at higher levels in Low Responsive than in Responsive and Very Responsive xenografts. The expression of STAT3 was found to be associated with lower survival (HR = 13.7; p = 0.013) in the TCGA patient data set. MMP9, CD44, DLL4, FOXP1, MERTK, and PTPRC genes were found more expressed in tumors re-growing after cisplatinum treatment than in untreated tumors. We here describe a new in vivo ovarian carcinoma experimental setting that will be instrumental for specific trials of combination therapy to counteract cisplatinum resistance in order to improve the prognosis of ovarian patients.

Upregulated ATM gene expression and activated DNA crosslink-induced damage response checkpoint in Fanconi anemia: implications for carcinogenesis.

PubMed

Yamamoto, Kazuhiko; Nihrane, Abdallah; Aglipay, Jason; Sironi, Juan; Arkin, Steven; Lipton, Jeffrey M; Ouchi, Toru; Liu, Johnson M

2008-01-01

Fanconi anemia (FA) predisposes to hematopoietic failure, birth defects, leukemia, and squamous cell carcinoma of the head and neck (HNSCC) and cervix. The FA/BRCA pathway includes 8 members of a core complex and 5 downstream gene products closely linked with BRCA1 or BRCA2. Precancerous lesions are believed to trigger the DNA damage response (DDR), and we focused on the DDR in FA and its putative role as a checkpoint barrier to cancer. In primary fibroblasts with mutations in the core complex FANCA protein, we discovered that basal expression and phosphorylation of ATM (ataxia telangiectasia mutated) and p53 induced by irradiation (IR) or mitomycin C (MMC) were upregulated. This heightened response appeared to be due to increased basal levels of ATM in cultured FANCA-mutant cells, highlighting the new observation that ATM can be regulated at the transcriptional level in addition to its well-established activation by autophosphorylation. Functional analysis of this response using gamma-H2AX foci as markers of DNA double-stranded breaks (DSBs) demonstrated abnormal persistence of only MMC- and not IR-induced foci. Thus, we describe a processing defect that leads to general DDR upregulation but specific persistence of DNA crosslinker-induced damage response foci. Underscoring the significance of these findings, we found resistance to DNA crosslinker-induced cell cycle arrest and apoptosis in a TP53-mutant, patient-derived HNSCC cell line, whereas a lymphoblastoid cell line derived from this same individual was not mutated at TP53 and retained DNA crosslinker sensitivity. Our results suggest that cancer in FA may arise from selection for cells that escape from a chronically activated DDR checkpoint.

Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome

PubMed Central

Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; Doeberitz, Magnus von Knebel

2014-01-01

High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer (HNPCC) or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites (cMS) and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n=69), healthy Lynch syndrome mutation carriers (n=31) and healthy controls (n=52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (p=0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients. PMID:19957108

Positional differences in the wound transcriptome of skin and oral mucosa

PubMed Central

2010-01-01

Background When compared to skin, oral mucosal wounds heal rapidly and with reduced scar formation. Recent studies suggest that intrinsic differences in inflammation, growth factor production, levels of stem cells, and cellular proliferation capacity may underlie the exceptional healing that occurs in oral mucosa. The current study was designed to compare the transcriptomes of oral mucosal and skin wounds in order to identify critical differences in the healing response at these two sites using an unbiased approach. Results Using microarray analysis, we explored the differences in gene expression in skin and oral mucosal wound healing in a murine model of paired equivalent sized wounds. Samples were examined from days 0 to 10 and spanned all stages of the wound healing process. Using unwounded matched tissue as a control, filtering identified 1,479 probe sets in skin wounds yet only 502 probe sets in mucosal wounds that were significantly differentially expressed over time. Clusters of genes that showed similar patterns of expression were also identified in each wound type. Analysis of functionally related gene expression demonstrated dramatically different reactions to injury between skin and mucosal wounds. To explore whether site-specific differences might be derived from intrinsic differences in cellular responses at each site, we compared the response of isolated epithelial cells from skin and oral mucosa to a defined in vitro stimulus. When cytokine levels were measured, epithelial cells from skin produced significantly higher amounts of proinflammatory cytokines than cells from oral mucosa. Conclusions The results provide the first detailed molecular profile of the site-specific differences in the genetic response to injury in mucosa and skin, and suggest the divergent reactions to injury may derive from intrinsic differences in the cellular responses at each site. PMID:20704739

Positional differences in the wound transcriptome of skin and oral mucosa.

PubMed

Chen, Lin; Arbieva, Zarema H; Guo, Shujuan; Marucha, Phillip T; Mustoe, Thomas A; DiPietro, Luisa A

2010-08-12

When compared to skin, oral mucosal wounds heal rapidly and with reduced scar formation. Recent studies suggest that intrinsic differences in inflammation, growth factor production, levels of stem cells, and cellular proliferation capacity may underlie the exceptional healing that occurs in oral mucosa. The current study was designed to compare the transcriptomes of oral mucosal and skin wounds in order to identify critical differences in the healing response at these two sites using an unbiased approach. Using microarray analysis, we explored the differences in gene expression in skin and oral mucosal wound healing in a murine model of paired equivalent sized wounds. Samples were examined from days 0 to 10 and spanned all stages of the wound healing process. Using unwounded matched tissue as a control, filtering identified 1,479 probe sets in skin wounds yet only 502 probe sets in mucosal wounds that were significantly differentially expressed over time. Clusters of genes that showed similar patterns of expression were also identified in each wound type. Analysis of functionally related gene expression demonstrated dramatically different reactions to injury between skin and mucosal wounds. To explore whether site-specific differences might be derived from intrinsic differences in cellular responses at each site, we compared the response of isolated epithelial cells from skin and oral mucosa to a defined in vitro stimulus. When cytokine levels were measured, epithelial cells from skin produced significantly higher amounts of proinflammatory cytokines than cells from oral mucosa. The results provide the first detailed molecular profile of the site-specific differences in the genetic response to injury in mucosa and skin, and suggest the divergent reactions to injury may derive from intrinsic differences in the cellular responses at each site.

Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome.

PubMed

Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; von Knebel Doeberitz, Magnus

2010-06-01

High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n = 69), healthy Lynch syndrome mutation carriers (n = 31) and healthy controls (n = 52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (P = 0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients.

Human cytokine responses induced by Gram-positive cell walls of normal intestinal microbiota

PubMed Central

Chen, T; Isomäki, P; Rimpiläinen, M; Toivanen, P

1999-01-01

The normal microbiota plays an important role in the health of the host, but little is known of how the human immune system recognizes and responds to Gram-positive indigenous bacteria. We have investigated cytokine responses of peripheral blood mononuclear cells (PBMC) to Gram-positive cell walls (CW) derived from four common intestinal indigenous bacteria, Eubacterium aerofaciens (Eu.a.), Eubacterium limosum(Eu.l.), Lactobacillus casei(L.c.), and Lactobacillus fermentum (L.f.). Our results indicate that Gram-positive CW of the normal intestinal microbiota can induce cytokine responses of the human PBMC. The profile, level and kinetics of these responses are similar to those induced by lipopolysaccharide (LPS) or CW derived from a pathogen, Streptococcus pyogenes (S.p.). Bacterial CW are capable of inducing production of a proinflammatory cytokine, tumour necrosis factor-alpha (TNF-α), and an anti-inflammatory cytokine, IL-10, but not that of IL-4 or interferon-gamma (IFN-γ). Monocytes are the main cell population in PBMC to produce TNF-α and IL-10. Induction of cytokine secretion is serum-dependent; both CD14-dependent and -independent pathways are involved. These findings suggest that the human cytokine responses induced by Gram-positive CW of the normal intestinal microbiota are similar to those induced by LPS or Gram-positive CW of the pathogens. PMID:10540188

Silibinin ameliorates Aβ25-35-induced memory deficits in rats by modulating autophagy and attenuating neuroinflammation as well as oxidative stress.

PubMed

Song, Xiaoyu; Zhou, Biao; Cui, Lingyu; Lei, Di; Zhang, Pingping; Yao, Guodong; Xia, Mingyu; Hayashi, Toshihiko; Hattori, Shunji; Ushiki-Kaku, Yuko; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

2017-04-01

Alzheimer's disease (AD) is a progressive, neurodegenerative disease. Accumulating evidence suggests that inflammatory response, oxidative stress and autophagy are involved in amyloid β (Aβ)-induced memory deficits. Silibinin (silybin), a flavonoid derived from the herb milk thistle, is well known for its hepatoprotective activities. In this study, we investigated the neuroprotective effect of silibinin on Aβ 25-35 -injected rats. Results demonstrated that silibinin significantly attenuated Aβ 25-35 -induced memory deficits in Morris water maze and novel object-recognition tests. Silibinin exerted anxiolytic effect in Aβ 25-35 -injected rats as determined in elevated plus maze test. Silibinin attenuated the inflammatory responses, increased glutathione (GSH) levels and decreased malondialdehyde (MDA) levels, and upregulated autophagy levels in the Aβ 25-35 -injected rats. In conclusion, silibinin is a potential candidate for AD treatment because of its anti-inflammatory, antioxidant and autophagy regulating activities.

Clozapine response and plasma catecholamines and their metabolites.

PubMed

Green, A I; Alam, M Y; Sobieraj, J T; Pappalardo, K M; Waternaux, C; Salzman, C; Schatzberg, A F; Schildkraut, J J

1993-02-01

The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

Development of an Earthquake Impact Scale

NASA Astrophysics Data System (ADS)

Wald, D. J.; Marano, K. D.; Jaiswal, K. S.

2009-12-01

With the advent of the USGS Prompt Assessment of Global Earthquakes for Response (PAGER) system, domestic (U.S.) and international earthquake responders are reconsidering their automatic alert and activation levels as well as their response procedures. To help facilitate rapid and proportionate earthquake response, we propose and describe an Earthquake Impact Scale (EIS) founded on two alerting criteria. One, based on the estimated cost of damage, is most suitable for domestic events; the other, based on estimated ranges of fatalities, is more appropriate for most global events. Simple thresholds, derived from the systematic analysis of past earthquake impact and response levels, turn out to be quite effective in communicating predicted impact and response level of an event, characterized by alerts of green (little or no impact), yellow (regional impact and response), orange (national-scale impact and response), and red (major disaster, necessitating international response). Corresponding fatality thresholds for yellow, orange, and red alert levels are 1, 100, and 1000, respectively. For damage impact, yellow, orange, and red thresholds are triggered by estimated losses exceeding 1M, 10M, and $1B, respectively. The rationale for a dual approach to earthquake alerting stems from the recognition that relatively high fatalities, injuries, and homelessness dominate in countries where vernacular building practices typically lend themselves to high collapse and casualty rates, and it is these impacts that set prioritization for international response. In contrast, it is often financial and overall societal impacts that trigger the level of response in regions or countries where prevalent earthquake resistant construction practices greatly reduce building collapse and associated fatalities. Any newly devised alert protocols, whether financial or casualty based, must be intuitive and consistent with established lexicons and procedures. In this analysis, we make an attempt at both simple and intuitive color-coded alerting criterion; yet, we preserve the necessary uncertainty measures by which one can gauge the likelihood for the alert to be over- or underestimated.

Derivation of an occupational exposure level for manganese in welding fumes.

PubMed

Bailey, Lisa A; Kerper, Laura E; Goodman, Julie E

2018-01-01

Exposure to high levels of manganese (Mn) in occupational settings is known to lead to adverse neurological effects. Since Mn is an essential nutrient, there are mechanisms that maintain its homeostatic control in the body, and there is some level of Mn in air that does not perturb Mn homeostasis. However, the Mn exposure concentrations at which no adverse effects are expected in occupational settings vary considerably across regulatory agencies. We set out to derive a Mn Occupational Exposure Level (OEL) for welders based on a review of studies that evaluated Mn exposure concentrations from welding fumes and: (1) neurological effects in welders; (2) levels of Mn in the brains of welders (via pallidal index [PI] estimated from magnetic resonance imaging [MRI]); (3) other biomarkers of Mn exposure in welders (i.e., blood and urine); and (4) Mn brain concentrations, PI, and corresponding neurological effects in non-human primates. Our analysis suggests uncertainty in quantifying dose-response associations for Mn from many of the occupational welding studies. The few welding studies that adequately estimate exposure suggest a possible OEL of 100-140μg/m 3 for respirable Mn. This range is consistent with other epidemiology studies, studies of biomarkers of Mn exposure in welders, and with studies in non-human primates, though future studies could provide a stronger basis for deriving a Mn occupational guideline for welders. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of strenuous physical exercise on circulating cell-derived microparticles.

PubMed

Chaar, Vicky; Romana, Marc; Tripette, Julien; Broquere, Cédric; Huisse, Marie-Geneviève; Hue, Olivier; Hardy-Dessources, Marie-Dominique; Connes, Philippe

2011-01-01

Strenuous exercise is associated with an inflammatory response involving the activation of several types of blood cells. In order to document the specific activation of these cell types, we studied the effect of three maximal exercise tests conducted to exhaustion on the quantitative and qualitative pattern of circulating cell-derived microparticles and inflammatory molecules in healthy subjects. This study mainly indicated that the plasma concentration of microparticles from platelets and polymorphonuclear neutrophils (PMN) was increased immediately after the strenuous exercise. In addition, the increase in plasma concentration of microparticles from PMN and platelets was still observed after 2 hours of recovery. A similar pattern was observed for the IL-6 plasma level. In contrast, no change was observed for either soluble selectins or plasma concentration of microparticles from red blood cells, monocytes and endothelial cells. In agreement, sVCAM-1 and sICAM-1 levels were not changed by the exercise. We conclude that a strenuous exercise is accompanied by platelet- and PMN-derived microparticle production that probably reflects the activation of these two cell types.

Exploring the role of genetic variability and lifestyle in oxidative stress response for healthy aging and longevity.

PubMed

Dato, Serena; Crocco, Paolina; D'Aquila, Patrizia; de Rango, Francesco; Bellizzi, Dina; Rose, Giuseppina; Passarino, Giuseppe

2013-08-08

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life.

Amniotic Fluid Protein Profiles of Intraamniotic Inflammatory Response to Ureaplasma spp. and Other Bacteria

PubMed Central

Kacerovsky, Marian; Celec, Peter; Vlkova, Barbora; Skogstrand, Kristin; Hougaard, David M.; Cobo, Teresa; Jacobsson, Bo

2013-01-01

Objective This study aimed to evaluate the amniotic fluid protein profiles and the intensity of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria, using the multiplex xMAP technology. Methods A retrospective cohort study was undertaken in the Department of Obstetrics and Gynecology, University Hospital Hradec Kralove, Czech Republic. A total of 145 pregnant women with preterm prelabor rupture of membranes between gestational age 24+0 and 36+6 weeks were included in the study. Amniocenteses were performed. The presence of Ureaplasma spp. and other bacteria was evaluated using 16S rRNA gene sequencing. The levels of specific proteins were determined using multiplex xMAP technology. Results The presence of Ureaplasma spp. and other bacteria in the amniotic fluid was associated with increased levels of interleukin (IL)-6, IL-8, IL-10, brain-derived neurotropic factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and matrix metalloproteinasis-9. Ureaplasma spp. were also associated with increased levels of neurotropin-3 and triggering receptor expressed on myeloid cells-1. Conclusions The presence of Ureaplasma spp. in the amniotic fluid is associated with a slightly different protein profile of inflammatory response, but the intensity of inflammatory response to Ureaplasma spp. is comparable with the inflammatory response to other bacteria. PMID:23555967

Amniotic fluid protein profiles of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria.

PubMed

Kacerovsky, Marian; Celec, Peter; Vlkova, Barbora; Skogstrand, Kristin; Hougaard, David M; Cobo, Teresa; Jacobsson, Bo

2013-01-01

This study aimed to evaluate the amniotic fluid protein profiles and the intensity of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria, using the multiplex xMAP technology. A retrospective cohort study was undertaken in the Department of Obstetrics and Gynecology, University Hospital Hradec Kralove, Czech Republic. A total of 145 pregnant women with preterm prelabor rupture of membranes between gestational age 24+0 and 36+6 weeks were included in the study. Amniocenteses were performed. The presence of Ureaplasma spp. and other bacteria was evaluated using 16S rRNA gene sequencing. The levels of specific proteins were determined using multiplex xMAP technology. The presence of Ureaplasma spp. and other bacteria in the amniotic fluid was associated with increased levels of interleukin (IL)-6, IL-8, IL-10, brain-derived neurotropic factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and matrix metalloproteinasis-9. Ureaplasma spp. were also associated with increased levels of neurotropin-3 and triggering receptor expressed on myeloid cells-1. The presence of Ureaplasma spp. in the amniotic fluid is associated with a slightly different protein profile of inflammatory response, but the intensity of inflammatory response to Ureaplasma spp. is comparable with the inflammatory response to other bacteria.

Flapping response characteristics of hingeless rotor blades by a gereralized harmonic balance method

NASA Technical Reports Server (NTRS)

Peters, D. A.; Ormiston, R. A.

1975-01-01

Linearized equations of motion for the flapping response of flexible rotor blades in forward flight are derived in terms of generalized coordinates. The equations are solved using a matrix form of the method of linear harmonic balance, yielding response derivatives for each harmonic of the blade deformations and of the hub forces and moments. Numerical results and approximate closed-form expressions for rotor derivatives are used to illustrate the relationships between rotor parameters, modeling assumptions, and rotor response characteristics. Finally, basic hingeless rotor response derivatives are presented in tabular and graphical form for a wide range of configuration parameters and operating conditions.

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion

PubMed Central

Carbonaro, Denise A.; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao-Jin; Skelton, Dianne C.; Dorey, Frederick; Kellems, Rodney E.; Blackburn, Michael R.

2008-01-01

Adenosine deaminase (ADA)–deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose–dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy. PMID:18356486

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion.

PubMed

Carbonaro, Denise A; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao-Jin; Skelton, Dianne C; Dorey, Frederick; Kellems, Rodney E; Blackburn, Michael R; Kohn, Donald B

2008-06-15

Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose-dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy.

Optimization of Paclitaxel Containing pH-Sensitive Liposomes By 3 Factor, 3 Level Box-Behnken Design.

PubMed

Rane, Smita; Prabhakar, Bala

2013-07-01

The aim of this study was to investigate the combined influence of 3 independent variables in the preparation of paclitaxel containing pH-sensitive liposomes. A 3 factor, 3 levels Box-Behnken design was used to derive a second order polynomial equation and construct contour plots to predict responses. The independent variables selected were molar ratio phosphatidylcholine:diolylphosphatidylethanolamine (X1), molar concentration of cholesterylhemisuccinate (X2), and amount of drug (X3). Fifteen batches were prepared by thin film hydration method and evaluated for percent drug entrapment, vesicle size, and pH sensitivity. The transformed values of the independent variables and the percent drug entrapment were subjected to multiple regression to establish full model second order polynomial equation. F was calculated to confirm the omission of insignificant terms from the full model equation to derive a reduced model polynomial equation to predict the dependent variables. Contour plots were constructed to show the effects of X1, X2, and X3 on the percent drug entrapment. A model was validated for accurate prediction of the percent drug entrapment by performing checkpoint analysis. The computer optimization process and contour plots predicted the levels of independent variables X1, X2, and X3 (0.99, -0.06, 0, respectively), for maximized response of percent drug entrapment with constraints on vesicle size and pH sensitivity.

Plants Regulate Soil Organic Matter Decomposition in Response to Sea Level Rise

NASA Astrophysics Data System (ADS)

Megonigal, P.; Mueller, P.; Jensen, K.

2014-12-01

Tidal wetlands have a large capacity for producing and storing organic matter, making their role in the global carbon budget disproportionate to their land area. Most of the organic matter stored in these systems is in soils where it contributes 2-5 times more to surface accretion than an equal mass of minerals. Soil organic matter (SOM) sequestration is the primary process by which tidal wetlands become perched high in the tidal frame, decreasing their vulnerability to accelerated sea level rise. Plant growth responses to sea level rise are well understood and represented in century-scale forecast models of soil surface elevation change. We understand far less about the response of soil organic matter decomposition to rapid sea level rise. Here we quantified the effects of sea level on SOM decomposition rates by exposing planted and unplanted tidal marsh monoliths to experimentally manipulated flood duration. The study was performed in a field-based mesocosm facility at the Smithsonian's Global Change Research Wetland. SOM decomposition rate was quantified as CO2 efflux, with plant- and SOM-derived CO2 separated with a two end-member δ13C-CO2 model. Despite the dogma that decomposition rates are inversely related to flooding, SOM mineralization was not sensitive to flood duration over a 35 cm range in soil surface elevation. However, decomposition rates were strongly and positively related to aboveground biomass (R2≥0.59, p≤0.01). We conclude that soil carbon loss through decomposition is driven by plant responses to sea level in this intensively studied tidal marsh. If this result applies more generally to tidal wetlands, it has important implications for modeling soil organic matter and surface elevation change in response to accelerated sea level rise.

Interaction with extracellular matrix proteins influences Lsh/Ity/Bcg (candidate Nramp) gene regulation of macrophage priming/activation for tumour necrosis factor-alpha and nitrite release.

PubMed

Formica, S; Roach, T I; Blackwell, J M

1994-05-01

The murine resistance gene Lsh/Ity/Bcg regulates activation of macrophages for tumour necrosis factor-alpha (TNF-alpha)-dependent production of nitric oxide mediating antimicrobial activity against Leishmania, Salmonella and Mycobacterium. As Lsh is differentially expressed in macrophages from different tissue sites, experiments were performed to determine whether interaction with extracellular matrix (ECM) proteins would influence the macrophage TNF-alpha response. Plating of bone marrow-derived macrophages onto purified fibrinogen or fibronectin-rich L929 cell-derived matrices, but not onto mannan, was itself sufficient to stimulate TNF-alpha release, with significantly higher levels released from congenic B10.L-Lshr compared to C57BL/10ScSn (Lshs) macrophages. Only macrophages plated onto fibrinogen also released measurable levels of nitrites, again higher in Lshr compared to Lshs macrophages. Addition of interferon-gamma (IFN-gamma), but not bacterial lipopolysaccharide or mycobacterial lipoarabinomannan, as a second signal enhanced the TNF-alpha and nitrite responses of macrophages plated onto fibrinogen, particularly in the Lshr macrophages. Interaction with fibrinogen and fibronectin also primed macrophages for an enhanced TNF-alpha response to leishmanial parasites, but this was only translated into enhanced nitrite responses in the presence of IFN-gamma. In these experiments, Lshr macrophages remained superior in their TNF-alpha responses throughout, but to a degree which reflected the magnitude of the difference observed on ECM alone. Hence, the specificity for the enhanced TNF-alpha responses of Lshr macrophages lay in their interaction with fibrinogen and fibronectin ECM, while a differential nitrite response was only observed with fibrinogen and/or IFN-gamma. The results are discussed in relation to the possible function of the recently cloned candidate gene Nramp, which has structural identity to eukaryote transporters and an N-terminal cytoplasmic proline/serine-rich putative SH3 binding domain.

Responses of neurogenesis and neuroplasticity related genes to elevated CO2 levels in the brain of three teleost species.

PubMed

Lai, Floriana; Fagernes, Cathrine E; Bernier, Nicholas J; Miller, Gabrielle M; Munday, Philip L; Jutfelt, Fredrik; Nilsson, Göran E

2017-08-01

The continuous increase of anthropogenic CO 2 in the atmosphere resulting in ocean acidification has been reported to affect brain function in some fishes. During adulthood, cell proliferation is fundamental for fish brain growth and for it to adapt in response to external stimuli, such as environmental changes. Here we report the first expression study of genes regulating neurogenesis and neuroplasticity in brains of three-spined stickleback ( Gasterosteus aculeatus ), cinnamon anemonefish ( Amphiprion melanopus ) and spiny damselfish ( Acanthochromis polyacanthus ) exposed to elevated CO 2 The mRNA expression levels of the neurogenic differentiation factor (NeuroD) and doublecortin (DCX) were upregulated in three-spined stickleback exposed to high-CO 2 compared with controls, while no changes were detected in the other species. The mRNA expression levels of the proliferating cell nuclear antigen (PCNA) and the brain-derived neurotrophic factor (BDNF) remained unaffected in the high-CO 2 exposed groups compared to the control in all three species. These results indicate a species-specific regulation of genes involved in neurogenesis in response to elevated ambient CO 2 levels. The higher expression of NeuroD and DCX mRNA transcripts in the brain of high-CO 2 -exposed three-spined stickleback, together with the lack of effects on mRNA levels in cinnamon anemonefish and spiny damselfish, indicate differences in coping mechanisms among fish in response to the predicted-future CO 2 level. © 2017 The Author(s).

Comparison of cellular responses of mesenchymal stem cells derived from bone marrow and synovium on combined silk scaffolds.

PubMed

Liu, Haifeng; Wei, Xing; Ding, Xili; Li, Xiaoming; Zhou, Gang; Li, Ping; Fan, Yubo

2015-01-01

As a brand new member in mesenchymal stem cells (MSCs) families, synovium-derived mesenchymal stem cells (SMSCs) have been increasingly regarded as a promising therapeutic cell species for musculoskeletal regeneration. However, there are few reports mentioning ligamentogenesis of SMSCs and especially null for their engineering use towards ligament regeneration. The aim of this study was to investigate and compare the cellular responses of MSCs derived from bone marrow and synovium on combined silk scaffolds that can be used to determine the cell source most appropriate for tissue-engineered ligament. Rabbit SMSCs and bone marrow-derived mesenchymal stem cells (BMSCs) were isolated and cultured in vitro for two weeks after seeding on the combined silk scaffolds. Samples were studied and compared for their cellular morphology, proliferation, collagen production, gene, and protein expression of ligament-related extracellular matrix (ECM) markers. In addition, the two cell types were transfected with green fluorescent protein to evaluate their fate after implantation in an intraarticular environment of the knee joint. After 14 days of culturing, SMSCs showed a significant increase in proliferation as compared with BMSCs. The transcript and protein expression levels of ligament-related ECM markers in SMSCs were significantly higher than those in BMSCs. Moreover, 6 weeks postoperatively, more viable cells were presented in SMSC-loaded constructs than in BMSC-loaded constructs. Therefore, based on the cellular response in vitro and in vivo, SMSCs may represent a more suitable cell source than BMSCs for further study and development of tissue-engineered ligament. © 2014 Wiley Periodicals, Inc.

Obesity-related chronic kidney disease is associated with spleen-derived IL-10.

PubMed

Gotoh, Koro; Inoue, Megumi; Masaki, Takayuki; Chiba, Seiichi; Shiraishi, Kentaro; Shimasaki, Takanobu; Matsuoka, Kazue; Ando, Hisae; Fujiwara, Kansuke; Fukunaga, Naoya; Aoki, Kohei; Nawata, Tomoko; Katsuragi, Isao; Kakuma, Tetsuya; Seike, Masataka; Yoshimatsu, Hironobu

2013-05-01

Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen. We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated. Obesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice. We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.

Analysing the bioactive makeup of demineralised dentine matrix on bone marrow mesenchymal stem cells for enhanced bone repair.

PubMed

Avery, S J; Sadaghiani, L; Sloan, A J; Waddington, R J

2017-07-10

Dentine matrix has proposed roles for directing mineralised tissue repair in dentine and bone; however, the range of bioactive components in dentine and specific biological effects on bone-derived mesenchymal stem cells (MSCs) in humans are less well understood. The aims of this study were to further elucidate the biological response of MSCs to demineralised dentine matrix (DDM) in enhancing wound repair responses and ascertain key contributing components. Dentine was obtained from human teeth and DDM proteins solubilised with ethylenediaminetetraacetic acid (EDTA). Bone marrow derived MSCs were commercially obtained. Cells with a more immature phenotype were then selected by preferential fibronectin adhesion (FN-BMMSCs) for use in subsequent in vitro assays. DDM at 10 µg/mL reduced cell expansion, attenuated apoptosis and was the minimal concentration capable of inducing osteoblastic differentiation. Enzyme-linked immunosorbent assay (ELISA) quantification of growth factors indicated physiological levels produced the above responses; transforming growth factor β (TGF-β1) was predominant (15.6 ng/mg DDM), with relatively lower concentrations of BMP-2, FGF, VEGF and PDGF (6.2-4.7 ng/mg DDM). Fractionation of growth factors from other DDM components by heparin affinity chromatography diminished osteogenic responses. Depletion of biglycan from DDM also attenuated osteogenic potency, which was partially rescued by the isolated biglycan. Decorin depletion from DDM had no influence on osteogenic potency. Collectively, these results demonstrate the potential of DDM for the delivery of physiological levels of growth factors for bone repair processes, and substantiate a role for biglycan as an additional adjuvant for driving osteogenic pathways.

Effect of baseline corrections on displacements and response spectra for several recordings of the 1999 Chi-Chi, Taiwan, earthquake

USGS Publications Warehouse

Boore, D.M.

2001-01-01

Displacements derived from many of the accelerogram recordings of the 1999 Chi-Chi, Taiwan, earthquake show drifts when only a simple baseline derived from the pre-event portion of the record is removed from the records. The appearance of the velocity and displacement records suggests that changes in the zero level of the acceleration are responsible for these drifts. The source of the shifts in zero level are unknown, but in at least one case it is almost certainly due to tilting of the ground. This article illustrates the effect on the ground velocity, ground displacement, and response spectra of several schemes for accounting for these baseline shifts. A wide range of final displacements can be obtained for various choices of baseline correction, and comparison with nearby GPS stations (none of which are colocated with the accelerograph stations) do not help in choosing the appropriate baseline correction. The results suggest that final displacements estimated from the records should be used with caution. The most important conclusion for earthquake engineering purposes, however, is that the response spectra for periods less than about 20 sec are usually unaffected by the baseline correction. Although limited to the analysis of only a small number of recordings, the results may have more general significance both for the many other recordings of this earthquake and for data that will be obtained in the future from similar high-quality accelerograph networks now being installed or soon to be installed in many parts of the world.

Adaptive Critic-based Neurofuzzy Controller for the Steam Generator Water Level

NASA Astrophysics Data System (ADS)

Fakhrazari, Amin; Boroushaki, Mehrdad

2008-06-01

In this paper, an adaptive critic-based neurofuzzy controller is presented for water level regulation of nuclear steam generators. The problem has been of great concern for many years as the steam generator is a highly nonlinear system showing inverse response dynamics especially at low operating power levels. Fuzzy critic-based learning is a reinforcement learning method based on dynamic programming. The only information available for the critic agent is the system feedback which is interpreted as the last action the controller has performed in the previous state. The signal produced by the critic agent is used alongside the backpropagation of error algorithm to tune online conclusion parts of the fuzzy inference rules. The critic agent here has a proportional-derivative structure and the fuzzy rule base has nine rules. The proposed controller shows satisfactory transient responses, disturbance rejection and robustness to model uncertainty. Its simple design procedure and structure, nominates it as one of the suitable controller designs for the steam generator water level control in nuclear power plant industry.

Effects of age, education, and sex on response bias in a recognition task.

PubMed

Marquié, J C; Baracat, B

2000-09-01

This study examined age-related differences in decision criteria and the extent to which inconsistencies in earlier findings could be due to sampling artifacts, especially the underlying effects of educational level and sex. Male and female participants (N = 3,059) from 4 age groups (32, 42, 52, and 62 years) and a wide range of educational levels performed a word recognition task. Response bias was assessed with a nonparametric index derived from signal detection theory. The analyses revealed no age differences except for the most educated subjects, for whom increased age was associated with stricter decision criteria. Lower levels of education and men as compared with women were associated with a more conservative bias. Controlling for the level of sensitivity did not significantly change this pattern of results. This finding stresses the need for caution in generalizing age differences obtained from samples that are only partly representative or imbalanced with respect to education and sex.

Differentiation of Inflammation-Responsive Astrocytes from Glial Progenitors Generated from Human Induced Pluripotent Stem Cells.

PubMed

Santos, Renata; Vadodaria, Krishna C; Jaeger, Baptiste N; Mei, Arianna; Lefcochilos-Fogelquist, Sabrina; Mendes, Ana P D; Erikson, Galina; Shokhirev, Maxim; Randolph-Moore, Lynne; Fredlender, Callie; Dave, Sonia; Oefner, Ruth; Fitzpatrick, Conor; Pena, Monique; Barron, Jerika J; Ku, Manching; Denli, Ahmet M; Kerman, Bilal E; Charnay, Patrick; Kelsoe, John R; Marchetto, Maria C; Gage, Fred H

2017-06-06

Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs) and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1β or tumor necrosis factor α elicits a strong and rapid pro-inflammatory response. RNA-sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin-1β. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells

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

Nijjar, Tarlochan; Bassett, Ekaterina; Garbe, James

2004-12-23

We have used cultured human mammary epithelial cells (HMEC) and breast tumor-derived lines to gain information on defects that occur during breast cancer progression. HMEC immortalized by a variety of agents (the chemical carcinogen benzo(a)pyrene, oncogenes c-myc and ZNF217, and/or dominant negative p53 genetic suppressor element GSE22) displayed marked up regulation (10-15 fold) of the telomere binding protein, TRF2. Up-regulation of TRF2 protein was apparently due to differences in post-transcriptional regulation, as mRNA levels remained comparable in finite life span and immortal HMEC. TRF2 protein was not up-regulated by the oncogenic agents alone in the absence of immortalization, nor bymore » expression of exogenously introduced hTERT genes. We found TRF2 levels to be at least 2-fold higher than in control cells in 11/15 breast tumor cell lines, suggesting that elevated TRF2 levels are a frequent occurrence during the transformation of breast tumor cells in vivo. The dispersed distribution of TRF2 throughout the nuclei in some immortalized and tumor-derived cells indicated that not all the TRF2 was associated with telomeres in these cells. The process responsible for accumulation of TRF2 in immortalized HMEC and breast tumor-derived cell lines may promote tumorigenesis by contributing to the cells ability to maintain an indefinite life span.« less

Versican-Derived Matrikines Regulate Batf3-Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer.

PubMed

Hope, Chelsea; Emmerich, Philip B; Papadas, Athanasios; Pagenkopf, Adam; Matkowskyj, Kristina A; Van De Hey, Dana R; Payne, Susan N; Clipson, Linda; Callander, Natalie S; Hematti, Peiman; Miyamoto, Shigeki; Johnson, Michael G; Deming, Dustin A; Asimakopoulos, Fotis

2017-09-01

Colorectal cancer originates within immunologically complex microenvironments. To date, the benefits of immunotherapy have been modest, except in neoantigen-laden mismatch repair-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. In this article, we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8 + T cell infiltration in colorectal cancer, regardless of mismatch repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8 + T cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8 + T cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). Versikine, a VCAN-derived matrikine, enhanced the generation of CD103 + CD11c hi MHCII hi conventional dendritic cells (cDCs) from Flt3L-mobilized primary bone marrow-derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors toward IRF8- and BATF3-expressing cDCs. Intratumoral BATF3-dependent DCs are critical determinants for T cell antitumor immunity, effector T cell trafficking to the tumor site, and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents. Copyright © 2017 by The American Association of Immunologists, Inc.

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

Favorite, Jeffrey A.

In transport theory, adjoint-based partial derivatives with respect to mass density are constant-volume derivatives. Likewise, adjoint-based partial derivatives with respect to surface locations (i.e., internal interface locations and the outer system boundary) are constant-density derivatives. This study derives the constant-mass partial derivative of a response with respect to an internal interface location or the outer system boundary and the constant-mass partial derivative of a response with respect to the mass density of a region. Numerical results are given for a multiregion two-dimensional (r-z) cylinder for three very different responses: the uncollided gamma-ray flux at an external detector point, k effmore » of the system, and the total neutron leakage. Finally, results from the derived formulas compare extremely well with direct perturbation calculations.« less

An empirical study of statistical properties of variance partition coefficients for multi-level logistic regression models

USGS Publications Warehouse

Li, Ji; Gray, B.R.; Bates, D.M.

2008-01-01

Partitioning the variance of a response by design levels is challenging for binomial and other discrete outcomes. Goldstein (2003) proposed four definitions for variance partitioning coefficients (VPC) under a two-level logistic regression model. In this study, we explicitly derived formulae for multi-level logistic regression model and subsequently studied the distributional properties of the calculated VPCs. Using simulations and a vegetation dataset, we demonstrated associations between different VPC definitions, the importance of methods for estimating VPCs (by comparing VPC obtained using Laplace and penalized quasilikehood methods), and bivariate dependence between VPCs calculated at different levels. Such an empirical study lends an immediate support to wider applications of VPC in scientific data analysis.

Geometric Energy Derivatives at the Complete Basis Set Limit: Application to the Equilibrium Structure and Molecular Force Field of Formaldehyde.

PubMed

Morgan, W James; Matthews, Devin A; Ringholm, Magnus; Agarwal, Jay; Gong, Justin Z; Ruud, Kenneth; Allen, Wesley D; Stanton, John F; Schaefer, Henry F

2018-03-13

Geometric energy derivatives which rely on core-corrected focal-point energies extrapolated to the complete basis set (CBS) limit of coupled cluster theory with iterative and noniterative quadruple excitations, CCSDTQ and CCSDT(Q), are used as elements of molecular gradients and, in the case of CCSDT(Q), expansion coefficients of an anharmonic force field. These gradients are used to determine the CCSDTQ/CBS and CCSDT(Q)/CBS equilibrium structure of the S 0 ground state of H 2 CO where excellent agreement is observed with previous work and experimentally derived results. A fourth-order expansion about this CCSDT(Q)/CBS reference geometry using the same level of theory produces an exceptional level of agreement to spectroscopically observed vibrational band origins with a MAE of 0.57 cm -1 . Second-order vibrational perturbation theory (VPT2) and variational discrete variable representation (DVR) results are contrasted and discussed. Vibration-rotation, anharmonicity, and centrifugal distortion constants from the VPT2 analysis are reported and compared to previous work. Additionally, an initial application of a sum-over-states fourth-order vibrational perturbation theory (VPT4) formalism is employed herein, utilizing quintic and sextic derivatives obtained with a recursive algorithmic approach for response theory.

Use of plant trait data in the ISBA-A-gs model

NASA Astrophysics Data System (ADS)

Calvet, Jean-Christophe

2014-05-01

ISBA-A-gs is a CO2-responsive LSM (Calvet et al., 1998; Gibelin et al., 2006), able to simulate the diurnal cycle of carbon and water vapour fluxes, together with LAI and soil moisture evolution. The various components of ISBA-A-gs are based to a large extent on meta-analyses of trait data. (1) Photosynthesis: ISBA-A-gs uses the model of Goudriaan et al. (1985) modified by Jacobs (1994) and Jacobs et al. (1996). The main parameter is mesophyll conductance (gm). Leaf-level photosynthesis observations were used together with canopy level flux observations to derive gm together with other key parameters of the Jacobs model, including in drought conditions. This permitted implementing detailed representations of the soil moisture stress. Two different types of drought responses are distinguished for both herbaceous vegetation (Calvet, 2000) and forests (Calvet et al., 2004), depending on the evolution of the water use efficiency (WUE) under moderate stress: WUE increases in the early soil water stress stages in the case of the drought-avoiding response, whereas WUE decreases or remains stable in the case of the drought-tolerant response. (2) Plant growth: the leaf biomass is provided by a growth model (Calvet et al., 1998; Calvet and Soussana, 2001) driven by photosynthesis. In contrast to other land surface models, no GDD-based phenology model is used in ISBA-A-gs, as the vegetation growth and senescence are entirely driven by photosynthesis. The leaf biomass is supplied with the carbon assimilated by photosynthesis, and decreased by a turnover and a respiration term. Turnover is increased by a deficit in photosynthesis. The leaf onset is triggered by sufficient photosynthesis levels and a minimum LAI value is prescribed. The maximum annual value of LAI is prognostic, i.e. it can be predicted by the model. LAI is derived from leaf biomass using SLA values. The latter are derived from the leaf nitrogen concentration using plasticity parameters. (3) CO2 effect: the photosynthesis model is able to represent the antitranspirant effect of CO2. The plant growth model represents the fertilization effect of CO2. However, the nitrogen dilution triggered by the CO2 increase has to be represented. A pragmatic solution consists in decreasing the leaf nitrogen concentration parameter in response to CO2, using existing meta-analyses of this parameter (Calvet et al., 2008). The TRY database could be used to improve the current parameterizations, together with the mapping of the model parameters.

Protective effect of vanilloids against tert-butyl hydroperoxide-induced oxidative stress in vero cells culture.

PubMed

Rosa, Antonella; Atzeri, Angela; Deiana, Monica; Melis, M Paola; Incani, Alessandra; Corona, Giulia; Loru, Debora; Appendino, Giovanni; Dessì, M Assunta

2008-05-28

This study investigated the effect of synthetic capsiate, a simplified analogue of capsiate, and vanillyl alcohol on the oxidative stress induced by tert-butyl hydroperoxide (TBH) in a line of fibroblasts derived from monkey kidney (Vero cells). In response to the TBH-mediated oxidative stress, a reduction of the levels of total unsaturated fatty acids and cholesterol was observed, and a rise in the concentrations of conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol. Pretreatment with both synthetic capsiate and vanillyl alcohol preserved Vero cells from oxidative damage and showed a remarkable protective effect on the reduction of the levels of total unsaturated fatty acids and cholesterol, inhibiting the increase of MDA, conjugated dienes fatty acids hydroperoxides, and 7-ketocholesterol. Both compounds were effective against peroxidation of cell membrane lipids induced by TBH, with synthetic capsiate essentially acting as a pro-drug of vanillyl alcohol, its hydrophilic hydrolytic derivative.

CCR5 Signal Transduction in Macrophages by Human Immunodeficiency Virus and Simian Immunodeficiency Virus Envelopes

PubMed Central

Arthos, James; Rubbert, Andrea; Rabin, Ronald L.; Cicala, Claudia; Machado, Elizabeth; Wildt, Kathryne; Hanbach, Meredith; Steenbeke, Tavis D.; Swofford, Ruth; Farber, Joshua M.; Fauci, Anthony S.

2000-01-01

The capacity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelopes to transduce signals through chemokine coreceptors on macrophages was examined by measuring the ability of recombinant envelope proteins to mobilize intracellular calcium stores. Both HIV and SIV envelopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were treated with MIP-1β. Distinct differences in the capacity of envelopes to mediate calcium mobilization were observed. Envelopes derived from viruses capable of replicating in macrophages mobilized relatively high levels of calcium, while envelopes derived from viruses incapable of replicating in macrophages mobilized relatively low levels of calcium. The failure to efficiently mobilize calcium was not restricted to envelopes derived from CXCR4-utilizing isolates but also included envelopes derived from CCR5-utilizing isolates that fail to replicate in macrophages. We characterized one CCR5-utilizing isolate, 92MW959, which entered macrophages but failed to replicate. A recombinant envelope derived from this virus mobilized low levels of calcium. When macrophages were inoculated with 92MW959 in the presence of MIP-1α, viral replication was observed, indicating that a CC chemokine-mediated signal provided the necessary stimulus to allow the virus to complete its replication cycle. Although the role that envelope-CCR5 signal transduction plays in viral replication is not yet understood, it has been suggested that envelope-mediated signals facilitate early postfusion events in viral replication. The data presented here are consistent with this hypothesis and suggest that the differential capacity of viral envelopes to signal through CCR5 may influence their ability to replicate in macrophages. PMID:10864653

CCR5 signal transduction in macrophages by human immunodeficiency virus and simian immunodeficiency virus envelopes.

PubMed

Arthos, J; Rubbert, A; Rabin, R L; Cicala, C; Machado, E; Wildt, K; Hanbach, M; Steenbeke, T D; Swofford, R; Farber, J M; Fauci, A S

2000-07-01

The capacity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelopes to transduce signals through chemokine coreceptors on macrophages was examined by measuring the ability of recombinant envelope proteins to mobilize intracellular calcium stores. Both HIV and SIV envelopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were treated with MIP-1beta. Distinct differences in the capacity of envelopes to mediate calcium mobilization were observed. Envelopes derived from viruses capable of replicating in macrophages mobilized relatively high levels of calcium, while envelopes derived from viruses incapable of replicating in macrophages mobilized relatively low levels of calcium. The failure to efficiently mobilize calcium was not restricted to envelopes derived from CXCR4-utilizing isolates but also included envelopes derived from CCR5-utilizing isolates that fail to replicate in macrophages. We characterized one CCR5-utilizing isolate, 92MW959, which entered macrophages but failed to replicate. A recombinant envelope derived from this virus mobilized low levels of calcium. When macrophages were inoculated with 92MW959 in the presence of MIP-1alpha, viral replication was observed, indicating that a CC chemokine-mediated signal provided the necessary stimulus to allow the virus to complete its replication cycle. Although the role that envelope-CCR5 signal transduction plays in viral replication is not yet understood, it has been suggested that envelope-mediated signals facilitate early postfusion events in viral replication. The data presented here are consistent with this hypothesis and suggest that the differential capacity of viral envelopes to signal through CCR5 may influence their ability to replicate in macrophages.

Small-Scale Waste-to-Energy Technology for Contingency Bases

DTIC Science & Technology

2012-05-24

Expedient, No Waste Sorting Technology Readiness Level High Fuel Demand Water Required Steam Infrastructure Required Air Emissions Gasification ...Full gasification system • Costs $26K • GM Industrial Engine (GM 4 Cylinder, 3.00 L) • MeccAlte Generator Head • Imbert type downdraft reactor...Solid waste volume reduction − Response to waste streams  biomass , refuse-derived fuel, shredded waste − Operation and maintenance requirements

Hippocampal Astrocyte Cultures from Adult and Aged Rats Reproduce Changes in Glial Functionality Observed in the Aging Brain.

PubMed

Bellaver, Bruna; Souza, Débora Guerini; Souza, Diogo Onofre; Quincozes-Santos, André

2017-05-01

Astrocytes are dynamic cells that maintain brain homeostasis, regulate neurotransmitter systems, and process synaptic information, energy metabolism, antioxidant defenses, and inflammatory response. Aging is a biological process that is closely associated with hippocampal astrocyte dysfunction. In this sense, we demonstrated that hippocampal astrocytes from adult and aged Wistar rats reproduce the glial functionality alterations observed in aging by evaluating several senescence, glutamatergic, oxidative and inflammatory parameters commonly associated with the aging process. Here, we show that the p21 senescence-associated gene and classical astrocyte markers, such as glial fibrillary acidic protein (GFAP), vimentin, and actin, changed their expressions in adult and aged astrocytes. Age-dependent changes were also observed in glutamate transporters (glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)) and glutamine synthetase immunolabeling and activity. Additionally, according to in vivo aging, astrocytes from adult and aged rats showed an increase in oxidative/nitrosative stress with mitochondrial dysfunction, an increase in RNA oxidation, NADPH oxidase (NOX) activity, superoxide levels, and inducible nitric oxide synthase (iNOS) expression levels. Changes in antioxidant defenses were also observed. Hippocampal astrocytes also displayed age-dependent inflammatory response with augmentation of proinflammatory cytokine levels, such as TNF-α, IL-1β, IL-6, IL-18, and messenger RNA (mRNA) levels of cyclo-oxygenase 2 (COX-2). Furthermore, these cells secrete neurotrophic factors, including glia-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B) protein, and transforming growth factor-β (TGF-β), which changed in an age-dependent manner. Classical signaling pathways associated with aging, such as nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NFκB), heme oxygenase-1 (HO-1), and p38 mitogen-activated protein kinase (MAPK), were also changed in adult and aged astrocytes and are probably related to the changes observed in senescence marker, glutamatergic metabolism, mitochondrial dysfunction, oxidative/nitrosative stress, antioxidant defenses, inflammatory response, and trophic factors release. Together, our results reinforce the role of hippocampal astrocytes as a target for understanding the mechanisms involved in aging and provide an innovative tool for studies of astrocyte roles in physiological and pathological aging brain.

Spiking Models for Level-Invariant Encoding

PubMed Central

Brette, Romain

2012-01-01

Levels of ecological sounds vary over several orders of magnitude, but the firing rate and membrane potential of a neuron are much more limited in range. In binaural neurons of the barn owl, tuning to interaural delays is independent of level differences. Yet a monaural neuron with a fixed threshold should fire earlier in response to louder sounds, which would disrupt the tuning of these neurons. How could spike timing be independent of input level? Here I derive theoretical conditions for a spiking model to be insensitive to input level. The key property is a dynamic change in spike threshold. I then show how level invariance can be physiologically implemented, with specific ionic channel properties. It appears that these ingredients are indeed present in monaural neurons of the sound localization pathway of birds and mammals. PMID:22291634

ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages.

PubMed

Feng, Min; Dai, Manman; Cao, Weisheng; Tan, Yan; Li, Zhenhui; Shi, Meiqing; Zhang, Xiquan

2017-01-01

Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte-derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1β (IL-1β) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1β (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-β (IFN-β) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape. © The Author 2016. Published by Oxford University Press on behalf of Poultry Science Association.

Testosterone regulates bone response to inflammation.

PubMed

Steffens, J P; Herrera, B S; Coimbra, L S; Stephens, D N; Rossa, C; Spolidorio, L C; Kantarci, A; Van Dyke, T E

2014-03-01

This study evaluated the alveolar bone response to testosterone and the impact of Resolvin D2 (RvD2) on testosterone-induced osteoblast function. For the in vivo characterization, 60 male adult rats were used. Treatments established sub-physiologic (L), normal (N), or supra-physiologic (H) concentrations of testosterone. Forty rats were subjected to orchiectomy; 20 rats received periodical testosterone injections while 20 rats received testicular sham-operation. Four weeks after the surgeries, 10 rats in each group received a subgingival ligature around the lower first molars to induce experimental periodontal inflammation and bone loss. In parallel, osteoblasts were differentiated from neonatal mice calvariae and treated with various doses of testosterone for 48 h. Cell lysates and conditioned media were used for the determination of alkaline phosphatase, osteocalcin, RANKL, and osteoprotegerin. Micro-computed tomography linear analysis demonstrated that bone loss was significantly increased for both L and H groups compared to animals with normal levels of testosterone. Gingival IL-1β expression was increased in the L group (p<0.05). Ten nM testosterone significantly decreased osteocalcin, RANKL, and OPG levels in osteoblasts; 100 nM significantly increased the RANKL:OPG ratio. RvD2 partially reversed the impact of 10 nM testosterone on osteocalcin, RANKL, and OPG. These findings suggest that both L and H testosterone levels increase inflammatory bone loss in male rats. While low testosterone predominantly increases the inflammatory response, high testosterone promotes a higher osteoblast-derived RANKL:OPG ratio. The proresolving mediator RvD2 ameliorates testosterone-derived downregulation of osteocalcin, RANKL, and OPG in primary murine osteoblasts suggesting a direct role of inflammation in osteoblast function. © Georg Thieme Verlag KG Stuttgart · New York.

SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy.

PubMed

Wang, Feng; Xia, Xiaojun; Yang, Chunying; Shen, Jianliang; Mai, Junhua; Kim, Han-Cheon; Kirui, Dickson; Kang, Ya'an; Fleming, Jason B; Koay, Eugene J; Mitra, Sankar; Ferrari, Mauro; Shen, Haifa

2018-03-30

Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by Flow Cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-L-cysteine) in SMAD4 -depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4 -depleted Panc-1 cells. SMAD4 -depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild type SMAD4 in SMAD4 -mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model ( P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Copyright ©2018, American Association for Cancer Research.

Hyperreactive malarial splenomegaly is associated with low levels of antibodies against red blood cell and Plasmodium falciparum derived glycolipids in Yanomami Amerindians from Venezuela.

PubMed

Vivas, Livia; O'Dea, Kieran P; Noya, Oscar; Pabon, Rosalba; Magris, Magda; Botto, Carlos; Holder, Anthony A; Brown, K Neil

2008-03-01

The immunological basis of the aberrant immune response in hyperreactive malarial splenomegaly (HMS) is poorly understood, but believed to be associated with polyclonal B cell activation by an unidentified malaria mitogen, leading to unregulated immunoglobulin and autoantibody production. HMS has been previously reported in Yanomami communities in the Upper Orinoco region of the Venezuelan Amazon. To investigate a possible association between antibody responses against Plasmodium falciparum and uninfected red blood cell (URBC) glycolipids and splenomegaly, a direct comparison of the parasite versus host anti-glycolipid antibody responses was made in an isolated community of this area. The anti-P. falciparum glycolipid (Pfglp) response was IgG3 dominated, whereas the uninfected red blood cell glycolipid (URBCglp) response showed a predominance of IgG1. The levels of IgG1 against Pfglp, and of IgG4 and IgM against URBCglp were significantly higher in women, while the anti-Pfglp or URBCglp IgM levels were inversely correlated with the degree of splenomegaly. Overall, these results suggest differential regulation of anti-parasite and autoreactive responses and that these responses may be linked to the development and evolution of HMS in this population exposed to endemic malaria. The high mortality rates associated with HMS point out that its early diagnosis together with the implementation of malaria control measures in these isolated Amerindian communities are a priority.

Inhibitory effects of methamphetamine on mast cell activation and cytokine/chemokine production stimulated by lipopolysaccharide in C57BL/6J mice.

PubMed

Xue, Li; Geng, Yan; Li, Ming; Jin, Yao-Feng; Ren, Hui-Xun; Li, Xia; Wu, Feng; Wang, Biao; Cheng, Wei-Ying; Chen, Teng; Chen, Yan-Jiong

2018-04-01

Previous studies have demonstrated that methamphetamine (MA) influences host immunity; however, the effect of MA on lipopolysaccharide (LPS)-induced immune responses remains unknown. Mast cells (MCs) are considered to serve an important role in the innate and acquired immune response, but it remains unknown whether MA modulates MC activation and LPS-stimulated cytokine production. The present study aimed to investigate the effect of MA on LPS-induced MC activation and the production of MC-derived cytokines in mice. Markers for MC activation, including cluster of differentiation 117 and the type I high affinity immunoglobulin E receptor, were assessed in mouse intestines. Levels of MC-derived cytokines in the lungs and thymus were also examined. The results demonstrated that cytokines were produced in the bone marrow-derived mast cells (BMMCs) of mice. The present study demonstrated that MA suppressed the LPS-mediated MC activation in mouse intestines. MA also altered the release of MC cytokines in the lung and thymus following LPS stimulation. In addition, LPS-stimulated cytokines were decreased in the BMMCs of mice following treatment with MA. The present study demonstrated that MA may regulate LPS-stimulated MC activation and cytokine production.

Roles of Sea Level and Climate Change in the Development of Holocene Deltaic Sequences in the Yellow Sea

NASA Astrophysics Data System (ADS)

Liu, J.; Milliman, J. D.

2002-12-01

Both post-glacial sea-level and climatic changes are preserved in the the shallow, low gradient, sediment-dominated Yellow Sea. As a result of rapid flooding during melt-water pulse (MWP) 1A, 14.3-14.1 ka BP, sea level reached the southern edge of the North Yellow Sea (NYS), and after MWP-1B (11.6-11.4 ka BP) sea level entered the Bohai Sea. The first major Yellow River-derived deltaic deposit formed in the NYS during decelerated transgression following MWP-1B and increased river discharge in response to re-intensification of the summer monsoon about 11 ka cal BP. A second subaqueous delta formed in the South Yellow Sea about 9-7 ka BP during decelerated transgression after MWP-1C flooding and in response to the southern shift of the Yellow River mouth. The modern subaqueous and subaerial deltas in the west Bahai Gulf and (to a lesser extent) along the Jiangus coast have formed during the modern sea-level highstand. These changing Holocene patterns are most clearly illustrated by a short film clip.

Multifunctional devices based on SnO2@rGO-coated fibers for human motion monitoring, ethanol detection, and photo response

NASA Astrophysics Data System (ADS)

Mi, Qing; Wang, Qi; Zang, Siyao; Chai, Zhaoer; Zhang, Jinnan; Ren, Xiaomin

2018-05-01

In this study, we developed a multifunctional device based on SnO2@rGO-coated fibers utilizing plasma treatment, dip coating, and microwave irradiation in sequence, and finally realized highly sensitive human motion monitoring, relatively good ethanol detection, and an obvious photo response. Moreover, the high level of comfort and compactness derived from highly elastic and comfortable fabrics contributes to the long-term availability and test accuracy. As an attempt at multifunctional integration of smart clothing, this work provides an attractive and relatively practical research direction.

Multifunctional devices based on SnO2@rGO-coated fibers for human motion monitoring, ethanol detection, and photo response.

PubMed

Mi, Qing; Wang, Qi; Zang, Siyao; Chai, Zhaoer; Zhang, Jinnan; Ren, Xiaomin

2018-05-11

In this study, we developed a multifunctional device based on SnO 2 @rGO-coated fibers utilizing plasma treatment, dip coating, and microwave irradiation in sequence, and finally realized highly sensitive human motion monitoring, relatively good ethanol detection, and an obvious photo response. Moreover, the high level of comfort and compactness derived from highly elastic and comfortable fabrics contributes to the long-term availability and test accuracy. As an attempt at multifunctional integration of smart clothing, this work provides an attractive and relatively practical research direction.

Methionine sulfoxide reductase A protects against lipopolysaccharide-induced septic shock via negative regulation of the proinflammatory responses.

PubMed

Singh, Mahendra Pratap; Kim, Ki Young; Kwak, Geun-Hee; Baek, Suk-Hwan; Kim, Hwa-Young

2017-10-01

Methionine sulfoxide reductase A (MsrA) is a major antioxidant enzyme that specifically catalyzes the reduction of methionine S-sulfoxide. In this study, we used MsrA gene-knockout (MsrA -/- ) mice and bone marrow-derived macrophages (BMDMs) to investigate the role of MsrA in the regulation of inflammatory responses induced by lipopolysaccharide (LPS). MsrA -/- mice were more susceptible to LPS-induced lethal shock than wild-type (MsrA +/+ ) mice. Serum levels of the proinflammatory cytokines IL-6 and TNF-α induced by LPS were higher in MsrA -/- than in MsrA +/+ mice. MsrA deficiency in the BMDMs also increased the LPS-induced cytotoxicity as well as TNF-α level. Basal and LPS-induced reactive oxygen species (ROS) levels were higher in MsrA -/- than in MsrA +/+ BMDMs. Phosphorylation levels of p38, JNK, and ERK were higher in MsrA -/- than in MsrA +/+ BMDMs in response to LPS, suggesting that MsrA deficiency increases MAPK activation. Furthermore, MsrA deficiency increased the expression and nuclear translocation of NF-κB and the expression of inducible nitric oxide synthase, a target gene of NF-κB, in response to LPS. Taken together, our results suggest that MsrA protects against LPS-induced septic shock, and negatively regulates proinflammatory responses via inhibition of the ROS-MAPK-NF-κB signaling pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Human macrophage ATP7A is localized in the trans-Golgi apparatus, controls intracellular copper levels, and mediates macrophage responses to dermal wounds.

PubMed

Kim, Ha Won; Chan, Qilin; Afton, Scott E; Caruso, Joseph A; Lai, Barry; Weintraub, Neal L; Qin, Zhenyu

2012-02-01

The copper transporter ATP7A has attracted significant attention since the discovery of its gene mutation leading to human Menkes disease. We previously reported that ATP7A is highly expressed in the human vasculature and identified a novel vascular function of ATP7A in modulation of the expression and activity of extracellular superoxide dismutase. We recently identified that ATP7A expression in THP-1 cells (a monocyte/macrophage model cell line) plays a role in the oxidation of low density lipoproteins, indicating that it is necessary to further investigate its expression and function in monocytes/macrophages. In the current study, we demonstrated the protein and mRNA expression of ATP7A in human peripheral blood mononuclear cell (PBMC)-derived macrophages and alveolar macrophages. ATP7A was strongly co-localized with the trans-Golgi apparatus in PBMC-derived macrophages. Intracellular copper, detected by synchrotron X-ray fluorescence microscopy, was found to be distributed to the nucleus and cytoplasm in human THP-1 cells. To confirm the role of endogenous ATP7A in macrophage copper homeostasis, we performed inductively coupled plasma mass spectrometry in murine peritoneal macrophages, which showed markedly increased intracellular copper levels in macrophages isolated from ATP7A-deficient mice versus control mice. Moreover, the role of ATP7A in regulating macrophage responses to dermal wounds was studied by introduction of control and ATP7A-downregulated THP-1 cells into dermal wounds of nude mice. Infiltration of THP-1 cells into the wounded area (detected by expression of human macrophage markers MAC2 and CD68) was reduced in response to downregulation of ATP7A, hinting decreased macrophage accumulation subsequent to dermal wounds. In summary, alongside our previous studies, these findings indicate that human macrophage ATP7A is localized in the trans-Golgi apparatus, regulates intracellular copper levels, and mediates macrophage responses to a dermal wound.

Modeling of uncertainties in biochemical reactions.

PubMed

Mišković, Ljubiša; Hatzimanikatis, Vassily

2011-02-01

Mathematical modeling is an indispensable tool for research and development in biotechnology and bioengineering. The formulation of kinetic models of biochemical networks depends on knowledge of the kinetic properties of the enzymes of the individual reactions. However, kinetic data acquired from experimental observations bring along uncertainties due to various experimental conditions and measurement methods. In this contribution, we propose a novel way to model the uncertainty in the enzyme kinetics and to predict quantitatively the responses of metabolic reactions to the changes in enzyme activities under uncertainty. The proposed methodology accounts explicitly for mechanistic properties of enzymes and physico-chemical and thermodynamic constraints, and is based on formalism from systems theory and metabolic control analysis. We achieve this by observing that kinetic responses of metabolic reactions depend: (i) on the distribution of the enzymes among their free form and all reactive states; (ii) on the equilibrium displacements of the overall reaction and that of the individual enzymatic steps; and (iii) on the net fluxes through the enzyme. Relying on this observation, we develop a novel, efficient Monte Carlo sampling procedure to generate all states within a metabolic reaction that satisfy imposed constrains. Thus, we derive the statistics of the expected responses of the metabolic reactions to changes in enzyme levels and activities, in the levels of metabolites, and in the values of the kinetic parameters. We present aspects of the proposed framework through an example of the fundamental three-step reversible enzymatic reaction mechanism. We demonstrate that the equilibrium displacements of the individual enzymatic steps have an important influence on kinetic responses of the enzyme. Furthermore, we derive the conditions that must be satisfied by a reversible three-step enzymatic reaction operating far away from the equilibrium in order to respond to changes in metabolite levels according to the irreversible Michelis-Menten kinetics. The efficient sampling procedure allows easy, scalable, implementation of this methodology to modeling of large-scale biochemical networks. © 2010 Wiley Periodicals, Inc.

The correlation between perceived social support, cortisol and brain derived neurotrophic factor levels in healthy women.

PubMed

Ma, Doy Yung; Chang, Wei Hung; Chi, Mei Hung; Tsai, Hsin Chun; Yang, Yen Kuang; Chen, Po See

2016-05-30

In this study, the role of brain derived neurotrophic factor (BDNF) in stress resilience was investigated. With a focus on healthy subjects, we explored whether plasma BDNF levels are correlated with the dexamethasone suppression test (DST) and subjectively perceived social support status. Moreover, we examined the possible interacting effect of DST status and perceived social support on BDNF levels. Seventy-two healthy volunteers, 44 females and 28 males, were recruited from the community and completed the perceived routine support subscale of Measurement of Support Function (PRS_MSF) questionnaire. Plasma BDNF levels and DST suppression rate with the low dose DST were measured. There was a significant positive correlation between BDNF and DST suppression rate in the female subjects. This was also true for the plasma BDNF levels and PRS_MSF in the female subjects. The positive correlation between BDNF and PRS_MSF was significant only in female subjects with low DST suppression rates. Plasma BDNF levels were associated with stress resilience in a sex-specific manner. Subjects' belief in social support might buffer the biological stress reactions. Differences in social perception and the biological stress response between men and women merits further investigation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Health-based Provisional Advisory Levels (PALs) for homeland security.

PubMed

Adeshina, Femi; Sonich-Mullin, Cynthia; Ross, Robert H; Wood, Carol S

2009-12-01

The Homeland Security Presidential Directive #8 (HSPD-8) for National Emergency Preparedness was issued to " establish policies to strengthen the preparedness of the United States to prevent and respond to threatened or actual domestic terrorist attacks, major disasters, and other emergencies by requiring a national domestic all- hazards preparedness goal. "In response to HSPD-8 and HSPD-22 (classified) on Domestic Chemical Defense, the US Environmental Protection Agency (US EPA) National Homeland Security Research Center (NHSRC) is developing health-based Provisional Advisory Levels (PALs) for priority chemicals (including chemical warfare agents, pesticides, and toxic industrial chemicals) in air and drinking water. PALs are temporary values that will neither be promulgated, nor be formally issued as regulatory guidance. They are intended to be used at the discretion of risk managers in emergency situations. The PAL Program provides advisory exposure levels for chemical agents to assist in emergency planning and response decision-making, and to aid in making informed risk management decisions for evacuation, temporary re-entry into affected areas, and resumed-use of infrastructure, such as water resources. These risk management decisions may be made at the federal, state, and local levels. Three exposure levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations for potential exposure to drinking water and ambient air by the general public. Developed PALs are evaluated both by a US EPA working group, and an external multidisciplinary panel to ensure scientific credibility and wide acceptance. In this Special Issue publication, we present background information on the PAL program, the methodology used in deriving PALs, and the technical support documents for the derivation of PALs for acrylonitrile, hydrogen sulfide, and phosgene.

Tissue distribution and effects of fasting and obesity on the ghrelin axis in mice.

PubMed

Morash, Michael G; Gagnon, Jeffrey; Nelson, Stephanie; Anini, Younes

2010-08-09

Ghrelin is a 28 amino acid peptide hormone derived from the 117 amino acid proghrelin, following cleavage by proprotein convertase 1 (PC1). In this study, we comprehensively assessed the tissue distribution and the effect of fasting and obesity on preproghrelin, Exon-4D, PC1 and GOAT expression and proghrelin-derived peptide (PGDP) secretion. The stomach was the major source of preproghrelin expression and PDGPs, followed by the small intestine. The remaining peripheral tissues (including the brain and pancreas) contained negligible expression levels. We detected obestatin in all stomach proghrelin cells, however, 22% of proghrelin cells in the small intestine did not express obestatin. There were strain differences in ghrelin secretion in response to fasting between CD1 and C57BL/6 mice. After a 24 hour-fast, CD1 mice had increased plasma levels of total ghrelin and obestatin with no change in preproghrelin mRNA or PGDP tissues levels. C57BL/6 mice showed a different response to a 24 hour-fast having increased proghrelin mRNA expression, stomach acylated ghrelin peptide and no change in plasma obestatin in C57BL/6 mice. In obese mice (ob/ob and diet-induced obesity (DIO)) there was a significant increase in preproghrelin mRNA levels while tissue and plasma PGDP levels were significantly reduced. Fasting did not affect PGDP in obese mice. Obese models displayed differences in GOAT expression, which was elevated in DIO mice, but reduced in ob/ob mice. We did not find co-localization of the leptin receptor in ghrelin expressing stomach cells, ruling out a direct effect of leptin on stomach ghrelin synthesis and secretion. Copyright (c) 2010 Elsevier B.V. All rights reserved.

An assessment of two-step linear regression and a multifactor probit analysis as alternatives to acute to chronic ratios in the estimation of chronic response from acute toxicity data to derive water quality guidelines.

PubMed

Slaughter, Andrew R; Palmer, Carolyn G; Muller, Wilhelmine J

2007-04-01

In aquatic ecotoxicology, acute to chronic ratios (ACRs) are often used to predict chronic responses from available acute data to derive water quality guidelines, despite many problems associated with this method. This paper explores the comparative protectiveness and accuracy of predicted guideline values derived from the ACR, linear regression analysis (LRA), and multifactor probit analysis (MPA) extrapolation methods applied to acute toxicity data for aquatic macroinvertebrates. Although the authors of the LRA and MPA methods advocate the use of extrapolated lethal effects in the 0.01% to 10% lethal concentration (LC0.01-LC10) range to predict safe chronic exposure levels to toxicants, the use of an extrapolated LC50 value divided by a safety factor of 5 was in addition explored here because of higher statistical confidence surrounding the LC50 value. The LRA LC50/5 method was found to compare most favorably with available experimental chronic toxicity data and was therefore most likely to be sufficiently protective, although further validation with the use of additional species is needed. Values derived by the ACR method were the least protective. It is suggested that there is an argument for the replacement of ACRs in developing water quality guidelines by the LRA LC50/5 method.

Sex Differences in Maturation of Human Embryonic Stem Cell-Derived β Cells in Mice.

PubMed

Saber, Nelly; Bruin, Jennifer E; O'Dwyer, Shannon; Schuster, Hellen; Rezania, Alireza; Kieffer, Timothy J

2018-04-01

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are now in clinical trials for insulin replacement in patients with type 1 diabetes. Animal studies indicate that pancreatic progenitor cells can mature into a mixed population of endocrine cells, including glucose-responsive β cells several months after implantion. However, it remains unclear how conditions in the recipient may influence the maturation and ultimately the function of these hESC-derived cells. Here, we investigated the effects of (1) pregnancy on the maturation of human stage 4 (S4) pancreatic progenitor cells and (2) the impact of host sex on both S4 cells and more mature stage 7 (S7) pancreatic endocrine cells implanted under the kidney capsule of immunodeficient SCID-beige mice. Pregnancy led to increased proliferation of endogenous pancreatic β cells, but did not appear to affect proliferation or maturation of S4 cells at midgestation. Interestingly, S4 and S7 cells both acquired glucose-stimulated C-peptide secretion in females before males. Moreover, S4 cells lowered fasting blood glucose levels in females sooner than in males, whereas the responses with S7 cells were similar. These data indicate that the host sex may impact the maturation of hESC-derived cells in vivo and that this effect can be minimized by more advanced differentiation of the cells before implantation.

Glucose Elevates NITRATE TRANSPORTER2.1 Protein Levels and Nitrate Transport Activity Independently of Its HEXOKINASE1-Mediated Stimulation of NITRATE TRANSPORTER2.1 Expression1[W][OPEN

PubMed Central

de Jong, Femke; Thodey, Kate; Lejay, Laurence V.; Bevan, Michael W.

2014-01-01

Mineral nutrient uptake and assimilation is closely coordinated with the production of photosynthate to supply nutrients for growth. In Arabidopsis (Arabidopsis thaliana), nitrate uptake from the soil is mediated by genes encoding high- and low-affinity transporters that are transcriptionally regulated by both nitrate and photosynthate availability. In this study, we have studied the interactions of nitrate and glucose (Glc) on gene expression, nitrate transport, and growth using glucose-insensitive2-1 (gin2-1), which is defective in sugar responses. We confirm and extend previous work by showing that HEXOKINASE1-mediated oxidative pentose phosphate pathway (OPPP) metabolism is required for Glc-mediated NITRATE TRANSPORTER2.1 (NRT2.1) expression. Treatment with pyruvate and shikimate, two products derived from intermediates of the OPPP that are destined for amino acid production, restores wild-type levels of NRT2.1 expression, suggesting that metabolites derived from OPPP metabolism can, together with Glc, directly stimulate high levels of NRT2.1 expression. Nitrate-mediated NRT2.1 expression is not influenced by gin2-1, showing that Glc does not influence NRT2.1 expression through nitrate-mediated mechanisms. We also show that Glc stimulates NRT2.1 protein levels and transport activity independently of its HEXOKINASE1-mediated stimulation of NRT2.1 expression, demonstrating another possible posttranscriptional mechanism influencing nitrate uptake. In gin2-1 plants, nitrate-responsive biomass growth was strongly reduced, showing that the supply of OPPP metabolites is essential for assimilating nitrate for growth. PMID:24272701

A Longitudinal Hepatitis B Vaccine Cohort Demonstrates Long-lasting Hepatitis B Virus (HBV) Cellular Immunity Despite Loss of Antibody Against HBV Surface Antigen.

PubMed

Simons, Brenna C; Spradling, Philip R; Bruden, Dana J T; Zanis, Carolyn; Case, Samantha; Choromanski, Tammy L; Apodaca, Minjun; Brogdon, Hazel D; Dwyer, Gaelen; Snowball, Mary; Negus, Susan; Bruce, Michael G; Morishima, Chihiro; Knall, Cindy; McMahon, Brian J

2016-07-15

Long-lasting protection resulting from hepatitis B vaccine, despite loss of antibody against hepatitis B virus (HBV) surface antigen (anti-HBs), is undetermined. We recruited persons from a cohort vaccinated with plasma-derived hepatitis B vaccine in 1981 who have been followed periodically since. We performed serological testing for anti-HBs and microRNA-155 and assessed HBV-specific T-cell responses by enzyme-linked immunospot and cytometric bead array. Study subgroups were defined 32 years after vaccination as having an anti-HBs level of either ≥10 mIU/mL (group 1; n = 13) or <10 mIU/mL (group 2; n = 31). All 44 participants, regardless of anti-HBs level, tested positive for tumor necrosis factor α, interleukin 10, or interleukin 6 production by HBV surface antigen-specific T cells. The frequency of natural killer T cells correlated with the level of anti-HBs (P = .008). The proportion of participants who demonstrated T-cell responses to HBV core antigen varied among the cytokines measured, suggesting some natural exposure to HBV in the study group. No participant had evidence of breakthrough HBV infection. Evidence of long-lasting cellular immunity, regardless of anti-HBs level, suggests that protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 32 years. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Structure-dependent efficacy of infectious bursal disease virus (IBDV) recombinant vaccines.

PubMed

Martinez-Torrecuadrada, Jorge L; Saubi, Narciís; Pagès-Manté, Albert; Castón, José R; Espuña, Enric; Casal, J Ignacio

2003-07-04

The immunogenicity and protective capability of several baculovirus-expressed infectious bursal disease virus (IBDV)-derived assemblies as VP2 capsids, VPX tubules and polyprotein (PP)-derived mixed structures, were tested. Four-week-old chickens were immunised subcutaneously with one dose of each particulate antigen. VP2 icosahedral capsids induced the highest neutralising response, followed by PP-derived structures and then VPX tubules. All vaccinated animals were protected when challenged with a very virulent IBDV (vvIBDV) isolate, however the degree of protection is directly correlated with the levels of neutralising antibodies. VP2 capsids elicited stronger protective immunity than tubular structures and 3 micrograms of them were sufficient to confer a total protection comparable to that induced by an inactivated vaccine. Therefore, VP2 capsids represent a suitable candidate recombinant vaccine instead of virus-like particles (VLPs) for IBDV infections. Our results also provide clear evidence that the recombinant IBDV-derived antigens are structure-dependent in order to be efficient as vaccine components.

Structure-dependent efficacy of infectious bursal disease virus (IBDV) recombinant vaccines.

PubMed

Martinez-Torrecuadrada, Jorge L; Saubi, Narcis; Pagès-Manté, Albert; Castón, José R; Espuña, Enric; Casal, J Ignacio

2003-05-16

The immunogenicity and protective capability of several baculovirus-expressed infectious bursal disease virus (IBDV)-derived assemblies as VP2 capsids, VPX tubules and polyprotein (PP)-derived mixed structures, were tested. Four-week-old chickens were immunised subcutaneously with one dose of each particulate antigen. VP2 icosahedral capsids induced the highest neutralising response, followed by PP-derived structures and then VPX tubules. All vaccinated animals were protected when challenged with a very virulent IBDV (vvIBDV) isolate, however the degree of protection is directly correlated with the levels of neutralising antibodies. VP2 capsids elicited stronger protective immunity than tubular structures and 3& mgr;g of them were sufficient to confer a total protection comparable to that induced by an inactivated vaccine. Therefore, VP2 capsids represent a suitable candidate recombinant vaccine instead of virus-like particles (VLPs) for IBDV infections. Our results also provide clear evidence that the recombinant IBDV-derived antigens are structure-dependent in order to be efficient as vaccine components.

Mesenchymal stem cells restore CCl4-induced liver injury by an antioxidative process.

PubMed

Cho, Kyung-Ah; Woo, So-Youn; Seoh, Ju-Young; Han, Ho-Seong; Ryu, Kyung-Ha

2012-01-01

We have investigated BM (bone marrow)-derived MSCs (mesenchymal stem cells) for the treatment of liver injury. It was hypothesized that MSC-mediated resolution of liver injury could occur through an antioxidative process. After being injected with CCl4 (carbon tetrachloride), mice were injected with syngenic BM-derived MSCs or normal saline. Oxidative stress activity of the MSCs was determined by the analysis of ROS (reactive oxygen species) and SOD (superoxide dismutase) activity. In addition, cytoprotective genes of the liver tissue were assessed by real-time PCR and ARE (antioxidant-response element) reporter assay. Up-regulated ROS of CCl4-treated liver cells was attenuated by co-culturing with MSCs. Suppression of SOD by adding an SOD inhibitor decreased the effect of MSCs on injured liver cells. MSCs significantly increased SOD activity and inhibited ROS production in the injured liver. The gene expression levels of Hmox-1 (haem oxygenase-1), BI-1 (Bax inhibitor-1), HGF (hepatocyte growth factor), GST (glutathione transferase) and Nrf2 (nuclear factor-erythoid 2 p45 subunit-related factor 20), attenuated by CCl4, were increased up to basal levels after MSC transplantation. In addition, MSCs induced an ARE, shown by luciferase activity, which represented a cytoprotective response in the injured liver. Evidence of a new cytoprotective effect is shown in which MSCs promote an antioxidant response and supports the potential of using MSC transplantation as an effective treatment modality for liver disease.

Soluble CD40 Ligand and Oxidative Response Are Reciprocally Stimulated during Shiga Toxin-Associated Hemolytic Uremic Syndrome

PubMed Central

Abrey Recalde, Maria J.; Alvarez, Romina S.; Alberto, Fabiana; Mejias, Maria P.; Ramos, Maria V.; Fernandez Brando, Romina J.; Bruballa, Andrea C.; Exeni, Ramon A.; Alconcher, Laura; Ibarra, Cristina A.; Amaral, María M.; Palermo, Marina S.

2017-01-01

Shiga toxin (Stx), produced by Escherichia coli, is the main pathogenic factor of diarrhea-associated hemolytic uremic syndrome (HUS), which is characterized by the obstruction of renal microvasculature by platelet-fibrin thrombi. It is well known that the oxidative imbalance generated by Stx induces platelet activation, contributing to thrombus formation. Moreover, activated platelets release soluble CD40 ligand (sCD40L), which in turn contributes to oxidative imbalance, triggering the release of reactive oxidative species (ROS) on various cellular types. The aim of this work was to determine if the interaction between the oxidative response and platelet-derived sCD40L, as consequence of Stx-induced endothelium damage, participates in the pathogenic mechanism during HUS. Activated human glomerular endothelial cells (HGEC) by Stx2 induced platelets to adhere to them. Although platelet adhesion did not contribute to endothelial damage, high levels of sCD40L were released to the medium. The release of sCD40L by activated platelets was inhibited by antioxidant treatment. Furthermore, we found increased levels of sCD40L in plasma from HUS patients, which were also able to trigger the respiratory burst in monocytes in a sCD40L-dependent manner. Thus, we concluded that platelet-derived sCD40L and the oxidative response are reciprocally stimulated during Stx2-associated HUS. This process may contribute to the evolution of glomerular occlusion and the microangiopathic lesions. PMID:29068360

The rostral medulla of bullfrog tadpoles contains critical lung rhythmogenic and chemosensitive regions across metamorphosis.

PubMed

Reed, Mitchell D; Iceman, Kimberly E; Harris, Michael B; Taylor, Barbara E

2018-06-08

The development of amphibian breathing provides insight into vertebrate respiratory control mechanisms. Neural oscillators in the rostral and caudal medulla drive ventilation in amphibians, and previous reports describe ventilatory oscillators and CO 2 sensitive regions arise during different stages of amphibian metamorphosis. However, inconsistent findings have been enigmatic, and make comparisons to potential mammalian counterparts challenging. In the current study we assessed amphibian central CO 2 responsiveness and respiratory rhythm generation during two different developmental stages. Whole-nerve recordings of respiratory burst activity in cranial and spinal nerves were made from intact or transected brainstems isolated from tadpoles during early or late stages of metamorphosis. Brainstems were transected at the level of the trigeminal nerve, removing rostral structures including the nucleus isthmi, midbrain, and locus coeruleus, or transected at the level of the glossopharyngeal nerve, removing the putative buccal oscillator and caudal medulla. Removal of caudal structures stimulated the frequency of lung ventilatory bursts and revealed a hypercapnic response in normally unresponsive preparations derived from early stage tadpoles. In preparations derived from late stage tadpoles, removal of rostral or caudal structures reduced lung burst frequency, while CO 2 responsiveness was retained. Our results illustrate that structures within the rostral medulla are capable of sensing CO 2 throughout metamorphic development. Similarly, the region controlling lung ventilation appears to be contained in the rostral medulla throughout metamorphosis. This work offers insight into the consistency of rhythmic respiratory and chemosensitive capacities during metamorphosis. Copyright © 2018. Published by Elsevier Inc.

Intrinsic Deregulation of Vascular Smooth Muscle and Myofibroblast Differentiation in Mesenchymal Stromal Cells from Patients with Systemic Sclerosis.

PubMed

Hegner, Björn; Schaub, Theres; Catar, Rusan; Kusch, Angelika; Wagner, Philine; Essin, Kirill; Lange, Claudia; Riemekasten, Gabriela; Dragun, Duska

2016-01-01

Obliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe systemic autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast differentiation in response to SSc-microenvironment defining growth factors and determined responsible mechanisms. We studied responses of multipotent MSCs from SSc-patients (SSc-MSCs) and healthy controls (H-MSCs) to long-term exposure to CTGF, b-FGF, PDGF-BB or TGF-β1. Differentiation towards VSMC and myofibroblast lineages was analyzed on phenotypic, biochemical, and functional levels. Intracellular signaling studies included analysis of TGF-β receptor regulation, SMAD, AKT, ERK1/2 and autocrine loops. VSMC differentiation towards both, contractile and synthetic VSMC phenotypes in response to CTGF and b-FGF was disturbed in SSc-MSCs. H-MSCs and SSc-MSCs responded equally to PDGF-BB with prototypic fibroblastic differentiation. TGF-β1 initiated myofibroblast differentiation in both cell types, yet with striking phenotypic and functional differences: In relation to H-MSC-derived myofibroblasts induced by TGF-β1, those obtained from SSc-MSCs expressed more contractile proteins, migrated towards TGF-β1, had low proliferative capacity, and secreted higher amounts of collagen paralleled by reduced MMP expression. Higher levels of TGF-β receptor 1 and enhanced canonical and noncanonical TGF-β signaling in SSc-MSCs accompanied aberrant differentiation response of SSc-MSCs in comparison to H-MSCs. Deregulated VSMC differentiation with a shift towards myofibroblast differentiation expands the concept of disturbed endogenous regenerative capacity of MSCs from SSc patients. Disease related intrinsic hyperresponsiveness to TGF-β1 with increased collagen production may represent one responsible mechanism. Better understanding of repair barriers and harnessing beneficial differentiation processes in MSCs could widen options of autologous MSC application in SSc patients.

Myeloid-derived suppressor cells in murine retrovirus-induced AIDS inhibit T- and B-cell responses in vitro that are used to define the immunodeficiency.

PubMed

Green, Kathy A; Cook, W James; Green, William R

2013-02-01

Myeloid-derived suppressor cells (MDSCs) have been characterized in several disease settings, especially in many tumor systems. Compared to their involvement in tumor microenvironments, however, MDSCs have been less well studied in their responses to infectious disease processes, in particular to retroviruses that induce immunodeficiency. Here, we demonstrate for the first time the development of a highly immunosuppressive MDSC population that is dependent on infection by the LP-BM5 retrovirus, which causes murine acquired immunodeficiency. These MDSCs express a cell surface marker signature (CD11b(+) Gr-1(+) Ly6C(+)) characteristic of monocyte-type MDSCs. Such MDSCs profoundly inhibit immune responsiveness by a cell dose- and substantially inducible nitric oxide synthase (iNOS)-dependent mechanism that is independent of arginase activity, PD-1-PD-L1 expression, and interleukin 10 (IL-10) production. These MDSCs display levels of immunosuppressive function in parallel with the extent of disease in LP-BM5-infected wild-type (w.t.) versus knockout mouse strains that are differentially susceptible to pathogenesis. These MDSCs suppressed not only T-cell but also B-cell responses, which are an understudied target for MDSC inhibition. The MDSC immunosuppression of B-cell responses was confirmed by the use of purified B responder cells, multiple B-cell stimuli, and independent assays measuring B-cell expansion. Retroviral load measurements indicated that the suppressive Ly6G(low/±) Ly6C(+) CD11b(+)-enriched MDSC subset was positive for LP-BM5, albeit at a significantly lower level than that of nonfractionated splenocytes from LP-BM5-infected mice. These results, including the strong direct MDSC inhibition of B-cell responsiveness, are novel for murine retrovirus-induced immunosuppression and, as this broadly suppressive function mirrors that of the LP-BM5-induced disease syndrome, support a possible pathogenic effector role for these retrovirus-induced MDSCs.

Influence of NaCl on Growth, Proline, and Phosphoenolpyruvate Carboxylase Levels in Mesembryanthemum crystallinum Suspension Cultures 1

PubMed Central

Thomas, John C.; De Armond, Richard L.; Bohnert, Hans J.

1992-01-01

The facultative halophyte Mesembryanthemum crystallinum responds to salt stress by increasing the levels of phosphoenolpyruvate carboxylase (PEPCase) and other enzymes associated with Crassulacean acid metabolism. A more common response to salt stress in sensitive and tolerant species, including M. crystallinum, is the accumulation of proline. We have established M. crystallinum suspension cultures to investigate whether both these salt-induced responses occur at the cellular level. Leaf-and root-derived cultures maintain 5% of the total soluble amino acids as proline. Cell culture growth slows upon addition of 400 millimolar NaCl, and proline levels increase to 40% of the total soluble amino acids. These results suggest a functional salt-stress and response program in Mesembryanthemum cells. Suspension cultures grown with or without 400 millimolar NaCl have PEPCase levels that compare with those from roots and unstressed leaves. The predominant protein cross-reacting with an anti-PEPCase antibody corresponds to 105 kilodaltons (apparent molecular mass), whereas a second species of approximately 110 kilodaltons is present at low levels. In salt-stressed leaves, the 110 kilodalton protein is more prevalent. Levels of mRNA for both ppc1 (salt stress induced in leaves) and ppc2 (constitutive) genes in salt-treated suspensions cultures are equal to unstressed leaves, and only twice the levels found in untreated suspension cultures. Whereas cells accumulate proline in response to NaCl, PEPCase protein amounts remain similar in salt-treated and untreated cultures. The induction upon salt stress of the 110 kilodalton PEPCase protein and other Crassulacean acid metabolism enzymes in organized tissues is not observed in cell culture and may depend on tissue-dependent or photoautotrophy-dependent programs. ImagesFigure 4Figure 5 PMID:16668687

Responsiveness to Change of Functional Limitation Reporting: Cross-sectional Study Using the Intermountain ROMS Scale in Outpatient Rehabilitation.

PubMed

Brennan, Gerard P; Hunter, Stephen J; Snow, Greg; Minick, Kate I

2017-12-01

The Centers for Medicare and Medicaid Services (CMS) require physical therapists document patients' functional limitations. The process is not standardized. 
A systematic approach to determine a patient's functional limitations and responsiveness to change is needed. The purpose of this study is to compare patient-reported outcomes (PROs) responsiveness to change using 7-level severity/complexity modifier scale proposed by Medicare to a derived scale implemented by Intermountain Healthcare's Rehabilitation Outcomes Management System (ROMS). This was a retrospective, observational cohort design. 165,183 PROs prior to July 1, 2013, were compared to 46,334 records from July 1, 2013, to December 31, 2015. Histograms and ribbon plots illustrate distribution and change of patients' scores. ROMS raw score ranges were calculated and compared to CMS' severity/complexity levels based on score percentage. Distribution of the population was compared based on the 2 methods. Sensitivity and specificity were compared for responsiveness to change based on minimal clinically important difference (MCID). Histograms demonstrated few patient scores placed in CMS scale levels at the extremes, whereas the majority of scores placed in 2 middle levels (CJ, CK). ROMS distributed scores more evenly across levels. Ribbon plots illustrated advantage of ROMS' using narrower score ranges. Greater chance for patients to change levels was observed with ROMS when an MCID was achieved. ROMS narrower scale levels resulted in greater sensitivity and good specificity. Geographic representation for the United States was limited. Without patients' global rating of change, a reference standard to gauge validation of improvement could not be provided. ROMS provides a standard approach to identify accurately functional limitation modifier levels and to detect improvement more accurately than a straight across transposition using the CMS scale. © 2017 American Physical Therapy Association

Shikonin and its derivatives: a patent review.

PubMed

Wang, Rubing; Yin, Runting; Zhou, Wen; Xu, Defeng; Li, Shaoshun

2012-09-01

Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects. Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed. At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.

In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor δ reflects donors' insulin sensitivity in vivo.

PubMed

Ordelheide, Anna-Maria; Heni, Martin; Thamer, Claus; Machicao, Fausto; Fritsche, Andreas; Stefan, Norbert; Häring, Hans-Ulrich; Staiger, Harald

2011-12-01

Peroxisome proliferator-activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity. Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR. Donors' insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp. Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0·0312 and P = 0·0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors' insulin sensitivity (P > 0·2, all). Treatment of myotubes with a selective high-affinity PPARδ agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13- and 16-fold, respectively (P < 0·0001, both). The individual PDK4 and ANGPTL4 expression levels reached upon GW501516 treatment were associated with donors' insulin sensitivity neither (P > 0·2, both). However, GW501516-mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARδ responsiveness, were positively associated with donors' insulin sensitivity derived from OGTT (P = 0·0182 and P = 0·0231, respectively) and hyperinsulinemic-euglycemic clamp (P = 0·0046 and P = 0·0258, respectively). Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARδ, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

Secretory immunity with special reference to the oral cavity

PubMed Central

Brandtzaeg, Per

2013-01-01

The two principal antibody classes present in saliva are secretory IgA (SIgA) and IgG; the former is produced as dimeric IgA by local plasma cells (PCs) in the stroma of salivary glands and is transported through secretory epithelia by the polymeric Ig receptor (pIgR), also named membrane secretory component (SC). Most IgG in saliva is derived from the blood circulation by passive leakage mainly via gingival crevicular epithelium, although some may be locally produced in the gingiva or salivary glands. Gut-associated lymphoid tissue (GALT) and nasopharynx-associated lymphoid tissue (NALT) do not contribute equally to the pool of memory/effector B cells differentiating to mucosal PCs throughout the body. Thus, enteric immunostimulation may not be the best way to activate the production of salivary IgA antibodies although the level of specific SIgA in saliva may still reflect an intestinal immune response after enteric immunization. It remains unknown whether the IgA response in submandibular/sublingual glands is better related to B-cell induction in GALT than the parotid response. Such disparity is suggested by the levels of IgA in submandibular secretions of AIDS patients, paralleling their highly upregulated intestinal IgA system, while the parotid IgA level is decreased. Parotid SIgA could more consistently be linked to immune induction in palatine tonsils/adenoids (human NALT) and cervical lymph nodes, as supported by the homing molecule profile observed after immune induction at these sites. Several other variables influence the levels of antibodies in salivary secretions. These include difficulties with reproducibility and standardization of immunoassays, the impact of flow rate, acute or chronic stress, protein loss during sample handling, and uncontrolled admixture of serum-derived IgG and monomeric IgA. Despite these problems, saliva is an easily accessible biological fluid with interesting scientific and clinical potentials. PMID:23487566

Involvement of Endogenous Brain-Derived Neurotrophic Factor in Hypothalamic-Pituitary-Adrenal Axis Activity.

PubMed

Naert, G; Zussy, C; Tran Van Ba, C; Chevallier, N; Tang, Y-P; Maurice, T; Givalois, L

2015-11-01

Brain-derived neurotrophic factor (BDNF) appears to be highly involved in hypothalamic-pituitary-adrenal (HPA) axis regulation during adulthood, playing an important role in homeostasis maintenance. The present study aimed to determine the involvement of BDNF in HPA axis activity under basal and stress conditions via partial inhibition of this endogenous neurotrophin. Experiments were conducted in rats and mice with two complementary approaches: (i) BDNF knockdown with stereotaxic delivery of BDNF-specific small interfering RNA (siRNA) into the lateral ventricle of adult male rats and (ii) genetically induced knockdown (KD) of BDNF expression specifically in the central nervous system during the first ontogenesis in mice (KD mice). Delivery of siRNA in the rat brain decreased BDNF levels in the hippocampus (-31%) and hypothalamus (-35%) but not in the amygdala, frontal cortex and pituitary. In addition, siRNA induced no change of the basal HPA axis activity. BDNF siRNA rats exhibited decreased BDNF levels and concomitant altered adrenocortoctrophic hormone (ACTH) and corticosterone responses to restraint stress, suggesting the involvement of BDNF in the HPA axis adaptive response to stress. In KD mice, BDNF levels in the hippocampus and hypothalamus were decreased by 20% in heterozygous and by 60% in homozygous animals compared to wild-type littermates. Although, in heterozygous KD mice, no significant change was observed in the basal levels of plasma ACTH and corticosterone, both hormones were significantly increased in homozygous KD mice, demonstrating that robust cerebral BDNF inhibition (60%) is necessary to affect basal HPA axis activity. All of these results in both rats and mice demonstrate the involvement and importance of a robust endogenous pool of BDNF in basal HPA axis regulation and the pivotal function of de novo BDNF synthesis in the establishment of an adapted response to stress. © 2015 British Society for Neuroendocrinology.

Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

PubMed

Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y Andrew; Mao, Hui; Yang, Lily

2015-01-01

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

A Novel Method to Increase LinLog CMOS Sensors’ Performance in High Dynamic Range Scenarios

PubMed Central

Martínez-Sánchez, Antonio; Fernández, Carlos; Navarro, Pedro J.; Iborra, Andrés

2011-01-01

Images from high dynamic range (HDR) scenes must be obtained with minimum loss of information. For this purpose it is necessary to take full advantage of the quantification levels provided by the CCD/CMOS image sensor. LinLog CMOS sensors satisfy the above demand by offering an adjustable response curve that combines linear and logarithmic responses. This paper presents a novel method to quickly adjust the parameters that control the response curve of a LinLog CMOS image sensor. We propose to use an Adaptive Proportional-Integral-Derivative controller to adjust the exposure time of the sensor, together with control algorithms based on the saturation level and the entropy of the images. With this method the sensor’s maximum dynamic range (120 dB) can be used to acquire good quality images from HDR scenes with fast, automatic adaptation to scene conditions. Adaptation to a new scene is rapid, with a sensor response adjustment of less than eight frames when working in real time video mode. At least 67% of the scene entropy can be retained with this method. PMID:22164083

A novel method to increase LinLog CMOS sensors' performance in high dynamic range scenarios.

PubMed

Martínez-Sánchez, Antonio; Fernández, Carlos; Navarro, Pedro J; Iborra, Andrés

2011-01-01

Images from high dynamic range (HDR) scenes must be obtained with minimum loss of information. For this purpose it is necessary to take full advantage of the quantification levels provided by the CCD/CMOS image sensor. LinLog CMOS sensors satisfy the above demand by offering an adjustable response curve that combines linear and logarithmic responses. This paper presents a novel method to quickly adjust the parameters that control the response curve of a LinLog CMOS image sensor. We propose to use an Adaptive Proportional-Integral-Derivative controller to adjust the exposure time of the sensor, together with control algorithms based on the saturation level and the entropy of the images. With this method the sensor's maximum dynamic range (120 dB) can be used to acquire good quality images from HDR scenes with fast, automatic adaptation to scene conditions. Adaptation to a new scene is rapid, with a sensor response adjustment of less than eight frames when working in real time video mode. At least 67% of the scene entropy can be retained with this method.

Atomic-scale origin of dynamic viscoelastic response and creep in disordered solids

NASA Astrophysics Data System (ADS)

Milkus, Rico; Zaccone, Alessio

2017-02-01

Viscoelasticity has been described since the time of Maxwell as an interpolation of purely viscous and purely elastic response, but its microscopic atomic-level mechanism in solids has remained elusive. We studied three model disordered solids: a random lattice, the bond-depleted fcc lattice, and the fcc lattice with vacancies. Within the harmonic approximation for central-force lattices, we applied sum rules for viscoelastic response derived on the basis of nonaffine atomic motions. The latter motions are a direct result of local structural disorder, and in particular, of the lack of inversion symmetry in disordered lattices. By defining a suitable quantitative and general atomic-level measure of nonaffinity and inversion symmetry, we show that the viscoelastic responses of all three systems collapse onto a master curve upon normalizing by the overall strength of inversion-symmetry breaking in each system. Close to the isostatic point for central-force lattices, power-law creep G (t ) ˜t-1 /2 emerges as a consequence of the interplay between soft vibrational modes and nonaffine dynamics, and various analytical scalings, supported by numerical calculations, are predicted by the theory.

The Induction of Pattern-Recognition Receptor Expression against Influenza A Virus through Duox2-Derived Reactive Oxygen Species in Nasal Mucosa.

PubMed

Kim, Hyun Jik; Kim, Chang-Hoon; Kim, Min-Ji; Ryu, Ji-Hwan; Seong, Sang Yeop; Kim, Sujin; Lim, Su Jin; Holtzman, Michael J; Yoon, Joo-Heon

2015-10-01

We studied the relative roles of Duox2-derived reactive oxygen species (ROS) in host defense against influenza A virus (IAV) infection in normal human nasal epithelial cells and mouse nasal mucosa. We found that Duox2 primarily generated ROS rapidly after IAV infection in normal human nasal epithelial cells and that knockdown of Duox2 aggravated IAV infection. In addition, Duox2-derived ROS enhancement significantly suppressed IAV infection in nasal epithelium. In particular, Duox2-derived ROS were required for the induction of retinoic acid-inducible gene (RIG)-I and melanoma differentiation-associated protein 5 (MDA5) transcription. After intranasal IAV inoculation into mice, viral infection was significantly aggravated from 3 days postinoculation (dpi) in the nasal mucosa, and the IAV viral titer was highest at 7 dpi. Both RIG-I and MDA5 messenger RNA levels increased dominantly in mouse nasal mucosa from 3 dpi; consistent with this, RIG-I and MDA5 proteins were also induced after IAV infection. RIG-I and MDA5 messenger RNA levels were induced to a lower extent in the nasal mucosa of the mice that were inoculated with Duox2 short hairpin RNA, and the IAV viral titer was significantly higher in nasal lavage. Taken together, Duox2-derived ROS are necessary for the innate immune response and trigger the induction of RIG-I and MDA5 to resist IAV infection in human nasal epithelium and mouse nasal mucosa.

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.

PubMed

Sansone, Pasquale; Berishaj, Marjan; Rajasekhar, Vinagolu K; Ceccarelli, Claudio; Chang, Qing; Strillacci, Antonio; Savini, Claudia; Shapiro, Lauren; Bowman, Robert L; Mastroleo, Chiara; De Carolis, Sabrina; Daly, Laura; Benito-Martin, Alberto; Perna, Fabiana; Fabbri, Nicola; Healey, John H; Spisni, Enzo; Cricca, Monica; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

2017-04-15

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ER lo /Notch hi feed-forward loop responsible for the generation of CD133 hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221 hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133 hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133 hi CSCs. Conversely, in models of CD133 neg , HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133 hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR . ©2017 American Association for Cancer Research.

Differentiation-Dependent Energy Production and Metabolite Utilization: A Comparative Study on Neural Stem Cells, Neurons, and Astrocytes.

PubMed

Jády, Attila Gy; Nagy, Ádám M; Kőhidi, Tímea; Ferenczi, Szilamér; Tretter, László; Madarász, Emília

2016-07-01

While it is evident that the metabolic machinery of stem cells should be fairly different from that of differentiated neurons, the basic energy production pathways in neural stem cells (NSCs) or in neurons are far from clear. Using the model of in vitro neuron production by NE-4C NSCs, this study focused on the metabolic changes taking place during the in vitro neuronal differentiation. O2 consumption, H(+) production, and metabolic responses to single metabolites were measured in cultures of NSCs and in their neuronal derivatives, as well as in primary neuronal and astroglial cultures. In metabolite-free solutions, NSCs consumed little O2 and displayed a higher level of mitochondrial proton leak than neurons. In stem cells, glycolysis was the main source of energy for the survival of a 2.5-h period of metabolite deprivation. In contrast, stem cell-derived or primary neurons sustained a high-level oxidative phosphorylation during metabolite deprivation, indicating the consumption of own cellular material for energy production. The stem cells increased O2 consumption and mitochondrial ATP production in response to single metabolites (with the exception of glucose), showing rapid adaptation of the metabolic machinery to the available resources. In contrast, single metabolites did not increase the O2 consumption of neurons or astrocytes. In "starving" neurons, neither lactate nor pyruvate was utilized for mitochondrial ATP production. Gene expression studies also suggested that aerobic glycolysis and rapid metabolic adaptation characterize the NE-4C NSCs, while autophagy and alternative glucose utilization play important roles in the metabolism of stem cell-derived neurons.

Intranasal vaccination with an inactivated whole influenza virus vaccine induces strong antibody responses in serum and nasal mucus of healthy adults

PubMed Central

Ainai, Akira; Tamura, Shin-ichi; Suzuki, Tadaki; van Riet, Elly; Ito, Ryo; Odagiri, Takato; Tashiro, Masato; Kurata, Takeshi; Hasegawa, Hideki

2013-01-01

Haemagglutination inhibition (HI) and neutralization (NT) titers as well as haemagglutinin (HA) specific antibody responses were examined in 50 healthy adults aged between 22 and 69 y old after two intranasal administrations of an inactivated whole virus vaccine derived from A/Victoria/210/2009 virus (45 μg HA per dose) at 3 week intervals. Serum HI titers after two-doses of the nasal vaccine showed >2.5-fold rise in the ratio of geometric mean titer upon vaccination, >40% of subjects with a ≥4-fold increase in titer and >70% of subjects with a titer of ≥1:40, all parameters associated with an effective outcome of vaccination in the criteria defined by the European Medicines Agency. Serum neutralizing antibody responses correlated with HI antibody responses, although NT titers were about 2-fold higher than HI titers. These high levels of serum responses were accompanied by high levels of HI and neutralizing antibody responses in nasal mucus as measured in concentrated nasal wash samples that were about 10 times diluted compared with natural nasal mucus. Serum and nasal HI and neutralizing antibody responses consisted of HA-specific IgG and IgA antibody responses, with IgG and IgA antibodies being dominant in serum and nasal responses, respectively. PMID:23896606

A model of the anterior esophagus in snakes, with functional and developmental implications.

PubMed

Cundall, David; Tuttman, Cassandra; Close, Matthew

2014-03-01

The gross anatomy of the mouth of snakes has always been interpreted as an evolutionary response to feeding demands. In most alethinophidian species, their anatomy allows limited functional independence of right and left sides and the roof and floor of the mouth as well as wide separation of the tips of the mandibles. However, locations of the tongue and glottis in snakes suggest extraordinary rearrangement of pharyngeal structures characteristic of all vertebrates. Serial histological sections through the heads of a number of colubroid species show muscularis mucosal smooth muscle fibers appearing in the paratracheal gutter of the lower jaw at varying levels between the eye and ear regions. Incomplete muscularis externa elements appear beneath the paratracheal gutter more caudally but typically at otic levels. Both muscle layers encompass more of the gut wall at more posterior levels, encircling the gut at the level of the atlas or axis. The pattern in snakes suggests developmental dissociation of dorsal and ventral splanchnic derivatives and extensive topological rearrangements of some ventral pharyngeal arch derivatives typical of most tetrapods. When snakes swallow large prey, the effective oral cavity becomes extremely short ventrally. The palatomaxillary arches function as ratchets packing the prey almost directly into the esophagus. Our findings raise questions about germ layer origins and regulation of differentiation of gut regions and derivatives in snakes and suggest that significant aspects of the evolution of lepidosaurs may be difficult to recover from bones or molecular sequence data alone. Copyright © 2014 Wiley Periodicals, Inc.

Modeling Protein Aggregation and the Heat Shock Response in ALS iPSC-Derived Motor Neurons.

PubMed

Seminary, Emily R; Sison, Samantha L; Ebert, Allison D

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in C9orf72, SOD1 , or TDP-43 are the most common causes of familial ALS, together responsible for at least 60% of these cases. Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62. These inclusions are normally prevented and cleared by heat shock proteins (Hsps), suggesting that ALS motor neurons have an impaired ability to induce the heat shock response (HSR). Accordingly, there is evidence of decreased induction of Hsps in ALS mouse models and in human post-mortem samples compared to unaffected controls. However, the role of Hsps in protein accumulation in human motor neurons has not been fully elucidated. Here, we generated motor neuron cultures from human induced pluripotent stem cell (iPSC) lines carrying mutations in SOD1, TDP-43 , or C9orf72 . In this study, we provide evidence that despite a lack of overt motor neuron loss, there is an accumulation of insoluble, aggregation-prone proteins in iPSC-derived motor neuron cultures but that content and levels vary with genetic background. Additionally, although iPSC-derived motor neurons are generally capable of inducing the HSR when exposed to a heat stress, protein aggregation itself is not sufficient to induce the HSR or stress granule formation. We therefore conclude that ALS iPSC-derived motor neurons recapitulate key early pathological features of the disease and fail to endogenously upregulate the HSR in response to increased protein burden.

Modeling Protein Aggregation and the Heat Shock Response in ALS iPSC-Derived Motor Neurons

PubMed Central

Seminary, Emily R.; Sison, Samantha L.; Ebert, Allison D.

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in C9orf72, SOD1, or TDP-43 are the most common causes of familial ALS, together responsible for at least 60% of these cases. Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62. These inclusions are normally prevented and cleared by heat shock proteins (Hsps), suggesting that ALS motor neurons have an impaired ability to induce the heat shock response (HSR). Accordingly, there is evidence of decreased induction of Hsps in ALS mouse models and in human post-mortem samples compared to unaffected controls. However, the role of Hsps in protein accumulation in human motor neurons has not been fully elucidated. Here, we generated motor neuron cultures from human induced pluripotent stem cell (iPSC) lines carrying mutations in SOD1, TDP-43, or C9orf72. In this study, we provide evidence that despite a lack of overt motor neuron loss, there is an accumulation of insoluble, aggregation-prone proteins in iPSC-derived motor neuron cultures but that content and levels vary with genetic background. Additionally, although iPSC-derived motor neurons are generally capable of inducing the HSR when exposed to a heat stress, protein aggregation itself is not sufficient to induce the HSR or stress granule formation. We therefore conclude that ALS iPSC-derived motor neurons recapitulate key early pathological features of the disease and fail to endogenously upregulate the HSR in response to increased protein burden. PMID:29515358

Extracellular Alkalinization as a Defense Response in Potato Cells.

PubMed

Moroz, Natalia; Fritch, Karen R; Marcec, Matthew J; Tripathi, Diwaker; Smertenko, Andrei; Tanaka, Kiwamu

2017-01-01

A quantitative and robust bioassay to assess plant defense response is important for studies of disease resistance and also for the early identification of disease during pre- or non-symptomatic phases. An increase in extracellular pH is known to be an early defense response in plants. In this study, we demonstrate extracellular alkalinization as a defense response in potatoes. Using potato suspension cell cultures, we observed an alkalinization response against various pathogen- and plant-derived elicitors in a dose- and time-dependent manner. We also assessed the defense response against a variety of potato pathogens, such as protists ( Phytophthora infestans and Spongospora subterranea ) and fungi ( Verticillium dahliae and Colletotrichum coccodes ). Our results show that extracellular pH increases within 30 min in proportion to the number of pathogen spores added. Consistently with the alkalinization effect, the higher transcription level of several defense-related genes and production of reactive oxygen species was observed. Our results demonstrate that the alkalinization response is an effective marker to study early stages of defense response in potatoes.

Cytotoxicity of bacterial-derived toxins to immortal lung epithelial and macrophage cells.

PubMed

Peterson, Dianne E; Collier, Jayne M; Katterman, Matthew E; Turner, Rachael A; Riley, Mark R

2010-03-01

Health risks associated with inhalation and deposition of biological materials have been a topic of great concern due to highly publicized cases of inhalation anthrax, of new regulations on the release of particulate matter, and to increased concerns on the hazards of indoor air pollution. Here, we present an evaluation of the sensitivity of two immortal cell lines (A549, human lung carcinoma epithelia) and NR8383 (rat alveolar macrophages) to a variety of bacterial-derived inhalation hazards and simulants including etoposide, gliotoxin, streptolysin O, and warfarin. The cell response is evaluated through quantification of changes in mitochondrial succinate dehydrogenase activity, release of lactate dehydrogenase, initiation of apoptosis, and through changes in morphology as determined by visible light microscopy and scanning electron microscopy. These cells display dose-response relations to each toxin, except for triton which has a step change response. The first observable responses of the epithelial cells to these compounds are changes in metabolism for one toxin (warfarin) and alterations in membrane permeability for another (gliotoxin). The other four toxins display a similar time course in response as gauged by changes in metabolism and loss of membrane integrity. Macrophages are more sensitive to most toxins; however, they display a lower level of stability. This information can be used in the design of cell-based sensors responding to these and similar hazards.

Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

PubMed

Tsuru, Jusen; Tanaka, Yoshihiro; Ishitobi, Yoshinobu; Maruyama, Yoshihiro; Inoue, Ayako; Kawano, Aimi; Ikeda, Rie; Ando, Tomoko; Oshita, Harumi; Aizawa, Saeko; Masuda, Koji; Higuma, Haruka; Kanehisa, Masayuki; Ninomiya, Taiga; Akiyoshi, Jotaro

2014-01-01

Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic-pituitary-adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

Blastocyst-Derived Stem Cell Populations under Stress: Impact of Nutrition and Metabolism on Stem Cell Potency Loss and Miscarriage.

PubMed

Yang, Yu; Bolnick, Alan; Shamir, Alexandra; Abdulhasan, Mohammed; Li, Quanwen; Parker, G C; Puscheck, Elizabeth E; Rappolee, D A

2017-08-01

Data from in vitro and in vivo models suggest that malnutrition and stress trigger adaptive responses, leading to small for gestational age (SGA) blastocysts with fewer cell numbers. These stress responses are initially adaptive, but become maladaptive with increasing stress exposures. The common stress responses of the blastocyst-derived stem cells, pluripotent embryonic and multipotent placental trophoblast stem cells (ESCs and TSCs), are decreased growth and potency, and increased, imbalanced and irreversible differentiation. SGA embryos may fail to produce sufficient antiluteolytic placental hormone to maintain corpus luteum progesterone secretion that provides nutrition at the implantation site. Myriad stress inputs for the stem cells in the embryo can occur in vitro during in vitro fertilization/assisted reproductive technology (IVF/ART) or in vivo. Paradoxically, stresses that diminish stem cell growth lead to a higher level of differentiation simultaneously which further decreases ESC or TSC numbers in an attempt to functionally compensate for fewer cells. In addition, prolonged or strong stress can cause irreversible differentiation. Resultant stem cell depletion is proposed as a cause of miscarriage via a "quiet" death of an ostensibly adaptive response of stem cells instead of a reactive, violent loss of stem cells or their differentiated progenies.

The Tomato Kinase Pti1 Contributes to Production of Reactive Oxygen Species in Response to Two Flagellin-Derived Peptides and Promotes Resistance to Pseudomonas syringae Infection.

PubMed

Schwizer, Simon; Kraus, Christine M; Dunham, Diane M; Zheng, Yi; Fernandez-Pozo, Noé; Pombo, Marina A; Fei, Zhangjun; Chakravarthy, Suma; Martin, Gregory B

2017-09-01

The Pti1 kinase was identified from a reverse genetic screen as contributing to pattern-triggered immunity (PTI) against Pseudomonas syringae pv. tomato (Pst). The tomato genome has two Pti1 genes, referred to as Pti1a and Pti1b. A hairpin-Pti1 (hpPti1) construct was developed and was used to generate two independent stable transgenic tomato lines that had reduced transcript abundance of both genes. In response to P. syringae pv. tomato inoculation, these hpPti1 plants developed more severe disease symptoms, supported higher bacterial populations, and had reduced transcript accumulation of PTI-associated genes, as compared with wild-type plants. In response to two flagellin-derived peptides, the hpPti1 plants produced lesser amounts of reactive oxygen species (ROS) but showed no difference in mitogen-activated protein kinase (MAPK). Synthetic Pti1a and Pti1b genes designed to avoid silencing were transiently expressed in the hpPti1 plants and restored the ability of the plants to produce wild-type levels of ROS. Our results identify a new component of PTI in tomato that, because it affects ROS production but not MAPK signaling, appears to act early in the immune response.

Biological Role of Trichoderma harzianum-Derived Platelet-Activating Factor Acetylhydrolase (PAF-AH) on Stress Response and Antagonism

PubMed Central

Yu, Chuanjin; Fan, Lili; Wu, Qiong; Fu, Kehe; Gao, Shigang; Wang, Meng; Gao, Jinxin; Li, Yaqian; Chen, Jie

2014-01-01

We investigated the properties of platelet-activating factor acetylhydrolase (PAF-AH) derived from Trichoderma harzianum. The enzyme, comprised of 572 amino acids, shares high homology with PAF-AH proteins from T. koningii and other microbial species. The optimum enzymatic activity of PAF-AH occurred at pH 6 in the absence of Ca2+ and it localized in the cytoplasm, and we observed the upregulation of PAF-AH expression in response to carbon starvation and strong heat shock. Furthermore, PAF-AH knockout transformant growth occurred more slowly than wild type cells and over-expression strains grown in SM medium at 37°C and 42°C. In addition, PAF-AH expression significantly increased under a series of maize root induction assay. Eicosanoic acid and ergosterol levels decreased in the PAF-AH knockouts compared to wild type cells, as revealed by GC/MS analysis. We also determined stress responses mediated by PAF-AH were related to proteins HEX1, Cu/Zn superoxide dismutase, and cytochrome c. Finally, PAF-AH exhibited antagonistic activity against Rhizoctonia solani in plate confrontation assays. Our results indicate PAF-AH may play an important role in T. harzianum stress response and antagonism under diverse environmental conditions. PMID:24964161

Biological role of Trichoderma harzianum-derived platelet-activating factor acetylhydrolase (PAF-AH) on stress response and antagonism.

PubMed

Yu, Chuanjin; Fan, Lili; Wu, Qiong; Fu, Kehe; Gao, Shigang; Wang, Meng; Gao, Jinxin; Li, Yaqian; Chen, Jie

2014-01-01

We investigated the properties of platelet-activating factor acetylhydrolase (PAF-AH) derived from Trichoderma harzianum. The enzyme, comprised of 572 amino acids, shares high homology with PAF-AH proteins from T. koningii and other microbial species. The optimum enzymatic activity of PAF-AH occurred at pH 6 in the absence of Ca2+ and it localized in the cytoplasm, and we observed the upregulation of PAF-AH expression in response to carbon starvation and strong heat shock. Furthermore, PAF-AH knockout transformant growth occurred more slowly than wild type cells and over-expression strains grown in SM medium at 37°C and 42°C. In addition, PAF-AH expression significantly increased under a series of maize root induction assay. Eicosanoic acid and ergosterol levels decreased in the PAF-AH knockouts compared to wild type cells, as revealed by GC/MS analysis. We also determined stress responses mediated by PAF-AH were related to proteins HEX1, Cu/Zn superoxide dismutase, and cytochrome c. Finally, PAF-AH exhibited antagonistic activity against Rhizoctonia solani in plate confrontation assays. Our results indicate PAF-AH may play an important role in T. harzianum stress response and antagonism under diverse environmental conditions.

Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults.

PubMed

Chio, Chung-Ching; Wei, Li; Chen, Tyng Guey; Lin, Chien-Min; Shieh, Ja-Ping; Yeh, Poh-Shiow; Chen, Ruei-Ming

2016-06-01

OBJECT Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. METHODS Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphology, cas-pase-3 activity, DNA fragmentation, and cell apoptosis were assayed to determine the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. RESULTS Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Additionally, OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. CONCLUSIONS This study shows that NOR-1 can transduce survival signals in neuronal cells responsible for hypoxiainduced apoptotic insults through activation of a CREB/cIAP2-dependent mechanism.

Profile of Arachidonic Acid-Derived Inflammatory Markers and Its Modulation by Nitro-Oleic Acid in an Inherited Model of Amyotrophic Lateral Sclerosis

PubMed Central

Trostchansky, Andrés; Mastrogiovanni, Mauricio; Miquel, Ernesto; Rodríguez-Bottero, Sebastián; Martínez-Palma, Laura; Cassina, Patricia; Rubbo, Homero

2018-01-01

The lack of current treatments for amyotrophic lateral sclerosis (ALS) highlights the need of a comprehensive understanding of the biological mechanisms of the disease. A consistent neuropathological feature of ALS is the extensive inflammation around motor neurons and axonal degeneration, evidenced by accumulation of reactive astrocytes and activated microglia. Final products of inflammatory processes may be detected as a screening tool to identify treatment response. Herein, we focus on (a) detection of arachidonic acid (AA) metabolization products by lipoxygenase (LOX) and prostaglandin endoperoxide H synthase in SOD1G93A mice and (b) evaluate its response to the electrophilic nitro-oleic acid (NO2-OA). Regarding LOX-derived products, a significant increase in 12-hydroxyeicosatetraenoic acid (12-HETE) levels was detected in SOD1G93A mice both in plasma and brain whereas no changes were observed in age-matched non-Tg mice at the onset of motor symptoms (90 days-old). In addition, 15-hydroxyeicosatetraenoic acid (15-HETE) levels were greater in SOD1G93A brains compared to non-Tg. Prostaglandin levels were also increased at day 90 in plasma from SOD1G93A compared to non-Tg being similar in both types of animals at later stages of the disease. Administration of NO2-OA 16 mg/kg, subcutaneously (s/c) three times a week to SOD1G93A female mice, lowered the observed increase in brain 12-HETE levels compared to the non-nitrated fatty acid condition, and modified many others inflammatory markers. In addition, NO2-OA significantly improved grip strength and rotarod performance compared to vehicle or OA treated animals. These beneficial effects were associated with increased hemeoxygenase 1 (HO-1) expression in the spinal cord of treated mice co-localized with reactive astrocytes. Furthermore, significant levels of NO2-OA were detected in brain and spinal cord from NO2-OA -treated mice indicating that nitro-fatty acids (NFA) cross brain–blood barrier and reach the central nervous system to induce neuroprotective actions. In summary, we demonstrate that LOX-derived oxidation products correlate with disease progression. Overall, we are proposing that key inflammatory mediators of AA-derived pathways may be useful as novel footprints of ALS onset and progression as well as NO2-OA as a promising therapeutic compound. PMID:29760648

Determining the Appropriate Size of the Contracting Workforce: Yes We Can!

DTIC Science & Technology

2011-04-30

visiting seminars at American University in Cairo and Instituto de Empresas in Madrid. His Air Force contracting experience includes F-22 Fighter, C...17 Cargo Transport , and serving as director of Joint Contracting Command-North, Kirkuk, Iraq. At the Pentagon, Dr. Reed was responsible for...Department of Transportation –Federal Aviation Administration. The model uses historical program data to derive recommended staffing levels for major

A comparison between exposure-response relationships for wind turbine annoyance and annoyance due to other noise sources.

PubMed

Janssen, Sabine A; Vos, Henk; Eisses, Arno R; Pedersen, Eja

2011-12-01

Surveys have shown that noise from wind turbines is perceived as annoying by a proportion of residents living in their vicinity, apparently at much lower noise levels than those inducing annoyance due to other environmental sources. The aim of the present study was to derive the exposure-response relationship between wind turbine noise exposure in L(den) and the expected percentage annoyed residents and to compare it to previously established relationships for industrial noise and transportation noise. In addition, the influence of several individual and situational factors was assessed. On the basis of available data from two surveys in Sweden (N=341, N=754) and one survey in the Netherlands (N=725), a relationship was derived for annoyance indoors and for annoyance outdoors at the dwelling. In comparison to other sources of environmental noise, annoyance due to wind turbine noise was found at relatively low noise exposure levels. Furthermore, annoyance was lower among residents who received economical benefit from wind turbines and higher among residents for whom the wind turbine was visible from the dwelling. Age and noise sensitivity had similar effects on annoyance to those found in research on annoyance by other sources. © 2011 Acoustical Society of America

Cancer imaging phenomics toolkit: quantitative imaging analytics for precision diagnostics and predictive modeling of clinical outcome.

PubMed

Davatzikos, Christos; Rathore, Saima; Bakas, Spyridon; Pati, Sarthak; Bergman, Mark; Kalarot, Ratheesh; Sridharan, Patmaa; Gastounioti, Aimilia; Jahani, Nariman; Cohen, Eric; Akbari, Hamed; Tunc, Birkan; Doshi, Jimit; Parker, Drew; Hsieh, Michael; Sotiras, Aristeidis; Li, Hongming; Ou, Yangming; Doot, Robert K; Bilello, Michel; Fan, Yong; Shinohara, Russell T; Yushkevich, Paul; Verma, Ragini; Kontos, Despina

2018-01-01

The growth of multiparametric imaging protocols has paved the way for quantitative imaging phenotypes that predict treatment response and clinical outcome, reflect underlying cancer molecular characteristics and spatiotemporal heterogeneity, and can guide personalized treatment planning. This growth has underlined the need for efficient quantitative analytics to derive high-dimensional imaging signatures of diagnostic and predictive value in this emerging era of integrated precision diagnostics. This paper presents cancer imaging phenomics toolkit (CaPTk), a new and dynamically growing software platform for analysis of radiographic images of cancer, currently focusing on brain, breast, and lung cancer. CaPTk leverages the value of quantitative imaging analytics along with machine learning to derive phenotypic imaging signatures, based on two-level functionality. First, image analysis algorithms are used to extract comprehensive panels of diverse and complementary features, such as multiparametric intensity histogram distributions, texture, shape, kinetics, connectomics, and spatial patterns. At the second level, these quantitative imaging signatures are fed into multivariate machine learning models to produce diagnostic, prognostic, and predictive biomarkers. Results from clinical studies in three areas are shown: (i) computational neuro-oncology of brain gliomas for precision diagnostics, prediction of outcome, and treatment planning; (ii) prediction of treatment response for breast and lung cancer, and (iii) risk assessment for breast cancer.

Establishment of primary mixed cell cultures from spontaneous canine mammary tumors: Characterization of classic and new cancer-associated molecules

PubMed Central

Gentile, Luciana B.; Nagamine, Marcia K.; Biondi, Luiz R.; Sanches, Daniel S.; Toyota, Fábio; Giovani, Tatiane M.; de Jesus, Isis P.; da Fonseca, Ivone I. M.; Queiroz-Hazarbassanov, Nicolle; Diaz, Bruno L.; Salles Gomes, Cristina de O. Massoco

2017-01-01

There are many factors which make canine cancer like cancer in humans. The occurrence of spontaneous mammary tumors in pet dogs, tumor genetics, molecular targets and exposure to the same environmental risk factors are among these factors. Therefore, the study of canine cancer can provide useful information to the oncology field. This study aimed to establish and characterize a panel of primary mixed cell cultures obtained from spontaneous canine mammary tumors. Eight established cell cultures obtained from one normal mammary gland, one complex adenoma, one mixed adenoma, two complex carcinomas and two mixed carcinomas were analyzed. The gene expression levels of classic molecular cancer players such as fibroblast growth factor receptor (FGFR) 2, breast cancer (BRCA) 1, BRCA2 and estrogen receptor (ESR) 1 were evaluated. For the first time, three orphan nuclear receptors, estrogen-related receptors (ERRs) α, β and γ were studied in canine mammary cancer. The highest expression level of ERRα was observed in complex carcinoma-derived cell culture, while the highest levels of ERRβ and γ were observed in cells derived from a mixed carcinoma. Meanwhile, complex carcinomas presented the highest levels of expression of ESR1, BRCA1 and FGFR2 among all samples. BRCA2 was found exclusively in complex adenoma. The transcription factor GATA3 had its highest levels in mixed carcinoma samples and its lowest levels in complex adenoma. Proliferation assays were also performed to evaluate the mixed cell cultures response to ER ligands, genistein and DES, both in normoxia and hypoxic conditions. Our results demonstrate that morphological and functional studies of primary mixed cell cultures derived from spontaneous canine mammary tumors are possible and provide valuable tool for the study of various stages of mammary cancer development. PMID:28945747

Combination therapy of menstrual derived mesenchymal stem cells and antibiotics ameliorates survival in sepsis.

PubMed

Alcayaga-Miranda, Francisca; Cuenca, Jimena; Martin, Aldo; Contreras, Luis; Figueroa, Fernando E; Khoury, Maroun

2015-10-16

Sepsis is a clinical syndrome associated with a severe systemic inflammation induced by infection. Although different anti-microbial drugs have been used as treatments, morbidity and mortality rates remain high. Mesenchymal stem cells (MSCs) derived from the bone marrow have demonstrated a partial protective effect in sepsis. Menstrual derived MSCs (MenSCs) emerge as an attractive candidate because they present important advantages over other sources, including improved proliferation rates and paracrine response under specific stress conditions. Here, we evaluate their therapeutic effect in a polymicrobial severe sepsis model. The antimicrobial activity of MenSCs was determined in vitro through direct and indirect bacterial growth assays and the measurement of the expression levels of different antimicrobial peptides (AMPs) by quantitative reverse transcription-polymerase chain reaction. The therapeutic effect of MenSCs was determined in the cecal ligation and puncture (CLP) mouse model. Mice were then treated with antibiotics (AB) or MenSCs alone or in combination. The survival rates and histological and biochemical parameters were evaluated, and the systemic levels of pro- and anti-inflammatory cytokines as well as the response of specific lymphocyte subsets were determined by flow cytometry. MenSCs exerted an important antimicrobial effect in vitro, mediated by a higher expression of the AMP-hepcidin. In the CLP mouse model, MenSCs in synergy with AB (a) improved the survival rate (95 %) in comparison with saline (6 %), AB (73 %), and MenSCs alone (48 %) groups; (b) enhanced bacterial clearance in the peritoneal fluids and blood; (c) reduced organ injuries evaluated by lower concentrations of the liver enzymes alanine aminotransferase and aspartate aminotransferase; and (d) modulated the inflammatory response through reduction of pro- and anti-inflammatory cytokines without significant loss of T and B lymphocytes. We conclude that MenSCs in combination with AB enhance survival in CLP-induced sepsis by acting on multiples targets. MenSCs thus constitute a feasible approach for the future clinical treatment of sepsis.

Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM).

PubMed

Demeure, Kevin; Fack, Fred; Duriez, Elodie; Tiemann, Katja; Bernard, Amandine; Golebiewska, Anna; Bougnaud, Sébastien; Bjerkvig, Rolf; Domon, Bruno; Niclou, Simone P

2016-02-01

Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM)*

PubMed Central

Demeure, Kevin; Fack, Fred; Duriez, Elodie; Tiemann, Katja; Bernard, Amandine; Golebiewska, Anna; Bougnaud, Sébastien; Bjerkvig, Rolf; Domon, Bruno; Niclou, Simone P.

2016-01-01

Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples. PMID:26243272

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice

PubMed Central

Shin, Jihyun; Yang, Soo Jin

2016-01-01

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1-α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1. PMID:28211759

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice.

PubMed

Shin, Jihyun; Yang, Soo Jin; Lim, Yunsook

2017-03-01

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1- α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1.

Re-examination of immune response and estimation of anti-Vi IgG protective threshold against typhoid fever-based on the efficacy trial of Vi conjugate in young children.

PubMed

Szu, Shousun C; Klugman, Keith P; Hunt, Steven

2014-04-25

The capsular polysaccharide of Salmonella enterica serovar Typhi, Vi antigen, is an essential virulence factor and a protective antigen. Similar to other polysaccharide vaccines, the protective action of Vi, both to the polysaccharide alone or when presented as a conjugate, is mediated by serum IgG Vi antibodies. The evaluation of Vi capsular polysaccharide based vaccines to prevent typhoid fever would be significantly facilitated by the identification of a "protective level" of serum antibodies to Vi antigen. The protective level of anti-Vi IgG against typhoid fever was derived from the protective efficacy and immune response of a Vi-rEPA conjugate vaccine efficacy trial. The estimation was derived by two methods: correlation of the percent efficacy and the antibody distribution profile in the vaccine group at a given period of observation, and use of the relative ratio of anti-Vi IgG levels between the vaccine and placebo groups greater or equal to the Relative Risk of typhoid fever used in the efficacy determination. Both methods predicted a similar range of a minimum protective level of anti-Vi IgG between 1.4 and 2.0μg/ml (short term threshold). When applying a protective threshold of 10μg/ml at 6 months post immunization, an IgG level in excess of 1.4μg/ml was achieved by 90% of children at 46 months post immunization, consistent with an 89% level of protection over the duration of the study. We thus suggest that the proportion of children with Vi IgG>10μg/ml (long term threshold) 6 months after immunization may reflect the proportion protected over at least a 4 year period. The current assignment of an anti-Vi IgG protective level may be of value when evaluating vaccine performance of future Vi conjugate vaccines. Published by Elsevier Ltd.

NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes.

PubMed

Ebrahimian, Téni G; Heymes, Christophe; You, Dong; Blanc-Brude, Olivier; Mees, Barend; Waeckel, Ludovic; Duriez, Micheline; Vilar, José; Brandes, Ralph P; Levy, Bernard I; Shah, Ajay M; Silvestre, Jean-Sébastien

2006-08-01

We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 microg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 micromol/L), or the p38MAPK inhibitor LY333351 (10 micromol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91(phox)-deficient diabetic mice increased neovascularization by approximately 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.

Spheroid-forming subpopulation of breast cancer cells demonstrates vasculogenic mimicry via hsa-miR-299–5p regulated de novo expression of osteopontin

PubMed Central

Shevde, Lalita A; Metge, Brandon J; Mitra, Aparna; Xi, Yaguang; Ju, Jingfang; King, Judy A; Samant, Rajeev S

2010-01-01

Abstract The growth of cancer cells as multicellular spheroids has frequently been reported to mimic the in vivo tumour architecture and physiology and has been utilized to study antitumour drugs. In order to determine the distinctive characteristics of the spheroid-derived cells compared to the corresponding monolayer-derived cells, we enriched multicellular spheroid-forming subpopulations of cells from three human breast cancer cell lines (MCF7, MCF10AT and MCF10DCIS.com). These spheroid-derived cells were injected into female athymic nude mice to assess their tumorigenic potential and were profiled for their characteristic miRNA signature. We discovered that the spheroid-derived cells expressed increased levels of osteopontin (OPN), an oncogenic protein that has been clinically correlated with increased tumour burden and adverse prognosis in patients with breast cancer metastasis. Our studies further show that increased OPN levels are brought about in part, by decreased levels of hsa-mir-299–5p in the spheroid-forming population from all three cell lines. Moreover, the spheroid-forming cells can organize into vascular structures in response to nutritional limitation; these structures recapitulate a vascular phenotype by the expression of endothelial markers CD31, Angiopoeitin-1 and Endoglin. In this study, we have validated that hsa-mir-299–5p targets OPN; de novo expression of OPN in turn plays a critical role in enhancing proliferation, tumorigenicity and the ability to display vasculogenic mimicry of the spheroid-forming cells. PMID:19538464

Identification of novel kynurenine production-inhibiting benzenesulfonamide derivatives in cancer cells.

PubMed

Nakano, Shintaro; Takai, Kazushige; Isaka, Yoshinobu; Takahashi, Susumu; Unno, Yuka; Ogo, Naohisa; Matsuno, Kenji; Takikawa, Osamu; Asai, Akira

2012-03-16

Kynurenine (Kyn), a metabolite of tryptophan (Trp), is known to be a key regulator of human immune responses including cancer immune tolerance. Therefore, abrogation of Kyn production from cancer cells by small molecules may be a promising approach to anticancer therapy. Indeed, several small molecule inhibitors of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the catabolism of Trp to Kyn, exert antitumor effects in animal models. We screened our chemical libraries using a cell-based Kyn production assay to identify a new type of small molecules that regulate Kyn production, and for the first time identified a benzenesulfonamide derivative (compound 1) as a hit with the ability to inhibit Kyn production in interferon-γ (IFN-γ)-stimulated A431 and HeLa cells. Unlike the previously identified S-benzylisothiourea derivative, compound 2, compound 1 had little effect on the enzymatic activity of recombinant human IDO in vitro but suppressed the expression of IDO at the mRNA level in cells. Furthermore, compound 1 suppressed STAT1-dependent transcriptional activity and DNA binding, whereas no decrement in either the expression or phosphorylation level of STAT1 was observed. The inhibition of IDO expression by several benzenesulfonamide derivatives is associated with the suppression of STAT1. Thus, compound 1 and its analogs might be useful for analyzing the regulation of IDO activation, and STAT1-targeting could be an alternative to the IDO-directed approach for the regulation of Kyn levels by small molecules in the tumor microenvironment. Copyright © 2012 Elsevier Inc. All rights reserved.

Rapid range shifts of species associated with high levels of climate warming.

PubMed

Chen, I-Ching; Hill, Jane K; Ohlemüller, Ralf; Roy, David B; Thomas, Chris D

2011-08-19

The distributions of many terrestrial organisms are currently shifting in latitude or elevation in response to changing climate. Using a meta-analysis, we estimated that the distributions of species have recently shifted to higher elevations at a median rate of 11.0 meters per decade, and to higher latitudes at a median rate of 16.9 kilometers per decade. These rates are approximately two and three times faster than previously reported. The distances moved by species are greatest in studies showing the highest levels of warming, with average latitudinal shifts being generally sufficient to track temperature changes. However, individual species vary greatly in their rates of change, suggesting that the range shift of each species depends on multiple internal species traits and external drivers of change. Rapid average shifts derive from a wide diversity of responses by individual species.

Experimental murine fascioliasis derives early immune suppression with increased levels of TGF-β and IL-4.

PubMed

Chung, Joon-Yong; Bae, Young-An; Yun, Doo-Hee; Yang, Hyun-Jong; Kong, Yoon

2012-12-01

In fascioliasis, T-helper 2 (Th2) responses predominate, while little is known regarding early immune phenomenon. We herein analyzed early immunophenotype changes of BALB/c, C57BL/6, and C3H/He mice experimentally infected with 5 Fasciola hepatica metacercariae. A remarkable expansion of CD19(+) B cells was observed as early as week 1 post-infection while CD4(+)/CD8(+) T cells were down-regulated. Accumulation of Mac1(+) cells with time after infection correlated well with splenomegaly of all mice strains tested. The expression of tumor necrosis factor (TNF)-α mRNA in splenocytes significantly decreased while that of IL-4 up-regulated. IL-1β expression was down-modulated in BALB/c and C57BL/6 mice, but not in C3H/He. Serum levels of transforming growth factor (TGF)-β were considerably elevated in all mice during 3 weeks of infection period. These collective results suggest that experimental murine fascioliasis might derive immune suppression with elevated levels of TGF-β and IL-4 during the early stages of infection.

Effect of chronic ethanol consumption on the response of parathyroid hormone to hypocalcemia in the pregnant rat.

PubMed

Duggal, Shalu; Simpson, Mary Elizabeth; Keiver, Kathy

2007-01-01

Chronic alcohol (ethanol) consumption during pregnancy results in maternal/fetal hypocalcemia, which may underlie some of ethanol's adverse effects on maternal and fetal bone, and fetal/neonatal health. Ethanol appears to alter the relationship between parathyroid hormone (PTH) and blood calcium (Ca) level, and PTH does not increase in response to ethanol-induced hypocalcemia. However, it is not known whether ethanol actually prevents PTH from responding, or whether the ability to regulate blood Ca is intact, but ethanol lowers the level of Ca maintained. The objective of this study was to determine whether chronic ethanol consumption impairs the ability of the pregnant female to increase PTH in response to acute hypocalcemia. Rats were fed isocaloric diets with ethanol (36% ethanol-derived calories, E group) or without ethanol [pair-fed (PF) and control (C) groups], before and throughout 21 days of gestation. On day 21 gestation, rats received an intraperitoneal injection of ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (300 or 500 mumol/kg body weight) or saline (saline group), or no injection (baseline group). Blood was collected from the baseline group, and at 30 or 60 minutes postinjection (saline and EGTA groups), and analyzed for ionized Ca (iCa), pH, and PTH. Consistent with previous studies, ethanol consumption decreased blood iCa levels at baseline, but PTH levels did not differ among groups. Administration of EGTA significantly decreased blood iCa levels by 30 minutes, but ethanol did not prevent PTH from increasing in response to the hypocalcemia. In all diet groups, PTH levels were significantly increased by 30 minutes. Ethanol did, however, appear to decrease the maximum PTH level achievable in blood. These data suggest that chronic ethanol consumption does not impair the ability of the pregnant rat to raise serum PTH levels in response to acute hypocalcemia, but ethanol's effect on maximal PTH secretion could impair the ability of the pregnant female to sustain high PTH levels in response to chronic hypocalcemia.

Linear response approach to active Brownian particles in time-varying activity fields

NASA Astrophysics Data System (ADS)

Merlitz, Holger; Vuijk, Hidde D.; Brader, Joseph; Sharma, Abhinav; Sommer, Jens-Uwe

2018-05-01

In a theoretical and simulation study, active Brownian particles (ABPs) in three-dimensional bulk systems are exposed to time-varying sinusoidal activity waves that are running through the system. A linear response (Green-Kubo) formalism is applied to derive fully analytical expressions for the torque-free polarization profiles of non-interacting particles. The activity waves induce fluxes that strongly depend on the particle size and may be employed to de-mix mixtures of ABPs or to drive the particles into selected areas of the system. Three-dimensional Langevin dynamics simulations are carried out to verify the accuracy of the linear response formalism, which is shown to work best when the particles are small (i.e., highly Brownian) or operating at low activity levels.

Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

PubMed Central

Li, Shunqiang; Shen, Dong; Shao, Jieya; Crowder, Robert; Liu, Wenbin; Prat, Aleix; He, Xiaping; Liu, Shuying; Hoog, Jeremy; Lu, Charles; Ding, Li; Griffith, Obi L.; Miller, Christopher; Larson, Dave; Fulton, Robert S.; Harrison, Michelle; Mooney, Tom; McMichael, Joshua F.; Luo, Jingqin; Tao, Yu; Goncalves, Rodrigo; Schlosberg, Christopher; Hiken, Jeffrey F.; Saied, Laila; Sanchez, Cesar; Giuntoli, Therese; Bumb, Caroline; Cooper, Crystal; Kitchens, Robert T.; Lin, Austin; Phommaly, Chanpheng; Davies, Sherri R.; Zhang, Jin; Kavuri, Megha Shyam; McEachern, Donna; Dong, Yi Yu; Ma, Cynthia; Pluard, Timothy; Naughton, Michael; Bose, Ron; Suresh, Rama; McDowell, Reida; Michel, Loren; Aft, Rebecca; Gillanders, William; DeSchryver, Katherine; Wilson, Richard K.; Wang, Shaomeng; Mills, Gordon B.; Gonzalez-Angulo, Ana; Edwards, John R.; Maher, Christopher; Perou, Charles M.; Mardis, Elaine R.; Ellis, Matthew J.

2013-01-01

SUMMARY To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation. PMID:24055055

Comparative analysis of biological activities of Der p I-derived peptides on Fc epsilon receptor-bearing cells from Dermatophagoides pteronyssinus-sensitive patients.

PubMed Central

Jeannin, P; Pestel, J; Bossus, M; Lassalle, P; Tartar, A; Tonnel, A B

1993-01-01

The ability of four uncoupled synthetic peptides (p52-71, p117-133, p176-187, p188-199) derived from Der p I, a major allergen from the house dust mite Dermatophagoides pteronyssinus (Dpt) to stimulate Fc epsilon R+ cells from Dpt-sensitive patients was comparatively analysed. Each free peptide may specifically stimulate basophils (Fc epsilon RI+ cells) and platelets (Fc epsilon RII+ cells) from patients with significant levels of anti-Der p I IgE antibodies; p52-71 and p117-133 appear the best cell stimulation inducers. Both concentration-dependent biological activities of Der p I-peptide on Fc epsilon R+ cells are enhanced by coupling peptide to a carrier (as human serum albumin). Interestingly each Der p I-sensitive patient tested presents an individual pattern of response to peptide. Thus, from our results it appears that different Der p I sequences could be involved in the immune response to Der p I. PMID:7682161

Comparative analysis of biological activities of Der p I-derived peptides on Fc epsilon receptor-bearing cells from Dermatophagoides pteronyssinus-sensitive patients.

PubMed

Jeannin, P; Pestel, J; Bossus, M; Lassalle, P; Tartar, A; Tonnel, A B

1993-04-01

The ability of four uncoupled synthetic peptides (p52-71, p117-133, p176-187, p188-199) derived from Der p I, a major allergen from the house dust mite Dermatophagoides pteronyssinus (Dpt) to stimulate Fc epsilon R+ cells from Dpt-sensitive patients was comparatively analysed. Each free peptide may specifically stimulate basophils (Fc epsilon RI+ cells) and platelets (Fc epsilon RII+ cells) from patients with significant levels of anti-Der p I IgE antibodies; p52-71 and p117-133 appear the best cell stimulation inducers. Both concentration-dependent biological activities of Der p I-peptide on Fc epsilon R+ cells are enhanced by coupling peptide to a carrier (as human serum albumin). Interestingly each Der p I-sensitive patient tested presents an individual pattern of response to peptide. Thus, from our results it appears that different Der p I sequences could be involved in the immune response to Der p I.

Large-scale modeled contemporary and future water temperature estimates for 10774 Midwestern U.S. Lakes

USGS Publications Warehouse

Winslow, Luke A.; Hansen, Gretchen J. A.; Read, Jordan S.; Notaro, Michael

2017-01-01

Climate change has already influenced lake temperatures globally, but understanding future change is challenging. The response of lakes to changing climate drivers is complex due to the nature of lake-atmosphere coupling, ice cover, and stratification. To better understand the diversity of lake responses to climate change and give managers insight on individual lakes, we modelled daily water temperature profiles for 10,774 lakes in Michigan, Minnesota, and Wisconsin for contemporary (1979–2015) and future (2020–2040 and 2080–2100) time periods with climate models based on the Representative Concentration Pathway 8.5, the worst-case emission scenario. In addition to lake-specific daily simulated temperatures, we derived commonly used, ecologically relevant annual metrics of thermal conditions for each lake. We include all supporting lake-specific model parameters, meteorological drivers, and archived code for the model and derived metric calculations. This unique dataset offers landscape-level insight into the impact of climate change on lakes.

Large-scale modeled contemporary and future water temperature estimates for 10774 Midwestern U.S. Lakes

PubMed Central

Winslow, Luke A.; Hansen, Gretchen J.A.; Read, Jordan S; Notaro, Michael

2017-01-01

Climate change has already influenced lake temperatures globally, but understanding future change is challenging. The response of lakes to changing climate drivers is complex due to the nature of lake-atmosphere coupling, ice cover, and stratification. To better understand the diversity of lake responses to climate change and give managers insight on individual lakes, we modelled daily water temperature profiles for 10,774 lakes in Michigan, Minnesota, and Wisconsin for contemporary (1979–2015) and future (2020–2040 and 2080–2100) time periods with climate models based on the Representative Concentration Pathway 8.5, the worst-case emission scenario. In addition to lake-specific daily simulated temperatures, we derived commonly used, ecologically relevant annual metrics of thermal conditions for each lake. We include all supporting lake-specific model parameters, meteorological drivers, and archived code for the model and derived metric calculations. This unique dataset offers landscape-level insight into the impact of climate change on lakes. PMID:28440790

Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.

PubMed

Cleaton, Mary A M; Dent, Claire L; Howard, Mark; Corish, Jennifer A; Gutteridge, Isabelle; Sovio, Ulla; Gaccioli, Francesca; Takahashi, Nozomi; Bauer, Steven R; Charnock-Jones, D Steven; Powell, Theresa L; Smith, Gordon C S; Ferguson-Smith, Anne C; Charalambous, Marika

2016-12-01

Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.

Pathogenic Fungi Regulate Immunity by Inducing Neutrophilic Myeloid-Derived Suppressor Cells

PubMed Central

Rieber, Nikolaus; Singh, Anurag; Öz, Hasan; Carevic, Melanie; Bouzani, Maria; Amich, Jorge; Ost, Michael; Ye, Zhiyong; Ballbach, Marlene; Schäfer, Iris; Mezger, Markus; Klimosch, Sascha N.; Weber, Alexander N.R.; Handgretinger, Rupert; Krappmann, Sven; Liese, Johannes; Engeholm, Maik; Schüle, Rebecca; Salih, Helmut Rainer; Marodi, Laszlo; Speckmann, Carsten; Grimbacher, Bodo; Ruland, Jürgen; Brown, Gordon D.; Beilhack, Andreas; Loeffler, Juergen; Hartl, Dominik

2015-01-01

Summary Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1β induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense. PMID:25771792

Large-scale modeled contemporary and future water temperature estimates for 10774 Midwestern U.S. Lakes

NASA Astrophysics Data System (ADS)

Winslow, Luke A.; Hansen, Gretchen J. A.; Read, Jordan S.; Notaro, Michael

2017-04-01

Climate change has already influenced lake temperatures globally, but understanding future change is challenging. The response of lakes to changing climate drivers is complex due to the nature of lake-atmosphere coupling, ice cover, and stratification. To better understand the diversity of lake responses to climate change and give managers insight on individual lakes, we modelled daily water temperature profiles for 10,774 lakes in Michigan, Minnesota, and Wisconsin for contemporary (1979-2015) and future (2020-2040 and 2080-2100) time periods with climate models based on the Representative Concentration Pathway 8.5, the worst-case emission scenario. In addition to lake-specific daily simulated temperatures, we derived commonly used, ecologically relevant annual metrics of thermal conditions for each lake. We include all supporting lake-specific model parameters, meteorological drivers, and archived code for the model and derived metric calculations. This unique dataset offers landscape-level insight into the impact of climate change on lakes.

CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages.

PubMed

Taylor, Jared P; Cash, Melanie N; Santostefano, Katherine E; Nakanishi, Mahito; Terada, Naohiro; Wallet, Mark A

2018-02-13

The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-α receptor 2 subunit (IFNAR2). Here, we demonstrate that USP18 expression is induced by HIV-1 in a T1 IFN-dependent manner. Experimental depletion of USP18 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing results in a significant restriction of HIV-1 replication in an induced pluripotent stem cell (iPSC)-derived macrophage model. In the absence of USP18, macrophages have increased responsiveness to stimulation with T1 IFNs with prolonged phosphorylation of STAT1 and STAT2 and increased expression of IFN-stimulated genes that are key for antiviral responses. Interestingly, HIV-1 requires some signaling through the T1 IFN receptor to replicate efficiently because a neutralizing antibody that inhibits T1 IFN activity reduces HIV-1 replication rate in monocyte-derived macrophages. USP18 induction by HIV-1 tunes the IFN response to optimal levels allowing for efficient transcription from the HIV-1 LTR promoter while minimizing the T1 IFN-induced antiviral response that would otherwise restrict viral replication and spread. Finally, iPSC and CRISPR/Cas9 gene targeting offer a powerful tool to study host factors that regulate innate immune responses. ©2018 Society for Leukocyte Biology.

Duox2-induced innate immune responses in the respiratory epithelium and intranasal delivery of Duox2 DNA using polymer that mediates immunization.

PubMed

Jeon, Yung Jin; Kim, Hyun Jik

2018-05-01

Respiratory mucosa especially nasal epithelium is well known as the first-line barrier of air-borne pathogens. High levels of reactive oxygen species (ROS) are detected in in vitro cultured human epithelial cells and in vivo lung. With identification of NADPH oxidase (Nox) system of respiratory epithelium, the antimicrobial role of ROS has been studied. Duox2 is the most abundant Nox isoform and produces the regulated amount of ROS in respiratory epithelium. Duox2-derived ROS are involved in antiviral innate immune responses but more studies are needed to verify the mechanism. In respiratory epithelium, Duox2-derived ROS is critical for recognition of virus through families retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) at the early stage of antiviral innate immune responses. Various secreted interferons (IFNs) play essential roles for antiviral host defense by downstream cell signaling, and transcription of IFN-stimulated genes is started to suppress viral replication. Type I and type III IFNs are verified more responsible for influenza A virus (IAV) infection in respiratory epithelium and Duox2 is required to regulate IFN-related immune responses. Transient overexpression of Duox2 using cationic polymer polyethylenimine (PEI) induces secretion of type I and type III IFNs and significantly attenuated IAV replication in respiratory epithelium. Here, we discuss Duox2-mediated antiviral innate immune responses and the role of Duox2 as a mucosal vaccine to resist respiratory viral infection.

Nitric oxide selective electrodes.

PubMed

Davies, Ian R; Zhang, Xueji

2008-01-01

Since nitric oxide (NO) was identified as the endothelial-derived relaxing factor in the late 1980s, many approaches have attempted to provide an adequate means for measuring physiological levels of NO. Although several techniques have been successful in achieving this aim, the electrochemical method has proved the only technique that can reliably measure physiological levels of NO in vitro, in vivo, and in real time. We describe here the development of electrochemical sensors for NO, including the fabrication of sensors, the detection principle, calibration, detection limits, selectivity, and response time. Furthermore, we look at the many experimental applications where NO selective electrodes have been successfully used.

The dose-response ratio in electroconvulsive therapy a preliminary study.

PubMed

Price, T R; Mackenzie, T B; Tucker, G J; Culver, C

1978-09-01

To investigate pretreatment patient variables that might correlate with dose-response characteristics of electroconvulsive therapy (ECT) and treatment outcomes, 14 patients were assessed on a daily basis, before and during treatment, using self-report affective scales, three simple paper-and-pencil tests of cognitive function,and finger-tapping speed. From these data, dose-response ratios and treatment outcome measures were derived. The dose-response ratio of ECT was found to correlate with age--the younger the patient, the more favorable the ratio. This finding is discussed in terms of the known relationships between brain monoamine oxidase levels and age, and the established relationship between seizure duration and treatment efficacy. The dose-response ratio over the first two electroconvulsive treatments as well as lesser degrees of initial congnitive and greater degrees of initial affective impairment correlated strongly with greater overall affective improvement. Some clinical and research implications of these findings are discussed.

Differential genetic regulation of motor activity and anxiety-related behaviors in mice using an automated home cage task.

PubMed

Kas, Martien J H; de Mooij-van Malsen, Annetrude J G; Olivier, Berend; Spruijt, Berry M; van Ree, Jan M

2008-08-01

Traditional behavioral tests, such as the open field test, measure an animal's responsiveness to a novel environment. However, it is generally difficult to assess whether the behavioral response obtained from these tests relates to the expression level of motor activity and/or to avoidance of anxiogenic areas. Here, an automated home cage environment for mice was designed to obtain independent measures of motor activity levels and of sheltered feeding preference during three consecutive days. Chronic treatment with the anxiolytic drug chlordiazepoxide (5 and 10 mg/kg/day) in C57BL/6J mice reduced sheltered feeding preference without altering motor activity levels. Furthermore, two distinct chromosome substitution strains, derived from C57BL/6J (host strain) and A/J (donor strain) inbred strains, expressed either increased sheltering preference in females (chromosome 15) or reduced motor activity levels in females and males (chromosome 1) when compared to C57BL/6J. Longitudinal behavioral monitoring revealed that these phenotypic differences maintained after adaptation to the home cage. Thus, by using new automated behavioral phenotyping approaches, behavior can be dissociated into distinct behavioral domains (e.g., anxiety-related and motor activity domains) with different underlying genetic origin and pharmacological responsiveness.

Cytokine Responses to Novel Antigens in a Peri-Urban Population in Brazil Exposed to Leishmania infantum chagasi

PubMed Central

Stober, Carmel B.; Jeronimo, Selma M. B.; Pontes, Nubia N.; Miller, E. Nancy; Blackwell, Jenefer M.

2012-01-01

Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-γ (IFN-γ) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-α (TNF-α) is also important in this process. We characterized human immune responses in three groups exposed to Leishmania infantum chagasi in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive Leishmania-specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude Leishmania antigen–driven IFN-γ, TNF-α, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN-γ, but higher levels of IL-10, to tryparedoxin peroxidase and Leishmania homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-γ:IL-10 and TNF-α:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36–71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates. PMID:22826477

Cytokine responses to novel antigens in a peri-urban population in Brazil exposed to Leishmania infantum chagasi.

PubMed

Stober, Carmel B; Jeronimo, Selma M B; Pontes, Nubia N; Miller, E Nancy; Blackwell, Jenefer M

2012-10-01

Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-γ (IFN-γ) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-α (TNF-α) is also important in this process. We characterized human immune responses in three groups exposed to Leishmania infantum chagasi in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive Leishmania-specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude Leishmania antigen-driven IFN-γ, TNF-α, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN-γ, but higher levels of IL-10, to tryparedoxin peroxidase and Leishmania homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-γ:IL-10 and TNF-α:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36-71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates.

Effect of systemic administration of lipopolysaccharides derived from Porphyromonas gingivalis on gene expression in mice kidney.

PubMed

Harada, Fumiya; Uehara, Osamu; Morikawa, Tetsuro; Hiraki, Daichi; Onishi, Aya; Toraya, Seiko; Adhikari, Bhoj Raj; Takai, Rie; Yoshida, Koki; Sato, Jun; Nishimura, Michiko; Chiba, Itsuo; Wu, Ching Zong; Abiko, Yoshihiro

2018-01-31

Although an association between periodontitis and chronic kidney disease (CKD) has been suggested, the mechanism involved remains unclear. Herein, we examined the global gene expression profile in a mouse model that showed no acute inflammation in the kidney following stimulation with lipopolysaccharides (LPS) derived from Porphyromonas gingivalis (PG-LPS). The mice were injected with PG-LPS at a concentration of 5 mg/kg intraperitoneally, every 3 days, for 1 month. Microarray analysis was used to identify 10 genes with the highest expression levels in the kidney stimulated with PG-LPS. Among them, the functions of five genes (Saa3, Ticam2, Reg3b, Ocxt2a, and Xcr1) were known. The upregulation of these genes was confirmed by quantitative polymerase chain reaction assay. Furthermore, we examined whether the expression of these upregulated genes were altered in endothelial cells derived from the kidney, in vitro. The mRNA expression levels of all five genes were significantly higher in the experimental group than in the controls (no LPS stimulation; *p < 0.05). In conclusion, the responses noted in the kidney may have arisen mainly from the endothelial cells. Moreover, upregulation of the expression levels of Saa3, Ticam2, Reg3b, Ocxt2a, and Xcr1 may be associated with the pathogenesis of CKD.

Viral Infection-Homograft Interactions in a Murine Model

PubMed Central

Hamilton, John D.; Fitzwilliam, James F.; Cheung, K. S.; Shelburne, John; Lang, David J.; Amos, D. B.

1978-01-01

The effects on some host defenses of murine cytomegalovirus (MCMV) and(or) EL4, a mouse ascites homograft, were studied in mice. Assays of cellular and humoral immunity in response to either or both of these perturbations were carried out by quantitation of various immune activities. Limited studies demonstrated no effect of EL4 inoculation on the host response to MCMV by organ viral titer, duration of viral persistence, or anti MCMV complement-fixing antibody titer. Prior infection with MCMV, however, resulted in greatly reduced numbers of splenocytes, the source in this study of immune effector cells. Residual splenocytes demonstrated less response to both phyto-hemagglutinin and lipopolysaccharide, particularly in the 2-3-wk interval after infection. Similarly, responder cells in mixed lymphocyte cultures were less reactive when derived from infected animals. Lymphocyte-mediated cytolysis of EL4 was significantly less in mice infected on the day of and 7, 14, and 21 days before the tumor homograft with a return to control levels by 28 days. 90% of the cell-mediated cytolysis could be eliminated by treatment with anti-theta serum. Serum-mediated cytolysis of EL4 was also reduced in infected animals. No suppressor cells or serum inhibitory factors could be identified in infected animals. Although alternative explanations exist, this study suggests that in infected animals there is a significant reduction in both the number and function of bone marrow-derived and thymus-derived cells directed against the alloantigens in EL4. PMID:219027

T cell-derived Lymphotoxin is Essential for anti-HSV-1 Humoral Immune Response.

PubMed

Yang, Kaiting; Liang, Yong; Sun, Zhichen; Xue, Diyuan; Xu, Hairong; Zhu, Mingzhao; Fu, Yang-Xin; Peng, Hua

2018-05-09

B cell-derived lymphotoxin (LT) is required for the development of follicular dendritic cell clusters for the formation of primary and secondary lymphoid follicles, but the role of T cell-derived LT in antibody response has not been well demonstrated. We observed that lymphotoxin-β-receptor (LTβR) signaling is essential for optimal humoral immune response and protection against an acute HSV-1 infection. Blocking the LTβR pathway caused poor maintenance of germinal center B (GC-B) cells and follicular helper T (Tfh) cells. Using bone marrow chimeric mice and adoptive transplantation, we determined that T cell-derived LT played an indispensable role in the humoral immune response to HSV-1. Up-regulation of IFNγ by the LTβR-Ig blockade impairs the sustainability of Tfh-like cells, thus leading to an impaired humoral immune response. Our findings have identified a novel role of T cell-derived LT in the humoral immune response against HSV-1 infection. IMPORTANCE Immunocompromised people are susceptible for HSV-1 infection and lethal recurrence, which could be inhibited by anti-HSV-1 humoral immune response in the host. This study sought to explore the role of T cell-derived LT in the anti-HSV-1 humoral immune response using LT-LTβR signaling deficient mice and the LTβR-Ig blockade. The data indicate that the T cell-derived LT may play an essential role in sustaining Tfh-like cells and ensure Tfh-like cells' migration into primary or secondary follicles for further maturation. This study provides insights for vaccine development against infectious diseases. Copyright © 2018 American Society for Microbiology.

A plant based protective antigen [PA(dIV)] vaccine expressed in chloroplasts demonstrates protective immunity in mice against anthrax.

PubMed

Gorantala, Jyotsna; Grover, Sonam; Goel, Divya; Rahi, Amit; Jayadev Magani, Sri Krishna; Chandra, Subhash; Bhatnagar, Rakesh

2011-06-15

The currently available anthrax vaccines are limited by being incompletely characterized, potentially reactogenic and have an expanded dosage schedule. Plant based vaccines offer safe alternative for vaccine production. In the present study, we expressed domain IV of Bacillus anthracis protective antigen gene [PA(dIV)] in planta (by nuclear agrobacterium and chloroplast transformation) and E. coli [rPA(dIV)]. The presence of transgene and the expression of PA(dIV) in planta was confirmed by molecular analysis. Expression levels up to 5.3% of total soluble protein (TSP) were obtained with AT rich (71.8% AT content) PA(dIV) gene in transplastomic plants while 0.8% of TSP was obtained in nuclear transformants. Further, we investigated the protective response of plant and E. coli derived PA(dIV) in mice by intraperitoneal (i.p.) and oral immunizations with or without adjuvant. Antibody titers of >10(4) were induced upon i.p. and oral immunizations with plant derived PA(dIV) and oral immunization with E. coli derived PA(dIV). Intraperitoneal injections with adjuvanted E. coli derived PA(dIV), generated highest antibody titers of >10(5). All the immunized groups demonstrated predominant IgG1 titers over IgG2a indicating a polarized Th2 type response. We also evaluated the mucosal antibody response in orally immunized groups. When fecal extracts were analyzed, low sIgA titer was demonstrated in adjuvanted plant and E. coli derived PA(dIV) groups. Further, PA(dIV) antisera enhanced B. anthracis spore uptake by macrophages in vitro and also demonstrated an anti-germinating effect suggesting a potent role at mucosal surfaces. The antibodies from various groups were efficient in neutralizing the lethal toxin in vitro. When mice were challenged with B. anthracis, mice immunized with adjuvanted plant PA(dIV) imparted 60% and 40% protection while E. coli derived PA(dIV) conferred 100% and 80% protection upon i.p. and oral immunizations. Thus, our study is the first attempt in highlighting the efficacy of plant expressed PA(dIV) by oral immunization in murine model. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ecophysiological and metabolic responses to interactive exposure to nutrients and copper excess in the brown macroalga Cystoseira tamariscifolia.

PubMed

Celis-Plá, Paula S M; Brown, Murray T; Santillán-Sarmiento, Alex; Korbee, Nathalie; Sáez, Claudio A; Figueroa, Félix L

2018-03-01

Global scenarios evidence that contamination due to anthropogenic activities occur at different spatial-temporal scales, being important stressors: eutrophication, due to increased nutrient inputs; and metal pollution, mostly derived from industrial activities. In this study, we investigated ecophysiological and metabolic responses to copper and nutrient excess in the brown macroalga Cystoseira tamariscifolia. Whole plants were incubated in an indoor system under control conditions, two levels of nominal copper (0.5 and 2.0μM), and two levels of nutrient supply for two weeks. Maximal quantum yield (F v /F m ) and maximal electron transport rate (ETR max ) increased under copper exposure. Photosynthetic pigments and phenolic compounds (PC) increased under the highest copper levels. The intra-cellular copper content increased under high copper exposure in both nutrient conditions. C. tamariscifolia from the Atlantic displayed efficient metal exclusion mechanisms, since most of the total copper accumulated by the cell was bound to the cell wall. Copyright © 2018 Elsevier Ltd. All rights reserved.

Distinct Roles of Jasmonates and Aldehydes in Plant-Defense Responses

PubMed Central

Chehab, E. Wassim; Kaspi, Roy; Savchenko, Tatyana; Rowe, Heather; Negre-Zakharov, Florence; Kliebenstein, Dan; Dehesh, Katayoon

2008-01-01

Background Many inducible plant-defense responses are activated by jasmonates (JAs), C6-aldehydes, and their corresponding derivatives, produced by the two main competing branches of the oxylipin pathway, the allene oxide synthase (AOS) and hydroperoxide lyase (HPL) branches, respectively. In addition to competition for substrates, these branch-pathway-derived metabolites have substantial overlap in regulation of gene expression. Past experiments to define the role of C6-aldehydes in plant defense responses were biased towards the exogenous application of the synthetic metabolites or the use of genetic manipulation of HPL expression levels in plant genotypes with intact ability to produce the competing AOS-derived metabolites. To uncouple the roles of the C6-aldehydes and jasmonates in mediating direct and indirect plant-defense responses, we generated Arabidopsis genotypes lacking either one or both of these metabolites. These genotypes were subsequently challenged with a phloem-feeding insect (aphids: Myzus persicae), an insect herbivore (leafminers: Liriomyza trifolii), and two different necrotrophic fungal pathogens (Botrytis cinerea and Alternaria brassicicola). We also characterized the volatiles emitted by these plants upon aphid infestation or mechanical wounding and identified hexenyl acetate as the predominant compound in these volatile blends. Subsequently, we examined the signaling role of this compound in attracting the parasitoid wasp (Aphidius colemani), a natural enemy of aphids. Principal Findings This study conclusively establishes that jasmonates and C6-aldehydes play distinct roles in plant defense responses. The jasmonates are indispensable metabolites in mediating the activation of direct plant-defense responses, whereas the C6-aldehyes are not. On the other hand, hexenyl acetate, an acetylated C6-aldehyde, is the predominant wound-inducible volatile signal that mediates indirect defense responses by directing tritrophic (plant-herbivore-natural enemy) interactions. Significance The data suggest that jasmonates and hexenyl acetate play distinct roles in mediating direct and indirect plant-defense responses. The potential advantage of this “division of labor” is to ensure the most effective defense strategy that minimizes incurred damages at a reduced metabolic cost. PMID:18382679

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

PubMed

Trabanelli, Sara; Chevalier, Mathieu F; Martinez-Usatorre, Amaia; Gomez-Cadena, Alejandra; Salomé, Bérengère; Lecciso, Mariangela; Salvestrini, Valentina; Verdeil, Grégory; Racle, Julien; Papayannidis, Cristina; Morita, Hideaki; Pizzitola, Irene; Grandclément, Camille; Bohner, Perrine; Bruni, Elena; Girotra, Mukul; Pallavi, Rani; Falvo, Paolo; Leibundgut, Elisabeth Oppliger; Baerlocher, Gabriela M; Carlo-Stella, Carmelo; Taurino, Daniela; Santoro, Armando; Spinelli, Orietta; Rambaldi, Alessandro; Giarin, Emanuela; Basso, Giuseppe; Tresoldi, Cristina; Ciceri, Fabio; Gfeller, David; Akdis, Cezmi A; Mazzarella, Luca; Minucci, Saverio; Pelicci, Pier Giuseppe; Marcenaro, Emanuela; McKenzie, Andrew N J; Vanhecke, Dominique; Coukos, George; Mavilio, Domenico; Curti, Antonio; Derré, Laurent; Jandus, Camilla

2017-09-19

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

GABA and Gap Junctions in the Development of Synchronized Activity in Human Pluripotent Stem Cell-Derived Neural Networks

PubMed Central

Mäkinen, Meeri Eeva-Liisa; Ylä-Outinen, Laura; Narkilahti, Susanna

2018-01-01

The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC)-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA) and gap junctions to the development of synchronous activity in hPSC-derived neural networks was studied with GABA agonist and antagonist and by blocking gap junctional communication, respectively. We characterized the dynamics of the network-wide synchrony in hPSC-derived neural networks with high spatial resolution (calcium imaging) and temporal resolution microelectrode array (MEA). We found that the emergence of synchrony correlates with a decrease in very strong GABA excitation. However, the synchronous network was found to consist of a heterogeneous mixture of synchronously active cells with variable responses to GABA, GABA agonists and gap junction blockers. Furthermore, we show how single-cell distributions give rise to the network effect of GABA, GABA agonists and gap junction blockers. Finally, based on our observations, we suggest that the earliest form of synchronous neuronal activity depends on gap junctions and a decrease in GABA induced depolarization but not on GABAA mediated signaling. PMID:29559893

Dynamic response of a collidant impacting a low pressure airbag

NASA Astrophysics Data System (ADS)

Dreher, Peter A.

There are many uses of low pressure airbags, both military and commercial. Many of these applications have been hampered by inadequate and inaccurate modeling tools. This dissertation contains the derivation of a four degree-of-freedom system of differential equations from physical laws of mass and energy conservation, force equilibrium, and the Ideal Gas Law. Kinematic equations were derived to model a cylindrical airbag as a single control volume impacted by a parallelepiped collidant. An efficient numerical procedure was devised to solve the simplified system of equations in a manner amenable to discovering design trends. The largest public airbag experiment, both in scale and scope, was designed and built to collect data on low-pressure airbag responses, otherwise unavailable in the literature. The experimental results were compared to computational simulations to validate the simplified numerical model. Experimental response trends are presented that will aid airbag designers. The two objectives of using a low pressure airbag to demonstrate the feasibility to (1) accelerate a munition to 15 feet per second velocity from a bomb bay, and (2) decelerate humans hitting trucks below the human tolerance level of 50 G's, were both met.

A numerical multi-scale model to predict macroscopic material anisotropy of multi-phase steels from crystal plasticity material definitions

NASA Astrophysics Data System (ADS)

Ravi, Sathish Kumar; Gawad, Jerzy; Seefeldt, Marc; Van Bael, Albert; Roose, Dirk

2017-10-01

A numerical multi-scale model is being developed to predict the anisotropic macroscopic material response of multi-phase steel. The embedded microstructure is given by a meso-scale Representative Volume Element (RVE), which holds the most relevant features like phase distribution, grain orientation, morphology etc., in sufficient detail to describe the multi-phase behavior of the material. A Finite Element (FE) mesh of the RVE is constructed using statistical information from individual phases such as grain size distribution and ODF. The material response of the RVE is obtained for selected loading/deformation modes through numerical FE simulations in Abaqus. For the elasto-plastic response of the individual grains, single crystal plasticity based plastic potential functions are proposed as Abaqus material definitions. The plastic potential functions are derived using the Facet method for individual phases in the microstructure at the level of single grains. The proposed method is a new modeling framework and the results presented in terms of macroscopic flow curves are based on the building blocks of the approach, while the model would eventually facilitate the construction of an anisotropic yield locus of the underlying multi-phase microstructure derived from a crystal plasticity based framework.

Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.

PubMed

Kim, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan; Kim, Juhee; Lee, Seunghee; Lee, Soo-Kyung; Lee, Jae W

2013-10-01

Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.

Evaluation of adjuvant activity of fractions derived from Agaricus blazei, when in association with the recombinant LiHyp1 protein, to protect against visceral leishmaniasis.

PubMed

de Jesus Pereira, Nathália Cristina; Régis, Wiliam César Bento; Costa, Lourena Emanuele; de Oliveira, Jamil Silvano; da Silva, Alanna Gomes; Martins, Vivian Tamietti; Duarte, Mariana Costa; de Souza, José Roberto Rodrigues; Lage, Paula Sousa; Schneider, Mônica Santos; Melo, Maria Norma; Soto, Manuel; Soares, Sandra Aguiar; Tavares, Carlos Alberto Pereira; Chávez-Fumagalli, Miguel Angel; Coelho, Eduardo Antonio Ferraz

2015-06-01

The development of effective prophylactic strategies to prevent leishmaniasis has become a high priority. No less important than the choice of an antigen, the association of an appropriate adjuvant is necessary to achieve a successful vaccination, as the majority of the tested antigens contain limited immunogenic properties, and need to be supplemented with immune response adjuvants in order to boost their immunogenicity. However, few effective adjuvants that can be used against leishmaniasis exist on the market today; therefore, it is possible to speculate that the research aiming to identify new adjuvants could be considered relevant. Recently, Agaricus blazei extracts have proved to be useful in enhancing the immune response to DNA vaccines against some diseases. This was based on the Th1 adjuvant activity of the polysaccharide-rich fractions from this mushroom. In this context, the present study evaluated purified fractions derived from Agaricus blazei as Th1 adjuvants through in vitro assays of their immune stimulation of spleen cells derived from naive BALB/c mice. Two of the tested six fractions (namely F2 and F4) were characterized as polysaccharide-rich fractions, and were able to induce high levels of IFN-γ, and low levels of IL-4 and IL-10 in the spleen cells. The efficacy of adjuvant action against L. infantum was evaluated in BALB/c mice, with these fractions being administered together with a recombinant antigen, LiHyp1, which was previously evaluated as a vaccine candidate, associated with saponin, against visceral leishmaniasis (VL). The associations between LiHyp1/F2 and LiHyp1/F4 were able to induce an in vivo Th1 response, which was primed by high levels of IFN-γ, IL-12, and GM-CSF, by low levels of IL-4 and IL-10; as well as by a predominance of IgG2a antibodies in the vaccinated animals. After infection, the immune profile was maintained, and the vaccines proved to be effective against L. infantum. The immune stimulatory effects in the BALB/c mice proved to be similar when comparing the F2 and F4 fractions with a known Th1 adjuvant (saponin), though animals vaccinated with saponin did present a slight to moderate inflammatory edema on their hind footpads. In conclusion, the F2 and F4 fractions appear to induce a Th1-type immune response and, in this context, they could be evaluated in association with other protective antigens against Leishmania, as well as in other disease models. Copyright © 2015 Elsevier Inc. All rights reserved.

Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a(-/-) Model.

PubMed

Urbanova, Jana; Andel, Michal; Potockova, Jana; Klima, Josef; Macek, Jan; Ptacek, Pavel; Mat'oska, Vaclav; Kumstyrova, Tereza; Heneberg, Petr

2015-01-01

Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity Onset Diabetes of the Young (MODY) caused by mutations in HNF-1α or HNF-4α despite the mechanism leading to their hypersensitivity is incompletely understood. In Hnf1a(-/-) mice, serum concentrations and half-life of sulfonylurea derivatives are strongly increased. We thus hypothesized that reduced sulfonylurea derivatives clearance stands behind their therapeutic potential in human HNF1A/HNF4A MODY subjects. Single doses of 3 mg glipizide and 5 mg glibenclamide/glyburide were administered sequentially to seven HNF1A/HNF4A MODY subjects and six control individuals matched for their age, BMI and CYP2C9 genotype. Pharmacokinetic (plasma concentration levels, Cmax, tmax, t1/2, AUC) and pharmacodynamic parameters (glycemia, C-peptide and insulin plasma levels) were followed for 24 hours after drug administration. We provide the first evidence on the pharmacokinetics and pharmacodynamics of sulfonylurea derivatives in human MODY subjects. The half-life of glipizide did not change, and reached 3.8±0.7 and 3.7±1.8 h in the MODY and control subjects, respectively. The half-life of glibenclamide was increased only in some MODY subjects (t1/2 9.5±6.7 and 5.0±1.4 h, respectively). Importantly, the intra- individual responses of MODY (but control) subjects to glipizide and glibenclamide treatment were highly correlated. With regards to pharmacodynamics, we observed a differential response of control but not MODY subjects to the doses of glipizide and glibenclamide applied. We rejected the hypothesis that all human MODY-associated mutations in HNF1A / HNF4A induce changes in the pharmacokinetics of sulfonylureas in humans analogically to the Hnf1a(-/-) mouse model.

The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.

PubMed

Dankovic, D A; Naumann, B D; Maier, A; Dourson, M L; Levy, L S

2015-01-01

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process.

Immunosuppression involving increased myeloid-derived suppressor cell levels, systemic inflammation and hypoalbuminemia are present in patients with anaplastic thyroid cancer

PubMed Central

SUZUKI, SHINICHI; SHIBATA, MASAHIKO; GONDA, KENJI; KANKE, YASUYUKI; ASHIZAWA, MAI; UJIIE, DAISUKE; SUZUSHINO, SEIKO; NAKANO, KEIICHI; FUKUSHIMA, TOSHIHIKO; SAKURAI, KENICHI; TOMITA, RYOUICHI; KUMAMOTO, KENSUKE; TAKENOSHITA, SEIICHI

2013-01-01

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive neoplasms in humans and myeloid-derived suppressor cells (MDSCs) contribute to the negative regulation of immune responses in the context of cancer and inflammation. In order to investigate the pathophysiology of thyroid cancer, peripheral blood mononuclear cells (PBMCs) were obtained from 49 patients with thyroid cancer, 18 patients with non-cancerous thyroid diseases and 22 healthy volunteers. The MDSC levels were found to be higher in patients with any type of thyroid cancer (P<0.05), patients with ATC (P<0.001) and patients with medullary thyroid carcinoma (P<0.05), when compared to patients with non-cancerous thyroid diseases. The MDSC levels were also higher in patients with stage III–IV thyroid cancer compared to those in patients with non-cancerous thyroid diseases (P<0.05). The stimulation index (SI) of phytohemagglutinin (PHA)-induced lymphocyte blastogenesis was significantly lower, the C-reactive protein (CRP) levels were significantly higher and the serum albumin levels were significantly lower in patients with ATC compared to those in patients with non-cancerous thyroid diseases. The SI was significantly lower in stage III and IV thyroid cancer compared to that in non-cancerous thyroid disease (P<0.05). Furthermore, the CRP levels were higher and the concentration of albumin was lower in stage IV thyroid cancer compared to those in non-cancerous thyroid disease (P<0.05). Patients with thyroid carcinoma were then classified into one of two groups according to a %PBMC of MDSC cut-off level of 1.578, which was the average %PBMC of MDSC of patients with any type of thyroid carcinoma. In patients with higher MDSC levels, the production of CRP and interleukin (IL)-10 was significantly higher (P<0.05) and the albumin levels were significantly lower (P<0.05) compared to those in patients with lower MDSC levels. These data indicate that MDSCs are increased in patients with ATC. Furthermore, these patients exhibited suppression of cell-mediated immune responses, chronic inflammation and nutritional impairment. PMID:24649277

Default operational intervention levels (OILs) for severe nuclear power plant or spent fuel pool emergencies.

PubMed

McKenna, T; Kutkov, V; Vilar Welter, P; Dodd, B; Buglova, E

2013-05-01

Experience and studies show that for an emergency at a nuclear power plant involving severe core damage or damage to the fuel in spent fuel pools, the following actions may need to be taken in order to prevent severe deterministic health effects and reduce stochastic health effects: (1) precautionary protective actions and other response actions for those near the facility (i.e., within the zones identified by the International Atomic Energy Agency) taken immediately upon detection of facility conditions indicating possible severe damage to the fuel in the core or in the spent fuel pool; and (2) protective actions and other response actions taken based on environmental monitoring and sampling results following a release. This paper addresses the second item by providing default operational intervention levels [OILs, which are similar to the U.S. derived response levels (DRLs)] for promptly assessing radioactive material deposition, as well as skin, food, milk and drinking water contamination, following a major release of fission products from the core or spent fuel pool of a light water reactor (LWR) or a high power channel reactor (RBMK), based on the International Atomic Energy Agency's guidance.

Genetic dissection of the maize (Zea mays L.) MAMP response.

PubMed

Zhang, Xinye; Valdés-López, Oswaldo; Arellano, Consuelo; Stacey, Gary; Balint-Kurti, Peter

2017-06-01

Loci associated with variation in maize responses to two microbe-associated molecular patterns (MAMPs) were identified. MAMP responses were correlated. No relationship between MAMP responses and quantitative disease resistance was identified. Microbe-associated molecular patterns (MAMPs) are highly conserved molecules commonly found in microbes which can be recognized by plant pattern recognition receptors. Recognition triggers a suite of responses including production of reactive oxygen species (ROS) and nitric oxide (NO) and expression changes of defense-related genes. In this study, we used two well-studied MAMPs (flg22 and chitooctaose) to challenge different maize lines to determine whether there was variation in the level of responses to these MAMPs, to dissect the genetic basis underlying that variation and to understand the relationship between MAMP response and quantitative disease resistance (QDR). Naturally occurring quantitative variation in ROS, NO production, and defense genes expression levels triggered by MAMPs was observed. A major quantitative traits locus (QTL) associated with variation in the ROS production response to both flg22 and chitooctaose was identified on chromosome 2 in a recombinant inbred line (RIL) population derived from the maize inbred lines B73 and CML228. Minor QTL associated with variation in the flg22 ROS response was identified on chromosomes 1 and 4. Comparison of these results with data previously obtained for variation in QDR and the defense response in the same RIL population did not provide any evidence for a common genetic basis controlling variation in these traits.

Placenta-derived hypo-serotonin situations in the developing forebrain cause autism.

PubMed

Sato, Kohji

2013-04-01

Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests. Although there are many theories and speculations about the pathogenetic causes of autism, the disruption of the serotonergic system is one of the most consistent and well-replicated findings. Recently, it has been reported that placenta-derived serotonin is the main source in embryonic day (E) 10-15 mouse forebrain, after that period, the serotonergic fibers start to supply serotonin into the forebrain. E 10-15 is the very important developing period, when cortical neurogenesis, migration and initial axon targeting are processed. Since all these events have been considered to be involved in the pathogenesis of autism and they are highly controlled by serotonin signals, the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. I, thus, postulate a hypothesis that placenta-derived hypo-serotonin situations in the developing forebrain cause autism. The hypothesis is as follows. Various factors, such as inflammation, dysfunction of the placenta, together with genetic predispositions cause a decrease of placenta-derived serotonin levels. The decrease of placenta-derived serotonin levels leads to hypo-serotonergic situations in the forebrain of the fetus. The paucity of serotonin in the forebrain leads to mis-wiring in important regions which are responsible for the theory of mind. The paucity of serotonin in the forebrain also causes over-growth of serotonergic fibers. These disturbances result in network deficiency and aberration of the serotonergic system, leading to the autistic phenotypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Generation-recombination noise in extrinsic photoconductive detectors

NASA Technical Reports Server (NTRS)

Brukilacchio, T. J.; Skeldon, M. D.; Boyd, R. W.

1984-01-01

A theory of generation-recombination noise is presented and applied to the analysis of the performance limitations of extrinsic photoconductive detectors. The theory takes account both of the photoinduced generation of carriers and of thermal generation that is due to the finite temperature of the detector. Explicit formulas are derived that relate the detector response time, responsivity, and noise equivalent power to the material properties of the photoconductor (such as the presence of compensating impurities) and to the detector's operating conditions, such as its temperature and the presence of background radiation. The detector's performance is shown to degrade at high background levels because of saturation effects.

Microbial response to different phytoplankton-derived dissolved organic matter sources in the Ross Sea, Antarctica

NASA Astrophysics Data System (ADS)

Sipler, R. E.; Spackeen, J.; McQuaid, J.; Bertrand, E. M.; Roberts, Q. N.; Baer, S. E.; Hutchins, D. A.; Allen, A. E.; Bronk, D. A.

2016-02-01

Western Antarctic shelves are highly productive regions that play an important role in global carbon and nitrogen cycles, specifically serving as a critical sink for carbon dioxide. Fixed carbon is stored within the phytoplankton cell as particulate organic matter or released into the surrounding water as dissolved organic matter (DOM). These phytoplankton-derived sources of organic matter support higher trophic levels as well as heterotrophic bacterial growth and respiration. The composition of the phytoplankton-derived organic matter is a function of the taxa as well as the environmental conditions under which it is produced. Phytoplankton community composition within western Antarctic Seas changes throughout Austral spring and summer with early production dominated by ice algae, switching to pelagic diatoms and flagellates later in the season. The goal of this study was to compare the response of Ross Sea microbial communities to DOM produced by ice algae or late season diatoms, specifically recent isolates of Pseudo nitzschia obtained from the Ross Sea. During 5-day bioassay studies, exudates from a natural ice algal community and from Pseudo nitzschia sp. isolates were added to natural microbial communities collected from two different Ross Sea locations, an ice-edge and an ice-covered site. The bacterial response to the DOM additions was greatest in the ice-covered community with a 5 and 3-fold higher bacterial abundance in the ice algae DOM and Pseudo nitzschia DOM treatments, respectively, relative to the control. The ice edge bacterial community responded similarly to both sources with a 2-fold increase in bacterial abundance compared to the control. Unlike the bacterial response, there was little difference in chlorophyll a concentrations between treatments, indicating that phytoplankton growth was not stimulated or inhibited by our additions.

Immediate and extended effects of sodium lauryl sulphate exposure on stratum corneum natural moisturizing factor.

PubMed

Hoffman, D R; Kroll, L M; Basehoar, A; Reece, B; Cunningham, C T; Koenig, D W

2014-02-01

Natural moisturizing factor (NMF) serves as the primary humectant of the stratum corneum (SC), principally comprised of hygroscopic amino acids and derivatives that absorb moisture. Barrier disruption has been shown to differentially affect the levels of specific NMF components, though the kinetics of NMF component restoration following disruption have not been examined. Here, we investigated the impact of barrier disruption caused by surfactant exposure on a subset of NMF components immediately following exposure and out to 10 days post-exposure. Volunteers wore patches containing either 1% w/v sodium lauryl sulphate (SLS) or distilled water on their forearms for 24 h. Measurements of transepidermal water loss, erythema, SC water content and a subset of SC NMF and lipid components were obtained at both sites before treatment, the day of patch removal, and 1, 2, 3, 6, and 10 days following treatment. Most measured NMF components decreased in response to SLS exposure. Exceptions were increases in lactate, ornithine and urea, and no difference in proline levels. In the days following exposure, reduced levels of several NMF components continued at the SLS site; however, all measured NMF components demonstrated equivalence to the vehicle control within 10 days. Histidine pH 7, lactate, ornithine and urea were the first to achieve levels equivalent to the vehicle control site, normalizing within 1 day after patch removal. Results imply that NMF components derived from sweat and urea cycling are least impacted by SLS exposure whereas NMF components derived from degradation of filaggrin and/or other S-100 proteins are most impacted. This implies the restoration of the processes responsible for S-100 protein processing into free amino acids takes several days to return to normal. Further examination of the enzymes involved in S-100 protein processing following barrier disruption would provide insight into the pathway(s) for NMF restoration during SC recovery. © 2013 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Criteria for a State-of-the-Art Vision Test System

DTIC Science & Technology

1985-05-01

tests are enumerated for possible inclusion in a battery of candidate vision tests to be statistically examined for validity as predictors of aircrew...derived subset thereof) of vision tests may be given to a series of individuals, and statistical tests may be used to determine which visual functions...no target. Statistical analysis of the responses would set a threshold level, which would define the smallest size - (most distant target) or least

Pulmonary immune responses to Mycobacterium tuberculosis in exposed individuals

PubMed Central

Ernst, Martin; Lange, Christoph; Stenger, Steffen; Kaufmann, Stefan H. E.; Reiling, Norbert; Schaberg, Tom; van der Merwe, Lize; Maertzdorf, Jeroen

2017-01-01

Background Blood based Interferon-(IFN)-γ release assays (IGRAs) have a poor predictive value for the development of tuberculosis. This study aimed to investigate the correlation between IGRAs and pulmonary immune responses in tuberculosis contacts in Germany. Methods IGRAs were performed on bronchoalveolar lavage (BAL) cells and peripheral blood from close healthy contacts of patients with culturally confirmed tuberculosis. Cellular BAL composition was determined by flow cytometry. BAL cells were co-cultured with three strains of Mycobacterium tuberculosis (Mtb) and Mtb derived antigens including Purified Protein Derivative (PPD), 6 kD Early Secretory Antigenic Target (ESAT-6) and 10 kD Culture Filtrate Protein (CFP-10). Levels of 29 cytokines and chemokines were analyzed in the supernatants by multiplex assay. Associations and effects were examined using linear mixed-effects models. Results There were wide variations of inter-individual cytokine levels in BAL cell culture supernatants. Mycobacterial infection and stimulation with PPD showed a clear induction of several macrophage and lymphocyte associated cytokines, reflecting activation of these cell types. No robust correlation between cytokine patterns and blood IGRA status of the donor was observed, except for slightly higher Interleukin-2 (IL-2) responses in BAL cells from IGRA-positive donors upon mycobacterial infection compared to cells from IGRA-negative donors. Stronger correlations were observed when cytokine patterns were stratified according to BAL IGRA status. BAL cells from donors with BAL IGRA-positive responses produced significantly more IFN-γ and IL-2 upon PPD stimulation and mycobacterial infection than cells from BAL IGRA-negative individuals. Correlations between BAL composition and basal cytokine release from unstimulated cells were suggestive of pre-activated lymphocytes but impaired macrophage activity in BAL IGRA-positive donors, in contrast to BAL IGRA-negative donors. Conclusions In vitro BAL cell cytokine responses to M. tuberculosis antigens or infection do not reflect blood IGRA status but do correlate with stronger cellular responses in BAL IGRA-positive donors. The cytokine patterns observed suggest a pre-activated state of lymphocytes and suppressed macrophage responsiveness in BAL cells from BAL IGRA-positive individuals. PMID:29125874

Binaural interaction in the auditory brainstem response: a normative study.

PubMed

Van Yper, Lindsey N; Vermeire, Katrien; De Vel, Eddy F J; Battmer, Rolf-Dieter; Dhooge, Ingeborg J M

2015-04-01

Binaural interaction can be investigated using auditory evoked potentials. A binaural interaction component can be derived from the auditory brainstem response (ABR-BIC) and is considered evidence for binaural interaction at the level of the brainstem. Although click ABR-BIC has been investigated thoroughly, data on 500 Hz tone-burst (TB) ABR-BICs are scarce. In this study, characteristics of click and 500 Hz TB ABR-BICs are described. Furthermore, reliability of both click and 500 Hz TB ABR-BIC are investigated. Eighteen normal hearing young adults (eight women, ten men) were included. ABRs were recorded in response to clicks and 500 Hz TBs. ABR-BICs were derived by subtracting the binaural response from the sum of the monaural responses measured in opposite ears. Good inter-rater reliability is obtained for both click and 500 Hz TB ABR-BICs. The most reliable peak in click ABR-BIC occurs at a mean latency of 6.06 ms (SD 0.354 ms). Reliable 500 Hz TB ABR-BIC are obtained with a mean latency of 9.47 ms (SD 0.678 ms). Amplitudes are larger for 500 Hz TB ABR-BIC than for clicks. The most reliable peak in click ABR-BIC occurs at the downslope of wave V. Five hundred Hertz TB ABR-BIC is characterized by a broad positivity occurring at the level of wave V. The ABR-BIC is a useful technique to investigate binaural interaction in certain populations. Examples are bilateral hearing aid users, bilateral cochlear implant users and bimodal listeners. The latter refers to the combination of unilateral cochlear implantation and contralateral residual hearing. The majority of these patients have residual hearing in the low frequencies. The current study suggests that 500 Hz TB ABR-BIC may be a suitable technique to assess binaural interaction in this specific population of cochlear implant users. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Systems Biology for Organotypic Cell Cultures

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

Grego, Sonia; Dougherty, Edward R.; Alexander, Francis J.

Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, “organotypic” cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomicmore » data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data. This consensus report summarizes the discussions held.« less

Workshop Report: Systems Biology for Organotypic Cell Cultures

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

Grego, Sonia; Dougherty, Edward R.; Alexander, Francis Joseph

Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, “organotypic” cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomicmore » data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data.« less

Workshop Report: Systems Biology for Organotypic Cell Cultures

DOE PAGES

Grego, Sonia; Dougherty, Edward R.; Alexander, Francis Joseph; ...

2016-11-14

Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, “organotypic” cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomicmore » data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data.« less

Systems biology for organotypic cell cultures.

PubMed

Grego, Sonia; Dougherty, Edward R; Alexander, Francis J; Auerbach, Scott S; Berridge, Brian R; Bittner, Michael L; Casey, Warren; Cooley, Philip C; Dash, Ajit; Ferguson, Stephen S; Fennell, Timothy R; Hawkins, Brian T; Hickey, Anthony J; Kleensang, Andre; Liebman, Michael N J; Martin, Florian; Maull, Elizabeth A; Paragas, Jason; Qiao, Guilin Gary; Ramaiahgari, Sreenivasa; Sumner, Susan J; Yoon, Miyoung

2017-01-01

Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, "organotypic" cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomic data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data.

Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells.

PubMed

Lee, Hui-Mei; Patel, Vyomesh; Shyur, Lie-Fen; Lee, Wai-Leng

2016-11-15

Oral cancer is the sixth most common cancer worldwide and 90% of oral malignancies are caused by oral squamous cell carcinoma (OSCC). Curcumin, a phytocompound derived from turmeric (Curcuma longa) was observed to have anti-cancer activity which can be developed as an alternative treatment option for OSCC. However, OSCC cells with various clinical-pathological features respond differentially to curcumin treatment. Intracellular copper levels have been reported to correlate with tumor pathogenesis and affect the sensitivity of cancer cells to cytotoxic chemotherapy. We hypothesized that intracellular copper levels may affect the sensitivity of oral cancer cells to curcumin. We analysed the correlation between intracellular copper levels and response to curcumin treatment in a panel of OSCC cell lines derived from oral cancer patients. Exogenous copper was supplemented in curcumin insensitive cell lines to observe the effect of copper on curcumin-mediated inhibition of cell viability and migration, as well as induction of oxidative stress and apoptosis. Protein markers of cell migration and oxidative stress were also analysed using Western blotting. Concentrations of curcumin which inhibited 50% OSCC cell viability (IC 50 ) was reduced up to 5 times in the presence of 250 µM copper. Increased copper level in curcumin-treated OSCC cells was accompanied by the induction of intracellular ROS and increased level of Nrf2 which regulates oxidative stress responses in cells. Supplemental copper also inhibited migration of curcumin-treated cells with enhanced level of E-cadherin and decreased vimentin, indications of suppressed epithelial-mesenchymal transition. Early apoptosis was observed in combined treatment but not in treatment with curcumin or copper alone. Supplement of copper significantly enhanced the inhibitory effect of curcumin treatment on migration and viability of oral cancer cells. Together, these findings provide molecular insight into the role of copper in overcoming insensitivity of oral cancer cells to curcumin treatment, suggesting a new strategy for cancer therapy. Copyright © 2016 Elsevier GmbH. All rights reserved.

Re-examination of immune response and estimation of anti-Vi IgG protective threshold against typhoid fever-based on the efficacy trial of Vi conjugate in young children

PubMed Central

Szu, Shousun C.; Klugman, Keith P.; Hunt, Steven

2014-01-01

Background The capsular polysaccharide of Salmonella enterica serovar Typhi, Vi antigen, is an essential virulence factor and a protective antigen. Similar to other polysaccharide vaccines, the protective action of Vi, both to the polysaccharide alone or when presented as a conjugate, is mediated by serum IgG Vi antibodies. The evaluation of Vi capsular polysaccharide based vaccines to prevent typhoid fever would be significantly facilitated by the identification of a “protective level” of serum antibodies to Vi antigen. Methods The protective level of anti-Vi IgG against typhoid fever was derived from the protective efficacy and immune response of a Vi-rEPA conjugate vaccine efficacy trial. The estimation was derived by two methods: correlation of the percent efficacy and the antibody distribution profile in the vaccine group at a given period of observation, and use of the relative ratio of anti-Vi IgG levels between the vaccine and placebo groups greater or equal to the Relative Risk of typhoid fever used in the efficacy determination. Results Both methods predicted a similar range of a minimum protective level of anti-Vi IgG between 1.4 and 2.0 μg/ml (short term threshold). When applying a protective threshold of 10 μg/ml at 6 months post immunization, an IgG level in excess of 1.4 μg/ml was achieved by 90% of children at 46 months post immunization, consistent with an 89% level of protection over the duration of the study. We thus suggest that the proportion of children with Vi IgG > 10 μg/ml (long term threshold) 6 months after immunization may reflect the proportion protected over at least a 4 year period. Conclusion The current assignment of an anti-Vi IgG protective level may be of value when evaluating vaccine performance of future Vi conjugate vaccines. PMID:24630869

Reality Monitoring and Feedback Control of Speech Production Are Related Through Self-Agency.

PubMed

Subramaniam, Karuna; Kothare, Hardik; Mizuiri, Danielle; Nagarajan, Srikantan S; Houde, John F

2018-01-01

Self-agency is the experience of being the agent of one's own thoughts and motor actions. The intact experience of self-agency is necessary for successful interactions with the outside world (i.e., reality monitoring) and for responding to sensory feedback of our motor actions (e.g., speech feedback control). Reality monitoring is the ability to distinguish internally self-generated information from outside reality (externally-derived information). In the present study, we examined the relationship of self-agency between lower-level speech feedback monitoring (i.e., monitoring what we hear ourselves say) and a higher-level cognitive reality monitoring task. In particular, we examined whether speech feedback monitoring and reality monitoring were driven by the capacity to experience self-agency-the ability to make reliable predictions about the outcomes of self-generated actions. During the reality monitoring task, subjects made judgments as to whether information was previously self-generated (self-agency judgments) or externally derived (external-agency judgments). During speech feedback monitoring, we assessed self-agency by altering environmental auditory feedback so that subjects listened to a perturbed version of their own speech. When subjects heard minimal perturbations in their auditory feedback while speaking, they made corrective responses, indicating that they judged the perturbations as errors in their speech output. We found that self-agency judgments in the reality-monitoring task were higher in people who had smaller corrective responses ( p = 0.05) and smaller inter-trial variability ( p = 0.03) during minimal pitch perturbations of their auditory feedback. These results provide support for a unitary process for the experience of self-agency governing low-level speech control and higher level reality monitoring.

TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts.

PubMed

Jovanović, Bojana; Pickup, Michael W; Chytil, Anna; Gorska, Agnieszka E; Johnson, Kimberly C; Moses, Harold L; Owens, Philip

2016-11-04

The TGF-β pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-β pathway in breast cancer, we performed laser capture microdissection (LCM) from breast cancer patients and reduction mammoplasty patients. Microdissected tumor stroma and normal breast stroma were examined for gene expression. Expression of the TGF-β type III receptor ( TGFBR3 ) was greatly decreased in the tumor stroma compared to control healthy breast tissue. These results demonstrated a 44-fold decrease in TGFBR3 mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified that TGFBR3 mRNA levels are decreased in tumor stroma. We next investigated fibroblast cell lines derived from cancerous and normal breast tissue and found that in addition to mRNA levels, TβRIII protein levels were significantly reduced. Having previously identified that cancer-associated fibroblasts secrete greater levels of tumor promoting cytokines, we investigated the consequences of soluble-TβRIII (sTβRIII) on fibroblasts. Fibroblast conditioned medium was analyzed for 102 human secreted cytokines and distinct changes in response to sTβRIII were observed. Next, we used the fibroblast-conditioned medium to stimulate human monocyte cell line THP-1. These results indicate a distinct transcriptional response depending on sTβRIII treatment and whether it was derived from normal or cancerous breast tissue. We conclude that the effect of TβRIII has distinct roles not only in cancer-associated fibroblasts but that sTβRIII has distinct paracrine functions in the tumor microenvironment.

Different levels of brain-derived neurotrophic factor and cortisol in healthy heavy smokers.

PubMed

Neves, C D C; Lacerda, A C R; Lima, L P; Lage, V K S; Balthazar, C H; Leite, H R; Mendonça, V A

2017-10-19

Studies suggest that brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis modulate dopaminergic activity in response to nicotine and that the concentrations of BDNF and cortisol seem to be dependent on the amount and duration of smoking. Therefore, we investigated BDNF and cortisol levels in smokers ranked by daily cigarette consumption. Twenty-seven adult males (13 non-smokers and 14 smokers) participated in the study. The smokers were divided in two groups: light (n=7) and heavy smokers (n=7). Anthropometric parameters and age were paired between the groups, and plasma BDNF and salivary cortisol levels were measured. Saliva samples were collected on awakening, 30 min after awakening, at 10:00 and 12:00 am, 5:00 and 10:00 pm. Additionally, cotinine serum levels were measured in smokers. Heavy smokers had higher mean values of BDNF compared to the control group (P=0.01), whereas no difference was observed in light smokers. Moreover, heavy smokers presented lower cortisol levels in the last collection (10:00 pm) than the control group (P=0.02) and presented statically higher values of cotinine than the light smokers (P=0.002). In conclusion, changes in BDNF and cortisol levels (10:00 pm) appear to be dependent on heavy cigarette smoking and can be involved in activation and in the relationship between the mesolimbic system and the HPA axis.

Different levels of brain-derived neurotrophic factor and cortisol in healthy heavy smokers

PubMed Central

Neves, C.D.C.; Lacerda, A.C.R.; Lima, L.P.; Lage, V.K.S.; Balthazar, C.H.; Leite, H.R.; Mendonça, V.A.

2017-01-01

Studies suggest that brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis modulate dopaminergic activity in response to nicotine and that the concentrations of BDNF and cortisol seem to be dependent on the amount and duration of smoking. Therefore, we investigated BDNF and cortisol levels in smokers ranked by daily cigarette consumption. Twenty-seven adult males (13 non-smokers and 14 smokers) participated in the study. The smokers were divided in two groups: light (n=7) and heavy smokers (n=7). Anthropometric parameters and age were paired between the groups, and plasma BDNF and salivary cortisol levels were measured. Saliva samples were collected on awakening, 30 min after awakening, at 10:00 and 12:00 am, 5:00 and 10:00 pm. Additionally, cotinine serum levels were measured in smokers. Heavy smokers had higher mean values of BDNF compared to the control group (P=0.01), whereas no difference was observed in light smokers. Moreover, heavy smokers presented lower cortisol levels in the last collection (10:00 pm) than the control group (P=0.02) and presented statically higher values of cotinine than the light smokers (P=0.002). In conclusion, changes in BDNF and cortisol levels (10:00 pm) appear to be dependent on heavy cigarette smoking and can be involved in activation and in the relationship between the mesolimbic system and the HPA axis. PMID:29069228

Handmade Cloned Buffalo (Bubalus bubalis) Embryos Produced from Somatic Cells Isolated from Milk and Ear Skin Differ in Their Developmental Competence, Epigenetic Status, and Gene Expression.

PubMed

Jyotsana, Basanti; Sahare, Amol A; Raja, Anuj K; Singh, Karn P; Singla, Suresh K; Chauhan, Manmohan S; Manik, Radhey S; Palta, Prabhat

2015-10-01

We compared the cloning efficiency of buffalo embryos produced by handmade cloning (HMC) using ear skin- and milk-derived donor cells. The blastocyst rate was lower (p < 0.05) for milk-derived than that for skin-derived embryos, whereas the total cell number and apoptotic index were similar. The global level of H3K9ac was higher (p < 0.05) in skin- than in milk-derived cells, whereas the level of H3K27me3 was similar in the two groups. The global level of H3K9ac was similar between milk-derived and in vitro-fertilized (IVF) blastocysts, which was higher (p < 0.05) than that in skin-derived blastocysts. The level of H3K27me3 was similar among the three groups. The expression level of IGF-1R and G6PD was higher (p < 0.05) in skin- than in milk-derived cells, whereas DNMT1, DNMT3a, and HDAC1 expression level was similar. In the blastocysts, the expression level of DNMT1, HDAC1, OCT4, and CDX2 was higher (p < 0.05) in skin-derived than that in IVF blastocysts. The expression level of DNMT3a and IGF-1R, was in the order (p < 0.05) skin-derived and IVF > milk-derived blastocysts and that of NANOG was (p < 0.05) IVF-> milk-derived > skin-derived blastocysts. The expression level of all these genes, except NANOG, was lower (p < 0.05) in milk- than in skin-derived or IVF blastocysts. In conclusion, milk-derived cells can be used for producing HMC embryos of quality similar to that of skin-derived embryos, although with a lower blastocyst rate.

Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies.

PubMed

Iqbal, Jamshed; El-Gamal, Mohammed I; Ejaz, Syeda Abida; Lecka, Joanna; Sévigny, Jean; Oh, Chang-Hyun

2018-12-01

Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC 50  = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC 50  = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes.

General hybrid projective complete dislocated synchronization with non-derivative and derivative coupling based on parameter identification in several chaotic and hyperchaotic systems

NASA Astrophysics Data System (ADS)

Sun, Jun-Wei; Shen, Yi; Zhang, Guo-Dong; Wang, Yan-Feng; Cui, Guang-Zhao

2013-04-01

According to the Lyapunov stability theorem, a new general hybrid projective complete dislocated synchronization scheme with non-derivative and derivative coupling based on parameter identification is proposed under the framework of drive-response systems. Every state variable of the response system equals the summation of the hybrid drive systems in the previous hybrid synchronization. However, every state variable of the drive system equals the summation of the hybrid response systems while evolving with time in our method. Complete synchronization, hybrid dislocated synchronization, projective synchronization, non-derivative and derivative coupling, and parameter identification are included as its special item. The Lorenz chaotic system, Rössler chaotic system, memristor chaotic oscillator system, and hyperchaotic Lü system are discussed to show the effectiveness of the proposed methods.

Phenotypic modulation of auto-reactive cells by insertion of tolerogenic molecules via MSC-derived exosomes.

PubMed

Mokarizadeh, Aram; Delirezh, Nowruz; Morshedi, Ahhmad; Mosayebi, Ghasem; Farshid, Amir-Abbas; Dalir-Naghadeh, Bahram

2012-01-01

Auto-reactive cells-mediated immune responses are responsible for the current tissue damages during autoimmunity. Accordingly, functional modulation of auto-reactive cells has been a pivotal aim in many of recent studies. In the current study, we investigated the possibility for insertion of regulatory molecules onto auto-reactive cells through exosomal nano-shuttles as a novel approach for phenotype modification of auto-reactive cells. The exosomes were isolated from supernatant of mesenchymal stem cells culture. Resultant exosomes co-cultured with lymphocytes were harvested from established EAE mice in the presence of antigenic MOG35-55 peptide. After 24 hr, insertion of exosomal tolerogenic molecules (PD-L1, TGF-β, galectin-1) onto auto-reactive cells were explored through flow cytometry. The potency of exosomal inserted membrane molecules to modulate phenotype of auto-reactive lymphocytes was assessed upon ELISA test for their-derived cytokines IFN-γ and IL-17. Incorporation of exosomal molecules into lymohocytes' membrane was confirmed by flow cytometric analyses for surface levels of mentioned molecules. Additionally, the decreased secretion of IFN-γ and IL-17 were detected in exosome pre-treated lymphocytes upon stimulation with MOG peptide. Mesenchymal stem cells -derived exosomes showed to be efficient organelles for insertion of bioactive tolerogenic molecules onto auto-reactive cells and modulation of their phenotypes.

Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

PubMed Central

Jensen, Kristoffer Jarlov; Larsen, Nanna; Biering-Sørensen, Sofie; Andersen, Andreas; Eriksen, Helle Brander; Monteiro, Ivan; Hougaard, David; Aaby, Peter; Netea, Mihai G.; Flanagan, Katie L.; Benn, Christine Stabell

2015-01-01

Background. Bacillus Calmette–Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia. Methods. Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD). Results. Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ. Conclusion. Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality. PMID:25210141

Increasing The Genetic Admixture of Available Lines of Human Pluripotent Stem Cells

PubMed Central

Tofoli, Fabiano A.; Dasso, Maximiliano; Morato-Marques, Mariana; Nunes, Kelly; Pereira, Lucas Assis; da Silva, Giselle Siqueira; Fonseca, Simone A. S.; Costas, Roberta Montero; Santos, Hadassa Campos; da Costa Pereira, Alexandre; Lotufo, Paulo A.; Bensenor, Isabela M.; Meyer, Diogo; Pereira, Lygia Veiga

2016-01-01

Human pluripotent stem cells (hPSCs) may significantly improve drug development pipeline, serving as an in vitro system for the identification of novel leads, and for testing drug toxicity. Furthermore, these cells may be used to address the issue of differential drug response, a phenomenon greatly influenced by genetic factors. This application depends on the availability of hPSC lines from populations with diverse ancestries. So far, it has been reported that most lines of hPSCs derived worldwide are of European or East Asian ancestries. We have established 23 lines of hPSCs from Brazilian individuals, and we report the analysis of their genomic ancestry. We show that embryo-derived PSCs are mostly of European descent, while induced PSCs derived from participants of a national-wide Brazilian cohort study present high levels of admixed European, African and Native American genomic ancestry. Additionally, we use high density SNP data and estimate local ancestries, particularly those of CYP genes loci. Such information will be of key importance when interpreting variation among cell lines with respect to cellular phenotypes of interest. The availability of genetically admixed lines of hPSCs will be of relevance when setting up future in vitro studies of drug response. PMID:27708369

The mechanisms of substance P-mediated migration of bone marrow-derived mesenchymal stem cell-like ST2 cells.

PubMed

Dubon, Maria Jose; Park, Ki-Sook

2016-04-01

Substance P (SP) is known to induce the mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) and thus participates in wound repair. However, the cellular and molecular mechanisms responsible for the SP-mediated migration of BM-MSCs were not fully understood. In the present study, we studied the molecular mechanisms that mediate the migration of the BM-derived MSC-like cell line ST2 in response to SP. Using a migration assay and western blot analysis, we noted that SP induced the chemotactic migration of ST2 cells through the intrinsic activation of extracellular signal-regulated kinases (ERKs) and protein kinase B (Akt), the phosphorylated expression levels of which were increased. We noted that Src is involved in the SP-mediated migration of ST2 cells and that focal adhesion kinase (FAK) was activated in the ST2 cells following SP treatment. Membrane ruffling increased in the ST2 cells after SP treatment, as was clearly demonstrated by immunocytochemical analysis. Importantly, using a blocking antibody against N-cadherin (GC-4), we studied cell migration and noted that SP mediated the migration of the ST2 cells through N-cadherin. The present study thus advanced our understanding of the mechanisms through which SP induces BM-MSC migration.

Agomelatine Increases BDNF Serum Levels in Depressed Patients in Correlation with the Improvement of Depressive Symptoms

PubMed Central

Pettorruso, Mauro; De Berardis, Domenico; Varasano, Paola Annunziata; Lucidi Pressanti, Gabriella; De Remigis, Valeria; Valchera, Alessandro; Ricci, Valerio; Di Nicola, Marco; Janiri, Luigi; Biggio, Giovanni; Di Giannantonio, Massimo

2016-01-01

Background: Agomelatine modulates brain-derived neurotrophic factor expression via its interaction with melatonergic and serotonergic receptors and has shown promising results in terms of brain-derived neurotrophic factor increase in animal models. Methods: Twenty-seven patients were started on agomelatine (25mg/d). Venous blood was collected and brain-derived neurotrophic factor serum levels were measured at baseline and after 2 and 8 weeks along with a clinical assessment, including Hamilton Depression Rating Scale and Snaith-Hamilton Pleasure Scale. Results: Brain-derived neurotrophic factor serum concentration increased after agomelatine treatment. Responders showed a significant increase in brain-derived neurotrophic factor levels after 2 weeks of agomelatine treatment; no difference was observed in nonresponders. Linear regression analysis showed that more prominent brain-derived neurotrophic factor level variation was associated with lower baseline BDNF levels and greater anhedonic features at baseline. Conclusions: Patients affected by depressive disorders showed an increase of brain-derived neurotrophic factor serum concentration after a 2-week treatment with agomelatine. The increase of brain-derived neurotrophic factor levels was found to be greater in patients with lower brain-derived neurotrophic factor levels and marked anhedonia at baseline. PMID:26775293

Modeling the time-varying and level-dependent effects of the medial olivocochlear reflex in auditory nerve responses.

PubMed

Smalt, Christopher J; Heinz, Michael G; Strickland, Elizabeth A

2014-04-01

The medial olivocochlear reflex (MOCR) has been hypothesized to provide benefit for listening in noisy environments. This advantage can be attributed to a feedback mechanism that suppresses auditory nerve (AN) firing in continuous background noise, resulting in increased sensitivity to a tone or speech. MOC neurons synapse on outer hair cells (OHCs), and their activity effectively reduces cochlear gain. The computational model developed in this study implements the time-varying, characteristic frequency (CF) and level-dependent effects of the MOCR within the framework of a well-established model for normal and hearing-impaired AN responses. A second-order linear system was used to model the time-course of the MOCR using physiological data in humans. The stimulus-level-dependent parameters of the efferent pathway were estimated by fitting AN sensitivity derived from responses in decerebrate cats using a tone-in-noise paradigm. The resulting model uses a binaural, time-varying, CF-dependent, level-dependent OHC gain reduction for both ipsilateral and contralateral stimuli that improves detection of a tone in noise, similarly to recorded AN responses. The MOCR may be important for speech recognition in continuous background noise as well as for protection from acoustic trauma. Further study of this model and its efferent feedback loop may improve our understanding of the effects of sensorineural hearing loss in noisy situations, a condition in which hearing aids currently struggle to restore normal speech perception.

Leptin and Leptin-Related Gene Polymorphisms, Obesity, and Influenza A/H1N1 Vaccine–Induced Immune Responses in Older Individuals

PubMed Central

Ovsyannikova, Inna G.; White, Sarah J.; Larrabee, Beth R.; Grill, Diane E.; Jacobson, Robert M.; Poland, Gregory A.

2014-01-01

Obesity is a risk factor for complicated influenza A/H1N1 disease and poor vaccine immunogenicity. Leptin, an adipocyte-derived hormone/cytokine, has many immune regulatory functions and therefore could explain susceptibility to infections and poor vaccine outcomes. We recruited 159 healthy adults (5074 years old) who were immunized with inactivated TIV influenza vacci–ne that contained A/California/7/2009/H1N1 virus. We found a strong correlation between leptin concentration and BMI (r=0.55, p<0.0001), but no association with hemagglutination antibody inhibition (HAI), B-cell, or granzyme B responses. We found a slight correlation between leptin concentration and an immunosenescence marker (TREC: T-cell receptor excision circles) level (r=0.23, p=0.01). We found eight SNPs in the LEP/LEPR/GHRL genes that were associated with leptin levels and four SNPs in the PTPN1/LEPR/STAT3 genes associated with peripheral blood TREC levels (p<0.05). Heterozygosity of the synonymous variant rs2230604 in the PTPN1 gene was associated with a significantly lower (531 vs. 259, p = 0.005) TREC level, as compared to the homozygous major variant. We also found eight SNPs in the LEP/PPARG/CRP genes associated with variations in influenza-specific HAI and B-cell responses (p<0.05). Our results suggest that specific allelic variations in the leptin-related genes may influence adaptive immune responses to influenza vaccine. PMID:24360890

Glucan-MOS® improved growth and innate immunity in pacu stressed and experimentally infected with Aeromonas hydrophila.

PubMed

Soares, Michelly Pereira; Oliveira, Fulvia Cristina; Cardoso, Israel Luz; Urbinati, Elisabeth Criscuolo; Meldau de Campos, Cristiane; Hisano, Hamilton

2018-02-01

We tested the efficacy of a commercial product (Glucan-MOS ® ) derived from yeast Saccharomyces cerevisiae, containing two combined products, β-1,3-1,6 glucans and mannans on the growth, feed efficiency, stress and innate immune responses of juvenile pacu (Piaractus mesopotamicus) after a stressful handling and bacterial inoculation. For this, we evaluated the serum cortisol and plasma glucose levels, the respiratory activity of leukocytes, the serum lysozyme levels, as well as the number of circulating erythrocytes and leukocytes of fish fed during 30 days with diets containing increased levels of Glucan-MOS (0.0, 0.1, 0.2, 0.4 and 0.8%). The supplementation of 0.1% improved weight gain, feed conversion and the protein efficiency ratio compared to a control diet. The 0.2 and 0.4% Glucan-MOS ® diets were sufficient to increase the respiratory burst of leukocytes and lysozyme activity, the number of thrombocytes, neutrophils and monocytes in the blood after a stressful handling and bacterial challenge, and minimized stress response as shown by decreased cortisol and glucose levels when compared to the control. The results of this work reinforce the benefits of the adoption of feeding strategies including combination of both β-1,3-1,6 glucans and mannans as a dietary supplement in periods prior to intensive management. The 30-day period was sufficient to stimulate growth performance, improve nutrient utilization, minimize stress response and modulate innate immunity responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Salmon carcasses increase stream productivity more than inorganic fertilizer pellets: A test on multiple trophic levels in streamside experimental channels

USGS Publications Warehouse

Wipfli, Mark S.; Hudson, John P.; Caouette, John P.; Mitchell, N.L.; Lessard, Joanna L.; Heintz, Ron A.; Chaloner, D.T.

2010-01-01

Inorganic nutrient amendments to streams are viewed as possible restoration strategies for re-establishing nutrients and stream productivity throughout the western coast of North America, where salmon runs and associated marine-derived nutrient subsidies have declined. In a mesocosm experiment, we examined the short-term (6 weeks) comparative effects of artificial nutrient pellets and salmon carcasses, alone (low and high amounts) and in combination, on stream food webs. Response variables included dissolved nutrient concentrations, biofilm ash-free dry mass (AFDM) and chlorophyll-alevels, macroinvertebrate density, growth and body condition of juvenile coho salmon Oncorhynchus kisutch, and whole-body lipid content of invertebrates and juvenile coho salmon. Most of the response variables were significantly influenced by carcass treatment; the only response variable significantly influenced by fertilizer pellet treatment was soluble reactive phosphorus (SRP) concentration. Ammonium-nitrogen concentration was the only response variable affected by both (low and high) levels of carcass treatment; all others showed no significant response to the two carcass treatment levels. Significant treatment × time interactions were observed for all responses except nitrate; for most responses, significant treatment effects were detected at certain time periods and not others. For example, significantly higher SRP concentrations were recorded earlier in the experiment, whereas significant fish responses were observed later. These results provide evidence that inorganic nutrient additions do not have the same ecological effects in streams as do salmon carcasses, potentially because inorganic nutrient additions lack carbon-based biochemicals and macromolecules that are sequestered directly or indirectly by consumers. Salmon carcasses, preferably deposited naturally during spawning migrations, appear to be far superior to inorganic nutrient amendments for sustaining and restoring stream productivity, including fish production, and should be chosen over artificial nutrient additions when feasible and practical.

Terminal-Nerve-Derived Neuropeptide Y Modulates Physiological Responses in the Olfactory Epithelium of Hungry Axolotls (Ambystoma mexicanum)

PubMed Central

Mousley, Angela; Polese, Gianluca; Marks, Nikki J.; Eisthen, Heather L.

2007-01-01

The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by L-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances. PMID:16855098

Terminal nerve-derived neuropeptide y modulates physiological responses in the olfactory epithelium of hungry axolotls (Ambystoma mexicanum).

PubMed

Mousley, Angela; Polese, Gianluca; Marks, Nikki J; Eisthen, Heather L

2006-07-19

The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full-length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by l-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances.

Expression of platelet-derived growth factor B is upregulated in patients with thoracic aortic dissection.

PubMed

Meng, Weixin; Liu, Shangdian; Li, Dandan; Liu, Zonghong; Yang, Hui; Sun, Bo; Liu, Hongyu

2018-04-20

Thoracic aortic dissection (TAD) is a serious condition requiring urgent treatment to avoid catastrophic consequences. The inflammatory response is involved in the occurrence and development of TAD, possibly potentiated by platelet-derived growth factors (PDGFs). This study aimed to determine whether expression of PDGF-B (a subunit of PDGF-BB) was increased in TAD patients and to explore the factors responsible for its upregulation and subsequent effects on TAD. Full-thickness ascending aorta wall specimens from TAD patients (n = 15) and control patients (n = 10) were examined for expression of PDGF-B and its receptor (PDGFRB) and in terms of morphology, inflammation, and fibrosis. Blood samples from TAD and control patients were collected to detect plasma levels of PDGF-BB and soluble elastins. Expression levels of PDGF-B, PDGFRB, and collagen I were significantly enhanced in ascending aorta wall specimens from TAD patients compared with controls. Furthermore, soluble elastic fragments and PDGF-BB were significantly increased in plasma from TAD patients compared with controls, and numerous irregular elastic fibers and macrophages were seen in the ascending aorta wall in TAD patients. An increase in elastic fragments in the aorta wall might be responsible for inducing the activation and migration of macrophages to injured sites, leading to elevated expression of PDGF-B, which in turn induces deposition of collagen, disrupts extracellular matrix homeostasis, and increases the stiffness of the aorta wall, resulting in compromised aorta compliance. Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and cortisol responses to corticotropin-releasing hormone test.

PubMed

Meczekalski, B; Tonetti, A; Monteleone, P; Bernardi, F; Luisi, S; Stomati, M; Luisi, M; Petraglia, F; Genazzani, A R

2000-03-01

Hypothalamic amenorrhea (HA) is a functional disorder caused by disturbances in gonadotropin-releasing hormone (GnRH) pulsatility. The mechanism by which stress alters GnRH release is not well known. Recently, the role of corticotropin-releasing hormone (CRH) and neurosteroids in the pathophysiology of HA has been considered. The aim of the present study was to explore further the role of the hypothalamic-pituitary-adrenal axis in HA. We included 8 patients (aged 23.16+/-1.72 years) suffering from hypothalamic stress-related amenorrhea with normal body weight and 8 age-matched healthy controls in the follicular phase of the menstrual cycle. We measured basal serum levels of FSH, LH, and estradiol and evaluated ACTH, allopregnanolone and cortisol responses to CRH test in both HA patients and healthy women. Serum basal levels of FSH, LH, and estradiol as well as basal levels of allopregnanolone were significantly lower in HA patients than in controls (P<0.001) while basal ACTH and cortisol levels were significantly higher in amenorrheic patients with respect to controls (P<0.001). The response (area under the curve) of ACTH, allopregnanolone and cortisol to CRH was significantly lower in amenorrheic women compared with controls (P<0.001, P<0.05, P<0.05 respectively). In conclusion, women with HA, despite the high ACTH and cortisol levels and, therefore, hypothalamus-pituitary-adrenal axis hyperactivity, are characterized by low allopregnanolone basal levels, deriving from an impairment of both adrenal and ovarian synthesis. The blunted ACTH, allopregnanolone and cortisol responses to CRH indicate that, in hypothalamic amenorrhea, there is a reduced sensitivity and expression of CRH receptor. These results open new perspectives on the role of neurosteroids in the pathogenesis of hypothalamic amenorrhea.

Maternal nutrient restriction in baboon programs later-life cellular growth and respiration of cultured skin fibroblasts: a potential model for the study of aging-programming interactions.

PubMed

Salmon, Adam B; Dorigatti, Jonathan; Huber, Hillary F; Li, Cun; Nathanielsz, Peter W

2018-05-25

Compelling data exist for programming of chronic later-life diseases and longevity by perinatal developmental programming challenges. Understanding mechanisms by which life course health trajectory and longevity are set is fundamental to understanding aging. Appropriate approaches are needed to determine programming effects on cellular function. We have developed a baboon model in which control mothers eat ad libitum while a second group eat 70% of the global diet fed controls, leading to male and female offspring intrauterine growth restriction (IUGR). We have shown that IUGR suffer from acceleration of several age-related physiological declines. Here, we report on a skin-derived fibroblast model with potential relevance for mechanistic studies on how IUGR impacts aging. Fibroblasts were cultured from the skin biopsies taken from adult baboons from control and IUGR cohorts. IUGR-derived fibroblasts grew in culture less well than controls and those derived from male, but not female, IUGR baboons had a significant reduction in maximum respiration rate compared to control-derived fibroblasts. We also show that relative levels of several mitochondrial protein subunits, including NDUFB8 and cytochrome c oxidase subunit IV, were reduced in IUGR-derived fibroblasts even after serial passaging in culture. The lower levels of electron transport system components provide potential mechanisms for accelerated life course aging in the setting of programmed IUGR. This observation fits with the greater sensitivity of males compared with females to many, but not all, outcomes in response to programming challenges. These approaches will be powerful in the determination of programming-aging interactions.

Derived Manding in Children with Autism: Synthesizing Skinner's Verbal Behavior with Relational Frame Theory

PubMed Central

2005-01-01

Mand functions for two stimuli (A1 and A2) were trained for 3 children with autism and were then incorporated into two related conditional discriminations (A1-B1/A2 -B2 and B1-C1/B2-C2). Tests were conducted to probe for a derived transfer of mand response functions from A1 and A2 to C1 and C2, respectively. When 1 participant failed to demonstrate derived transfer of mand response functions, transfer training using exemplars was conducted. When participants had demonstrated derived transfer of mand functions, the X1 and X2 tokens that were employed as reinforcers for mand responses were incorporated into two conditional discriminations (X1-Y1/X2-Y2 and Y1-Z1/Y2-Z2). Tests were conducted for derived transfer of reinforcing functions. Finally, tests were conducted to determine if the participants would demonstrate derived manding for the derived reinforcers (present C1 and C2 to mand for Z1 and Z2, respectively). Derived transfer of functions was observed when the sequence of training and testing was reversed (i.e., training and testing reinforcing functions before mand response functions) and when only minimal instructions were provided. PMID:16463526

Differentiation of embryonic stem cells into hepatocytes that coexpress coagulation factors VIII and IX.

PubMed

Cao, Jun; Shang, Chang-zhen; Lü, Li-hong; Qiu, De-chuan; Ren, Meng; Chen, Ya-jin; Min, Jun

2010-11-01

To establish an efficient culture system to support embryonic stem (ES) cell differentiation into hepatocytes that coexpress F-VIII and F-IX. Mouse E14 ES cells were cultured in differentiation medium containing sodium butyrate (SB), basic fibroblast growth factor (bFGF), and/or bone morphogenetic protein 4 (BMP4) to induce the differentiation of endoderm cells and hepatic progenitor cells. Hepatocyte growth factor, oncostatin M, and dexamethasone were then used to induce the maturation of ES cell-derived hepatocytes. The mRNA expression levels of endoderm-specific genes and hepatocyte-specific genes, including the levels of F-VIII and F-IX, were detected by RT-PCR and real-time PCR during various stages of differentiation. Protein expression was examined by immunofluorescence and Western blot. At the final stage of differentiation, flow cytometry was performed to determine the percentage of cells coexpressing F-VIII and F-IX, and ELISA was used to detect the levels of F-VIII and F-IX protein secreted into the culture medium. The expression of endoderm-specific and hepatocyte-specific markers was upregulated to highest level in response to the combination of SB, bFGF, and BMP4. Treatment with the three inducers during hepatic progenitor differentiation significantly enhanced the mRNA and protein levels of F-VIII and F-IX in ES cell-derived hepatocytes. More importantly, F-VIII and F-IX were coexpressed with high efficiency at the final stage of differentiation, and they were also secreted into the culture medium. We have established a novel in vitro differentiation protocol for ES-derived hepatocytes that coexpress F-VIII and F-IX that may provide a foundation for stem cell replacement therapy for hemophilia.

The TFPI-2 derived peptide EDC34 improves outcome of gram-negative sepsis.

PubMed

Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E; Malmsten, Martin; Mörgelin, Matthias; Schmidtchen, Artur

2013-01-01

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections.

The TFPI-2 Derived Peptide EDC34 Improves Outcome of Gram-Negative Sepsis

PubMed Central

Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E.; Malmsten, Martin; Mörgelin, Matthias; Schmidtchen, Artur

2013-01-01

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections. PMID:24339780

Clinical correlates of plasma brain-derived neurotrophic factor in post-traumatic stress disorder spectrum after a natural disaster.

PubMed

Stratta, Paolo; Sanità, Patrizia; Bonanni, Roberto L; de Cataldo, Stefano; Angelucci, Adriano; Rossi, Rodolfo; Origlia, Nicola; Domenici, Luciano; Carmassi, Claudia; Piccinni, Armando; Dell'Osso, Liliana; Rossi, Alessandro

2016-10-30

Clinical correlates of plasma Brain-Derived Neurotrophic Factor (BDNF) have been investigated in a clinical population with Post Traumatic Stress Disorder (PTSD) symptoms and healthy control subjects who survived to the L'Aquila 2009 earthquake. Twenty-six outpatients and 14 control subjects were recruited. Assessments included: Structured Clinical Interview for DSM-IV Axis-I disorders Patient Version, Trauma and Loss Spectrum-Self Report (TALS-SR) for post-traumatic spectrum symptoms. Thirteen patients were diagnosed as Full PTSD and 13 as Partial PTSD. The subjects with full-blown PTSD showed lower BDNF level than subjects with partial PTSD and controls. Different relationship patterns of BDNF with post-traumatic stress spectrum symptoms have been reported in the three samples. Our findings add more insight on the mechanisms regulating BDNF levels in response to stress and further proofs of the utility of the distinction of PTSD into full and partial categories. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A new azine derivative colorimetric and fluorescent dual-channel probe for cyanide detection

NASA Astrophysics Data System (ADS)

Yu, Bin; Li, Chun-Yu; Sun, Yin-Xia; Jia, Hao-Ran; Guo, Jian-Qiang; Li, Jing

2017-09-01

A novel azine derivative colorimetric and fluorescent dual-channel probe salicylaldehyde hydrazine-3,5-dibromosalicylaldehyde (1) has been designed, synthesized and characterized. The probe 1 is confirmed to have especial selectivity and good sensitivity on detecting CN- via UV-vis absorption and fluorescence spectrum in aqueous solution (H2O/DMSO, 1:4, v/v). This colorimetric and fluorescent dual-channel probe response to CN- owed to the deprotonation process and established the mechanism by using 1H NMR spectroscopy. Further researches showed that the detection limit of the probe 1 to CN- anions is 8.01 × 10- 9 M, significantly lower than the maximum level 1.9 × 10- 6 M in potable water from WHO guidelines.

Roughness induced transition and heat transfer augmentation in hypersonic environments

NASA Astrophysics Data System (ADS)

Wassel, A. T.; Shih, W. C. L.; Courtney, J. F.

Boundary layer transition and surface heating distributions on graphite, fine weave carbon-carbon, and metallic nosetip materials were derived from surface temperature responses measured in nitrogen environments during both free-flight and track-guided testing in hypersonic environments. Innovative test procedures were developed, and heat transfer results were validated against established theory through experiments using a super-smooth tungsten model. Quantitative definitions of mean transition front locations were established by deriving heat flux distributions from measured temperatures, and comparisons made with existing nosetip transition correlations. Qualitative transition locations were inferred directly from temperature distributions to investigate preferred orientations on fine weave nosetips. Levels of roughness augmented heat transfer were generally shown to be below values predicted by state-of-the-art methods.

Functional characterization of human pluripotent stem cell-derived arterial endothelial cells.

PubMed

Zhang, Jue; Chu, Li-Fang; Hou, Zhonggang; Schwartz, Michael P; Hacker, Timothy; Vickerman, Vernella; Swanson, Scott; Leng, Ning; Nguyen, Bao Kim; Elwell, Angela; Bolin, Jennifer; Brown, Matthew E; Stewart, Ron; Burlingham, William J; Murphy, William L; Thomson, James A

2017-07-25

Here, we report the derivation of arterial endothelial cells from human pluripotent stem cells that exhibit arterial-specific functions in vitro and in vivo. We combine single-cell RNA sequencing of embryonic mouse endothelial cells with an EFNB2-tdTomato/EPHB4-EGFP dual reporter human embryonic stem cell line to identify factors that regulate arterial endothelial cell specification. The resulting xeno-free protocol produces cells with gene expression profiles, oxygen consumption rates, nitric oxide production levels, shear stress responses, and TNFα-induced leukocyte adhesion rates characteristic of arterial endothelial cells. Arterial endothelial cells were robustly generated from multiple human embryonic and induced pluripotent stem cell lines and have potential applications for both disease modeling and regenerative medicine.

Response kinetics of tethered bacteria to stepwise changes in nutrient concentration.

PubMed

Chernova, Anna A; Armitage, Judith P; Packer, Helen L; Maini, Philip K

2003-09-01

We examined the changes in swimming behaviour of the bacterium Rhodobacter sphaeroides in response to stepwise changes in a nutrient (propionate), following the pre-stimulus motion, the initial response and the adaptation to the sustained concentration of the chemical. This was carried out by tethering motile cells by their flagella to glass slides and following the rotational behaviour of their cell bodies in response to the nutrient change. Computerised motion analysis was used to analyse the behaviour. Distributions of run and stop times were obtained from rotation data for tethered cells. Exponential and Weibull fits for these distributions, and variability in individual responses are discussed. In terms of parameters derived from the run and stop time distributions, we compare the responses to stepwise changes in the nutrient concentration and the long-term behaviour of 84 cells under 12 propionate concentration levels from 1 nM to 25 mM. We discuss traditional assumptions for the random walk approximation to bacterial swimming and compare them with the observed R. sphaeroides motile behaviour.

Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells.

PubMed Central

Gauldie, J; Richards, C; Harnish, D; Lansdorp, P; Baumann, H

1987-01-01

One of the oldest and most preserved of the homeostatic responses of the body to injury is the acute phase protein response associated with inflammation. The liver responds to hormone-like mediators by the increased synthesis of a series of plasma proteins called acute phase reactants. In these studies, we examined the relationship of hepatocyte-stimulating factor derived from peripheral blood monocytes to interferon beta 2 (IFN-beta 2), which has been cloned. Antibodies raised against fibroblast-derived IFN-beta having neutralizing activity against both IFN-beta 1 and -beta 2 inhibited the major hepatocyte-stimulating activity derived from monocytes. Fibroblast-derived mediator elicited the identical stimulated response in human HepG2 cells and primary rat hepatocytes as the monocyte cytokine. Finally, recombinant-derived human B-cell stimulatory factor type 2 (IFN-beta 2) from Escherichia coli induced the synthesis of all major acute phase proteins studied in human hepatoma HepG2 and primary rat hepatocyte cultures. These data demonstrate that monocyte-derived hepatocyte-stimulating factor and IFN-beta 2 share immunological and functional identity and that IFN-beta 2, also known as B-cell stimulatory factor and hybridoma plasmacytoma growth factor, has the hepatocyte as a major physiologic target and thereby is essential in controlling the hepatic acute phase response. Images PMID:2444978

Systemic Nutrient and Stress Signaling via Myokines and Myometabolites.

PubMed

Rai, Mamta; Demontis, Fabio

2016-01-01

Homeostatic systems mount adaptive responses to meet the energy demands of the cell and to compensate for dysfunction in cellular compartments. Such surveillance systems are also active at the organismal level: Nutrient and stress sensing in one tissue can lead to changes in other tissues. Here, we review the emerging understanding of the role of skeletal muscle in regulating physiological homeostasis and disease progression in other tissues. Muscle-specific genetic interventions can induce systemic effects indirectly, via changes in the mass and metabolic demand of muscle, and directly, via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) in response to nutrients and stress. In turn, myokines and myometabolites signal to various target tissues in an autocrine, paracrine, and endocrine manner, thereby determining organismal resilience to aging, disease, and environmental challenges. We propose that tailoring muscle systemic signaling by modulating myokine and myometabolite levels may combat many degenerative diseases and delay aging.

Is depression an inflammatory condition? A review of available evidence.

PubMed

Hashmi, Ali Madeeh; Butt, Zeeshan; Umair, Muhammad

2013-07-01

The current review examines the relationship between depression and the inflammatory immune response. Mood disorders are a significant cause of morbidity and the etiology of depression is still not clearly understood. Many studies have shown links between inflammatory cytokines and mood disorders, including elevated level of cytokines like tumour necrosis factor-alpha (TNF alpha), Interleukins (IL-1,IL-6) and others. Raised levels of cytokines have been shown to increase depressive behaviour in animal models, while many anti-depressants reverse this behaviour alongside reducing the Central Nervous System (CNS) inflammatory response and reduction in the amounts of inflammatory cytokines. Cytokines reduce neurogenesis, Brain Derived Neurotrophic Factor (BDNF) and neuronal plasticity in the CNS, while many anti-depressants have been shown to reverse these processes. The considerations of anti-depressants as anti-inflammatory agents, and implication of other anti-inflammatory therapeutics for the treatment of depression are pointed out.

Sea-level Fingerprinting, Vertical Crustal Motion from GIA, and Projections of Relative Sea-level Change in the Canadian Arctic

NASA Astrophysics Data System (ADS)

James, Thomas; Simon, Karen; Forbes, Donald; Dyke, Arthur; Mazzotti, Stephane

2010-05-01

We present projections of relative sea-level rise in the 21st century for communities in the Canadian Arctic. First, for selected communities, we determine the sea-level fingerprinting response from Antarctica, Greenland, and mountain glaciers and ice caps. Then, for various published projections of global sea-level change in the 21st century, we determine the local amount of "absolute" sea-level change. We next determine the vertical land motion arising from glacial isostatic adjustment (GIA) and incorporate this into the estimates of absolute sea-level change to obtain projections of relative sea-level change. The sea-level fingerprinting effect is especially important in the Canadian Arctic owing to proximity to Arctic ice caps and especially to the Greenland ice sheet. Its effect is to reduce the range of projected relative sea-level change compared to the range of global sea-level projections. Vertical crustal motion is assessed through empirically derived regional isobases, the Earth's predicted response to ice-sheet loading and unloading by the ICE-5G ice sheet reconstruction, and Global Positioning System vertical velocities. Owing to the large rates of crustal uplift from glacial isostatic adjustment across a large region of central Arctic Canada, many communities are projected to experience relative sea-level fall despite projections of global sea-level rise. Where uplift rates are smaller, such as eastern Baffin Island and the western Canadian Arctic, sea-level is projected to rise.

Development and evaluation of consensus-based sediment effect concentrations for polychlorinated biphenyls

USGS Publications Warehouse

MacDonald, Donald D.; Dipinto, Lisa M.; Field, Jay; Ingersoll, Christopher G.; Long, Edward R.; Swartz, Richard C.

2000-01-01

Sediment-quality guidelines (SQGs) have been published for polychlorinated biphenyls (PCBs) using both empirical and theoretical approaches. Empirically based guidelines have been developed using the screening-level concentration, effects range, effects level, and apparent effects threshold approaches. Theoretically based guidelines have been developed using the equilibrium-partitioning approach. Empirically-based guidelines were classified into three general categories, in accordance with their original narrative intents, and used to develop three consensus-based sediment effect concentrations (SECs) for total PCBs (tPCBs), including a threshold effect concentration, a midrange effect concentration, and an extreme effect concentration. Consensus-based SECs were derived because they estimate the central tendency of the published SQGs and, thus, reconcile the guidance values that have been derived using various approaches. Initially, consensus-based SECs for tPCBs were developed separately for freshwater sediments and for marine and estuarine sediments. Because the respective SECs were statistically similar, the underlying SQGs were subsequently merged and used to formulate more generally applicable SECs. The three consensus-based SECs were then evaluated for reliability using matching sediment chemistry and toxicity data from field studies, dose-response data from spiked-sediment toxicity tests, and SQGs derived from the equilibrium-partitioning approach. The results of this evaluation demonstrated that the consensus-based SECs can accurately predict both the presence and absence of toxicity in field-collected sediments. Importantly, the incidence of toxicity increases incrementally with increasing concentrations of tPCBs. Moreover, the consensus-based SECs are comparable to the chronic toxicity thresholds that have been estimated from dose-response data and equilibrium-partitioning models. Therefore, consensus-based SECs provide a unifying synthesis of existing SQGs, reflect causal rather than correlative effects, and accurately predict sediment toxicity in PCB-contaminated sediments.

Regulation of GluR2 promoter activity by neurotrophic factors via a neuron-restrictive silencer element.

PubMed

Brené, S; Messer, C; Okado, H; Hartley, M; Heinemann, S F; Nestler, E J

2000-05-01

The AMPA glutamate receptor subunit GluR2, which plays a critical role in regulation of AMPA channel function, shows altered levels of expression in vivo after several chronic perturbations. To evaluate the possibility that transcriptional mechanisms are involved, we studied a 1254-nucleotide fragment of the 5'-promoter region of the mouse GluR2 gene in neural-derived cell lines. We focused on regulation of GluR2 promoter activity by two neurotrophic factors, which are known to be altered in vivo in some of the same systems that show GluR2 regulation. Glial-cell line derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) both induced GluR2 promoter activity. This was associated with increased expression of endogenous GluR2 immunoreactivity in the cells as measured by Western blotting. The effect of GDNF and BDNF appeared to be mediated via a NRSE (neuron-restrictive silencer element) present within the GluR2 promoter. The response to these neurotrophic factors was lost upon mutating or deleting this site, but not several other putative response elements present within the promoter. Moreover, overexpression of REST (restrictive element silencer transcription factor; also referred to as NRSF or neuron restrictive silencer factor), which is known to act on NRSEs in other genes to repress gene expression, blocked the ability of GDNF to induce GluR2 promoter activity. However, GDNF did not alter endogenous levels of REST in the cells. Together, these findings suggest that GluR2 expression can be regulated by neurotrophic factors via an apparently novel mechanism involving the NRSE present within the GluR2 gene promoter.

Differentiation-Dependent Energy Production and Metabolite Utilization: A Comparative Study on Neural Stem Cells, Neurons, and Astrocytes

PubMed Central

Jády, Attila Gy.; Nagy, Ádám M.; Kőhidi, Tímea; Ferenczi, Szilamér; Tretter, László

2016-01-01

While it is evident that the metabolic machinery of stem cells should be fairly different from that of differentiated neurons, the basic energy production pathways in neural stem cells (NSCs) or in neurons are far from clear. Using the model of in vitro neuron production by NE-4C NSCs, this study focused on the metabolic changes taking place during the in vitro neuronal differentiation. O2 consumption, H+ production, and metabolic responses to single metabolites were measured in cultures of NSCs and in their neuronal derivatives, as well as in primary neuronal and astroglial cultures. In metabolite-free solutions, NSCs consumed little O2 and displayed a higher level of mitochondrial proton leak than neurons. In stem cells, glycolysis was the main source of energy for the survival of a 2.5-h period of metabolite deprivation. In contrast, stem cell-derived or primary neurons sustained a high-level oxidative phosphorylation during metabolite deprivation, indicating the consumption of own cellular material for energy production. The stem cells increased O2 consumption and mitochondrial ATP production in response to single metabolites (with the exception of glucose), showing rapid adaptation of the metabolic machinery to the available resources. In contrast, single metabolites did not increase the O2 consumption of neurons or astrocytes. In “starving” neurons, neither lactate nor pyruvate was utilized for mitochondrial ATP production. Gene expression studies also suggested that aerobic glycolysis and rapid metabolic adaptation characterize the NE-4C NSCs, while autophagy and alternative glucose utilization play important roles in the metabolism of stem cell-derived neurons. PMID:27116891

Immunomodulatory effects of the aromatic geranyl derivative filifolinone tested by the induction of cytokine expression.

PubMed

Valenzuela, Beatriz; Imarai, Mónica; Torres, René; Modak, Brenda

2013-12-01

Fish farming crops are constantly exposed to infectious diseases due to intensive production conditions under which microorganisms develop and spread easily, resulting in severe economic losses. The massive use of antibiotics to control these diseases has lead to the accumulation of residues and the development of drug resistance. Consequently, it is urgent to develop new pharmacological tools to stimulate protective immune responses in salmonids to combat infectious diseases. We evaluated the immunostimulant activity of terpenoid derivatives isolated from species of the Heliotropium genus, which had previously shown antiviral activity in salmon. The immunomodulatory effects of the 3 H-spiro [1-benzofuran-2,1'-ciclohexane] derivative called filifolinone, were studied in vitro using the SHK-1 cell line derived from leucocytes of salmon head kidney and in vivo in Atlantic salmon. For the evaluation, we studied the effect of this compound in the expression of various cytokines. The results showed that Filifolinone increases the levels of expression of pro-inflammatory and anti-inflammatory cytokines. This suggests that Filifolinone is a potential alternative immunomodulator for veterinary purposes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Optimization of Penicillium aurantiogriseum protease immobilization on magnetic nanoparticles for antioxidant peptides' obtainment.

PubMed

Duarte Neto, José Manoel Wanderley; Maciel, Jackeline da Costa; Campos, Júlia Furtado; Carvalho Junior, Luiz Bezerra de; Marques, Daniela Araújo Viana; Lima, Carolina de Albuquerque; Porto, Ana Lúcia Figueiredo

2017-08-09

This work reports an optimization of protease from Penicillium aurantiogriseum immobilization on polyaniline-coated magnetic nanoparticles for antioxidant peptides' obtainment derived from bovine casein. Immobilization process was optimized using a full two-level factorial design (2 4 ) followed by a response surface methodology. Using the derivative, casein was hydrolyzed uncovering its peptides that were sequenced and had antioxidant properties tested through (2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt) (ABTS) radical scavenging and hydrogen peroxide scavenging assays. Optimal conditions for immobilization were 2 hr of immobilization, offered protein amount of 200 µg/mL, immobilization pH of 6.3 and 7.3 hr of activation. Derivative keeps over 74% of its original activity after reused five times. Free and immobilized enzyme casein hydrolysates presented similar peptide mass fingerprints, and prevalent peptides could be sequenced. Hydrolysates presented more than 2.5× higher ROS scavenging activity than nonhydrolyzed casein, which validates the immobilized protease capacity to develop casein-derived natural ingredients with potential for functional foods.

Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

PubMed Central

Barker, Jacqueline M.; Taylor, Jane R.; De Vries, Taco J.; Peters, Jamie

2015-01-01

Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural circuits are responsible for storing and executing drug-procuring motor programs, whereas other neural circuits are responsible for the active suppression of these “seeking” systems. These seeking-circuits are established as associations are formed between drug-associated cues and the conditioned responses they elicit. Such conditioned responses (e.g. drug seeking) can be diminished either through a passive weakening of seeking-circuits or an active suppression of those circuits through extinction. Extinction learning occurs when the association between cues and drug are violated, for example, by cue exposure without the drug present. Cue exposure therapy has been proposed as a therapeutic avenue for the treatment of addictions. Here we explore the role of BDNF in extinction circuits, compared to seeking-circuits that “incubate” over prolonged withdrawal periods. We begin by discussing the role of BDNF in extinction memory for fear and cocaine-seeking behaviors, where extinction circuits overlap in infralimbic prefrontal cortex (PFC). We highlight the ability of estrogen to promote BDNF-like effects in hippocampal–prefrontal circuits and consider the role of sex differences in extinction and incubation of drug-seeking behaviors. Finally, we examine how opiates and alcohol “break the mold” in terms of BDNF function in extinction circuits. PMID:25451116

Effects of phenolic constituents of daylily flowers on corticosterone- and glutamate-treated PC12 cells.

PubMed

Tian, Huan; Yang, Fei-Fei; Liu, Chun-Yu; Liu, Xin-Min; Pan, Rui-Le; Chang, Qi; Zhang, Ze-Sheng; Liao, Yong-Hong

2017-01-21

Daylily flowers, the flower and bud parts of Hemerocallis citrina or H. fulva, are well known as Wang-You-Cao in Chinese, meaning forget-one's sadness plant. However, the major types of active constituents responsible for the neurological effects remain unclear. This study was to examine the protective effects of hydroalcoholic extract and fractions and to identify the active fractions. The extract of daylily flowers was separated with AB-8 resin into different fractions containing non-phenolic compounds, phenolic acid derivatives and flavonoids as determined using UPLC-DAD chromatograms. The neuroprotective activity was measured by evaluating the cell viability and lactate dehydrogenase release using PC12 cell damage models induced by corticosterone and glutamate. The neurological mechanisms were explored by determining their effect on the levels of dopamine (DA), 5-hydroxy tryptamine (5-HT), γ-aminobutyric acid (GABA), noradrenaline (NE) and acetylcholine (ACh) in the cell culture medium measured using an LC-MS/MS method. Pretreatment of PC12 cells with the extract and phenolic fractions of daylily flowers at concentrations ranging from 0.63 to 5 mg raw material/mL significantly reversed corticosterone- and glutamate-induced neurotoxicity in a dose-dependent manner. The fractions containing phenolic acid derivatives (0.59% w/w in the flowers) and/or flavonoids (0.60% w/w) exerted similar dose-dependent neuroprotective effect whereas the fractions with non-phenolic compounds exhibited no activity. The presence of phenolic acid derivatives in the corticosterone- and glutamate-treated PC12 cells elevated the DA level in the cell culture medium whereas flavonoids resulted in increased ACH and 5-HT levels. Phenolic acid derivatives and flavonoids were likely the active constituents of daylily flowers and they conferred a similar extent of neuroprotection, but affected the release of neurotransmitters in a different manner.

Interaction between environment, nutrient-derived metabolites and immunity: A possible role in malaria susceptibility/resistance in Fulani and Dogon of Mali

PubMed Central

Traore, Karim; Thera, Mahamadou A; Bienvenu, Anne-Lise; Arama, Charles; Bonnot, Guillaume; Lavoignat, Adeline; Doumbo, Ogobara K; Picot, Stephane

2017-01-01

The role of some nutrient-derived metabolites on the innate and adaptive immune responses is now established. Global research approach investigating the interplay between environment, lifestyle and the host’s immune responses is crucial in the understanding of malaria susceptibility. Advanced Glycation end products (AGE), which are food-derived metabolites result from the link between reducing sugar and amino group of proteins, lipids or nucleic acids. The level of exposure to AGEs varies depending on the type of diet. The dysfunction of the immune system induced by AGE and the cellular receptors for AGEs (RAGE) in susceptibility to bacterial infection has been described. But no study has yet explored their role in susceptibility to malaria. Therefore, we aimed to evaluate systemic AGE and RAGE gene polymorphism in two sympatric populations with previously described difference of susceptibility to malaria. We measured by ELISA the plasma levels of AGEs, and their soluble receptors (sRAGE) from 170 volunteers (68 Fulani and 102 Dogon). We also determined by real-time quantitative PCR the expression of RAGE, and the -374 T/A, -429 T/C polymorphisms and 63 bp deletion by fragment length restriction polymorphism. The prevalence rate of Plasmodium in Fulani and Dogon were respectively 42.64% and 51.30% for P. falciparum, 5.88% and 6.5% for P. malariae, 0% and 2.6% for P. ovale. The average AGE was 12.65 μg/ml, and 496.48pg/ml for sRAGE. Highest levels of sRAGE were observed in Fulani (563,07pg/ml, 95% CI [547.81–580.13] vs 465.68pg/ml, 95% CI [331.19–467.51]) for Dogon, p = 0.00001. Fulani had the lowest mean of AGE (10.21μg/ml, 95% CI [8.02–10.92]) compared to Dogon (16.88μg/ml, 95% CI [13.92–17.96]; p = 0.00001. RAGE was more expressed in Dogon than Fulani (0.08 vs 0.04), P = 0.08. The -374A polymorphism vas more frequent in Fulani (32%) compared to Dogon (20%). The chronic exposure to dietary AGE could lead to immune responses impairment and polymorphism with implications in malaria susceptibility. More studies are necessary to better investigate this hypothesis. PMID:29261755

Interaction between environment, nutrient-derived metabolites and immunity: A possible role in malaria susceptibility/resistance in Fulani and Dogon of Mali.

PubMed

Traore, Karim; Thera, Mahamadou A; Bienvenu, Anne-Lise; Arama, Charles; Bonnot, Guillaume; Lavoignat, Adeline; Doumbo, Ogobara K; Picot, Stephane

2017-01-01

The role of some nutrient-derived metabolites on the innate and adaptive immune responses is now established. Global research approach investigating the interplay between environment, lifestyle and the host's immune responses is crucial in the understanding of malaria susceptibility. Advanced Glycation end products (AGE), which are food-derived metabolites result from the link between reducing sugar and amino group of proteins, lipids or nucleic acids. The level of exposure to AGEs varies depending on the type of diet. The dysfunction of the immune system induced by AGE and the cellular receptors for AGEs (RAGE) in susceptibility to bacterial infection has been described. But no study has yet explored their role in susceptibility to malaria. Therefore, we aimed to evaluate systemic AGE and RAGE gene polymorphism in two sympatric populations with previously described difference of susceptibility to malaria. We measured by ELISA the plasma levels of AGEs, and their soluble receptors (sRAGE) from 170 volunteers (68 Fulani and 102 Dogon). We also determined by real-time quantitative PCR the expression of RAGE, and the -374 T/A, -429 T/C polymorphisms and 63 bp deletion by fragment length restriction polymorphism. The prevalence rate of Plasmodium in Fulani and Dogon were respectively 42.64% and 51.30% for P. falciparum, 5.88% and 6.5% for P. malariae, 0% and 2.6% for P. ovale. The average AGE was 12.65 μg/ml, and 496.48pg/ml for sRAGE. Highest levels of sRAGE were observed in Fulani (563,07pg/ml, 95% CI [547.81-580.13] vs 465.68pg/ml, 95% CI [331.19-467.51]) for Dogon, p = 0.00001. Fulani had the lowest mean of AGE (10.21μg/ml, 95% CI [8.02-10.92]) compared to Dogon (16.88μg/ml, 95% CI [13.92-17.96]; p = 0.00001. RAGE was more expressed in Dogon than Fulani (0.08 vs 0.04), P = 0.08. The -374A polymorphism vas more frequent in Fulani (32%) compared to Dogon (20%). The chronic exposure to dietary AGE could lead to immune responses impairment and polymorphism with implications in malaria susceptibility. More studies are necessary to better investigate this hypothesis.

Single-Cell Detection of Secreted Aβ and sAPPα from Human IPSC-Derived Neurons and Astrocytes.

PubMed

Liao, Mei-Chen; Muratore, Christina R; Gierahn, Todd M; Sullivan, Sarah E; Srikanth, Priya; De Jager, Philip L; Love, J Christopher; Young-Pearse, Tracy L

2016-02-03

Secreted factors play a central role in normal and pathological processes in every tissue in the body. The brain is composed of a highly complex milieu of different cell types and few methods exist that can identify which individual cells in a complex mixture are secreting specific analytes. By identifying which cells are responsible, we can better understand neural physiology and pathophysiology, more readily identify the underlying pathways responsible for analyte production, and ultimately use this information to guide the development of novel therapeutic strategies that target the cell types of relevance. We present here a method for detecting analytes secreted from single human induced pluripotent stem cell (iPSC)-derived neural cells and have applied the method to measure amyloid β (Aβ) and soluble amyloid precursor protein-alpha (sAPPα), analytes central to Alzheimer's disease pathogenesis. Through these studies, we have uncovered the dynamic range of secretion profiles of these analytes from single iPSC-derived neuronal and glial cells and have molecularly characterized subpopulations of these cells through immunostaining and gene expression analyses. In examining Aβ and sAPPα secretion from single cells, we were able to identify previously unappreciated complexities in the biology of APP cleavage that could not otherwise have been found by studying averaged responses over pools of cells. This technique can be readily adapted to the detection of other analytes secreted by neural cells, which would have the potential to open new perspectives into human CNS development and dysfunction. We have established a technology that, for the first time, detects secreted analytes from single human neurons and astrocytes. We examine secretion of the Alzheimer's disease-relevant factors amyloid β (Aβ) and soluble amyloid precursor protein-alpha (sAPPα) and present novel findings that could not have been observed without a single-cell analytical platform. First, we identify a previously unappreciated subpopulation that secretes high levels of Aβ in the absence of detectable sAPPα. Further, we show that multiple cell types secrete high levels of Aβ and sAPPα, but cells expressing GABAergic neuronal markers are overrepresented. Finally, we show that astrocytes are competent to secrete high levels of Aβ and therefore may be a significant contributor to Aβ accumulation in the brain. Copyright © 2016 the authors 0270-6474/16/361730-17$15.00/0.

Modulation of IL-33/ST2-TIR and TLR signalling pathway by fingolimod and analogues in immune cells.

PubMed

Rüger, K; Ottenlinger, F; Schröder, M; Zivković, A; Stark, H; Pfeilschifter, J M; Radeke, H H

2014-12-01

For the immune modulatory drug fingolimod (FTY720), lymphocyte sequestration has been extensively studied and accepted as mode of action. Further, direct effects on immune cell signalling are incompletely understood. Herein, we used the parent drug and newly synthesized analogues to investigate their effects on dendritic cell (DC) calcium signalling and on Th1, Th2 and Th17 responses. DC calcium signalling was determined with a single cell-based confocal assay and IL-33/ST2-TIR Th2-like response with ST2-transduced EL4-6.1 thymoma cells. The Th1/Th17 responses were examined with a LPS/TLR-enhanced antigen presentation assay with OVA-TCRtg CD4 and CD8 spleen cells. Our results revealed a comparable influence of fingolimod and S1P on intracellular calcium level in DC, while an oxy-derivative of fingolimod exhibited an EC50 of 3.3 nm, being 14 times more potent than FTY720-P. The IL-33/ST2-TIR Th2-like response in ST2-EL4 cells was inhibited by fingolimod and analogues at varying degrees. Using the OVA-TCRtg LPS/TLR-enhanced spleen cell assay, we found that fingolimod inhibited both IL-17 and IFN-γ production. In contrast, fingolimod phosphate failed to decrease Th1 cytokines. Interestingly, the effects of the parent compound fingolimod were modulated by the PP2A inhibitor okadaic acid, thus suggesting PP2A as relevant intracellular target. These studies describe detailed immune-modulating properties of fingolimod, including interference with a prototypical Th2 response via IL-33/ST2-TIR. Moreover, differential effects of fingolimod versus its phosphorylated derivative on TLR-activated and antigen-dependent Th1 activation suggest PP2A as an additional target of fingolimod immune therapy. Together with the analogues tested, these data may guide the development of more specific fingolimod derivatives. © 2014 John Wiley & Sons Ltd.

Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro.

PubMed

Ozaki, Masahiro; Iwanami, Akio; Nagoshi, Narihito; Kohyama, Jun; Itakura, Go; Iwai, Hiroki; Nishimura, Soraya; Nishiyama, Yuichiro; Kawabata, Soya; Sugai, Keiko; Iida, Tsuyoshi; Matsubayashi, Kohei; Isoda, Miho; Kashiwagi, Rei; Toyama, Yoshiaki; Matsumoto, Morio; Okano, Hideyuki; Nakamura, Masaya

2017-03-01

To achieve the goal of a first-in-human trial for human induced pluripotent stem cell (hiPSC)-based transplantation for the treatment of various diseases, allogeneic human leukocyte antigen (HLA)-matched hiPSC cell banks represent a realistic tool from the perspective of quality control and cost performance. Furthermore, considering the limited therapeutic time-window for acute injuries, including neurotraumatic injuries, an iPS cell bank is of potential interest. However, due to the relatively immunoprivileged environment of the central nervous system, it is unclear whether HLA matching is required in hiPSC-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for the treatment of neurodegenerative diseases and neurotraumatic injuries. In this study, we evaluated the significance of HLA matching in hiPSC-NS/PC transplantation by performing modified mixed lymphocyte reaction (MLR) assays with hiPSC-NS/PCs. Compared to fetus-derived NS/PCs, the expression levels of human leukocyte antigen-antigen D related (HLA-DR) and co-stimulatory molecules on hiPSC-NS/PCs were significantly low, even with the addition of tumor necrosis factor-α (TNFα) and/or interferon-γ (IFNγ) to mimic the inflammatory environment surrounding transplanted hiPSC-NS/PCs in injured tissues. Interestingly, both the allogeneic HLA-matched and the HLA-mismatched responses were similarly low in the modified MLR assay. Furthermore, the autologous response was also similar to the allogeneic response. hiPSC-NS/PCs suppressed the proliferative responses of allogeneic HLA-mismatched peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Thus, the low antigen-presenting function and immunosuppressive effects of hiPSC-NS/PCs result in a depressed immune response, even in an allogeneic HLA-mismatched setting. It is crucial to verify whether these in vitro results are reproducible in a clinical setting. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

IWGT report on quantitative approaches to genotoxicity risk ...

EPA Pesticide Factsheets

This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose–response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clast

Increase in dermcidin-derived peptides in sweat of patients with atopic eczema caused by a humorous video.

PubMed

Kimata, Hajime

2007-01-01

Dermcidin (DCD)-derived peptide is an antimicrobial peptide produced by the sweat glands. However, the levels of DCD-derived peptide in sweat were decreased in patients with atopic eczema (AE). The effect of viewing a humorous video on the levels of DCD-derived peptide was studied. Twenty patients with AE viewed an 87-min humorous video (Modern Times, featuring Charlie Chaplin). Just before and immediately after viewing, sweat was collected, and the levels of DCD-derived peptide and total protein in sweat were measured. Viewing a humorous video increased the levels of DCD-derived peptide without affecting the levels of total protein in sweat. Viewing a humorous video increased DCD-derived peptide in sweat of patients with AE, and thus, it may be helpful in the treatment of skin infection of AE.

Effect of photodynamic therapy using benzoporphyrin derivative on the cutaneous immune response

NASA Astrophysics Data System (ADS)

Simkin, Guillermo O.; Obochi, Modestus; Hunt, David W. C.; Chan, Agnes H.; Levy, Julia G.

1995-05-01

In this study, the effect of transdermal photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD) on the development of the immunologically mediated contact hypersensitivity (CHS) response against the hapten dinitrofluorobenzene (DNFB) and on the duration of skin allograft acceptance has been evaluated. In the CHS model it was found that the treatment of hairless strain mice with whole-body transdermal PDT using BPD (1 mg/kg) and LED light (15 J/cm2) resulted in a profound suppression of the CHS reaction if treatment was applied either 48 or 24 hours prior or up to 72 hours after sensitization of abdominal skin with DNFB. Less inhibition of the CHS response was observed if PDT was given one day before the ear challenge with DNFB which was applied 5 days following the initial DNFB sensitization. However, DNFB-exposed, PDT-treated mice retained the capacity to respond maximally to the unrelated contact sensitizer oxazolone. These results are consistent with other models of experimentally induced immune tolerance. allogeneic skin graft studies demonstrated that pretreatment of skin with BPD and light, at levels that did not cause significant tissue damage, significantly enhanced the length of engraftment. Using a separate protocol, photodynamic treatment of recipient mice at various times after transplant had no significant effect on allograft acceptance. Irradiation of skin in the presence of BPD may significantly inhibit the initiation of certain immunological responses within these tissues.

Antithetical effects of hemicellulase-treated Agaricus blazei on the maturation of murine bone-marrow-derived dendritic cells

PubMed Central

Kawamura, Masaki; Kasai, Hirotake; He, Limin; Deng, Xuewen; Yamashita, Atsuya; Terunuma, Hiroshi; Horiuchi, Isao; Tanabe, Fuminori; Ito, Masahiko

2005-01-01

We report the effects of hemicellulase-treated Agaricus blazei (ABH) on the maturation of bone-marrow-derived dendritic cells (BMDCs). ABH activated immature BMDCs, inducing up-regulation of surface molecules, such as CD40, CD80 and major histocompatibility complex class I antigens, as well as inducing allogeneic T-cell proliferation and T helper type 1 cell development. However, unlike lipopolysaccharide (LPS), ABH did not stimulate the BMDCs to produce proinflammatory cytokines, such as interleukin-12 (IL-12) p40, tumour necrosis factor-α, or IL-1β. In addition, ABH suppressed LPS-induced DC responses. Pretreatment of DCs with ABH markedly reduced the levels of LPS-induced cytokine secretion, while only slightly decreasing up-regulation of the surface molecules involved in maturation. ABH also had a significant impact on peptidoglycan-induced or CpG oligodeoxynucleotide-induced IL-12p40 production in DCs. The inhibition of LPS-induced responses was not associated with a cytotoxic effect of ABH nor with an anti-inflammatory effect of IL-10. However, ABH decreased NF-κB-induced reporter gene expression in LPS-stimulated J774.1 cells. Interestingly, DCs preincubated with ABH and then stimulated with LPS augmented T helper type 1 responses in culture with allogeneic T cells as compared to LPS-stimulated but non-ABH-pretreated DCs. These observations suggest that ABH regulates DC-mediated responses. PMID:15720441

A novel anti-inflammatory role for spleen-derived interleukin-10 in obesity-induced inflammation in white adipose tissue and liver.

PubMed

Gotoh, Koro; Inoue, Megumi; Masaki, Takayuki; Chiba, Seiichi; Shimasaki, Takanobu; Ando, Hisae; Fujiwara, Kansuke; Katsuragi, Isao; Kakuma, Tetsuya; Seike, Masataka; Sakata, Toshiie; Yoshimatsu, Hironobu

2012-08-01

Obesity is associated with systemic low-grade inflammation and obesity-related metabolic disorders. Considering that obesity decreases the expression of proinflammatory cytokines in the spleen, we assessed the role of interleukin (IL)-10, an anti-inflammatory cytokine produced by the spleen, in the pathogenesis of obesity. Changes in obesity-related pathogenesis, including inflammatory responses in multiple organs, were assessed after systemic administration of exogenous IL-10 to splenectomy (SPX)-treated obese wild-type and IL-10 knockout (IL-10KO) mice. Obesity resulted in the inability of the spleen to synthesize cytokines, including IL-10, and proinflammatory cytokines in obesity are then likely to emerge from tissues other than the spleen because serum levels of IL-10, but not proinflammatory cytokines, decreased despite the expression of these cytokines in the spleen being reduced in high fat-induced obese mice. SPX aggravated the inflammatory response in white adipose tissue (WAT) and the liver and suppressed adiposity in WAT. However, it accentuated adiposity in the liver. These SPX-induced changes were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on the inflammatory responses in WAT and the liver of IL-10KO mice. These data show the role of spleen-derived IL-10 in diet-induced changes as a result of inflammatory responses in WAT and the liver.

Flight-determined derivatives and dynamic characteristics for the HL-10 lifting body vehicle at subsonic and transonic Mach numbers

NASA Technical Reports Server (NTRS)

Strutz, L. W.

1972-01-01

The HL-10 lifting body stability and control derivatives were determined by using an analog-matching technique and compared with derivatives obtained from wind-tunnel results. The flight derivatives were determined as a function of angle of attack for a subsonic configuration at Mach 0.7 and for a transonic configuration at Mach 0.7, 0.9, and 1.2. At an angle of attack of 14 deg, data were obtained for a Mach number range from 0.6 to 1.4. The flight and wind-tunnel derivatives were in general agreement, with the possible exception of the longitudinal and lateral damping derivatives. Some differences were noted between the vehicle dynamic response characteristics calculated from flight-determined derivatives and those predicted by the wind-tunnel results. However, the only difference the pilots noted between the response of the vehicle in flight and the response of a simulator programed with wind-tunnel-predicted data was that the damping generally was higher in the flight vehicle.

Peracetylated hydroxytyrosol, a new hydroxytyrosol derivate, attenuates LPS-induced inflammatory response in murine peritoneal macrophages via regulation of non-canonical inflammasome, Nrf2/HO1 and JAK/STAT signaling pathways.

PubMed

Montoya, Tatiana; Aparicio-Soto, Marina; Castejón, María Luisa; Rosillo, María Ángeles; Sánchez-Hidalgo, Marina; Begines, Paloma; Fernández-Bolaños, José G; Alarcón-de-la-Lastra, Catalina

2018-03-18

The present study was designed to investigate the anti-inflammatory effects of a new derivative of hydroxytyrosol (HTy), peracetylated hydroxytyrosol (Per-HTy), compared with its parent, HTy, on lipopolysaccharide (LPS)-stimulated murine macrophages as well as potential signaling pathways involved. In particular, we attempted to characterize the role of the inflammasome underlying Per-HTy possible anti-inflammatory effects. Isolated murine peritoneal macrophages were treated with HTy or its derivative in the presence or absence of LPS (5 μg/ml) for 18 h. Cell viability was determined using sulforhodamine B (SRB) assay. Nitric oxide (NO) production was analyzed by Griess method. Production of pro-inflammatory cytokines was evaluated by enzyme-linked immunosorbent assay (ELISA) and inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway (STAT3), haem oxigenase 1 (HO1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and mitogen-activated protein kinases (MAPKs) activation was determined by Western blot. Per-HTy significantly reduced the levels of NO and pro-inflammatory cytokines as well as both COX-2 and iNOS expressions. Furthermore, Per-HTy treatment inhibited STAT3 and increased Nrf2 and HO1 protein levels in murine macrophages exposed to LPS. In addition, Per-HTy anti-inflammatory activity was related with an inhibition of non-canonical nucleotide binding domain (NOD)-like receptor (NLRP3) inflammasome pathways by decreasing pro-inflammatory interleukin (IL)-1β and IL-18 cytokine levels as consequence of regulation of cleaved caspase-11 enzyme. These results support that this new HTy derivative may offer a new promising nutraceutical therapeutic strategy in the management of inflammatory-related pathologies. Copyright © 2018. Published by Elsevier Inc.

Photometry with FORS

NASA Astrophysics Data System (ADS)

Freudling, W.; Møller, P.; Patat, F.; Moehler, S.; Romaniello, M.; Jehin, E.; O'Brien, K.; Izzo, C.; Pompei, E.

Photometric calibration observations are routinely carried out with all ESO imaging cameras in every clear night. The nightly zeropoints derived from these observations are accurate to about 10%. Recently, we have started the FORS Absolute Photometry Project (FAP) to investigate, if and how percent-level absolute photometric accuracy can be achieved with FORS1, and how such photometric calibration can be offered to observers. We found that there are significant differences between the sky-flats and the true photometric response of the instrument which partially depend on the rotator angle. A second order correction to the sky-flat significantly improves the relative photometry within the field. We demonstrate the feasibility of percent level photometry and describe the calibrations necessary to achieve that level of accuracy.

Dynamic contrast-enhanced (DCE) MRI derived kinetic perfusion indices may help predicting seizure control in single calcified neurocysticercosis.

PubMed

Singh, Alok Kumar; Garg, Ravindra Kumar; Gupta, Rakesh Kumar; Malhotra, Hardeep Singh; Agrawal, Gaurav Raj; Husain, Nuzhat; Pandey, Chandra Mani; Sahoo, Prativa; Kumar, Neeraj

2018-06-01

The factors responsible for seizure recurrence in patients with Solitary calcified neurocysticercosis (NCC) are not well understood. Blood brain barrier (BBB) breach may be associated with seizure recurrence. Dynamic contrast enhanced (DCE) MRI derived indices k ep, k trans and v e are useful in quantifying BBB permeability. In this study, we assessed the possible role of DCE-MRI and matrix metalloproteinases (MMP)-9 levels in predicting seizure recurrence. In this prospective-observational study, patients with new-onset seizures and a solitary calcified NCC were included. DCE-MRI was done to quantify BBB integrity. DCE-MRI parameters were measured as k ep , k trans and v e . MMP-9 levels were estimated. Patients were followed for 1 year, when DCE-MRI and MMP-9 levels were repeated. Patients were classified into two groups on the basis of seizure recurrence, which was defined as the recurrence of an episode of seizure at least 1 week after the initiation of the anti-epileptic drugs. Logistic regression analysis was done. At 1-year of follow up, 8 out of 32 patients had seizure recurrence. Baseline DCE-MRI derived k ep (p = 0.015) and MMP-9 levels (p = 0.019) were significantly higher in the seizure "recurrence" group compared with the "no recurrence" group. On within-group analysis, a significant increase in k ep (p = 0.012), v e (p = 0.012), and MMP-9 levels (p = 0.017) was observed in the seizure "recurrence" group while a decrease was seen in v e and MMP-9 levels in the "no recurrence" group. Higher values of DCE-MRI indices and MMP-9 levels, with a corresponding trend in the follow-up, can be useful in predicting lesions with a higher propensity for seizure recurrence. Copyright © 2018 Elsevier Inc. All rights reserved.

Four-point bending protocols to study the effects of dynamic strain in osteoblastic cells in vitro.

PubMed

Galea, Gabriel L; Price, Joanna S

2015-01-01

Strain engendered within bone tissue by mechanical loading of the skeleton is a major influence on the processes of bone modeling and remodeling and so a critical determinant of bone mass and architecture. The cells best placed to respond to strain in bone tissue are the resident osteocytes and osteoblasts. To address the mechanisms of strain-related responses in osteoblast-like cells, our group uses both in vivo and in vitro approaches, including a system of four-point bending of the substrate on which cells are cultured. A range of cell lines can be studied using this system but we routinely compare their responses to those in primary cultures of osteoblast-like cells derived from explants of mouse long bones. These cells show a range of well-characterized responses to physiological levels of strain, including increased proliferation, which in vivo is a feature of the osteogenic response.

Dyadic confirmatory factor analysis of the inflammatory bowel disease family responsibility questionnaire.

PubMed

Greenley, Rachel Neff; Reed-Knight, Bonney; Blount, Ronald L; Wilson, Helen W

2013-09-01

Evaluate the factor structure of youth and maternal involvement ratings on the Inflammatory Bowel Disease Family Responsibility Questionnaire, a measure of family allocation of condition management responsibilities in pediatric inflammatory bowel disease. Participants included 251 youth aged 11-18 years with inflammatory bowel disease and their mothers. Item-level descriptive analyses, subscale internal consistency estimates, and confirmatory factor analyses of youth and maternal involvement were conducted using a dyadic data-analytic approach. Results supported the validity of 4 conceptually derived subscales including general health maintenance, social aspects, condition management tasks, and nutrition domains. Additionally, results indicated adequate support for the factor structure of a 21-item youth involvement measure and strong support for a 16-item maternal involvement measure. Additional empirical support for the validity of the Inflammatory Bowel Disease Family Responsibility Questionnaire was provided. Future research to replicate current findings and to examine the measure's clinical utility is warranted.

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

Kateley, J.R.; Patel, C.B. Friedman, H.

The immune response at the level of individual immunocytes to the somatic lipopolysaccharide antigen derived from whole Vibrio cholerae and to the purified protein exotoxin from this organism were studied in terms of the role of T- and B-lymphocytes. By adoptive cell transfer studies with irradiated recipient mice, it was shown that normal spleen cells from normal syngeneic mice could readily transfer the capability of responding to both types of cholera antigens. However, when the spleen cells were depleted of T-cells with anti-theta serum and complement, antibody responsiveness to the LPS antigen, but not the exotoxin, could be achieved inmore » recipients. Furthermore, by appropriate transfer of either bone marrow, thymus, or thymus-marrow cell mixtures to irradiated mice, it was shown that the response to the cholera somatic antigen was relatively independent of thymus cells, whereas the response to exotoxin required ''helper'' T-cells.« less

Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer.

PubMed

Wesolowski, Robert; Duggan, Megan C; Stiff, Andrew; Markowitz, Joseph; Trikha, Prashant; Levine, Kala M; Schoenfield, Lynn; Abdel-Rasoul, Mahmoud; Layman, Rachel; Ramaswamy, Bhuvaneswari; Macrae, Erin R; Lustberg, Maryam B; Reinbolt, Raquel E; Mrozek, Ewa; Byrd, John C; Caligiuri, Michael A; Mace, Thomas A; Carson, William E

2017-11-01

This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were <1. Mean G-MDSC% and 95% confidence intervals were 0.88 (0.23-1.54), 5.07 (2.45-7.69), 9.32 (4.02-14.61) and 1.97 (0.53-3.41) at draws 1-4. The increase in G-MDSC by draw 3 was significant (p < 0.0001) in all breast cancer types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14-2.16) versus patients with no pCR (2.71; 95% CI 0-5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.

Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies.

PubMed

Lee, Seung-Hee; Hao, Ergeng; Savinov, Alexei Y; Geron, Ifat; Strongin, Alex Y; Itkin-Ansari, Pamela

2009-04-15

Islet transplantation is limited by the need for chronic immunosuppression and the paucity of donor tissue. As new sources of human beta-cells are developed (e.g., stem cell-derived tissue), transplanting them in a durable device could obviate the need for immunosuppression, while also protecting the patient from any risk of tumorigenicity. Here, we studied (1) the survival and function of encapsulated human beta-cells and their progenitors and (2) the engraftment of encapsulated murine beta-cells in allo- and autoimmune settings. Human islets and human fetal pancreatic islet-like cell clusters were encapsulated in polytetrafluorethylene devices (TheraCyte) and transplanted into immunodeficient mice. Graft survival and function was measured by immunohistochemistry, circulating human C-peptide levels, and blood glucose levels. Bioluminescent imaging was used to monitor encapsulated neonatal murine islets. Encapsulated human islet-like cell clusters survived, replicated, and acquired a level of glucose responsive insulin secretion sufficient to ameliorate hyperglycemia in diabetic mice. Bioluminescent imaging of encapsulated murine neonatal islets revealed a dynamic process of cell death followed by regrowth, resulting in robust long-term allograft survival. Further, in the non-obese diabetic (NOD) mouse model of type I diabetes, encapsulated primary beta-cells ameliorated diabetes without stimulating a detectable T-cell response. We demonstrate for the first time that human beta-cells function is compatible with encapsulation in a durable, immunoprotective device. Moreover, our study suggests that encapsulation of beta-cells before terminal differentiation will be a successful approach for new cell-based therapies for diabetes, such as those derived from stem cells.

Serum derivative of reactive oxygen metabolites (d-ROMs) in pediatric hemato-oncological patients with neutropenic fever.

PubMed

Nishikawa, Takuro; Okamoto, Yasuhiro; Kodama, Yuichi; Tanabe, Takayuki; Shinkoda, Yuichi; Kawano, Yoshifumi

2010-07-15

Early markers for predicting the severity of neutropenic fever (NF) in patients with hemato-oncological patients have not yet been established. Reactive oxygen species are known to play an important role in the antimicrobial function of neutrophils. The aim of this study was to determine the serum levels of derivatives of reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) levels in these patients, and to investigate the associations between these levels and the severity of NF. Twenty-seven pediatric hemato-oncological patients were enroled in this prospective study. Their median age was 10 years (range 1-19). Laboratory samples for C-reactive protein (CRP), d-ROMs, and BAP were collected at the onset of NF. The Free Radical Analytical System 4(R) was used to measure levels of d-ROMs and BAP. A total 36 NF episodes were evaluated. Levels of d-ROMs in NF patients with systemic inflammatory response syndrome (SIRS, n = 7) were significantly lower than those in subjects without SIRS (n = 29; 197.6 vs. 314.1 U.CARR, P = 0.017). There were no statistically significant differences in CRP, BAP, WBC count, or neutrophil count at the onset. The peak levels of CRP were significantly higher in patients with SIRS than in those without SIRS (23.9 vs. 6.1 mg/dl, P = 0.0003). Patients with low level of d-ROMs at the onset of NF should be observed stringently since they possibly have severe NF.

Molecular-Level Analysis of Shock-Wave Physics and Derivation of the Hugoniot Relations for Fused Silica

DTIC Science & Technology

2012-06-01

product manufacturing are associated with relatively low costs; and ( c ) ballistic and blast impact survivability of ceramic glasses can be substantially...19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT unclassified c . THIS PAGE unclassified Standard Form 298 (Rev. 8-98...b) continuum-material approximations (Ref 5–7, 15–18); and ( c ) meso-length scale models based on explicit representation of cracks (Ref 19, 20

Ion-cyclotron-frequency stabilization of internal kink mode and sawtooth oscillations in tokamaks

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

Litwin, C.

It is proposed that the ponderomotive force due to applied ion-cyclotron resonance-frequency waves can stabilize the internal kink mode in tokamaks. The sufficient stability criterion is derived and the necessary power estimated. It is concluded that at the rf power level, present in the Joint European Torus experiment, the ponderomotive force effects are significant and may be responsible for the modification of the sawtooth activity observed in recent experiments.

Ground-water appraisal of the Pineland Sands area, central Minnesota

USGS Publications Warehouse

Helgesen, J.O.

1977-01-01

Results of model analysis show that present development (withdrawals totaling 3.3 cubic feet per second) has no significant effect on the aquifer system. Simulations of hypothetical withdrawals of 60 to 120 cubic feet per second resulted in computed water-table declines as great as 12 feet in places. Most pumpage is derived from intercepted base flow to streams, thus reducing streamflow. Similarly, some lake levels can be expected to decline in response to nearby intensive development.

Stimulatory effect of clebopride on human prolactin secretion.

PubMed

Perez-Lopez, F R; Legido, A; Sisskin, M; Abos, M D

1980-11-01

Serum levels of prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in normally cycling women and normal men before and after oral admiministration of 1 mg of clebopride, a derivative of procainamide used in the treatment of gastrointestinal diseases. Clebopride produced a significant increase (P < 0.001) in serum PRL to a 6-fold peak as compared with basal levels. After 240 minutes the levels remained significantly higher (P < 0.05) than the mean basal level at -30 and 0 minutes. No significant effects of clebopride were noted upon the circulating levels of LH and FSH. The peak PRL response to clebopride was unaffected by pretreatment with 100 mg of nomifensine, although the secretory area from 120 to 210 minutes after clebopride was greater (P < 0.05) in the nomifensine-treated group than in the control experiment. When 5 mg of bromocriptine were given before clebopride, the PRL response was completely abolished as compared with the control experiment (P < 0.001). Our data provide new evidence that dopaminergic receptors of the adeylate cyclase system are involved in the regulation of PRL secretion, acting at the pituitary level rather than acting on the hypothalamus. The PRL-releasing activity of clebopride could be the explanation for the occasional menstrual disorders and galactorrhea registered in some cases of long-term treatment.

Optimization and formulation design of gels of Diclofenac and Curcumin for transdermal drug delivery by Box-Behnken statistical design.

PubMed

Chaudhary, Hema; Kohli, Kanchan; Amin, Saima; Rathee, Permender; Kumar, Vikash

2011-02-01

The aim of this study was to develop and optimize a transdermal gel formulation for Diclofenac diethylamine (DDEA) and Curcumin (CRM). A 3-factor, 3-level Box-Behnken design was used to derive a second-order polynomial equation to construct contour plots for prediction of responses. Independent variables studied were the polymer concentration (X(1)), ethanol (X(2)) and propylene glycol (X(3)) and the levels of each factor were low, medium, and high. The dependent variables studied were the skin permeation rate of DDEA (Y(1)), skin permeation rate of CRM (Y(2)), and viscosity of the gels (Y(3)). Response surface plots were drawn, statistical validity of the polynomials was established to find the compositions of optimized formulation which was evaluated using the Franz-type diffusion cell. The permeation rate of DDEA increased proportionally with ethanol concentration but decreased with polymer concentration, whereas the permeation rate of CRM increased proportionally with polymer concentration. Gels showed a non-Fickian super case II (typical zero order) and non-Fickian diffusion release mechanism for DDEA and CRM, respectively. The design demonstrated the role of the derived polynomial equation and contour plots in predicting the values of dependent variables for the preparation and optimization of gel formulation for transdermal drug release. Copyright © 2010 Wiley-Liss, Inc.

Kinetic Inductance Detectors for Measuring the Polarization of the Cosmic Microwave Background

NASA Astrophysics Data System (ADS)

Flanigan, Daniel

Kinetic inductance detectors (KIDs) are superconducting thin-film microresonators that are sensitive photon detectors. These detectors are a candidate for the next generation of experiments designed to measure the polarization of the cosmic microwave background (CMB). I discuss the basic theory needed to understand the response of a KID to light, focusing on the dynamics of the quasiparticle system. I derive an equation that describes the dynamics of the quasiparticle number, solve it in a simplified form not previously published, and show that it can describe the dynamic response of a detector. Magnetic flux vortices in a superconducting thin film can be a significant source of dissipation, and I demonstrate some techniques to prevent their formation. Based on the presented theory, I derive a corrected version of a widely-used equation for the quasiparticle recombination noise in a KID. I show that a KID consisting of a lumped-element resonator can be sensitive enough to be limited by photon noise, which is the fundamental limit for photometry, at a level of optical loading below levels in ground-based CMB experiments. Finally, I describe an ongoing project to develop multichroic KID pixels that are each sensitive to two linear polarization states in two spectral bands, intended for the next generation of CMB experiments. I show that a prototype 23-pixel array can detect millimeter-wave light, and present characterization measurements of the detectors.

Small RNA Profiling in Dengue Virus 2-Infected Aedes Mosquito Cells Reveals Viral piRNAs and Novel Host miRNAs.

PubMed

Miesen, Pascal; Ivens, Alasdair; Buck, Amy H; van Rij, Ronald P

2016-02-01

In Aedes mosquitoes, infections with arthropod-borne viruses (arboviruses) trigger or modulate the expression of various classes of viral and host-derived small RNAs, including small interfering RNAs (siRNAs), PIWI interacting RNAs (piRNAs), and microRNAs (miRNAs). Viral siRNAs are at the core of the antiviral RNA interference machinery, one of the key pathways that limit virus replication in invertebrates. Besides siRNAs, Aedes mosquitoes and cells derived from these insects produce arbovirus-derived piRNAs, the best studied examples being viruses from the Togaviridae or Bunyaviridae families. Host miRNAs modulate the expression of a large number of genes and their levels may change in response to viral infections. In addition, some viruses, mostly with a DNA genome, express their own miRNAs to regulate host and viral gene expression. Here, we perform a comprehensive analysis of both viral and host-derived small RNAs in Aedes aegypti Aag2 cells infected with dengue virus 2 (DENV), a member of the Flaviviridae family. Aag2 cells are competent in producing all three types of small RNAs and provide a powerful tool to explore the crosstalk between arboviral infection and the distinct RNA silencing pathways. Interestingly, besides the well-characterized DENV-derived siRNAs, a specific population of viral piRNAs was identified in infected Aag2 cells. Knockdown of Piwi5, Ago3 and, to a lesser extent, Piwi6 results in reduction of vpiRNA levels, providing the first genetic evidence that Aedes PIWI proteins produce DENV-derived small RNAs. In contrast, we do not find convincing evidence for the production of virus-derived miRNAs. Neither do we find that host miRNA expression is strongly changed upon DENV2 infection. Finally, our deep-sequencing analyses detect 30 novel Aedes miRNAs, complementing the repertoire of regulatory small RNAs in this important vector species.

Small RNA Profiling in Dengue Virus 2-Infected Aedes Mosquito Cells Reveals Viral piRNAs and Novel Host miRNAs

PubMed Central

Miesen, Pascal; Ivens, Alasdair; Buck, Amy H.; van Rij, Ronald P.

2016-01-01

In Aedes mosquitoes, infections with arthropod-borne viruses (arboviruses) trigger or modulate the expression of various classes of viral and host-derived small RNAs, including small interfering RNAs (siRNAs), PIWI interacting RNAs (piRNAs), and microRNAs (miRNAs). Viral siRNAs are at the core of the antiviral RNA interference machinery, one of the key pathways that limit virus replication in invertebrates. Besides siRNAs, Aedes mosquitoes and cells derived from these insects produce arbovirus-derived piRNAs, the best studied examples being viruses from the Togaviridae or Bunyaviridae families. Host miRNAs modulate the expression of a large number of genes and their levels may change in response to viral infections. In addition, some viruses, mostly with a DNA genome, express their own miRNAs to regulate host and viral gene expression. Here, we perform a comprehensive analysis of both viral and host-derived small RNAs in Aedes aegypti Aag2 cells infected with dengue virus 2 (DENV), a member of the Flaviviridae family. Aag2 cells are competent in producing all three types of small RNAs and provide a powerful tool to explore the crosstalk between arboviral infection and the distinct RNA silencing pathways. Interestingly, besides the well-characterized DENV-derived siRNAs, a specific population of viral piRNAs was identified in infected Aag2 cells. Knockdown of Piwi5, Ago3 and, to a lesser extent, Piwi6 results in reduction of vpiRNA levels, providing the first genetic evidence that Aedes PIWI proteins produce DENV-derived small RNAs. In contrast, we do not find convincing evidence for the production of virus-derived miRNAs. Neither do we find that host miRNA expression is strongly changed upon DENV2 infection. Finally, our deep-sequencing analyses detect 30 novel Aedes miRNAs, complementing the repertoire of regulatory small RNAs in this important vector species. PMID:26914027

Fatty Acid Synthase Cooperates with Glyoxalase 1 to Protect against Sugar Toxicity

PubMed Central

Garrido, Damien; Rubin, Thomas; Poidevin, Mickael; Maroni, Brigitte; Le Rouzic, Arnaud; Parvy, Jean-Philippe; Montagne, Jacques

2015-01-01

Fatty acid (FA) metabolism is deregulated in several human diseases including metabolic syndrome, type 2 diabetes and cancers. Therefore, FA-metabolic enzymes are potential targets for drug therapy, although the consequence of these treatments must be precisely evaluated at the organismal and cellular levels. In healthy organism, synthesis of triacylglycerols (TAGs)—composed of three FA units esterified to a glycerol backbone—is increased in response to dietary sugar. Saturation in the storage and synthesis capacity of TAGs is associated with type 2 diabetes progression. Sugar toxicity likely depends on advanced-glycation-end-products (AGEs) that form through covalent bounding between amine groups and carbonyl groups of sugar or their derivatives α-oxoaldehydes. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that is derived from glycolysis through a non-enzymatic reaction. Glyoxalase 1 (Glo1) works to neutralize MG, reducing its deleterious effects. Here, we have used the power of Drosophila genetics to generate Fatty acid synthase (FASN) mutants, allowing us to investigate the consequence of this deficiency upon sugar-supplemented diets. We found that FASN mutants are lethal but can be rescued by an appropriate lipid diet. Rescued animals do not exhibit insulin resistance, are dramatically sensitive to dietary sugar and accumulate AGEs. We show that FASN and Glo1 cooperate at systemic and cell-autonomous levels to protect against sugar toxicity. We observed that the size of FASN mutant cells decreases as dietary sucrose increases. Genetic interactions at the cell-autonomous level, where glycolytic enzymes or Glo1 were manipulated in FASN mutant cells, revealed that this sugar-dependent size reduction is a direct consequence of MG-derived-AGE accumulation. In summary, our findings indicate that FASN is dispensable for cell growth if extracellular lipids are available. In contrast, FA-synthesis appears to be required to limit a cell-autonomous accumulation of MG-derived-AGEs, supporting the notion that MG is the most deleterious α-oxoaldehyde at the intracellular level. PMID:25692475

78 FR 32191 - Derivatives

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-29

...This proposed rule permits credit unions to engage in limited derivatives activities for the purpose of mitigating interest rate risk. This proposed rule applies to federal credit unions and any federally insured, state-chartered credit unions that are permitted under applicable state law to engage in derivatives transactions. It requires any credit union seeking derivatives authority to submit an application for one of two levels of authority. Level I and Level II authority differ on the permissible levels of transactions as well as the application, expertise, and systems requirements associated with operating a derivatives program.

Shikonin derivatives inhibited LPS-induced NOS in RAW 264.7 cells via downregulation of MAPK/NF-kappaB signaling.

PubMed

Cheng, Yu Wen; Chang, Ching Yi; Lin, Kou Lung; Hu, Chien Ming; Lin, Cheng Hui; Kang, Jaw Jou

2008-11-20

Shikonin/alkannin (SA) derivatives, analogs of naphthoquinone pigments, are the major components of root extracts of the Chinese medicinal herb (Lithospermum erythrorhizon; LE) and widely distributed in several folk medicines. In the present study, the effect and the underline molecular mechanism of shikonin derivatives isolated from root extracts of Lithospermum euchroma on lipopolysaccharide (LPS)-induced inflammatory response were investigated. Effects of five SA derivatives, including SA, acetylshikonin, beta,beta-dimethylacrylshikonin, 5,8-dihydroxy-1.4-naphthoquinone, and 1,4-naphthoquinone on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in mouse macrophage RAW264.7 cells were examined. Data suggested that SA derivatives inhibited LPS-induced NO and PGE(2) production, and iNOS protein expression. RT-PCR analysis showed that SA derivatives diminished LPS-induced iNOS mRNA expression. Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in LPS-stimulated RAW 264.7 cells was concentration-dependently suppressed by SA derivatives. SA inhibited NF-kappaB activation by prevention of the degradation of inhibitory factor-kappaB and p65 level in nuclear fractions induced by LPS. Taken together, these results suggest that the anti-inflammatory properties of SA derivatives might result from inhibition of iNOS protein expression through the downregulation of NF-kappaB activation via suppression of phosphorylation of ERK, in LPS-stimulated RAW 264.7 cells.

(U) Second-Order Sensitivity Analysis of Uncollided Particle Contributions to Radiation Detector Responses Using Ray-Tracing

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

Favorite, Jeffrey A.

The Second-Level Adjoint Sensitivity System (2nd-LASS) that yields the second-order sensitivities of a response of uncollided particles with respect to isotope densities, cross sections, and source emission rates is derived in Refs. 1 and 2. In Ref. 2, we solved problems for the uncollided leakage from a homogeneous sphere and a multiregion cylinder using the PARTISN multigroup discrete-ordinates code. In this memo, we derive solutions of the 2nd-LASS for the particular case when the response is a flux or partial current density computed at a single point on the boundary, and the inner products are computed using ray-tracing. Both themore » PARTISN approach and the ray-tracing approach are implemented in a computer code, SENSPG. The next section of this report presents the equations of the 1st- and 2nd-LASS for uncollided particles and the first- and second-order sensitivities that use the solutions of the 1st- and 2nd-LASS. Section III presents solutions of the 1st- and 2nd-LASS equations for the case of ray-tracing from a detector point. Section IV presents specific solutions of the 2nd-LASS and derives the ray-trace form of the inner products needed for second-order sensitivities. Numerical results for the total leakage from a homogeneous sphere are presented in Sec. V and for the leakage from one side of a two-region slab in Sec. VI. Section VII is a summary and conclusions.« less

Aromatic inhibitors derived from ammonia-pretreated lignocellulose hinder bacterial ethanologenesis by activating regulatory circuits controlling inhibitor efflux and detoxification

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

Keating, David H.; Zhang, Yaoping; Ong, Irene M.

2014-08-13

Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass), phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH). To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and proteinmore » levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(P)H, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation, whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.« less

Influence of rpoS mutations on the response of Salmonella enterica serovar Typhimurium to solar radiation.

PubMed

Oppezzo, Oscar J; Costa, Cristina S; Pizarro, Ramón A

2011-01-10

Salmonella enterica serovar Typhimurium is an important pathogen, and exhibits considerable resistance to the lethal effects of solar radiation. To evaluate the involvement of the RpoS transcription factor in the defense mechanisms of this organism, the sunlight response of a wild type strain (ATCC14028) was compared with that of an rpoS mutant, which exhibited increased sensitivity. Kinetics of cell death was complex in both strains, probably due to the presence of a variety of targets for the radiation. When ultraviolet radiation was excluded from the incident sunlight, lethal effects were abolished independently of the allelic state of rpoS. Reduction of oxygen concentration in the irradiation medium provided moderate protection to ATCC14028, but notably improved survival of the mutant. Similar assays were developed with another S. enterica strain (DA1468), which is a derivative of strain LT2 and produces low levels of RpoS. In this strain the loss of viability reveals the dependence on solar ultraviolet and oxygen concentration found for ATCC14028, but radiation resistance was slightly reduced. Increased sensitivity was observed in an rpoS mutant derived from DA1468, indicating that RpoS functions related to photoprotection are conserved in this strain. In addition, notable differences in the shape of the survival curves obtained for mutants derived from ATCC14028 and DA1468 were found, suggesting that genes beyond RpoS control are relevant in the sunlight response of these mutants. Copyright © 2010 Elsevier B.V. All rights reserved.

Adaptation responses of individuals to environmental changes in the ciliate Euplotes crassus

NASA Astrophysics Data System (ADS)

Kim, Se-Joo; Kim, Jin-Hyoung; Ju, Se-Jong

2017-03-01

Although the response unit of living organisms to environmental changes is at the individual level, most experiments on the adaptation responses of ciliates have been conducted in batches, comprising multiple-individuals, due to their microscopic size. However, here, we confirmed that individuals undergo different division cycles in monocultures of Euplotes crassus. They also exhibited transcript variations of 4.63-fold in SSU and of 22.78- fold in Hsp70. Additionally, in salt-stressed E. crassus individuals, SSU transcripts of individuals varied by 6.92-fold at 27 psu, 8.69- fold at 32 psu, and 2.51-fold at 37 psu. However, the maximum difference in Hsp70 was only 4.23-fold under all conditions. These results suggest there may be different biological rhythms even in siblings derived from the same parent. It can also be inferred that various environmental factors have different effects on different E. crassus individuals. Therefore, to elucidate relationships between organism adaptations and environmental changes, studies at the individual level should be conducted with multi-individual approaches.

Marine CDOM accumulation during a coastal Arctic mesocosm experiment: No response to elevated pCO2 levels

NASA Astrophysics Data System (ADS)

Pavlov, Alexey K.; Silyakova, Anna; Granskog, Mats A.; Bellerby, Richard G. J.; Engel, Anja; Schulz, Kai G.; Brussaard, Corina P. D.

2014-06-01

A large-scale multidisciplinary mesocosm experiment in an Arctic fjord (Kongsfjorden, Svalbard; 78°56.2'N) was used to study Arctic marine food webs and biogeochemical elements cycling at natural and elevated future carbon dioxide (CO2) levels. At the start of the experiment, marine-derived chromophoric dissolved organic matter (CDOM) dominated the CDOM pool. Thus, this experiment constituted a convenient case to study production of autochthonous CDOM, which is typically masked by high levels of CDOM of terrestrial origin in the Arctic Ocean proper. CDOM accumulated during the experiment in line with an increase in bacterial abundance; however, no response was observed to increased pCO2 levels. Changes in CDOM absorption spectral slopes indicate that bacteria were most likely responsible for the observed CDOM dynamics. Distinct absorption peaks (at 330 and 360 nm) were likely associated with mycosporine-like amino acids (MAAs). Due to the experimental setup, MAAs were produced in absence of ultraviolet exposure providing evidence for MAAs to be considered as multipurpose metabolites rather than simple photoprotective compounds. We showed that a small increase in CDOM during the experiment made it a major contributor to total absorption in a range of photosynthetically active radiation (PAR, 400-700 nm) and, therefore, is important for spectral light availability and may be important for photosynthesis and phytoplankton groups composition in a rapidly changing Arctic marine ecosystem.

Active CREB1 promotes a malignant TGFβ2 autocrine loop in glioblastoma.

PubMed

Rodón, Laura; Gonzàlez-Juncà, Alba; Inda, María del Mar; Sala-Hojman, Ada; Martínez-Sáez, Elena; Seoane, Joan

2014-10-01

In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. ©2014 American Association for Cancer Research.

In vitro exposure to isoprene-derived secondary organic aerosol by direct deposition and its effects on COX-2 and IL-8 gene expression

NASA Astrophysics Data System (ADS)

Arashiro, Maiko; Lin, Ying-Hsuan; Sexton, Kenneth G.; Zhang, Zhenfa; Jaspers, Ilona; Fry, Rebecca C.; Vizuete, William G.; Gold, Avram; Surratt, Jason D.

2016-11-01

Atmospheric oxidation of isoprene, the most abundant non-methane hydrocarbon emitted into Earth's atmosphere primarily from terrestrial vegetation, is now recognized as a major contributor to the global secondary organic aerosol (SOA) burden. Anthropogenic pollutants significantly enhance isoprene SOA formation through acid-catalyzed heterogeneous chemistry of epoxide products. Since isoprene SOA formation as a source of fine aerosol is a relatively recent discovery, research is lacking on evaluating its potential adverse effects on human health. The objective of this study was to examine the effect of isoprene-derived SOA on inflammation-associated gene expression in human lung cells using a direct deposition exposure method. We assessed altered expression of inflammation-related genes in human bronchial epithelial cells (BEAS-2B) exposed to isoprene-derived SOA generated in an outdoor chamber facility. Measurements of gene expression of known inflammatory biomarkers interleukin 8 (IL-8) and cyclooxygenase 2 (COX-2) in exposed cells, together with complementary chemical measurements, showed that a dose of 0.067 µg cm-2 of SOA from isoprene photooxidation leads to statistically significant increases in IL-8 and COX-2 mRNA levels. Resuspension exposures using aerosol filter extracts corroborated these findings, supporting the conclusion that isoprene-derived SOA constituents induce the observed changes in mRNA levels. The present study is an attempt to examine the early biological responses of isoprene SOA exposure in human lung cells.

Adiponectin deficiency suppresses lymphoma growth in mice by modulating NK cells, CD8 T cells, and myeloid-derived suppressor cells.

PubMed

Han, Sora; Jeong, Ae Lee; Lee, Sunyi; Park, Jeong Su; Kim, Kwang Dong; Choi, Inpyo; Yoon, Suk Ran; Lee, Myung Sok; Lim, Jong-Seok; Han, Seung Hyun; Yoon, Do Young; Yang, Young

2013-05-01

Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. Although the antitumor function of APN has been reported in several types of solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. We observed attenuated EL4 growth in the APNKO mice. Increased numbers of splenic NK cells and splenic CTLs were identified under naive conditions and EL4-challenged conditions, respectively. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation. Additionally, there were decreased levels of myeloid-derived suppressor cell accumulation in the EL4-bearing APNKO mice. Enforced MHC class I expression on B16F10 cells led to attenuated growth of these tumors in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is not only due to an enhanced antitumor immune response but also to a high level of MHC class I expression.

Dietary Levels of Pure Flavonoids Improve Spatial Memory Performance and Increase Hippocampal Brain-Derived Neurotrophic Factor

PubMed Central

Rendeiro, Catarina; Vauzour, David; Rattray, Marcus; Waffo-Téguo, Pierre; Mérillon, Jean Michel; Butler, Laurie T.; Williams, Claire M.; Spencer, Jeremy P. E.

2013-01-01

Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01), suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods. PMID:23723987

Urinary brain-derived neurotrophic factor as a biomarker of executive functioning.

PubMed

Koven, Nancy S; Collins, Larisa R

2014-01-01

Neurotrophins such as brain-derived neurotrophic factor (BDNF) are vital for neuronal survival and adaptive plasticity. With high BDNF gene expression in the prefrontal cortex, BDNF is a potential regulatory factor for building and maintaining cognitive reserves. Recent studies suggest that individual differences in executive functioning, a broad cognitive domain reliant upon frontal lobe structure and function, are governed in part by variance in BDNF polymorphisms. However, as neurogenetic data are not necessarily indicative of in vivo neurochemistry, this study examines the relationship between executive functioning and the neurotransmitter by measuring peripheral BDNF levels. Fifty-two healthy young adults completed a battery of standardized executive function tests. BDNF levels, adjusted for creatinine, were quantified with enzyme-linked immunosorbent assay of urine samples taken at the time of testing. BDNF concentration was positively associated with cognitive flexibility but had no relationship with working memory, abstract reasoning/planning, self-monitoring/response inhibition, or fluency. These results individuate cognitive flexibility as the specific facet of executive functioning associated with in vivo BDNF levels. This study also validates urinary BDNF as a peripheral biomarker of cognition in healthy adults. © 2014 S. Karger AG, Basel.

Neuronal overexpression of cyclooxygenase-2 does not alter the neuroinflammatory response during brain innate immune activation.

PubMed

Aid, Saba; Parikh, Nishant; Palumbo, Sara; Bosetti, Francesca

2010-07-12

Neuroinflammation is a critical component in the progression of several neurological and neurodegenerative diseases and cyclooxygenases (COX)-1 and -2 are key regulators of innate immune responses. We recently demonstrated that COX-1 deletion attenuates, whereas COX-2 deletion enhances, the neuroinflammatory response, blood-brain barrier permeability and leukocyte recruitment during lipopolysaccharide (LPS)-induced innate immune activation. Here, we used transgenic mice, which overexpressed human COX-2 via neuron-specific Thy-1 promoter (TgCOX-2), causing elevated prostaglandins (PGs) levels. We tested whether neuronal COX-2 overexpression affects the glial response to a single intracerebroventricular injection of LPS, which produces a robust neuroinflammatory reaction. Relative to non-transgenic controls (NTg), 7 month-old TgCOX-2 did not show any basal neuroinflammation, as assessed by gene expression of markers of inflammation and oxidative stress, neuronal damage, as assessed by Fluoro-JadeB staining, or systemic inflammation, as assessed by plasma levels of IL-1beta and corticosterone. Twenty-four hours after LPS injection, all mice showed increased microglial activation, as indicated by Iba1 immunostaining, neuronal damage, mRNA expression of cytokines (TNF-alpha, IL-6), reactive oxygen expressing enzymes (iNOS and NADPH oxidase subunits), endogenous COX-2, cPLA(2) and mPGES-1, and hippocampal and cortical IL-1beta levels. However, the increases were similar in TgCOX-2 and NTg. In NTg, LPS increased brain PGE(2) to the levels observed in TgCOX-2. These results suggest that PGs derived from neuronal COX-2 do not play a role in the neuroinflammatory response to acute activation of brain innate immunity. This is likely due to the direct effect of LPS on glial rather than neuronal cells. Published by Elsevier Ireland Ltd.

Activated leucocyte cell adhesion molecule (ALCAM/CD166) regulates T cell responses in a murine model of food allergy.

PubMed

Kim, Y S; Kim, M N; Lee, K E; Hong, J Y; Oh, M S; Kim, S Y; Kim, K W; Sohn, M H

2018-05-01

Food allergy is a major public health problem. Studies have shown that long-term interactions between activated leucocyte cell adhesion molecule (ALCAM/CD166) on the surface of antigen-presenting cells, and CD6, a co-stimulatory molecule, influence immune responses. However, there are currently no studies on the functions of ALCAM in food allergy. Therefore, we aimed to identify the functions of ALCAM in ovalbumin (OVA)-induced food allergy using ALCAM-deficient mice. Wild-type (WT) and ALCAM-deficient (ALCAM -/- ) mice were sensitized intraperitoneally and with orally fed OVA. The mice were killed, and parameters related to food allergy and T helper type 2 (Th2) immune responses were analysed. ALCAM serum levels increased and mRNA expression decreased in OVA-challenged WT mice. Serum immunoglobulin (Ig)E levels, Th2 cytokine mRNA and histological injuries were higher in OVA-challenged WT mice than in control mice, and these were attenuated in ALCAM -/- mice. T cell proliferation of total cells, CD3 + CD4 + T cells and activated T cells in immune tissues were diminished in OVA-challenged ALCAM -/- mice. Proliferation of co-cultured T cells and dendritic cells (DCs) was decreased by the anti-CD6 antibody. In addition, WT mice sensitized by adoptive transfer of OVA-pulsed ALCAM -/- BM-derived DCs showed reduced immune responses. Lastly, serum ALCAM levels were higher in children with food allergy than in control subjects. In this study, serum levels of ALCAM were elevated in food allergy-induced WT mice and children with food allergy. Moreover, immune responses and T cell activation were attenuated in OVA-challenged ALCAM -/- mice. These results indicate that ALCAM regulates food allergy by affecting T cell activation. © 2018 British Society for Immunology.

Paradox of enrichment: A fractional differential approach with memory

NASA Astrophysics Data System (ADS)

Rana, Sourav; Bhattacharya, Sabyasachi; Pal, Joydeep; N'Guérékata, Gaston M.; Chattopadhyay, Joydev

2013-09-01

The paradox of enrichment (PoE) proposed by Rosenzweig [M. Rosenzweig, The paradox of enrichment, Science 171 (1971) 385-387] is still a fundamental problem in ecology. Most of the solutions have been proposed at an individual species level of organization and solutions at community level are lacking. Knowledge of how learning and memory modify behavioral responses to species is a key factor in making a crucial link between species and community levels. PoE resolution via these two organizational levels can be interpreted as a microscopic- and macroscopic-level solution. Fractional derivatives provide an excellent tool for describing this memory and the hereditary properties of various materials and processes. The derivatives can be physically interpreted via two time scales that are considered simultaneously: the ideal, equably flowing homogeneous local time, and the cosmic (inhomogeneous) non-local time. Several mechanisms and theories have been proposed to resolve the PoE problem, but a universally accepted theory is still lacking because most studies have focused on local effects and ignored non-local effects, which capture memory. Here we formulate the fractional counterpart of the Rosenzweig model and analyze the stability behavior of a system. We conclude that there is a threshold for the memory effect parameter beyond which the Rosenzweig model is stable and may be used as a potential agent to resolve PoE from a new perspective via fractional differential equations.

Esculin improves dyslipidemia, inflammation and renal damage in streptozotocin-induced diabetic rats.

PubMed

Wang, Yue-Hua; Liu, Yan-Hong; He, Guo-Rong; Lv, Yang; Du, Guan-Hua

2015-11-09

Increasing studies have shown that dyslipidemia and inflammatory responses play important roles in the progression of microvascular diabetic complications. Esculin (ES), a coumarin derivative, was extracted from Fraxinus rhynchophylla. The present study was to evaluate the potential effects of ES on lipid metabolism, inflammation responses and renal damage in streptozotocin (STZ)-induced experimental diabetic rats and explore the possible mechanism. Diabetic rat model was established by administration high-glucose-fat diet and intraperitoneal injection of STZ 45 mg/kg. ES was administrated to diabetic rats intragastrically at 10, 30 and 90 mg/kg for 10 weeks respectively. The levels of triglycerides (TG), total cholesterol (T-CHO), low density lipoproteins (LDL), and high-density-cholesterol (HDL-C) in serum were measured. IL-1, IL-6, ICAM-1, NO, NAGL, and AGEs level in serum were detected by ELISA assay. The accumulation of AGEs in kidney tissue was examined by immunohistochemistry assay. The results showed that ES could decrease TG, T-CHO, LDL levels in serum of diabetic rats in a dose dependent manner. ES also decreased IL-1, IL-6, ICAM-1, NO and NGAL levels in serum of diabetic rats in a dose dependent manner. Furthermore, ES at 30 and 90 mg/kg significantly decreased AGEs level in serum and alleviated AGEs accumulation in renal in diabetic rats. Our findings indicate that ES could improve dyslipidemia, inflammation responses, renal damage in STZ-induced diabetic rats and the possible mechanism might be associated with the inhibition of AGEs formation.

Imbalance of tumor necrosis factor receptors during progression in bovine leukemia virus infection

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

Konnai, Satoru; Usui, Tatsufumi; Ikeda, Manabu

2005-09-01

Previously, we found an up-regulation of tumor necrosis factor alpha (TNF)-{alpha} and an imbalance of TNF receptors in sheep experimentally infected with bovine leukemia virus (BLV). In order to investigate the different TNF-{alpha}-induced responses, in this study we examined the TNF-{alpha}-induced proliferative response and the expression levels of two distinct TNF receptors on peripheral blood mononuclear cells (PBMC) derived from BLV-uninfected cattle and BLV-infected cattle that were aleukemic (AL) or had persistent lymphocytosis (PL). The proliferative response of PBMC isolated from those cattle with PL in the presence of recombinant bovine TNF-{alpha} (rTNF-{alpha}) was significantly higher than those from ALmore » cattle and uninfected cattle and the cells from PL cattle expressed significantly higher mRNA levels of TNF receptor type II (TNF-RII) than those from AL and BLV-uninfected cattle. No difference was found in TNF-RI mRNA levels. Most cells expressing TNF-RII in PL cattle were CD5{sup +} or sIgM{sup +} cells and these cells showed resistance to TNF-{alpha}-induced apoptosis. Additionally, there were significant positive correlations between the changes in provirus load and TNF-RII mRNA levels, and TNF-{alpha}-induced proliferation and TNF-RII mRNA levels. These data suggest that imbalance in the expression of TNF receptors could at least in part contribute to the progression of lymphocytosis in BLV infection.« less

Environmental controls on δ13C variations of Sphagnum derived n-alkanes in the Dajiuhu peatland, central China

NASA Astrophysics Data System (ADS)

Huang, X.; Xue, J.; Wang, X.; WANG, H.; Meyers, P. A.; Qin, Y.; Gong, L.; Ding, W.

2012-12-01

Northern peatlands are one of the very important atmospheric carbon sinks and represent about 30% of the global soil organic carbon (Gorham, 1991). In peatland conditions, high water levels and consequent anoxia make them an important source of methane. A recent study revealed that methanotrophic bacteria growing on stems or in hyaline cells of Sphagnum can provide methane derived carbon for photosynthesis (Raghoebarsing et al., 2005). This interaction has been found to be globally prevalent in peat-moss ecosystems and can contribute up to 30% of carbon for Sphagnum photosynthesis (Kip et al., 2010). Due to the uptake of 13C-depleted methane-derived CO2 and the sensitivity of methane oxidizing bacteria to the surface wetness, the carbon isotopic signatures of Sphagnum derived lipids have the potential to be used as a proxy for the surface wetness in peatlands and hence as paleoclimate archives (Nichols et al., 2009). In this study, we report the δ13C variations of the Sphagnum derived n-C23 alkane in both fresh Sphagnum and surface peat samples in the Dajiuhu peatland, a small fen located in the Shennongjia forestry region, Hubei province, central China. The δ13C23 values of Sphagnum show a negative correlation with the water level, supporting the idea that that the carbon isotope fractionation of Sphagnum is mainly manifested by the diffusion resistance of CO2 in hyaline cells of Sphagnum. However, δ13C23 values of surface peats collected in Sphagnum dominated ecosystems display a positive relation with the water level when the water level is less than 30 cm. Such an inconsistency probably results from the higher potential for methane-oxidizing activity in the lower parts of Sphagnum in fen meadows. When the water level is higher than 30 cm, the influence of symbiotic methanotrophic bacteria on Sphagnum derived n-C23 alkane is weak or nearly absent. These findings provide direct evidence to support the hypothesis that the carbon isotopic signatures of Sphagnum derived lipids can be used as a proxy of surface wetness in peatlands. References Gorham, E., 1991. Northern peatlands: role in the carbon cycle and probable responses to climatic warming. Ecological Applications, 1, 182-195. Kip, N., van Winden, J.F., Pan, Y., et al., 2010. Global prevalence of methane oxidation by symbiotic bacteria in peat-moss ecosystems. Nature Geosciences 3, 617-621. Nichols, JE, Walcott, M, Bradley, R., et al., 2009. Quantitative assessment of precipitation seasonality and summer surface wetness using ombrotrophic sediments from an Arctic Norwegian peatland. Quaternary Research, 2009, 72: 443-451. Raghoebarsing, A.A., Smolders, A.J.P., Schmid, M.C., et al., 2005. Methanotrophic symbionts provide carbon for photosynthesis in peat bogs. Nature 436, 1153-1156.