Eating high-fat chow enhances sensitization to the effects of methamphetamine on locomotion in rats.

PubMed

McGuire, Blaine A; Baladi, Michelle G; France, Charles P

2011-05-11

Eating high-fat chow can modify the effects of drugs acting directly or indirectly on dopamine systems and repeated intermittent drug administration can markedly increase sensitivity (i.e., sensitization) to the behavioral effects of indirect-acting dopamine receptor agonists (e.g., methamphetamine). This study examined whether eating high-fat chow alters the sensitivity of male Sprague Dawley rats to the locomotor stimulating effects of acute or repeated administration of methamphetamine. The acute effects of methamphetamine on locomotion were not different between rats (n=6/group) eating high-fat or standard chow for 1 or 4 weeks. Sensitivity to the effects of methamphetamine (0.1-10mg/kg, i.p.) increased progressively across 4 once per week tests; this sensitization developed more rapidly and to a greater extent in rats eating high-fat chow as compared with rats eating standard chow. Thus, while eating high-fat chow does not appear to alter sensitivity of rats to acutely-administered methamphetamine, it significantly increases the sensitization that develops to repeated intermittent administration of methamphetamine. These data suggest that eating certain foods influences the development of sensitization to drugs acting on dopamine systems. Copyright © 2011 Elsevier B.V. All rights reserved.

Osthole enhances TRAIL-mediated apoptosis through downregulation of c-FLIP expression in renal carcinoma Caki cells.

PubMed

Min, Kyoung-Jin; Han, Min Ae; Kim, Shin; Park, Jong-Wook; Kwon, Taeg Kyu

2017-04-01

Osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, has been shown to induce various beneficial biochemical effects such as anti-inflammatory and antitumor. In the present study, we examined whether osthole could sensitize TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma Caki cells. We found that osthole and TRAIL alone, had no effect on apoptosis, but combined treatment with osthole and TRAIL markedly induced apoptosis in Caki (renal carcinoma), U251MG (glioma) and MDA-MB-231 (breast carcinoma) cells. In contrast, combined treatment with osthole and TRAIL did not induce apoptosis in normal human skin fibroblast cells. Osthole induced downregulation of cellular FLICE-like inhibitory protein (c-FLIP) expression, and overexpression of c-FLIP markedly blocked apoptosis induced by the combined treatment with osthole and TRAIL. In addition, osthole markedly reduced mitochondrial membrane potential levels, and increased cytosolic cytochrome c release in combined treatment with osthole and TRAIL. Therefore, these data suggest that osthole may be an efficient TRAIL sensitizer.

Intracellular sodium concentration and transport in red cells in essential hypertension, hyperthyroidism, pregnancy and hypokalemia.

PubMed

Gless, K H; Sütterlin, U; Schaz, K; Schütz, V; Hunstein, W

1986-01-01

Intracellular sodium content ([Nai]), ouabain-sensitive ('Na-K ATPase') and ouabain-insensitive ('passive permeability') sodium efflux, Na-K cotransport and Na-Li ('Na-Na') countertransport were estimated in erythrocytes in 39 control subjects, 20 patients with essential hypertension, 14 patients with hypokalemia of renal or unknown etiology, 13 hyperthyroid patients and 19 pregnant women. In normokalemic essential hypertension there was only a moderate, but significant elevation of the activity of the Na-Li countertransport system. In the group of patients with hypokalemia, there was a significant increase of [Nai], ouabain-insensitive sodium efflux and Na-Li countertransport. In hyperthyroidism, a marked decrease of Na-Li countertransport was associated with a marked elevation of [Nai], in pregnancy an elevation of the Na-Li countertransport with a [Nai] 43% lower than the control values. The ouabain-sensitive sodium efflux was elevated in hyperthyroidism and hypokalemia, in which [Nai] was increased. In the control subjects there was a positive linear correlation between ouabain-sensitive sodium efflux and [Nai]. The sodium component of the Na-K cotransport was decreased to about one third of the unchanged furosemide-sensitive potassium component during pregnancy. The changes of cellular sodium metabolism in essential hypertension are of minor degree as compared to those in the other conditions studied. Cellular sodium metabolism in blood cells is influenced by thyroid hormones and metabolic disorders. Na-Li countertransport, i.e. Na-Na countertransport, seems to be involved in the regulation of [Nai]: an increase of its activity diminishes [Nai] (pregnancy); a decrease elevates [Nai] (hyperthyroidism). Ouabain-sensitive sodium efflux, i.e. 'Na-K ATPase', is mainly regulated by its substrate, [Nai].

Current issues in determining dietary protein quality and metabolic utilization

USDA-ARS?s Scientific Manuscript database

In resource-limited settings, poor dietary quality has a marked negative impact on health, especially during the sensitive periods of pregnancy and first 2 years of life (the first 1000 days) when stunting, poor development and increased risk of later disease develop. Protein quality is often poor o...

Gravitropism in higher plant shoots. V - Changing sensitivity to auxin

NASA Technical Reports Server (NTRS)

Salisbury, Frank B.; Gillespie, Linda; Rorabaugh, Patricia

1988-01-01

The relationship in plants between the sensitivity to auxin and differential growth and bending was investigated experimentally. Decapitated and marked sunflower hypocotyl sections were immersed in buffered auxin solutions of different concentrations (0, 10 to the -8th, or 0.001 molar) and were photographed at 1/2 hr intervals; the negatives were analyzed with a digitizer/computer to evaluate surface-length changes in terms of Michaelis-Menten enzyme kinetics. It was found that bending decreased with increasing concentration of auxin. Increasing the auxin concentration inhibits the elongation growth of lower surfaces but promotes upper-surface growth, indicating that the lower surfaces have a greater Km sensitivity to applied auxin than the upper surfaces. At optimum auxin levels (maximum growth), the growth of bottom surfaces exceeded that of top surfaces, indicating that bottom tissues had a greater Vmax sensitivity.

Identification of Proteus mirabilis Mutants with Increased Sensitivity to Antimicrobial Peptides

PubMed Central

McCoy, Andrea J.; Liu, Hongjian; Falla, Timothy J.; Gunn, John S.

2001-01-01

Antimicrobial peptides (APs) are important components of the innate defenses of animals, plants, and microorganisms. However, some bacterial pathogens are resistant to the action of APs. For example, Proteus mirabilis is highly resistant to the action of APs, such as polymyxin B (PM), protegrin, and the synthetic protegrin analog IB-367. To better understand this resistance, a transposon mutagenesis approach was used to generate P. mirabilis mutants sensitive to APs. Four unique PM-sensitive mutants of P. mirabilis were identified (these mutants were >2 to >128 times more sensitive than the wild type). Two of these mutants were also sensitive to IB-367 (16 and 128 times more sensitive than the wild type). Lipopolysaccharide (LPS) profiles of the PM- and protegrin-sensitive mutants demonstrated marked differences in both the lipid A and O-antigen regions, while the PM-sensitive mutants appeared to have alterations of either lipid A or O antigen. Matrix-assisted laser desorption ionization–time of flight mass spectrometry analysis of the wild-type and PM-sensitive mutant lipid A showed species with one or two aminoarabinose groups, while lipid A from the PM- and protegrin-sensitive mutants was devoid of aminoarabinose. When the mutants were streaked on an agar-containing medium, the swarming motility of the PM- and protegrin-sensitive mutants was completely inhibited and the swarming motility of the mutants sensitive to only PM was markedly decreased. DNA sequence analysis of the mutagenized loci revealed similarities to an O-acetyltransferase (PM and protegrin sensitive) and ATP synthase and sap loci (PM sensitive). These data further support the role of LPS modifications as an elaborate mechanism in the resistance of certain bacterial species to APs and suggest that LPS surface charge alterations may play a role in P. mirabilis swarming motility. PMID:11408219

Common Risk Factors for Urinary House Soiling (Periuria) in Cats and Its Differentiation: The Sensitivity and Specificity of Common Diagnostic Signs

PubMed Central

Barcelos, Ana Maria; McPeake, Kevin; Affenzeller, Nadja; Mills, Daniel Simon

2018-01-01

Urinary house soiling (periuria) in the home is a common but serious behaviour problem in cats. Although many specific risk factors and triggers have been postulated, their importance is largely unknown. This study assessed: (1) the significance of purported risk factors for periuria as well as specifically marking and latrine behaviour in the home; (2) the specificity and sensitivity of signs commonly used to differentiate latrine and marking behaviour. Owner responses to an internet survey (n = 245) were classified into three groups: control, marking and latrine behaviour, along with 41 potential risk factors and 15 predictors used to diagnose marking and latrine problems. Univariate statistical analyses and non-parametric tests of association were used to determine simple associations. In addition the sensitivity and specificity of four cardinal signs (posture to urinate, attempt to cover soiled area, surface chosen and volume of urine deposited) were calculated. Significant potential risk factors were: age (marking cats were older than the other two groups); multi-cat household (increased risk of marking and latrine behaviours); free outside access and cat flaps in the house (higher frequency of marking); outside access in general (lower prevalence of latrine behaviour); defecation outside the litter box (higher frequency of latrine behaviour); a heavy dependence by the cat on its owner (lower frequency of latrine behaviour) and a relaxed personality (lower risk of marking behaviour). Litterbox attributes and disease related factors were not significant. Individual cardinal signs were generally not good predictors of diagnosis. This study challenges the poor quality of evidence that has underpinned some of the hypotheses concerning the causes of periuria in cats. The results, in particular, highlight the general importance of the social environment, with the presence of other cats in the household, the cat-owner bond and personality related factors, alongside factors like the use of a cat flap which might also alter the social environment, all implicated as significant risk factors. While the physical environment may be important in specific cases, it seems this is less important as a general risk factor. The findings quantify the risk of misdiagnosis if a single sign is considered sufficient for diagnosis. PMID:29892606

Paraquat toxicity is increased in Escherichia coli defective in the synthesis of polyamines.

PubMed

Minton, K W; Tabor, H; Tabor, C W

1990-04-01

We have shown that toxicity of paraquat for Escherichia coli is increased over 10-fold in strains defective in the biosynthesis of spermidine compared to isogenic strains containing spermidine. The increased sensitivity of these spermidine-deficient mutants to paraquat is eliminated by growth in medium containing spermidine or by endogenous supplementation of spermidine by the use of a speE+D+ plasmid. No paraquat toxicity is seen in the absence of oxygen, even in amine-deficient strains, indicating that superoxide is the agent responsible for the increased toxicity. However, the specific mechanisms responsible for the increased paraquat toxicity in the spermidine-deficient mutants remain to be determined. The marked sensitivity to paraquat of E. coli deficient in spermidine is of particular interest, since such mutants have no other phenotypic properties that can be easily assayed. This increased sensitivity has been used as the basis of a convenient method for scoring for mutants in polyamine biosynthesis and for the detection of plasmids containing the biosynthetic genes.

Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys.

PubMed

Schelegle, Edward S; Miller, Lisa A; Gershwin, Laurel J; Fanucchi, Michelle V; Van Winkle, Laura S; Gerriets, Joan E; Walby, William F; Mitchell, Valerie; Tarkington, Brian K; Wong, Viviana J; Baker, Gregory L; Pantle, Lorraine M; Joad, Jesse P; Pinkerton, Kent E; Wu, Reen; Evans, Michael J; Hyde, Dallas M; Plopper, Charles G

2003-08-15

Twenty-four infant rhesus monkeys (30 days old) were exposed to 11 episodes of filtered air (FA), house dust mite allergen aerosol (HDMA), ozone (O3), or HDMA + O3 (5 days each followed by 9 days of FA). Ozone was delivered for 8 h/day at 0.5 ppm. Twelve of the monkeys were sensitized to house dust mite allergen (Dermatophagoides farinae) at ages 14 and 28 days by subcutaneous inoculation (SQ) of HDMA in alum and intraperitoneal injection of heat-killed Bordetella pertussis cells. Sensitized monkeys were exposed to HDMA aerosol for 2 h/day on days 3-5 of either FA (n = 6) or O3 (n = 6) exposure. Nonsensitized monkeys were exposed to either FA (n = 6) or O3 (n = 6). During the exposure regimen, parameters of allergy (i.e., serum IgE, histamine, and eosinophilia), airways resistance, reactivity, and structural remodeling were evaluated. Eleven repeated 5-day cycles of inhaling 0.5 ppm ozone over a 6-month period had only mild effects on the airways of nonsensitized infant rhesus monkeys. Similarly, the repeated inhalation of HDMA by HDMA-sensitized infant monkeys resulted in only mild airway effects, with the exception of a marked increase in proximal airway and terminal bronchiole content of eosinophils. In contrast, the combined cyclic inhalation of ozone and HDMA by HDMA sensitized infants monkeys resulted in a marked increase in serum IgE, serum histamine, and airways eosinophilia. Furthermore, combined cyclic inhalation of ozone and HDMA resulted in even greater alterations in airway structure and content that were associated with a significant elevation in baseline airways resistance and reactivity. These results suggest that ozone can amplify the allergic and structural remodeling effects of HDMA sensitization and inhalation.

The Processing of Case in Near-Native Spanish

ERIC Educational Resources Information Center

Jegerski, Jill

2015-01-01

This article reports a study that sought to determine whether non-native sentence comprehension can show sensitivity to two different types of Spanish case marking. Sensitivity to case violations was generally more robust with indirect objects in ditransitive constructions than with differential object marking of animate direct objects, even among…

ONTOGENY OF HEPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN AGE-DEPENDENT ACUTE NEUROTOXICITY.

EPA Science Inventory

Deltamethrin is a reltively potent and widely used pyrethroid pesticide that is known to be markedly more toxic to young animals. The data presented in this paper shed light on the mechanisms for this increased sensitivity in the young. Young animals lack the ability to efficient...

Method and apparatus for ultra-high-sensitivity, incremental and absolute optical encoding

NASA Technical Reports Server (NTRS)

Leviton, Douglas B. (Inventor)

1999-01-01

An absolute optical linear or rotary encoder which encodes the motion of an object (3) with increased resolution and encoding range and decreased sensitivity to damage to the scale includes a scale (5), which moves with the object and is illuminated by a light source (11). The scale carries a pattern (9) which is imaged by a microscope optical system (13) on a CCD array (17) in a camera head (15). The pattern includes both fiducial markings (31) which are identical for each period of the pattern and code areas (33) which include binary codings of numbers identifying the individual periods of the pattern. The image of the pattern formed on the CCD array is analyzed by an image processor (23) to locate the fiducial marking, decode the information encoded in the code area, and thereby determine the position of the object.

[The molecular-cellular mechanisms of learning in the edible snail].

PubMed

Nikitin, V P

1993-01-01

Elaboration of sensitization and associative habit of a rejection of a certain kind of food is accompanied by short-term and long-term changes of behaviour, bioelectric activity and the dynamics of bound calcium (Ca-b) level in the command neurons of defensive behaviour. Approximately in the course of an hour from the moment of the beginning of learning were revealed in general similar behavioural and neurophysiological effects during elaboration of both these habits. During elaboration of sensitization the responses to testing tactile stimulations, quinine and carrot juice applications appeared and/or markedly increased beginning from 50-60 minutes from the moment of the first sensitizing stimulation. During conditioning the responses to sensory stimulations characterizing the state of sensitization were also facilitated in 50-60 minutes. At the same time, responses to a conditioned stimulus appeared and increased approximately 30 minutes later. Protein synthesis blockers anisomycin and cyclohexamide blocked the development of the long-term neurophysiological and metabolic Ca-b effects during elaboration of sensitization.

Furosemide- and bumetanide-sensitive ion transport and volume control in primary astrocyte cultures from rat brain.

PubMed

Kimelberg, H K; Frangakis, M V

1985-12-30

K+ and Cl- transport using 42K+ and 36Cl- was studied in primary astrocyte cultures prepared from neonatal rat brains. A component of 42K+ uptake was sensitive to both furosemide and bumetanide with maximum inhibition being obtained at 1 and 0.01 mM concentrations of the inhibitors, respectively. Furosemide and bumetanide also markedly inhibited uptake of 36Cl-. 42K+ uptake in the presence of ouabain was also sensitive to the omission of medium Na+ and Cl-. These results suggest the existence of a K+ + Na+ + Cl- cotransport system in astrocyte cultures which in many cells has been shown to be involved in volume regulation. We studied volume changes using uptake of [14C]3-O- methyl-D-glucose ([14C]3-OMG), and also ion transport, in attached cells in response to exposure to hyper- or hypotonic medium. Exposure to medium made hypertonic with mannitol resulted in shrinkage of the [14C]3-OMG space of the cells, but did not affect 36Cl- content, expressed as nmol/mg protein. Exposure to hypotonic medium led to a marked increase in the [14C]3-OMG space, rapidly followed by a decrease towards control values. After the cells were then exposed to isotonic medium there was an immediate decrease followed by a slower increase in the [14C]3-OMG space. The increase in the [14C]3-OMG space was partially inhibited by 1 mM furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)

PillCam(TradeMark), a Noninvasive Endoscopic Device for the Measurement of Gastrointestinal Motility Changes

NASA Technical Reports Server (NTRS)

Vaksman, Zahman; Crady, Camille; Raju, G. S.; Putcha, Lakshmi

2007-01-01

Introduction: Bioavailability and effectiveness of drugs given by mouth are governed in part by gastrointestinal (GI) motility and function. Microgravity has been shown to decrease GI motility as indicated by a 3 fold increase in gastrointestinal transit time (GITT). The PillCam(TradeMark), an endoscopic camera embedded in a capsule, is a novel noninvasive and unobtrusive device that is used for the diagnosis of GI pathology. The purpose of this study is to evaluate the usefulness of PillCam(TradeMark) as an alternative to the Lactulose Breath Hydrogen Test (LBHT) for estimating GI motility. The sensitivity and applicability of this device for detection and estimation of the effect of promethazine, a deterrent, and caffeine, a prokinetic, on GI motility were also examined. Method: In this semi-randomized cross-over design study, six male and six female subjects were administered the following 4 treatments: PillCam(TradeMark) alone, PillCam(TradeMark)+Lactulose (10g), PillCam(TradeMark)+caffeine (200mg), and PillCam(TradeMark)+Promethazine (50mg). Results: GITT ranged between 1:24 and 7:52 hr:min. Lactulose did not alter GITT. A significant increase in GITT was noticed after administration of PMZ when compared to values from PillCam(TradeMark) treatment alone or PillCam(TradeMark)+Lactulose treatment. No difference in GITT after caffeine treatment was noticed. While there were no gender related differences in GITT after administration of PillCam(TradeMark) or with lactulose, a significant difference (p<.05) between genders was observed after promethazine administration with mean GITT higher in males (5:50 hr:min) than females (4:15 hr:min). Conclusion: The PillCam(TradeMark) capsule is applicable for the determination of GITT using time stamped GI images. It can be successfully used for the assessment of drug induced changes in GI motility and therefore, may be applicable for microgravity and analog environment studies on GI motility and function.

Dimethylarginine Dimethylaminohydrolase Overexpression enhances Insulin Sensitivity

PubMed Central

Sydow, Karsten; Mondon, Carl E.; Schrader, Joerg; Konishi, Hakuoh; Cooke, John P.

2011-01-01

Objective Previous studies suggest that nitric oxide (NO) may modulate insulin-induced uptake of glucose in insulin-sensitive tissues. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We hypothesized that a reduction in endogenous ADMA would increase NO synthesis and thereby enhance insulin sensitivity. Methods and Results To test this hypothesis we employed a transgenic mouse in which we overexpressed human dimethylarginine dimethylaminohydrolase (DDAH-I). The DDAH-I mice had lower plasma ADMA at all ages (22–70 weeks) by comparison to wild-type (WT) littermates. With a glucose challenge, WT mice showed a prompt increase in ADMA, whereas DDAH-I mice had a blunted response. Furthermore, DDAH-I mice had a blunted increase in plasma insulin and glucose levels after glucose challenge, with a 50% reduction in the insulin resistence index, consistent with enhanced sensitivity to insulin. In liver, we observed an increased Akt phosphorylation in the DDAH-I mice after i.p. glucose challenge. Incubation of skeletal muscle from WT mice ex vivo with ADMA (2μM) markedly suppressed insulin-induced glycogen synthesis in fast-twitch but not slow-twitch muscle. Conclusions These findings suggest that the endogenous NOS inhibitor ADMA reduces insulin sensitivity, consistent with previous observations that NO plays a role in insulin sensitivity. PMID:18239148

Sparing of Sensitivity to Biological Motion but Not of Global Motion after Early Visual Deprivation

ERIC Educational Resources Information Center

Hadad, Bat-Sheva; Maurer, Daphne; Lewis, Terri L.

2012-01-01

Patients deprived of visual experience during infancy by dense bilateral congenital cataracts later show marked deficits in the perception of global motion (dorsal visual stream) and global form (ventral visual stream). We expected that they would also show marked deficits in sensitivity to biological motion, which is normally processed in the…

Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome

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

Ottenheijm, Coen A.C.; Voermans, Nicol C.; Hudson, Bryan D.

Tenascin-X (TNX) is an extracellular matrix glycoprotein whose absence leads to Ehlers-Danlos Syndrome (EDS). TNX-deficient EDS patients present with joint hypermobility and muscle weakness attributable to increased compliance of the extracellular matrix. We hypothesized that in response to the increased compliance of the extracellular matrix in TNX-deficient EDS patients, intracellular adaptations take place in the elastic properties of the giant muscle protein titin. We performed extensive single muscle fiber mechanical studies to determine active and passive properties in TNX-deficient EDS patients. Gel-electrophoresis, Western blotting, and microarray studies were used to evaluate titin expression and phosphorylation. X-ray diffraction was used tomore » measure myofilament lattice spacing. Passive tension of muscle fibers from TNX-deficient EDS patients was markedly increased. Myofilament extraction experiments indicated that the increased passive tension is attributable to changes in the properties of the sarcomeric protein titin. Transcript and protein data indicated no changes in titin isoform expression. Instead, differences in posttranslational modifications within titin's elastic region were found. In patients, active tension was not different at maximal activation level, but at submaximal activation level it was augmented attributable to increased calcium sensitivity. This increased calcium sensitivity might be attributable to stiffer titin molecules. In response to the increased compliance of the extracellular matrix in muscle of TNX-deficient EDS patients, a marked intracellular stiffening occurs of the giant protein titin. The stiffening of titin partly compensates for the muscle weakness in these patients by augmenting submaximal active tension generation.« less

49 CFR 1520.13 - Marking SSI.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY SECURITY RULES FOR ALL MODES OF TRANSPORTATION PROTECTION OF SENSITIVE SECURITY INFORMATION § 1520.13 Marking SSI. (a) Marking of paper records. In the case of paper records...

A study of the properties of compacts from silicified microcrystalline celluloses.

PubMed

Muzíková, Jitka; Nováková, Petra

2007-07-01

The paper deals with a study of tensile strength and disintegration time of compacts made from silicified microcrystalline celluloses, Prosolv SMCC 90, and Prosolv HD 90, in dependence on compression force, addition of two types of lubricants, and two active ingredients. The lubricants were magnesium stearate and sodium stearyl fumarate in a concentration of 0.5%, the active ingredients being ascorbic acid and acetylsalicylic acid in a concentration of 50%. Prosolv SMCC 90 proved to be better compatible than Prosolv HD 90; the compacts were of higher strength, which was markedly increased with increasing compression force. Prosolv HD 90 was more sensitive to additions of lubricants, and a greater decrease in strength was recorded due to the influence of sodium stearyl fumarate. The effect of lubricants on the strength of compacts in the presence of active ingredients was not identical. The disintegration time of compacts from Prosolv HD 90 without as well as with lubricants was shorter than from Prosolv SMCC 90 and was increasing with increasing compression force. Disintegration time was increased with added lubricants, and it was markedly shortened by addition of active ingredients. Compacts containing ascorbic acid possessed a shorter disintegration time than those containing acetylsalicylic acid, and it was not markedly influenced by the presence of lubricants.

Strophanthidin-sensitive sodium fluxes in metabolically poisoned frog skeletal muscle

PubMed Central

1976-01-01

Strophanthidin-sensitive and insensitive unidirectional fluxes of Na were measured in fog sartorius muscles whose internal Na levels were elevated by overnight storage in the cold. ATP levels were lowered, and ADP levels raised, by metabolic poisoning with either 2,4- dinitrofluorobenzene or iodoacetamide. Strophanthidin-sensitive Na efflux and influx both increased after poisoning, while strophanthidin- insensitives fluxes did not. The increase in efflux did not require the presence of external K but was greatly attenuated when Li replaced Na as the major external cation. Membrane potential was not markedly altered by 2,4-dinitrofluorobenzene. These observations indicate that the sodium pump of frog skeletal muscle resembles that of squid giant axon and human erythrocyte in its ability to catalyze Na-Na exchange to an extent determined by intracellular ATP/ADP levels. PMID:1086888

Mark Roschewski awarded USPHS Research Physician of the Year | Center for Cancer Research

Cancer.gov

Mark Roschewski, M.D., Staff Clinician in CCR’s Lymphoid Malignancies Branch, received the Research Physician of the Year award from the Physicians Professional Advisory Committee to the Surgeon General of the U.S. Public Health Service. According to the website, this award “recognizes individual initiative, accomplishment, and accountability for actions that increase the overall effectiveness of the HHS through research.” Bill Dahut, M.D., CCR Scientific Director for Clinical Research, says, “He has the unusual ability to combine the unique sensitivity of clinical research and patient care, which has impacted patients with life-devastating lymphomas.”

Measurement of B sup 0 -- B sup 0 mixing using the MARK II at PEP

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

Porter, F.

B{sup 0}{bar B}{sup 0} mixing has been observed now by several experiments. The signature is the observation of an excess of same-sign dilepton events in datasets containing semileptonic B decays. Several years ago the MARK II published an upper limit on B{sup 0}{bar B}{sup 0} mixing at E{sub cm} = 29 GeV, using data taken at the e{sup +}e{sup {minus}} storage ring PEP. Here we report on the results of a new analysis with increased statistics, using refined methods with better sensitivity and control of systematic effects. 10 refs., 2 figs., 2 tab.

Avian behavior and mortality at power lines in coastal South Carolina

USGS Publications Warehouse

Savereno, A.J.; Savereno, L.A.; Boettcher, R.; Haig, S.M.

1996-01-01

We compared avian behavior and mortality associated with two 115-kV transmission lines on the central South Carolina coast during 3,392 hours of observation from May 1991 through May 1994. One line was marked with 30-cm-diameter yellow aviation markers. The second line was unmarked, but was similar in most other aspects. We conducted ground searches (n = 445) beneath each line year-round to document avian mortality due to power-line collisions. At marked lines, birds that approached at line height changed behavior more at unmarked lines (P< 0.001), and fewer crossed between static and conductor wires. Collision rate was 53% lower at marked than unmarked lines. Among collisions at both sites, 82% of birds collided with static wires. Based on observed collisions and carcass recoveries, wading birds particularly appeared to be at risk. We concluded that aviation markers were effective at increasing line visibility and reducing collisions and recommend marking static wires of power lines in potentially sensitive areas.

Infrared technique for decoding of invisible laser markings

NASA Astrophysics Data System (ADS)

Haferkamp, Heinz; Jaeschke, Peter; Stein, Johannes; Goede, Martin

2002-03-01

Counterfeiting and product piracy continues to be an important issue not only for the Western industry, but also for the society in general. Due to the drastic increase in product imitation and the request for plagiarism protection as well as for reducing thefts there is a high interest in new protection methods providing new security features. The method presented here consists of security markings which are included below paint layers. These markings are invisible for the human eye due to the non-transparency of the upper layers in the visible spectral range. However, the markings can be detected by an infrared technique taking advantage on the partial transparency of the upper paint layers in the IR-region. Metal sheets are marked using laser radiation. The beam of a Nd:YAG-laser provides a modification of the surface structure, resulting in dark markings due to the annealing effect. After coating of the laser-marked material, the markings are invisible for the bare eye. In order to read out the invisible information below the coating, an infrared reflection technique is used. The samples are illuminated with halogen lamps or infrared radiators. Many coating materials (i. e. paints) show a certain transparency in the mid-infrared region, especially between 3 - 5 micrometers . The reflected radiation is detected using an IR-camera with a sensitivity range from 3.4 - 5 micrometers . Due to the different reflection properties between the markings and their surrounding, the information can be detected.

A demonstration of athermal effects of continuous microwave irradiation on the growth and antibiotic sensitivity of Pseudomonas aeruginosa PAO1.

PubMed

Nakouti, Ismini; Hobbs, Glyn; Teethaisong, Yothin; Phipps, David

2017-01-01

Stress, caused by exposure to microwaves (2.45 GHz) at constant temperature (37 ± 0.5°C), alters the growth profile of Pseudomonas aeruginosa PAO1. In the absence of microwave treatment a simple, highly reproducible growth curve was observed over 24 h or more. Microwave treatment caused no reduction in growth during the first 6 h, but at a later stage (>12 h) the growth was markedly different to the controls. Secondary growth, typical of the presence of persisters clearly became apparent, as judged by both the dissolved oxygen and the cell density profiles. These treated cells showed distinct morphological changes, but on regrowth these cells reverted to normal. The microwave induced persisters were subject to antibiotic challenge (tobramycin) and showed increased sensitivity when compared to the unstressed planktonic cells. This is in marked contrast to antibiotic induced persisters which show increased resistance. This provides evidence for both a nonthermal effect of microwaves and a previously undescribed route to a novel form of antibiotic susceptible persister cells. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:37-44, 2017. © 2016 American Institute of Chemical Engineers.

Acute stress-induced sensitization of the pituitary-adrenal response to heterotypic stressors: independence of glucocorticoid release and activation of CRH1 receptors.

PubMed

Belda, Xavier; Daviu, Núria; Nadal, Roser; Armario, Antonio

2012-09-01

A single exposure to some severe stressors causes sensitization of the hypothalamic-pituitary-adrenal (HPA) response to novel stressors. However, the putative factors involved in stress-induced sensitization are not known. In the present work we studied in adult male rats the possible role of glucocorticoids and CRH type 1 receptor (CRH-R1), using an inhibitor of glucocorticoid synthesis (metyrapone, MET), the glucocorticoid receptor (GR) antagonist RU38486 (mifepristone) and the non-peptide CRH-R1 antagonist R121919. In a first experiment we demonstrated with different doses of MET (40-150 mg/kg) that the highest dose acted as a pharmacological stressor greatly increasing ACTH release and altering the normal circadian pattern of HPA hormones, but no dose affected ACTH responsiveness to a novel environment as assessed 3 days after drug administration. In a second experiment, we found that MET, at a dose (75 mg/kg) that blocked the corticosterone response to immobilization (IMO), did not alter IMO-induced ACTH sensitization. Finally, neither the GR nor the CRH-R1 antagonists blocked IMO-induced ACTH sensitization on the day after IMO. Thus, a high dose of MET, in contrast to IMO, was unable to sensitize the HPA response to a novel environment despite the huge activation of the HPA axis caused by the drug. Neither a moderate dose of MET that markedly reduced corticosterone response to IMO, nor the blockade of GR or CRH-R1 receptors was able to alter stress-induced HPA sensitization. Therefore, stress-induced sensitization is not the mere consequence of a marked HPA activation and does not involve activation of glucocorticoid or CRH-R1 receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

Deletion of the alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity.

PubMed

Chutkow, William A; Birkenfeld, Andreas L; Brown, Jonathan D; Lee, Hui-Young; Frederick, David W; Yoshioka, Jun; Patwari, Parth; Kursawe, Romy; Cushman, Samuel W; Plutzky, Jorge; Shulman, Gerald I; Samuel, Varman T; Lee, Richard T

2010-06-01

Thioredoxin interacting protein (Txnip), a regulator of cellular oxidative stress, is induced by hyperglycemia and inhibits glucose uptake into fat and muscle, suggesting a role for Txnip in type 2 diabetes pathogenesis. Here, we tested the hypothesis that Txnip-null (knockout) mice are protected from insulin resistance induced by a high-fat diet. Txnip gene-deleted (knockout) mice and age-matched wild-type littermate control mice were maintained on a standard chow diet or subjected to 4 weeks of high-fat feeding. Mice were assessed for body composition, fat development, energy balance, and insulin responsiveness. Adipogenesis was measured from ex vivo fat preparations, and in mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes after forced manipulation of Txnip expression. Txnip knockout mice gained significantly more adipose mass than controls due to a primary increase in both calorie consumption and adipogenesis. Despite increased fat mass, Txnip knockout mice were markedly more insulin sensitive than controls, and augmented glucose transport was identified in both adipose and skeletal muscle. RNA interference gene-silenced preadipocytes and Txnip(-/-) MEFs were markedly adipogenic, whereas Txnip overexpression impaired adipocyte differentiation. As increased adipogenesis and insulin sensitivity suggested aspects of augmented peroxisome proliferator-activated receptor-gamma (PPARgamma) response, we investigated Txnip's regulation of PPARgamma function; manipulation of Txnip expression directly regulated PPARgamma expression and activity. Txnip deletion promotes adiposity in the face of high-fat caloric excess; however, loss of this alpha-arrestin protein simultaneously enhances insulin responsiveness in fat and skeletal muscle, revealing Txnip as a novel mediator of insulin resistance and a regulator of adipogenesis.

Neonatal status epilepticus alters prefrontal-striatal circuitry and enhances methamphetamine-induced behavioral sensitization in adolescence.

PubMed

Lin, Tzu-Chao; Huang, Li-Tung; Huang, Ya-Ni; Chen, Gunng-Shinng; Wang, Jia-Yi

2009-02-01

Neonatal seizures may alter the developing neurocircuitry and cause behavioral abnormalities in adulthood. We found that rats previously subjected to lithium-pilocarpine (LiPC)-induced neonatal status epilepticus (NeoSE) exhibited enhanced behavioral sensitization to methamphetamine (MA) in adolescence. Neurochemically, dopamine (DA) and metabolites were markedly decreased in prefrontal cortex (PFC) and insignificantly changed in striatum by NeoSE, but were increased in both PFC and striatum by NeoSE+MA. Glutamate levels were increased in both PFC and striatum in the NeoSE+MA group. DA turnover, an index of utilization and activity, was increased by NeoSE but reversed by MA in PFC. Gene expression of the regulator of G-protein signaling 4 (RGS4) was downregulated in PFC and striatum by NeoSE and further suppressed by MA. These findings suggest NeoSE affects both dopaminergic and glutamatergic systems in the prefrontal-striatal circuitry that manifests as enhanced behavioral sensitization to MA in adolescence.

Insulin Resistance of Puberty.

PubMed

Kelsey, Megan M; Zeitler, Philip S

2016-07-01

Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.

Recovering obliterated engraved marks on aluminium surfaces by etching technique.

PubMed

Baharum, Mohd Izhar Mohd; Kuppuswamy, R; Rahman, Azari Abd

2008-05-20

A study has been made of the characteristics of restoration of obliterated engraved marks on aluminium surfaces by etching technique. By etching different reagents on 0.61mm thick sheets of aluminium (99wt%) on which some engraved marks had been erased to different depths it was found that the reagent 60% hydrochloric acid and 40% sodium hydroxide on alternate swabbing on the surfaces was found to be the most sensitive one for these metal surfaces. This reagent was able to restore marks in the above plates erased down to 0.04mm below the bottom of the engraving. The marks also presented excellent contrast with the background. This reagent was further experimented with similar aluminium surfaces, but of relatively greater thickness of 1.5mm. It was noticed that the recovery depth increased slightly to 0.06mm; this suggested the dependence of recovery depth on the thickness of the sheet metal. Further, the depth of restoration decreased in cases where the original number was erased and over which a new number was engraved; the latter results are similar to those of steel surfaces reported earlier [M.A.M. Zaili, R. Kuppuswamy, H. Harun, Restoration of engraved marks on steel surfaces by etching technique, Forensic Sci. Int. 171 (2007) 27-32].

Inhomogeneous Forcing and Transient Climate Sensitivity

NASA Technical Reports Server (NTRS)

Shindell, Drew T.

2014-01-01

Understanding climate sensitivity is critical to projecting climate change in response to a given forcing scenario. Recent analyses have suggested that transient climate sensitivity is at the low end of the present model range taking into account the reduced warming rates during the past 10-15 years during which forcing has increased markedly. In contrast, comparisons of modelled feedback processes with observations indicate that the most realistic models have higher sensitivities. Here I analyse results from recent climate modelling intercomparison projects to demonstrate that transient climate sensitivity to historical aerosols and ozone is substantially greater than the transient climate sensitivity to CO2. This enhanced sensitivity is primarily caused by more of the forcing being located at Northern Hemisphere middle to high latitudes where it triggers more rapid land responses and stronger feedbacks. I find that accounting for this enhancement largely reconciles the two sets of results, and I conclude that the lowest end of the range of transient climate response to CO2 in present models and assessments (less than 1.3 C) is very unlikely.

Discrimination between weaned and unweaned Atlantic cod (Gadus morhua) in capture-based aquaculture (CBA) by X-ray imaging and radio-frequency metal detector.

PubMed

Misimi, Ekrem; Martinsen, Svein; Mathiassen, John Reidar; Erikson, Ulf

2014-01-01

The aim of this study was to investigate the feasibility of two detection methods for use in discrimination and sorting of adult Atlantic cod (about 2 kg) in the small scale capture-based aquaculture (CBA). Presently, there is no established method for discrimination of weaned and unweaned cod in CBA. Generally, 60-70% of the wild-caught cod in the CBA are weaned into commercial dry feed. To increase profitability for the fish farmers, unweaned cod must be separated from the stock, meaning the fish must be sorted into two groups - unweaned and weaned from moist feed. The challenges with handling of large numbers of fish in cages, defined the limits of the applied technology. As a result, a working model was established, focusing on implementing different marking materials added to the fish feed, and different technology for detecting the feed presence in the fish gut. X-ray imaging in two modes (planar and dual energy band) and sensitive radio-frequency metal detection were the detection methods that were chosen for the investigations. Both methods were tested in laboratory conditions using dead fish with marked feed inserted into the gut cavity. In particular, the sensitive radio-frequency metal detection method with carbonyl powder showed very promising results in detection of marked feed. Results show also that Dual energy band X-ray imaging may have potential for prediction of fat content in the feed. Based on the investigations it can be concluded that both X-ray imaging and sensitive radio-frequency metal detector technology have the potential for detecting cod having consumed marked feed. These are all technologies that may be adapted to large scale handling of fish from fish cages. Thus, it may be possible to discriminate between unweaned and weaned cod in a large scale grading situation. Based on the results of this study, a suggestion for evaluation of concept for in-situ sorting system is presented.

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

PubMed Central

Spurlock, Charles F.; Aune, Zachary T.; Tossberg, John T.; Collins, Patrick L.; Aune, Jessica P.; Huston, Joseph W.; Crooke, Philip S.; Olsen, Nancy J.; Aune, Thomas M.

2011-01-01

Objective Low-dose methotrexate [MTX] is an effective therapy for rheumatoid arthritis yet its mechanism of action is incompletely understood. Here, we explored induction of apoptosis by MTX. Methods We employed flow cytometry to assess changes in levels of intracellular proteins, reactive oxygen species [ROS], and apoptosis.Quantitative polymerase chain reaction was usedtoassess changes in transcript levels of select target genes in response to MTX. Results MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN. Conclusions Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease. PMID:21618198

Urine Scent Marking (USM): A Novel Test for Depressive-Like Behavior and a Predictor of Stress Resiliency in Mice

PubMed Central

Lehmann, Michael L.; Geddes, Claire E.; Lee, Jennifer L.; Herkenham, Miles

2013-01-01

Decreased interest in pleasurable stimuli including social withdrawal and reduced libido are some of the key symptomatic criteria for major depression, and thus assays that measure social and sexual behavior in rodents may be highly appropriate for modeling depressive states. Here we present a novel approach for validating rodent models of depression by assessing male urine scent marking (USM) made in consequence to a spot of urine from a proestrous female. USM is an ethologically important form of sexual communication expressed by males to attract females. The expression of this behavior is highly sensitive and adaptive to environmental cues and social status. We hypothesized that male USM behavior offers a naturalistic measure of social motivation that can be used to evaluate hedonic behaviors relevant to the study of mood disorders. We demonstrated that 1) adult male mice displayed a strong preference for marking proestrous female urine with a high degree of specificity, 2) exposure to chronic social defeat profoundly decreased USM whereas exposure to environmental enrichment increased USM, 3) the standard antidepressant fluoxetine reversed declines in USM induced by social defeat, 4) USM behavior closely correlated with other hedonic measures, and 5) USM scores in non-stressed mice predicted behavioral outcomes after defeat exposure such that mice displaying high preference for marking female urine prior to social defeat showed behavioral resiliency after social defeat. The findings indicate that the USM test is a sensitive, validated measure of psychosocial stress effects that has high predictive value for examination of stress resiliency and vulnerability and their neurobiological substrates. PMID:23875001

Extraction photometric determination of yperite by phthaleins.

PubMed

Halámek, E; Kobliha, Z

1999-01-01

Extraction spectrophotometric determination of sulfidic yperite, based on the reaction with four phthaleins, was developed. The method is technically simpler than the determination of yperites with reagent T-135 (alkaline-aqueous ethanolic thymolphthalein solution) because it does not require heating at 80 degrees C, cooling and acidification of the reaction mixture. Selection of the appropriate phthalein, and particularly optimization of the reagent composition and extraction of the coloured reaction product in chloroform, markedly increased the selectivity of the determination of yperites (HD, HN-3). The reaction is performed in a medium of increased polarity due to the low content of alcohol which enables the reaction to proceed at temperatures of 5-20 degrees C without any marked loss of sensitivity. Using (1)H and (13)C NMR spectroscopy, the reaction products of HD and o-cresolphthalein were identified and an ionic mechanism for the reaction of HD with phthaleins is suggested.

You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists

PubMed Central

Baladi, Michelle G; Daws, Lynette C; France, Charles P

2012-01-01

The important role of dopamine (DA) in mediating feeding behavior and the positive reinforcing effects of some drugs is well recognized. Less widely studied is how feeding conditions might impact the sensitivity of drugs acting on DA systems. Food restriction, for example, has often been the focus of aging and longevity studies; however, other studies have demonstrated that mild food restriction markedly increases sensitivity to direct- and indirect-acting DA receptor agonists. Moreover, it is becoming clear that not only the amount of food, but the type of food, is an important factor in modifying the effects of drugs. Given the increased consumption of high fat and sugary foods, studies are exploring how consumption of highly palatable food impacts DA neurochemistry and the effects of drugs acting on these systems. For example, eating high fat chow increases sensitivity to some behavioral effects of direct- as well as indirect-acting DA receptor agonists. A compelling mechanistic possibility is that the central DA pathways that mediate the effects of some drugs are regulated by one or more of the endocrine hormones (e.g. insulin) that undergo marked changes during food restriction or after consuming high fat or sugary foods. Although traditionally recognized as an important signaling molecule in regulating energy homeostasis, insulin can also regulate DA neurochemistry. Because direct- and indirect-acting DA receptor drugs are used therapeutically and some are abused, a better understanding of how food intake impacts response to these drugs would likely facilitate improved treatment of clinical disorders and provide information that would be relevant to the causes of vulnerability to abuse drugs. PMID:22710441

The effect of CO2 on ventilation and breath-holding during exercise and while breathing through an added resistance.

PubMed

Clark, T J; Godfrey, S

1969-05-01

1. Ventilation was measured while subjects were made to rebreathe from a bag containing CO(2) and O(2) in order to expose them to a steadily rising CO(2) tension (P(CO2)). The object of the experiments was to determine the effect of a variety of stimuli upon the increase in ventilation and fall in breath-holding time which occurs in response to the rising P(CO2).2. Steady-state exercise at 200 kg.m/min resulted in a small fall in the slope of the ventilation-CO(2) response curve (S(V)) and a small, though not statistically significant, fall in the P(CO2) at which ventilation would be zero by extrapolation (B(V)). There was a marked fall in the slope of the breath-holding-CO(2) response curve (S(BH)) and an increase in the P(CO2) at which breath-holding time became zero by extrapolation (B(BH)).3. These results have been interpreted with the aid of a model of the control of breath-holding and it is suggested that there is no change in CO(2) sensitivity on exercise, either during rebreathing or breath-holding.4. An increase in the resistance to breathing caused a marked reduction in S(V) and B(V), but no change in the breath-holding-CO(2) response curve. These findings suggest that the flattening of the ventilation-CO(2) response curve is mechanical in origin and acute airway obstruction produces no change in CO(2) sensitivity.5. On the basis of these results, we suggest that more information about CO(2) sensitivity can be obtained by a combination of ventilation and breath-holding-CO(2) response curves.

Engineering an Anti-Transferrin Receptor ScFv for pH-Sensitive Binding Leads to Increased Intracellular Accumulation.

PubMed

Tillotson, Benjamin J; Goulatis, Loukas I; Parenti, Isabelle; Duxbury, Elizabeth; Shusta, Eric V

2015-01-01

The equilibrium binding affinity of receptor-ligand or antibody-antigen pairs may be modulated by protonation of histidine side-chains, and such pH-dependent mechanisms play important roles in biological systems, affecting molecular uptake and trafficking. Here, we aimed to manipulate cellular transport of single-chain antibodies (scFvs) against the transferrin receptor (TfR) by engineering pH-dependent antigen binding. An anti-TfR scFv was subjected to histidine saturation mutagenesis of a single CDR. By employing yeast surface display with a pH-dependent screening pressure, scFvs having markedly increased dissociation from TfR at pH 5.5 were identified. The pH-sensitivity generally resulted from a central cluster of histidine residues in CDRH1. When soluble, pH-sensitive, scFv clone M16 was dosed onto live cells, the internalized fraction was 2.6-fold greater than scFvs that lacked pH-sensitive binding and the increase was dependent on endosomal acidification. Differences in the intracellular distribution of M16 were also observed consistent with an intracellular decoupling of the scFv M16-TfR complex. Engineered pH-sensitive TfR binding could prove important for increasing the effectiveness of TfR-targeted antibodies seeking to exploit endocytosis or transcytosis for drug delivery purposes.

Engineering an Anti-Transferrin Receptor ScFv for pH-Sensitive Binding Leads to Increased Intracellular Accumulation

PubMed Central

Tillotson, Benjamin J.; Goulatis, Loukas I.; Parenti, Isabelle; Duxbury, Elizabeth; Shusta, Eric V.

2015-01-01

The equilibrium binding affinity of receptor-ligand or antibody-antigen pairs may be modulated by protonation of histidine side-chains, and such pH-dependent mechanisms play important roles in biological systems, affecting molecular uptake and trafficking. Here, we aimed to manipulate cellular transport of single-chain antibodies (scFvs) against the transferrin receptor (TfR) by engineering pH-dependent antigen binding. An anti-TfR scFv was subjected to histidine saturation mutagenesis of a single CDR. By employing yeast surface display with a pH-dependent screening pressure, scFvs having markedly increased dissociation from TfR at pH 5.5 were identified. The pH-sensitivity generally resulted from a central cluster of histidine residues in CDRH1. When soluble, pH-sensitive, scFv clone M16 was dosed onto live cells, the internalized fraction was 2.6-fold greater than scFvs that lacked pH-sensitive binding and the increase was dependent on endosomal acidification. Differences in the intracellular distribution of M16 were also observed consistent with an intracellular decoupling of the scFv M16-TfR complex. Engineered pH-sensitive TfR binding could prove important for increasing the effectiveness of TfR-targeted antibodies seeking to exploit endocytosis or transcytosis for drug delivery purposes. PMID:26713870

On the sensitivity of some common metallographic reagents to restoring obliterated marks on medium carbon (0.31% C) steel surfaces.

PubMed

Yin, Siaw Hui; Kuppuswamy, R

2009-01-10

Chemical etching, which is the most sensitive method to recover obliterated serial numbers on metal surfaces, has been practised quite successfully in forensic science laboratories all over the world. A large number of etchants suitable for particular metal surfaces based on empirical studies is available in the literature. This article reviews the sensitivity and efficacy of some popular etchants for recovering obliterated marks on medium carbon steel (0.31% C with ferrite-pearlite microstructure) used in automobile parts. The experiments involved engraving these carbon steel plates with some alphanumeric characters using a computer controlled machine "Gravograph" and erasing them to several depths below the bottom of their engraving depth. Seven metallographic reagents of which most of them were copper containing compounds were chosen for etching. The erased plates were etched with every one of these etchants using swabbing method. The results have revealed that Fry's reagent comprising cupric chloride 90 g, hydrochloric acid 120 mL and water 100mL provided the necessary contrast and was concluded to be the most sensitive. The same reagent was recommended by earlier workers for revealing strain lines in steel surfaces. Earlier, another reagent containing 5 g copper sulphate, 60 mL water, 30 mL (conc.) ammonium hydroxide, and 60 mL (conc.) hydrochloric acid was proved to be more sensitive to restore erased marks on low carbon steel (0.1% C with ferrite-pearlite structure) [M.A.M. Zaili, R. Kuppuswamy, H. Harun, Restoration of engraved marks on steel surfaces by etching technique, Forensic Sci. Int. 171 (2007) 27-32]. Thus the sensitivity of the etching reagent on steel surfaces appeared to be dependent on the content of carbon in the steel.

Increase of dopamine D2(High) receptors in the striatum of rats sensitized to caffeine motor effects.

PubMed

Simola, Nicola; Morelli, Micaela; Seeman, Philip

2008-05-01

It has been previously demonstrated how rats can develop behavioral dopamine supersensitivity after long-term administration of caffeine. Since behavioral dopamine supersensitivity in rats is usually accompanied by an elevation in striatal dopamine D2(High) receptors, we examined whether alterations in D2(High) receptors occurred in the striatum of rats administered caffeine according to a regimen capable of eliciting behavioral dopamine supersensitivity (15 mg/kg i.p. every other day for 14 days). An increase of 126% in striatal D2(High) receptors was found in caffeine-sensitized rats. This marked elevation in D2(High) receptors may account for the caffeine-induced behavioral dopamine supersensitivity and may help elucidate the interactions between caffeine and dopamine neurotransmission. (c) 2008 Wiley-Liss, Inc.

Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells

PubMed Central

Klattenhoff, Alex W.; Thakur, Megha; Chu, Christopher S.; Ray, Debolina; Habib, Samy L.; Kidane, Dawit

2017-01-01

DNA endonuclease eight-like glycosylase 3 (NEIL3) is one of the DNA glycosylases that removes oxidized DNA base lesions from single-stranded DNA (ssDNA) and non-B DNA structures. Approximately seven percent of human tumors have an altered NEIL3 gene. However, the role of NEIL3 in replication-associated repair and its impact on modulating treatment response is not known. Here, we report that NEIL3 is localized at the DNA double-strand break (DSB) sites during oxidative DNA damage and replication stress. Loss of NEIL3 significantly increased spontaneous replication-associated DSBs and recruitment of replication protein A (RPA). In contrast, we observed a marked decrease in Rad51 on nascent DNA strands at the replication fork, suggesting that HR-dependent repair is compromised in NEIL3-deficient cells. Interestingly, NEIL3-deficient cells were sensitive to ataxia–telangiectasia and Rad3 related protein (ATR) inhibitor alone or in combination with PARP1 inhibitor. This study elucidates the mechanism by which NEIL3 is critical to overcome oxidative and replication-associated genotoxic stress. Our findings may have important clinical implications to utilize ATR and PARP1 inhibitors to enhance cytotoxicity in tumors that carry altered levels of NEIL3. PMID:29348879

Microglia Priming with Aging and Stress.

PubMed

Niraula, Anzela; Sheridan, John F; Godbout, Jonathan P

2017-01-01

The population of aged individuals is increasing worldwide and this has significant health and socio-economic implications. Clinical and experimental studies on aging have discovered myriad changes in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation. In rodent models of aging, these alterations are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges. In rodents, caloric restriction and young blood-induced revitalization reverses the behavioral effects of aging. The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia. For example, microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors. Importantly, the heightened inflammatory profile of microglia in aging is associated with a 'sensitized' or 'primed' phenotype. Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress. Conversely, psychological stress may also induce aging-like sensitization of microglia and increase reactivity to secondary challenges. This review delves into the characteristics of neuroinflammatory signaling and microglial sensitization in aging, its implications in psychological stress, and interventions that reverse aging-associated deficits.

Microglia Priming with Aging and Stress

PubMed Central

Niraula, Anzela; Sheridan, John F; Godbout, Jonathan P

2017-01-01

The population of aged individuals is increasing worldwide and this has significant health and socio-economic implications. Clinical and experimental studies on aging have discovered myriad changes in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation. In rodent models of aging, these alterations are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges. In rodents, caloric restriction and young blood-induced revitalization reverses the behavioral effects of aging. The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia. For example, microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors. Importantly, the heightened inflammatory profile of microglia in aging is associated with a ‘sensitized' or ‘primed' phenotype. Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress. Conversely, psychological stress may also induce aging-like sensitization of microglia and increase reactivity to secondary challenges. This review delves into the characteristics of neuroinflammatory signaling and microglial sensitization in aging, its implications in psychological stress, and interventions that reverse aging-associated deficits. PMID:27604565

Antimicrobial action of silver nitrate.

PubMed

Richards, R M

1981-01-01

Silver nitrate 3 mug/ml prevented the separation into two daughter cells of sensitive dividing cells of Pseudomonas aeruginosa growing in nutrient broth plus the chemical. Cell size of sensitive cells was increased and the cytoplasmic contents, cytoplasmic membrane and external cell envelope structures were all abnormal. P. aeruginosa cells grown in the presence of silver nitrate 9 mug/ml showed all these changes to a marked degree except inhibition of cell division was not observed. Silver nitrate (1.5 mug/ml) in distilled water inactivated bacteriophage T2 particles as determined by their infectivity to Escherichia coli B cultures. Lysozyme (50 mug/ml) reduced, and sodium chloride (0.9%) blocked this activity.

Effects of experimental exposure to triethylamine on vision and the eye

PubMed Central

Jarvinen, P.; Engstrom, K.; Riihimaki, V.; Ruusuvaara, P.; Setala, K.

1999-01-01

OBJECTIVES: To determine the effect of triethylamine (TEA) on the cornea and to evaluate the cause of blurred vision. To find the lowest observed effect concentration of exposure to TEA. METHODS: Four people were exposed to TEA for 4 hours at concentrations of 40.6, 6.5, and 3.0 mg/m3. Before and after every exposure, symptoms and ocular microscopy findings were recorded. Binocular visual acuity and contrast sensitivity at 2.5% contrast were also measured. Also, before and after the 40.6 mg/m3 exposure, corneal thickness was measured and ocular dimensions were recorded by ultrasonography, endothelial cells of the cornea were analysed, and serum and lacrimal specimens were collected for the analysis of TEA. RESULTS: After exposure to 40.6 mg/m3 TEA there was a marked oedema in the corneal epithelium and subepithelial microcysts. However, corneal thickness increased only minimally because of the epithelial oedema. The lacrimal concentrations of TEA were, on average (range) 41 (18-83) times higher than the serum TEA concentrations. The vision was blurred in all subjects and visual acuity and contrast sensitivity had decreased in three of the four subjects. After exposure to TEA at 6.5 mg/m3 two subjects experienced symptoms, and contrast sensitivity had decreased in three of the four subjects. There were no symptoms or decreases in contrast sensitivity after exposure to a TEA concentration of 3.0 mg/m3. CONCLUSIONS: TEA caused a marked oedema and microcysts in corneal epithelium but only minor increases in corneal thickness. The effects may be mediated by the lacrimal fluid owing to its high TEA concentration. Four hour exposure to a TEA concentration of 3.0 mg/m3 seemed to cause no effects, whereas exposure to 6.5 mg/m3 for the same period caused blurred vision and a decrease in contrast sensitivity.   PMID:10341738

Laser-Marking Mechanism of Thermoplastic Polyurethane/Bi2O3 Composites.

PubMed

Zhong, Wei; Cao, Zheng; Qiu, Pengfei; Wu, Dun; Liu, Chunlin; Li, Huili; Zhu, He

2015-11-04

Using bismuth oxide (Bi2O3) as a laser-marking additive and thermoplastic polyurethane (TPU) as the matrix, TPU/Bi2O3 composite materials were prepared by melt blending in a torque rheometer. The sheet samples prepared from the TPU/Bi2O3 composites were treated in air by scanning with a neodymium-doped yttrium aluminum garnet (Nd: YAG) pulsed laser beam at a wavelength of 1064 nm. Compared with the pure TPU sample, the laser-marked composite samples exhibited differences in marking contrast as the Bi2O3 content increased from 0.1% to 1.0% based on stereomicroscope analysis. Scanning electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, thermogravimetry analysis, and X-ray diffraction were used to characterize the laser-marked surface material of the composite samples. Furthermore, a mechanism for the laser-effected darkening of the TPU/Bi2O3 composites was proposed. The results herein indicated that the addition of the Bi2O3 laser-sensitive additive to TPU resulted in laser darkening of the TPU/Bi2O3 composites. The marking contrast and visual appearance of the surface of the TPU/Bi2O3 composites after laser irradiation was due to a synergistic effect consisting of carbonization via TPU pyrolysis and reduction of Bi2O3 to black bismuth metal.

Isolation and characterization of chromosome-gain and increase-in-ploidy mutants in yeast.

PubMed

Chan, C S; Botstein, D

1993-11-01

We have developed a colony papillation assay for monitoring the copy number of genetically marked chromosomes II and III in Saccharomyces cerevisiae. The unique feature of this assay is that it allows detection of a gain of the marked chromosomes even if there is a gain of the entire set of chromosomes (increase-in-ploidy). This assay was used to screen for chromosome-gain or increase-in-ploidy mutants. Five complementation groups have been defined for recessive mutations that confer an increase-in-ploidy (ipl) phenotype, which, in each case, cosegregates with a temperature-sensitive growth phenotype. Four new alleles of CDC31, which is required for spindle pole body duplication, were also recovered from this screen. Temperature-shift experiments with ipl1 cells show that they suffer severe nondisjunction at 37 degrees. Similar experiments with ipl2 cells show that they gain entire sets of chromosomes and become arrested as unbudded cells at 37 degrees. Molecular cloning and genetic mapping show that IPL1 is a newly identified gene, whereas IPL2 is allelic to BEM2, which is required for normal bud growth.

Effect of Turbine Axial Nozzle-Wheel Clearance on Performance of Mark 25 Torpedo Power Plant

NASA Technical Reports Server (NTRS)

Hoyt, Jack W.; Kottas, Harry

1948-01-01

Investigations were made of the turbine from a Mark 25 torpedo to determine the performance of the unit with three different turbine nozzles at various axial nozzle-wheel clearances. Turbine efficiency with a reamed nondivergent nozzle that uses the axial clearance space for gas expansion was little affected by increasing the axial running clearance from 0.030 to 0.150 inch. Turbine efficiency with cast nozzles that expanded the gas inside the nozzle passage was found to be sensitive to increased axial nozzle-wheel clearance. A cast nozzle giving a turbine brake efficiency of 0.525 at an axial running clearance of 0.035 inch gave a brake efficiency of 0.475 when the clearance was increased to 0.095 inch for the same inlet-gas conditions and blade-jet speed ratio. If the basis for computing the isentropic power available to the turbine is the temperature inside the nozzle rather then the temperature in the inlet-gas pipe, an increase in turbine efficiency of about 0.01 is indicated.

Modelling the dependence of contrast sensitivity on grating area and spatial frequency.

PubMed

Rovamo, J; Luntinen, O; Näsänen, R

1993-12-01

We modelled the human foveal visual system in a detection task as a simple image processor comprising (i) low-pass filtering due to the optical transfer function of the eye, (ii) high-pass filtering of neural origin, (iii) addition of internal neural noise, and (iv) detection by a local matched filter. Its detection efficiency for gratings was constant up to a critical area but then decreased with increasing area. To test the model we measured Michelson contrast sensitivity as a function of grating area at spatial frequencies of 0.125-32 c/deg for simple vertical and circular cosine gratings. In circular gratings luminance was sinusoidally modulated as a function of the radius of the grating field. In agreement with the model, contrast sensitivity at all spatial frequencies increased in proportion to the square-root of grating area at small areas. When grating area exceeded critical area, the increase saturated and contrast sensitivity became independent of area at large grating areas. Spatial integration thus obeyed Piper's law at small grating areas. The critical area of spatial integration, marking the cessation of Piper's law, was constant in solid degrees at low spatial frequencies but inversely proportional to spatial frequency squared at medium and high spatial frequencies. At low spatial frequencies the maximum contrast sensitivity obtainable by spatial integration increased in proportion to spatial frequency but at high spatial frequencies it decreased in proportion to the cube of the increasing spatial frequency. The increase was due to high-pass filtering of neural origin (lateral inhibition) and the decrease was mainly due to the optical transfer function of the eye. Our model explained 95% of the total variance of the contrast sensitivity data.

Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations

PubMed Central

Vrbikova, Jana; Kunesova, Marie; Kyrou, Ioannis; Tura, Andrea; Hill, Martin; Grimmichova, Tereza; Dvorakova, Katerina; Sramkova, Petra; Dolezalova, Karin; Lischkova, Olga; Vcelak, Josef; Hainer, Vojtech; Bendlova, Bela; Kumar, Sudhesh; Fried, Martin

2017-01-01

Objective To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). Methods A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Results Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. Conclusion We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity. PMID:27951535

Plant cell pH-static circuit mediated by fusicoccin-binding proteins.

PubMed

Drabkin, A V; Trofimova, M S; Smolenskaya, I N; Klychnikov, O I; Chelysheva, V V; Babakov, A V

1997-03-24

On sugar beet protoplasts that carry two types of fusicoccin-binding sites, a pH downshift in a physiological range (7.0-6.6) markedly enhanced the efficiency of fusicoccin (FC) binding, mainly owing to increased avidity of low-affinity FC-binding sites. This may allow the FC-binding proteins to act as pH-sensitive modulators of cell activity, for instance, via plasma membrane H+-ATPase or potassium channels.

Pseudohypoparathyroidism: defective excretion of 3′,5′-AMP in response to parathyroid hormone

PubMed Central

Chase, Lewis R.; Melson, G. Leland; Aurbach, G. D.

1969-01-01

Urinary excretion of cyclic adenosine 3′,5′-monophosphate (3′,5′-AMP) was tested in normal subjects and patients with pseudohypoparathyroidism, idiopathic hypoparathyroidism, surgical hypoparathyroidism, and pseudopseudohypoparathyroidism under basal conditions and after a 15 min infusion of purified parathyroid hormone. Basal excretion of the nucleotide was less than normal in the patients with hypocalcemic disorders and greater than normal in pseudopseudohypoparathyroidism. Parathyroid hormone caused a marked increase in excretion of 3′,5′-AMP in all subjects except those with pseudohypoparathyroidism; nine patients with this disorder did not respond to the hormone and four showed a markedly deficient response. Radioimmunoassay showed that parathyroid hormone circulated in increased amounts in plasma from patients with pseudohypoparathyroidism and became undetectable when serum calcium was increased above 12 mg/100 ml. Suppression of parathyroid hormone secretion by induction of hypercalcemia did not alter the deficient response to exogenous hormone. The results indicate that: (a) parathyroid hormone circulates in abnormally high concentrations in pseudohypoparathyroidism and secretion of the hormone responds normally to physiological control by calcium; (b) testing urinary excretion of 3′,5′-AMP in response to infusion of purified parathyroid hormone appears to be an accurate and sensitive index for establishing the diagnosis of pseudohypoparathyroidism; and (c) the metabolic defect of the disorder can be accounted for by a lack of or defective form of parathyroid hormone-sensitive adenyl cyclase in bone and kidney. PMID:4309802

Effects of electrostatic discharge on three cryogenic temperature sensor models

NASA Astrophysics Data System (ADS)

Courts, S. Scott; Mott, Thomas B.

2014-01-01

Cryogenic temperature sensors are not usually thought of as electrostatic discharge (ESD) sensitive devices. However, the most common cryogenic thermometers in use today are thermally sensitive diodes or resistors - both electronic devices in their base form. As such, they are sensitive to ESD at some level above which either catastrophic or latent damage can occur. Instituting an ESD program for safe handling and installation of the sensor is costly and it is desirable to balance the risk of ESD damage against this cost. However, this risk cannot be evaluated without specific knowledge of the ESD vulnerability of the devices in question. This work examines three types of cryogenic temperature sensors for ESD sensitivity - silicon diodes, Cernox{trade mark, serif} resistors, and wire wound platinum resistors, all manufactured by Lake Shore Cryotronics, Inc. Testing was performed per TIA/EIA FOTP129 (Human Body Model). Damage was found to occur in the silicon diode sensors at discharge levels of 1,500 V. For Cernox{trade mark, serif} temperature sensors, damage was observed at 3,500 V. The platinum temperature sensors were not damaged by ESD exposure levels of 9,900 V. At the lower damage limit, both the silicon diode and the Cernox{trade mark, serif} temperature sensors showed relatively small calibration shifts of 1 to 3 K at room temperature. The diode sensors were stable with time and thermal cycling, but the long term stability of the Cernox{trade mark, serif} sensors was degraded. Catastrophic failure occurred at higher levels of ESD exposure.

MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

PubMed Central

Pereira, Diane M.; Simões, André E. S.; Gomes, Sofia E.; Castro, Rui E.; Carvalho, Tânia; Rodrigues, Cecília M. P.; Borralho, Pedro M.

2016-01-01

The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53−/− cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted in hibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment. PMID:27144434

Visualization under ultraviolet light enhances 100-fold the sensitivity of peroxidase-stained blots.

PubMed

Domingo, A; Marco, R

1989-10-01

As described in this article, visualization and/or photography under uv light of 4-chloro-1-naphthol-developed, peroxidase-marked immunoblots allows an increase in sensitivity of more than 100 times over the apparent staining results observable under normal visible white light. This increase in sensitivity can be obtained with the minimal additional requirement of an uv lamp, with the actual chloronaphthol staining procedure remaining unaltered and thereby allowing the monitoring of specific reactions with much smaller quantities of antigen or antibodies. Substantial shortening of the procedure is another advantage, making it possible to complete in 20 min or even less a procedure usually requiring 3 to 6 h. The phenomenon depends on the uv absorption and the fluorescence quenching properties of the products of the peroxidase reaction. The absorption spectra of the membranes with or without peroxidase products indicate that an intermediate in the peroxidase reaction is responsible for the absorption under uv light. This intermediate accumulates under conditions where the final product absorbing in the visible light has not begun to be produced, thus explaining the large increase in sensitivity. The behaviors of three types of membranes, nitrocellulose, nylon, and Immobilon (PVDF), are compared. Due to its lower uv absorption, PVDF gives by far the best results, followed by nitrocellulose.

Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention.

PubMed

Post, Robert M

2016-06-01

The process of sensitization (increased responsivity) to the recurrence of stressors, affective episodes, and bouts of substance abuse that can drive illness progression in the recurrent affective disorders requires a memory of and increased reactivity to the prior exposures. A wealth of studies now supports the postulate that epigenetic mechanisms underlie both normal and pathological memory processes. We selectively reviewed the literature pertinent to the role of epigenetics in behavioral sensitization phenomena and discuss its clinical implications. Epigenetics means above genetics and refers to environmental effects on the chemistry of DNA, histones (around which DNA is wound), and microRNA that change how easily genes are turned on and off. The evidence supports that sensitization to repeated stressor, affective episodes, and substance is likely based on epigenetic mechanisms and that these environmentally based processes can then become targets for prevention, early intervention, and ongoing treatment. Sensitization processes are remediable or preventable risk factors for a poor illness outcome and deserve increased clinical, public health, and research attention in the hopes of making the recurrent unipolar and bipolar affective disorders less impairing, disabling, and lethal by suicide and increased medical mortality. The findings that epigenetic chemical marks, which change in the most fundamental way how genes are regulated, mediate the long-term increased responsivity to recurrent stressors, mood episodes, and bouts of substance abuse should help change how the affective disorders are conceptualized and move treatment toward earlier, more comprehensive, and sustained pharmacoprophylaxis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Autophagic cell death induced by reactive oxygen species is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells.

PubMed

Yuan, Guang-Jin; Deng, Jun-Jian; Cao, De-Dong; Shi, Lei; Chen, Xin; Lei, Jin-Ju; Xu, Xi-Ming

2017-08-14

To investigate whether autophagic cell death is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells, and to explore the underlying mechanism. Human hepatocellular carcinoma cells were treated with hyperthermia and ionizing radiation. MTT and clonogenic assays were performed to determine cell survival. Cell autophagy was detected using acridine orange staining and flow cytometric analysis, and the expression of autophagy-associated proteins, LC3 and p62, was determined by Western blot analysis. Intracellular reactive oxygen species (ROS) were quantified using the fluorescent probe DCFH-DA. Treatment with hyperthermia and ionizing radiation significantly decreased cell viability and surviving fraction as compared with hyperthermia or ionizing radiation alone. Cell autophagy was significantly increased after ionizing radiation combined with hyperthermia treatment, as evidenced by increased formation of acidic vesicular organelles, increased expression of LC3II and decreased expression of p62. Intracellular ROS were also increased after combined treatment with hyperthermia and ionizing radiation. Pretreatment with N-acetylcysteine, an ROS scavenger, markedly inhibited the cytotoxicity and cell autophagy induced by hyperthermia and ionizing radiation. Autophagic cell death is involved in hyperthermic sensitization of cancer cells to ionizing radiation, and its induction may be due to the increased intracellular ROS.

Directional detector of gamma rays

DOEpatents

Cox, Samson A.; Levert, Francis E.

1979-01-01

A directional detector of gamma rays comprises a strip of an electrical cuctor of high atomic number backed with a strip of a second electrical conductor of low atomic number. These elements are enclosed within an electrical conductor that establishes an electrical ground, maintains a vacuum enclosure and screens out low-energy gamma rays. The detector exhibits a directional sensitivity marked by an increased output in the favored direction by a factor of ten over the output in the unfavored direction.

Meadow sensitivity to natural and anthropogenic disturbance [chapter 5

Treesearch

Jerry R. Miller; Mark L. Lord; Dru Germanoski

2011-01-01

Investigations of geomorphic responses to natural and anthropogenic disturbances have revealed marked differences in the rate, magnitude, and nature by which different watersheds, or components of a given watershed, adjust to perturbations. These differences in response are often characterized using the concept of landform sensitivity. The term sensitivity has been...

Metabolic effects of cortisol, ACTH, adrenalin and insulin in the marsupial sugar glider, Petaurus breviceps.

PubMed

Bradley, A J; Stoddart, D M

1990-11-01

The effects of cortisol, ACTH, adrenalin and insulin on indices of carbohydrate, fat and protein metabolism were investigated in the conscious marsupial sugar glider Petaurus breviceps. Short-term i.v. infusion of cortisol at dose rates of 0.02, 0.2 and 1.0 mg/kg per h caused the plasma glucose concentration to rise sharply from the normal range of 3.3-4.4 to 8.1-8.7 mmol/l at the end of the infusion period without significant alteration in plasma free fatty acid (FFA), amino acid or urea concentrations. Infusions of ACTH at dose rates of 0.02, 0.06 and 0.45 IU/kg per h caused a similar rise in plasma glucose concentration; however, this was now accompanied by an elevation in plasma FFA concentration, but again without significant changes in either plasma amino acid or urea concentrations. Infusion of adrenalin at 10 micrograms/kg per h caused an increase in the plasma concentrations of both glucose and FFA. Intravenous injections of 0.15 IU insulin/kg caused a rapid and marked decrease in the plasma glucose concentration within 30 min and an increase in the plasma free cortisol concentration. Associated with this change was a marked rise in the plasma concentration of both FFA and free cortisol. The rise in free cortisol was, however, significantly reduced by infusion of glucose. Pretreatment with five daily i.m. injections of 1 mg cortisol acetate/kg, which produced an increase in plasma free cortisol concentration to near the maximum of the physiological range, caused a marked reduction in insulin sensitivity. Cortisol pretreatment caused an increase in the plasma FFA and amino acid concentrations. Petaurus breviceps is highly sensitive to the metabolic effects of glucocorticoids and is similar in this respect to the brush-tailed possum Trichosurus vulpecula. The interactive effects between insulin and glucocorticoids on carbohydrate, fat and protein metabolism in Petaurus breviceps are similar to those shown by Trichosurus vulpecula and some eutherian mammals but contrast with the pattern described for two macropodid marsupials, the red kangaroo Macropus rufus and the quokka Setonix brachyurus.

A blood biomarker for monitoring response to anti-EGFR therapy.

PubMed

Hughes, Nicholas P; Xu, Lingyun; Nielsen, Carsten H; Chang, Edwin; Hori, Sharon S; Natarajan, Arutselvan; Lee, Samantha; Kjær, Andreas; Kani, Kian; Wang, Shan X; Mallick, Parag; Gambhir, Sanjiv Sam

2018-04-13

To monitor therapies targeted to epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC), we investigated Peroxiredoxin 6 (PRDX6) as a biomarker of response to anti-EGFR agents. We studied cells that are sensitive (H3255, HCC827) or resistant (H1975, H460) to gefitinib. PRDX6 was examined with either gefitinib or vehicle treatment using enzyme-linked immunosorbent assays. We created xenograft models from one sensitive (HCC827) and one resistant cell line (H1975) and monitored serum PRDX6 levels during treatment. PRDX6 levels in cell media from sensitive cell lines increased significantly after gefitinib treatment vs. vehicle, whereas there was no significant difference for resistant lines. PRDX6 accumulation over time correlated positively with gefitinib sensitivity. Serum PRDX6 levels in gefitinib-sensitive xenograft models increased markedly during the first 24 hours of treatment and then decreased dramatically during the following 48 hours. Differences in serum PRDX6 levels between vehicle and gefitinib-treated animals could not be explained by differences in tumor burden. Our results show that changes in serum PRDX6 during the course of gefitinib treatment of xenograft models provide insight into tumor response and such an approach offers several advantages over imaging-based strategies for monitoring response to anti-EGFR agents.

Effects of increased temperature on metabolic activity and oxidative stress in the first life stages of marble trout (Salmo marmoratus).

PubMed

Simčič, Tatjana; Jesenšek, Dušan; Brancelj, Anton

2015-08-01

Climate change may result in future alterations in thermal regime which could markedly affect the early developmental stages of cold water fish due to their expected high sensitivity to increasing temperature. In the present study, the effect of temperature increase of 2, 4 and 6°C on the oxygen consumption rate (R), the activity of respiratory electron transport system (ETS) and oxidative stress have been studied in four developmental stages of the marble trout (Salmo marmoratus)-eyed eggs, yolk-sac larvae and juveniles of 1 and 3 months. Oxygen consumption rate and ETS activity increased with level of development and with temperature in all four stages. ETS/R ratios decreased during development and correlated with temperature in eyed eggs, larvae and juveniles of 1 month, but not in juveniles of 3 months. Low ETS/R ratios at higher temperatures indicate stress response in eyed eggs, the most temperature sensitive developmental stage. Catalase (CAT) and glutathione reductase (GR) activities increased during development, but responded differently to elevated temperature in the different developmental stages. Stress in eyed eggs, caused by higher temperatures, resulted in increased oxygen consumption rate and increased activities of CAT and GR. Larvae were sensitive to increased temperature only at the highest experimental temperature of 16°C. Increased temperature did not stress the metabolism of the juveniles, since they were able to compensate their metabolic activity. The earlier developmental stages of marble trout are thus more sensitive to temperature increase than juveniles and therefore more endangered by higher water temperatures. This is the first report connecting oxygen consumption, ETS activity and ETS/R ratio with the activities of antioxidant enzymes in relation to increased temperature in salmonids.

[Silencing MSH3 expression enhances cisplatin sensitivity of human tongue cancer cells].

PubMed

Fan, Xiao-Sheng; Cao, Fang-Yun; Li, Kuang-Zheng

2016-08-20

To explore the effect of MSH3 knock-down on sensitivity of tongue cancer cells to cisplatin. Three small interfering RNA (siRNA) fragments targeting MSH3 CDS region were synthesized and transfected into CAL27 cells via Lipofectamine. Real-time PCR and Western blotting were used to assess the efficiency of MSH3 silencing. MTS, apoptosis staining and cell immunofluorescence assay were used to examine the cisplatin sensitivity, apoptosis and DNA repair of transfected CAL27 cells. s One of the 3 siRNAs was found to significantly reduce the expression of MSH3 protein in CAL27 cells (P<0.05). MTS assay showed that MSH3 silencing resulted in an significant reduction of IC50 of cisplatin from 21.32 to 13.95 µmol/L (P<0.05) and increased the apoptotic index of the exposed cells from 4.23∓1.27 to 11.32∓1.82 (P<0.05). Immunofluorescence assay demonstrated that silencing MSH3 markedly reduced the number of γ-H2AX foci. Silencing MSH3 can significantly increase cisplatin sensitivity of tongue cancer cells, the mechanism of which involves mainly attenuation of repair of DNA double-strand damage in the cells.

Quantification of extracellular levels of corticosterone in the basolateral amygdaloid complex of freely-moving rats: a dialysis study of circadian variation and stress-induced modulation.

PubMed

Bouchez, Gaëlle; Millan, Mark J; Rivet, Jean-Michel; Billiras, Rodolphe; Boulanger, Raphaël; Gobert, Alain

2012-05-03

Corticosterone influences emotion and cognition via actions in a diversity of corticolimbic structures, including the amygdala. Since extracellular levels of corticosterone in brain have rarely been studied, we characterized a specific and sensitive enzymatic immunoassay for microdialysis quantification of corticosterone in the basolateral amygdaloid complex of freely-moving rats. Corticosterone levels showed marked diurnal variation with an evening (dark phase) peak and stable, low levels during the day (light phase). The "anxiogenic agents", FG7142 (20 mg/kg) and yohimbine (10 mg/kg), and an environmental stressor, 15-min forced-swim, induced marked and sustained (1-3 h) increases in dialysis levels of corticosterone in basolateral amygdaloid complex. They likewise increased dialysis levels of dopamine and noradrenaline, but not serotonin and GABA. As compared to basal corticosterone levels of ~200-300 pg/ml, the elevation provoked by forced-swim was ca. 20-fold and this increase was abolished by adrenalectomy. Interestingly, stress-induced rises of corticosterone levels in basolateral amygdaloid complex were abrogated by combined but not separate administration of the corticotrophin releasing factor(1) (CRF(1)) receptor antagonist, CP154,526, and the vasopressin(1b) (V(1b)) receptor antagonist, SSR149,415. Underpinning their specificity, they did not block forced-swim-induced elevations in dopamine and noradrenaline. In conclusion, extracellular levels of corticosterone in the basolateral amygdaloid complex display marked diurnal variation. Further, they are markedly elevated by acute stressors, the effects of which are mediated (in contrast to concomitant elevations in levels of monoamines) by co-joint recruitment of CRF(1) and V(1b) receptors. Copyright © 2012 Elsevier B.V. All rights reserved.

Restoration of engraved marks on steel surfaces by etching technique.

PubMed

Zaili, Mohd Azlan Mohd; Kuppuswamy, R; Harun, Hafizah

2007-08-24

It is known that restoration of erased engraved identification marks on the engine and the chassis of a car or on a firearm has low success rate. Unlike stamping, engraving on a metal surface leaves no pronounced, permanent subsurface deformation in the crystalline structure, also called dislocation that can be revealed by suitable methods. Hence, the current research work investigated whether metallographic reagents used in the restoration of stamp (compression) marks could be applied to recover engraved marks on steel surfaces and also to establish the sensitivity and effectiveness of some of these reagents for the restoration of the marks. Experiments were conducted by mechanically engraving alphanumeric characters on several steel plates using a computer controlled engraving machine called Gravograph. The markings were later erased from the above steel plates by removing the metal in stages of 0.01 mm through 0.04 mm below the bottom of the engraving. Several plates were thus prepared wherein each one had been abraded to a specific depth. Then eight metallographic reagents were tested on each one of the above erased plates using a swabbing technique. The results had shown that while most of the reagents were able to restore marks up to certain levels of erasure, the reagent 5 g copper sulphate, 60 ml water, 30 ml concentrated ammonium hydroxide and 60 ml concentrated hydrochloric acid restored marks erased to a depth of 0.04 mm below the engraving depth, thus presenting itself the most sensitive reagent. Quite significantly, the above reagent was also able to decipher successfully the original engraved marks that had been erased and engraved with a new number, or obliterated by centre punching. The results of this research work should benefit the forensic practitioners engaged in the serial number recovery on vehicles, firearms and other objects.

Detailed Functional and Proteomic Characterization of Fludarabine Resistance in Mantle Cell Lymphoma Cells

PubMed Central

Lorkova, Lucie; Scigelova, Michaela; Arrey, Tabiwang Ndipanquang; Vit, Ondrej; Pospisilova, Jana; Doktorova, Eliska; Klanova, Magdalena; Alam, Mahmudul; Vockova, Petra; Maswabi, Bokang

2015-01-01

Mantle cell lymphoma (MCL) is a chronically relapsing aggressive type of B-cell non-Hodgkin lymphoma considered incurable by currently used treatment approaches. Fludarabine is a purine analog clinically still widely used in the therapy of relapsed MCL. Molecular mechanisms of fludarabine resistance have not, however, been studied in the setting of MCL so far. We therefore derived fludarabine-resistant MCL cells (Mino/FR) and performed their detailed functional and proteomic characterization compared to the original fludarabine sensitive cells (Mino). We demonstrated that Mino/FR were highly cross-resistant to other antinucleosides (cytarabine, cladribine, gemcitabine) and to an inhibitor of Bruton tyrosine kinase (BTK) ibrutinib. Sensitivity to other types of anti-lymphoma agents was altered only mildly (methotrexate, doxorubicin, bortezomib) or remained unaffacted (cisplatin, bendamustine). The detailed proteomic analysis of Mino/FR compared to Mino cells unveiled over 300 differentially expressed proteins. Mino/FR were characterized by the marked downregulation of deoxycytidine kinase (dCK) and BTK (thus explaining the observed crossresistance to antinucleosides and ibrutinib), but also by the upregulation of several enzymes of de novo nucleotide synthesis, as well as the up-regulation of the numerous proteins of DNA repair and replication. The significant upregulation of the key antiapoptotic protein Bcl-2 in Mino/FR cells was associated with the markedly increased sensitivity of the fludarabine-resistant MCL cells to Bcl-2-specific inhibitor ABT199 compared to fludarabine-sensitive cells. Our data thus demonstrate that a detailed molecular analysis of drug-resistant tumor cells can indeed open a way to personalized therapy of resistant malignancies. PMID:26285204

Scent marking behavior as an odorant communication in mice

PubMed Central

Arakawa, Hiroyuki; Blanchard, D. Caroline; Arakawa, Keiko; Dunlap, Christopher; Blanchard, Robert J.

2008-01-01

In rodents, where chemical signals play a particularly important role in determining intraspecies interactions including social dominance and intersexual relationships, various studies have shown that behavior is sensitive to conspecific odor cues. Mice use urinary scent marks for communication with individual conspecifics in many social contexts. Urinary scent involves genetic information about individuals such as species, sex, and individual identity as well as metabolic information such as social dominance, and reproductive and health status, which are mediated by chemical proteins in scent marks including the major histocompatibility complex and the major urinary proteins. The odor of the predator which can be considered to be a threatening signal for the prey also modulate mouse behavior in which scent marking is suppressed in response to the cat odor exposure in mice. These odorant chemicals are detected and recognized through two olfactory bulbs, the role of which in detection of chemosignals with biological relevant appears to be differential, but partly overlapped. Mice deposit scent marks toward conspecifics to maintain their social relationships, and inhibit scent marking in a context where natural predator, cat odor is contained. This suppression of scent marking is long-lasting (for at least 7 days) and context-dependent, while the odorant signaling to conspecifics tends to appear frequently (over 24 hrs but less than 7 days intervals) depending on the familiarity of each signal-recipient. It has been discussed that scent marking is a communicative behavior associated with territoriality toward conspecifics, indicating that the social signaling within species are sensitive to predator odor cues in terms of vulnerability to predation risk. PMID:18565582

ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content

PubMed Central

Joseph, Roy; Poschmann, Jeremie; Sukarieh, Rami; Too, Peh Gek; Julien, Sofi G.; Xu, Feng; Teh, Ai Ling; Holbrook, Joanna D.; Ng, Kai Lyn; Chong, Yap Seng; Gluckman, Peter D.; Prabhakar, Shyam

2015-01-01

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals. PMID:25915184

ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content.

PubMed

Joseph, Roy; Poschmann, Jeremie; Sukarieh, Rami; Too, Peh Gek; Julien, Sofi G; Xu, Feng; Teh, Ai Ling; Holbrook, Joanna D; Ng, Kai Lyn; Chong, Yap Seng; Gluckman, Peter D; Prabhakar, Shyam; Stünkel, Walter

2015-06-01

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.

Isolation and Characterization of Chromosome-Gain and Increase-in-Ploidy Mutants in Yeast

PubMed Central

Chan, CSM.; Botstein, D.

1993-01-01

We have developed a colony papillation assay for monitoring the copy number of genetically marked chromosomes II and III in Saccharomyces cerevisiae. The unique feature of this assay is that it allows detection of a gain of the marked chromosomes even if there is a gain of the entire set of chromosomes (increase-in-ploidy). This assay was used to screen for chromosome-gain or increase-in-ploidy mutants. Five complementation groups have been defined for recessive mutations that confer an increase-in-ploidy (ipl) phenotype, which, in each case, cosegregates with a temperature-sensitive growth phenotype. Four new alleles of CDC31, which is required for spindle pole body duplication, were also recovered from this screen. Temperature-shift experiments with ipl1 cells show that they suffer severe nondisjunction at 37°. Similar experiments with ipl2 cells show that they gain entire sets of chromosomes and become arrested as unbudded cells at 37°. Molecular cloning and genetic mapping show that IPL1 is a newly identified gene, whereas IPL2 is allelic to BEM2, which is required for normal bud growth. PMID:8293973

D-dimer: An Overview of Hemostasis and Fibrinolysis, Assays, and Clinical Applications.

PubMed

Olson, John D

2015-01-01

D-dimer is the smallest fibrinolysis-specific degradation product found in the circulation. The origins, assays, and clinical use of D-dimer will be addressed. Hemostasis (platelet and vascular function, coagulation, fibrinolysis, hemostasis) is briefly reviewed. D-dimer assays are reviewed. The D-dimer is very sensitive to intravascular thrombus and may be markedly elevated in disseminated intravascular coagulation, acute aortic dissection, and pulmonary embolus. Because of its exquisite sensitivity, negative tests are useful in the exclusion venous thromboembolism. Elevations occur in normal pregnancy, rising two- to fourfold by delivery. D-dimer also rises with age, limiting its use in those >80 years old. There is a variable rise in D-dimer in active malignancy and indicates increased thrombosis risk in active disease. Elevated D-dimer following anticoagulation for a thrombotic event indicates increased risk of recurrent thrombosis. These and other issues are addressed. © 2015 Elsevier Inc. All rights reserved.

Fluorescent sensing with Fresnel microlenses for optofluidic systems

NASA Astrophysics Data System (ADS)

Siudzińska, Anna; Miszczuk, Andrzej; Marczak, Jacek; Komorowska, Katarzyna

2017-05-01

The concept of fluorescent sensing in a microchannel equipped with focusing light Fresnel lenses has been demonstrated. The concept employs a line or array of Fresnel lenses generating a line or array of focused light spots within a microfluidic channel, to increase the sensitivity of fluorescent signal detection in the system. We have presented efficient methods of master mold fabrication based on the lithography method and focused ion beam milling. The flexible microchannel was fabricated by an imprint process with new thiolene-epoxy resin with a good ability to replicate even submicron-size features. For final imprinted lenses, the measured background to peak signal level shows more than nine times the increase in brightness at the center of the focal spot for the green part of the spectrum (532 nm). The effectiveness of the microlenses in fluorescent-marked Escherichia coli bacteria was confirmed in a basic fluoroscope experiment, showing the increase of the sensitivity of the detection by the order of magnitude.

Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2.

PubMed

Scapa, Erez F; Pocai, Alessandro; Wu, Michele K; Gutierrez-Juarez, Roger; Glenz, Lauren; Kanno, Keishi; Li, Hua; Biddinger, Sudha; Jelicks, Linda A; Rossetti, Luciano; Cohen, David E

2008-07-01

Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is a highly specific intracellular lipid binding protein with accentuated expression in oxidative tissues. Here we show that decreased plasma concentrations of glucose and free fatty acids in fasting PC-TP-deficient (Pctp(-/-)) mice are attributable to increased hepatic insulin sensitivity. In hyperinsulinemic-euglycemic clamp studies, Pctp(-/-) mice exhibited profound reductions in hepatic glucose production, gluconeogenesis, glycogenolysis, and glucose cycling. These changes were explained in part by the lack of PC-TP expression in liver per se and in part by marked alterations in body fat composition. Reduced respiratory quotients in Pctp(-/-) mice were indicative of preferential fatty acid utilization for energy production in oxidative tissues. In the setting of decreased hepatic fatty acid synthesis, increased clearance rates of dietary triglycerides and increased hepatic triglyceride production rates reflected higher turnover in Pctp(-/-) mice. Collectively, these data support a key biological role for PC-TP in the regulation of energy substrate utilization.

INF-γ sensitizes head and neck squamous cell carcinoma cells to chemotherapy-induced apoptosis and necroptosis through up-regulation of Egr-1.

PubMed

Xu, Bei; Shu, Yongqian; Liu, Peng

2014-11-01

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Acquired resistance to standard chemotherapy accounts for most of treatment failure. Here we demonstrate that Interferon-γ (INF-γ) may up-regulate Egr-1 gene expression in HNSCC cell line SCC-25. Forced expression of Egr-1 sensitizes SCC-25 cells to chemotherapy-induced apoptosis and necroptosis, a novel form of programmed cell death. Egr-1 up-regulation also significantly increases the production of Thrombospondin-1 (TSP-1), a matricellular glycoprotein which has been described to induce cell death in HNSCC. Moreover, INF-γ-induced sensitization of cells to chemotherapy-mediated cell death and TSP-1 production could be markedly abolished by Egr-1 silencing. The present investigation provides the first evidence that INF-γ may sensitize HNSCC cells to chemotherapy-induced apoptosis and necroptosis through up-regulation of Egr-1. These data support the combination use of INF-γ and cytotoxic drugs for HNSCC Therapy.

Heart rate and blood pressure variabilities in salt-sensitive hypertension.

PubMed

Piccirillo, G; Bucca, C; Durante, M; Santagada, E; Munizzi, M R; Cacciafesta, M; Marigliano, V

1996-12-01

In salt-sensitive hypertension, a high sodium intake causes plasma catecholamines to rise and pulmonary baroreceptor plasticity to fall. In salt-sensitive and salt-resistant hypertensive subjects during low and high sodium intakes, we studied autonomic nervous system activity by power spectral analysis of heart rate and arterial pressure variabilities and baroreceptor sensitivity. In all subjects, high sodium intake significantly enhanced the low-frequency power of heart rate and arterial pressures at rest and after sympathetic stress. It also increased heart rate and arterial pressure variabilities. During high sodium intake, salt-sensitive hypertensive subjects had significantly higher low-frequency powers of systolic arterial pressure (7.5 mm Hg2, P < .05) and of heart rate at rest (59.2 +/- 2.4 normalized units [NU], P < .001) than salt-resistant subjects (6.6 +/- 0.3 mm Hg2, 55.0 +/- 3.2 NU) and normotensive control subjects (5.1 +/- 0.5 mm Hg2, 41.6 +/- 2.9 NU). In salt-sensitive subjects, low sodium intake significantly reduced low-frequency normalized units (P < .001) and the ratio of low- to high-power frequency (P < .001). High-sodium intake significantly increased baroreflex sensitivity in control subjects (from 10.0 +/- 0.7 to 17.5 +/- 0.7 ms/mm Hg, P < .001) and salt-resistant subjects (from 6.9 +/- 0.7 to 13.9 +/- 0.9, P < .05) but not in salt-sensitive subjects (7.4 +/- 0.3 to 7.9 +/- 0.4). In conclusion, a high sodium intake markedly enhances cardiac sympathetic activity in salt-sensitive and salt-resistant hypertension. In contrast, although reduced sodium intake lowers arterial pressure and sympathetic activity, it does so only in salt-sensitive subjects. Hence, in salt-resistant subjects, neither arterial pressure nor sympathetic activity depends on salt intake. During a high sodium intake in normotensive subjects and salt-resistant hypertensive subjects, increased sympathetic activity is probably compensated by enhanced baroreflex sensitivity.

"Imposed" and "inherent" mucosal activity patterns. Their composite representation of olfactory stimuli

PubMed Central

1987-01-01

Both regional differences in mucosal sensitivity and a gas chromatography-like process along the mucosal sheet have been separately proposed in two sets of earlier studies to produce different odorant-dependent activity patterns across the olfactory mucosa. This investigation evaluated, in one study, whether and to what degree these two mechanisms contribute to the generation of these activity patterns. Summated multiunit discharges were simultaneously recorded from lateral (LN) and medial (MN) sites on the bullfrog's olfactory nerve to sample the mucosal activity occurring near the internal and external nares, respectively. Precisely controlled sniffs of four odorants (benzaldehyde, butanol, geraniol, and octane) were drawn through the frog's olfactory sac in both the forward (H1) and reverse (H2) hale directions. By combining the four resulting measurements, LNH1, LNH2, MNH1, and MNH2, in different mathematical expressions, indexes reflecting the relative effects of the chromatographic process, regional sensitivity, and hale direction could be calculated. Most importantly, the chromatographic process and the regional sensitivity differences both contributed significantly to the mucosal activity patterns. However, their relative roles varied markedly among the four odorants, ranging from complete dominance by either one to substantial contributions from each. In general, the more strongly an odorant was sorbed by the mucosa, the greater was the relative effect of the chromatographic process; the weaker the sorption, the greater the relative effect of regional sensitivity. Similarly, the greater an odorant's sorption, the greater was the effect of hale direction. Other stimulus variables (sniff volume, sniff duration, and the number of molecules within the sniff) had marked effects upon the overall size of the response. For strongly sorbed odorants, the effect of increasing volume was positive; for a weakly sorbed odorant, it was negative. The reverse may be true for duration. In contrast, the effect of increasing the number of molecules was uniformly positive for all four odorants. However, there was little evidence that these other stimulus variables had a major influence upon the effects of the chromatographic process and regional sensitivity differences in their generation of mucosal activity patterns. PMID:3500998

The role of changes in the sensitivity of hepatic mitochondrial overt carnitine palmitoyltransferase in determining the onset of the ketosis of starvation in the rat.

PubMed Central

Drynan, L; Quant, P A; Zammit, V A

1996-01-01

The relationships between the increase in blood ketone-body concentrations and several parameters that can potentially influence the rate of hepatic fatty acid oxidation were studied during progressive starvation (up to 24 h) in the rat in order to discover whether the sensitivity of mitochondrial overt carnitine palmitoyltransferase (CPT I) to malonyl-CoA plays an important part in determining the intrahepatic potential for fatty acid oxidation during the onset of ketogenic conditions. A rapid increase in blood ketone-body concentration occurred between 12 and 16 h of starvation, several hours after the marked fall in hepatic malonyl-CoA and in serum insulin concentrations and doubling of plasma non-esterfied fatty acid (NEFA) concentration. Consequently, both the changes in hepatic malonyl-CoA and serum NEFA preceded the increase in blood ketone-body concentration by several hours. The maximal activity of CPT I increased gradually throughout the 24 h period of starvation, but the increases did not become significant before 18 h of starvation. By contrast, the sensitivity of CPT I to malonyl-CoA and the increase in blood ketone-body concentration followed an identical time course, demonstrating the central importance of this parameter in determining the ketogenic response of the liver to the onset of the starved state. PMID:8836117

You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists.

PubMed

Baladi, Michelle G; Daws, Lynette C; France, Charles P

2012-07-01

The important role of dopamine (DA) in mediating feeding behavior and the positive reinforcing effects of some drugs is well recognized. Less widely studied is how feeding conditions might impact the sensitivity of drugs acting on DA systems. Food restriction, for example, has often been the focus of aging and longevity studies; however, other studies have demonstrated that mild food restriction markedly increases sensitivity to direct- and indirect-acting DA receptor agonists. Moreover, it is becoming clear that not only the amount of food, but the type of food, is an important factor in modifying the effects of drugs. Given the increased consumption of high fat and sugary foods, studies are exploring how consumption of highly palatable food impacts DA neurochemistry and the effects of drugs acting on these systems. For example, eating high fat chow increases sensitivity to some behavioral effects of direct- as well as indirect-acting DA receptor agonists. A compelling mechanistic possibility is that central DA pathways that mediate the effects of some drugs are regulated by one or more of the endocrine hormones (e.g. insulin) that undergo marked changes during food restriction or after consuming high fat or sugary foods. Although traditionally recognized as an important signaling molecule in regulating energy homeostasis, insulin can also regulate DA neurochemistry. Because direct- and indirect-acting DA receptor drugs are used therapeutically and some are abused, a better understanding of how food intake impacts response to these drugs would likely facilitate improved treatment of clinical disorders and provide information that would be relevant to the causes of vulnerability to abuse drugs. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits.

PubMed

Prior, Larissa J; Eikelis, Nina; Armitage, James A; Davern, Pamela J; Burke, Sandra L; Montani, Jean-Pierre; Barzel, Benjamin; Head, Geoffrey A

2010-04-01

The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 microg) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: -54%, paraventricular: -69%, and dorsomedial hypothalamus: -65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals.

DNA repair properties of Escherichia coli tif-1, recAo281 and lexA1 strains deficient in single-strand DNA binding protein.

PubMed

Whittier, R F; Chase, J W

1983-01-01

Mutations affecting single-strand DNA binding protein (SSB) impair induction of mutagenic (SOS) repair. To further investigate the role of SSB in SOS induction and DNA repair, isogenic strains were constructed combining the ssb+, ssb-1 or ssb-113 alleles with one or more mutations known to alter regulation of damage inducible functions. As is true in ssb+ strains tif-1 (recA441) was found to allow thermal induction of prophage lambda + and Weigle reactivation in ssb-1 and ssb-113 strains. Furthermore, tif-1 decreased the UV sensitivity of the ssb-113 strain slightly and permitted UV induction of prophage lambda + at 30 degrees C. Strains carrying the recAo281 allele were also constructed. This mutation causes high constitutive levels of RecA protein synthesis and relieves much of the UV sensitivity conferred by lexA- alleles without restoring SOS (error-prone) repair. In contrast, the recAo281 allele failed to alleviate the UV sensitivity associated with either ssb- mutation. In a lexA1 recAo281 background the ssb-1 mutation increased the extent of postirradiation DNA degradation and concommitantly increased UV sensitivity 20-fold to the level exhibited by a recA1 strain. The ssb-113 mutation also increased UV sensitivity markedly in this background but did so without greatly increasing postirradiation DNA degradation. These results suggest a direct role for SSB in recombinational repair apart from and in addition to its role in facilitating induction of the recA-lexA regulon.

Tension responses to rapid pressure release in glycerinated rabbit muscle fibers.

PubMed Central

Fortune, N S; Geeves, M A; Ranatunga, K W

1991-01-01

We have previously shown that the isometric tension of a fully calcium-activated skinned rabbit psoas muscle fiber is reversibly depressed by increased hydrostatic pressure. We report here the characterization of tension transients induced by a rapid (less than 1-ms) release of increased pressure at 12 degrees C. The tension transient consists of three clear phases, an initial further decrease of tension in phase with pressure change followed by two phases of tension increase back to the level recorded at ambient pressure. The mean reciprocal relaxation time for phase 2 (1/tau 2) was approximately 17 s-1 and that for phase 3 (1/tau 3) was 3 s-1. The presence of 20 mM inorganic phosphate markedly increased 1/tau 2 to approximately 52 s-1 and decreased 1/tau 3 to approximately 1.7 s-1. These observations are interpreted in terms of a pressure-sensitive transition between two attached crossbridge states of low (or zero) and higher force. This is compatible with the pressure-sensitive isomerization of actomyosin previously observed in solution. The results presented allow us to propose a coupling between a specific pressure-sensitive isomerization of purified actomyosin, the phosphate release step of the ATPase pathway, and the force-generating event of the cross-bridge cycle. PMID:1871140

Prostatic relaxation induced by agmatine is decreased in spontaneously hypertensive rats.

PubMed

Lee, Liang-Ming; Tsai, Tsung-Chin; Chung, Hsien-Hui; Tong, Yat-Ching; Cheng, Juei-Tang

2012-09-01

What's known on the subject? and What does the study add? Neurotransmitters are known to control prostate contractility. Agmatine is one of them and induces relaxation through imidazoline receptors. The paper shows that the action of agmatine is reduced in hypertensive rats, and that this change is related to the decrease of ATP-sensitive potassium channels in the prostate. The findings can increase our understanding of the possible underlying mechanism for the development of clinical benign prostatic hyperplasia. To compare agmatine-induced prostatic relaxation in hypertensive and control rats. To investigate the responsible mechanism(s) and the role of the ATP-sensitive potassium channel. Prostate strips were isolated from male spontaneously hypertensive (SH) rats and normal Wistar-Kyoto (WKY) rats for measurement of isometric tension. The strips were precontracted with 1 µmol/L phenylephrine or 50 mmol/L KCl. Dose-dependent relaxation of the prostatic strips was studied by cumulative administration of agmatine, 1 to 100 µmol/L, into the organ bath. Effects of specific antagonists on agmatine-induced relaxation were studied. Western blotting analysis was used to measure the gene expression of the ATP-sensitive potassium channel in the rat prostate. Prostatic relaxation induced by agmatine was markedly reduced in SH rats compared with WKY rats. The relaxation caused by agmatine was abolished by BU224, a selective imidazoline I(2)-receptor antagonist, but was not modified by efaroxan at a dose sufficient to block imidazoline I(1)-receptors. The relaxation induced by diazoxide at a concentration sufficient to activate ATP-sensitive potassium channels was markedly reduced in the SH rat prostate. Expressions of ATP-sensitive potassium channel sulphonylurea receptor and inwardly rectifying potassium channel (Kir) 6.2 subunits were both decreased in the prostate of SH rats. The decrease of agmatine-induced prostatic relaxation in SH rats is related to the change in ATP-sensitive potassium channels. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.

Anti-lipoteichoic acid antibodies enhance release of cytokines by monocytes sensitized with lipoteichoic acid.

PubMed Central

Mancuso, G; Tomasello, F; Ofek, I; Teti, G

1994-01-01

Lipoteichoic acid (LTA) from gram-positive bacteria can stimulate monocytes to produce cytokines. To ascertain whether aggregation of LTA receptors can contribute to this effect, human monocytes were sensitized with LTA from Streptococcus pyogenes, washed, and treated with anti-LTA antibodies. The addition of anti-LTA antibodies or F(ab')2 fragments markedly enhanced the aggregation of LTA receptors, as evidenced by indirect immunofluorescence and the release of tumor necrosis factor alpha and interleukin-1 beta. These findings suggest that aggregation of LTA receptors of monocytes is required for triggering marked cytokine responses. PMID:8132355

Simulator study of conventional general aviation instrument displays in path-following tasks with emphasis on pilot-induced oscillations

NASA Technical Reports Server (NTRS)

Adams, J. J.

1980-01-01

A study of the use of conventional general aviation instruments by general aviation pilots in a six degree of freedom, fixed base simulator was conducted. The tasks performed were tracking a VOR radial and making an ILS approach to landing. A special feature of the tests was that the sensitivity of the displacement indicating instruments (the RMI, CDI, and HSI) was kept constant at values corresponding to 5 n. mi. and 1.25 n. mi. from the station. Both statistical and pilot model analyses of the data were made. The results show that performance in path following improved with increases in display sensitivity up to the highest sensitivity tested. At this maximum test sensitivity, which corresponds to the sensitivity existing at 1.25 n. mi. for the ILS glide slope transmitter, tracking accuracy was no better than it was at 5 n. mi. from the station and the pilot aircraft system exhibited a marked reduction in damping. In some cases, a pilot induced, long period unstable oscillation occurred.

Cellular Action of Vasopressin in Medullary Tubules of Mice with Hereditary Nephrogenic Diabetes Insipidus

PubMed Central

Jackson, Brian A.; Edwards, Richard M.; Valtin, Heinz; Dousa, Thomas P.

1980-01-01

Our previous studies (1974. J. Clin. Invest.54: 753-762.) suggested that impaired metabolism of cyclic AMP (cAMP) may be involved in the renal unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI). To localize such a defect to specific segments of the nephron, we studied the activities of VP-sensitive adenylate cyclase, cAMP phosphodiesterase (cAMP-PDIE), as well as accumulation of cAMP in medullary collecting tubules (MCT) and in medullary thick ascending limbs of Henle's loop (MAL) microdissected from control mice with normal concentrating ability and from mice with hereditary NDI. Adenylate cyclase activity stimulated by VP or by NaF was only slightly lower (−24%) in MCT from NDI mice, compared with controls. In MAL of NDI mice, basal, VP-sensitive, and NaF-sensitive adenylate cyclase was markedly (> −60%) lower compared with MAL of controls. The specific activity of cAMP-PDIE was markedly higher in MCT of NDI mice compared with controls, but was not different between MAL of control and NDI mice. Under present in vitro conditions, incubation of intact MCT from control mice with VP caused a striking increase in cAMP levels (>10), but VP failed to elicit a change in cAMP levels in MCT from NDI mice. When the cAMP-PDIE inhibitor 1-methyl-3-isobutyl xanthine (MIX) was added to the above incubation, VP caused a significant increase in cAMP levels in MCT from both NDI mice and control mice. Under all tested conditions, cAMP levels in MCT of NDI mice were lower than corresponding values in control MCT. Under the present experimental setting, VP and other stimulating factors (MIX, cholera toxin) did not change cAMP levels in MAL from either control mice or from NDI mice. The results of the present in vitro experiments suggest that the functional unresponsiveness of NDI mice to VP is perhaps mainly the result of the inability of collecting tubules to increase intracellular cAMP levels in response to VP. In turn, this inability to increase cAMP in response to VP is at least partly the result of abnormally high activity of cAMP-PDIE, a somewhat lower activity of VP-sensitive adenylate cyclase in MCT of NDI mice, and perhaps to a deficiency of some other as yet unidentified factors. The possible contribution of low VP-sensitive adenylate cyclase activity in MAL of NDI mice to the renal resistance to VP remains to be defined. PMID:6249843

Computerized analysis of coronary artery disease: Performance evaluation of segmentation and tracking of coronary arteries in CT angiograms

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

Zhou, Chuan, E-mail: chuan@umich.edu; Chan, Heang-Ping; Chughtai, Aamer

2014-08-15

Purpose: The authors are developing a computer-aided detection system to assist radiologists in analysis of coronary artery disease in coronary CT angiograms (cCTA). This study evaluated the accuracy of the authors’ coronary artery segmentation and tracking method which are the essential steps to define the search space for the detection of atherosclerotic plaques. Methods: The heart region in cCTA is segmented and the vascular structures are enhanced using the authors’ multiscale coronary artery response (MSCAR) method that performed 3D multiscale filtering and analysis of the eigenvalues of Hessian matrices. Starting from seed points at the origins of the left andmore » right coronary arteries, a 3D rolling balloon region growing (RBG) method that adapts to the local vessel size segmented and tracked each of the coronary arteries and identifies the branches along the tracked vessels. The branches are queued and subsequently tracked until the queue is exhausted. With Institutional Review Board approval, 62 cCTA were collected retrospectively from the authors’ patient files. Three experienced cardiothoracic radiologists manually tracked and marked center points of the coronary arteries as reference standard following the 17-segment model that includes clinically significant coronary arteries. Two radiologists visually examined the computer-segmented vessels and marked the mistakenly tracked veins and noisy structures as false positives (FPs). For the 62 cases, the radiologists marked a total of 10191 center points on 865 visible coronary artery segments. Results: The computer-segmented vessels overlapped with 83.6% (8520/10191) of the center points. Relative to the 865 radiologist-marked segments, the sensitivity reached 91.9% (795/865) if a true positive is defined as a computer-segmented vessel that overlapped with at least 10% of the reference center points marked on the segment. When the overlap threshold is increased to 50% and 100%, the sensitivities were 86.2% and 53.4%, respectively. For the 62 test cases, a total of 55 FPs were identified by radiologist in 23 of the cases. Conclusions: The authors’ MSCAR-RBG method achieved high sensitivity for coronary artery segmentation and tracking. Studies are underway to further improve the accuracy for the arterial segments affected by motion artifacts, severe calcified and noncalcified soft plaques, and to reduce the false tracking of the veins and other noisy structures. Methods are also being developed to detect coronary artery disease along the tracked vessels.« less

Loss of Par-1a/MARK3/C-TAK1 kinase leads to reduced adiposity, resistance to hepatic steatosis, and defective gluconeogenesis.

PubMed

Lennerz, Jochen K; Hurov, Jonathan B; White, Lynn S; Lewandowski, Katherine T; Prior, Julie L; Planer, G James; Gereau, Robert W; Piwnica-Worms, David; Schmidt, Robert E; Piwnica-Worms, Helen

2010-11-01

Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a(-/-) but not in control or Par-1b(-/-) mice. The intercrossing of Par-1a(-/-) with Par-1b(-/-) mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a(-/-) mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b(-/-) mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice.

Curcumin increases the sensitivity of Paclitaxel-resistant NSCLC cells to Paclitaxel through microRNA-30c-mediated MTA1 reduction.

PubMed

Lu, Yimin; Wang, Jun; Liu, Lei; Yu, Lequn; Zhao, Nian; Zhou, Xingju; Lu, Xudong

2017-04-01

Non-small-cell lung cancer is one of the most lethal cancers in the worldwide. Although Paclitaxel-based combinational therapies have long been used as a standard treatment in aggressive non-small-cell lung cancers, Paclitaxel resistance emerges as a major clinical problem. It has been demonstrated that Curcumin from Curcuma longa as a traditional Chinese medicine can inhibit cancer cell proliferation. However, the role of Curcumin in Paclitaxel-resistant non-small-cell lung cancer cells is not clear. In this study, we investigated the effect of Curcumin on the Paclitaxel-resistant non-small-cell lung cancer cells and found that Curcumin treatment markedly increased the sensitivity of Paclitaxel-resistant non-small-cell lung cancer cells to Paclitaxel. Mechanically, the study revealed that Curcumin could reduce the expression of metastasis-associated gene 1 (MTA1) gene through upregulation of microRNA-30c in Paclitaxel-resistant non-small-cell lung cancer cells. During the course, MTA1 reduction sensitized Paclitaxel-resistant non-small-cell lung cancer cells and enhanced the effect of Paclitaxel. Taken together, our studies indicate that Curcumin increases the sensitivity of Paclitaxel-resistant non-small-cell lung cancer cells to Paclitaxel through microRNA-30c-mediated MTA1 reduction. Curcumin might be a potential adjuvant for non-small-cell lung cancer patients during Paclitaxel treatment.

Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

PubMed Central

2012-01-01

Background The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib. PMID:23234355

Decrease of Plasma Glucose by Hibiscus taiwanensis in Type-1-Like Diabetic Rats

PubMed Central

Wang, Lin-Yu; Chung, Hsien-Hui

2013-01-01

Hibiscus taiwanensis (Malvaceae) is widely used as an alternative herb to treat disorders in Taiwan. In the present study, it is used to screen the effect on diabetic hyperglycemia in streptozotocin-induced diabetic rats (STZ-diabetic rats). The extract of Hibiscus taiwanensis showed a significant plasma glucose-lowering action in STZ-diabetic rats. Stems of Hibiscus taiwanensis are more effective than other parts to decrease the plasma glucose in a dose-dependent manner. Oral administration of Hibiscus taiwanensis three times daily for 3 days into STZ-diabetic rats increased the sensitivity to exogenous insulin showing an increase in insulin sensitivity. Moreover, similar repeated administration of Hibiscus taiwanensis for 3 days in STZ-diabetic rats produced a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. Taken together, our results suggest that Hibiscus taiwanensis has the ability to lower plasma glucose through an increase in glucose utilization via elevation of skeletal GLUT 4 and decrease of hepatic PEPCK in STZ-diabetic rats. PMID:23690841

German Children’s Use of Word Order and Case Marking to Interpret Simple and Complex Sentences: Testing Differences Between Constructions and Lexical Items

PubMed Central

Brandt, Silke; Lieven, Elena; Tomasello, Michael

2016-01-01

ABSTRACT Children and adults follow cues such as case marking and word order in their assignment of semantic roles in simple transitives (e.g., the dog chased the cat). It has been suggested that the same cues are used for the interpretation of complex sentences, such as transitive relative clauses (RCs) (e.g., that’s the dog that chased the cat) (Bates, Devescovi, & D’Amico, 1999). We used a pointing paradigm to test German-speaking 3-, 4-, and 6-year-old children’s sensitivity to case marking and word order in their interpretation of simple transitives and transitive RCs. In Experiment 1, case marking was ambiguous. The only cue available was word order. In Experiment 2, case was marked on lexical NPs or demonstrative pronouns. In Experiment 3, case was marked on lexical NPs or personal pronouns. Whereas the younger children mainly followed word order, the older children were more likely to base their interpretations on the more reliable case-marking cue. In most cases, children from both age groups were more likely to use these cues in their interpretation of simple transitives than in their interpretation of transitive RCs. Finally, children paid more attention to nominative case when it was marked on first-person personal pronouns than when it was marked on third-person lexical NPs or demonstrative pronouns, such as der Löwe ‘the-NOM lion’ or der ‘he-NOM.’ They were able to successfully integrate this case-marking cue in their sentence processing even when it appeared late in the sentence. We discuss four potential reasons for these differences across development, constructions, and lexical items. (1) Older children are relatively more sensitive to cue reliability. (2) Word order is more reliable in simple transitives than in transitive RCs. (3) The processing of case marking might initially be item-specific. (4) The processing of case marking might depend on its saliency and position in the sentence. PMID:27019652

Pulse-modulated second harmonic imaging microscope quantitatively demonstrates marked increase of collagen in tumor after chemotherapy

NASA Astrophysics Data System (ADS)

Raja, Anju M.; Xu, Shuoyu; Sun, Wanxin; Zhou, Jianbiao; Tai, Dean C. S.; Chen, Chien-Shing; Rajapakse, Jagath C.; So, Peter T. C.; Yu, Hanry

2010-09-01

Pulse-modulated second harmonic imaging microscopes (PM-SHIMs) exhibit improved signal-to-noise ratio (SNR) over conventional SHIMs on sensitive imaging and quantification of weak collagen signals inside tissues. We quantify the spatial distribution of sparse collagen inside a xenograft model of human acute myeloid leukemia (AML) tumor specimens treated with a new drug against receptor tyrosine kinase (ABT-869), and observe a significant increase in collagen area percentage, collagen fiber length, fiber width, and fiber number after chemotherapy. This finding reveals new insights into tumor responses to chemotherapy and suggests caution in developing new drugs and therapeutic regimens against cancers.

Co-delivery of docetaxel and verapamil by reduction-sensitive PEG-PLGA-SS-DTX conjugate micelles to reverse the multi-drug resistance of breast cancer.

PubMed

Guo, Yuanyuan; He, Wenxiu; Yang, Shengfeng; Zhao, Dujuan; Li, Zhonghao; Luan, Yuxia

2017-03-01

The clinical usage of docetaxel (DTX) has been blocked in the clinic because of its poor solubility and tumour multi-drug resistance (MDR). The dominating mechanism of MDR is the over-expression of p-gp on tumour cells. Traditional nano-medicines, such as nanoparticles and micelles, have been used to physically entrap DTX to improve their solubility, while the drug loading content was very low and the tumour resistance was neglected. In this study, the synthesized reduction-sensitive mPEG-PLGA-SS-DTX conjugate was utilized to load the p-gp inhibitor veraparmil (VRP) to prepare DTX and VRP co-delivered mPEG-PLGA-SS-DTX/VRP (PP-SS-DTX/VRP) multi-functional micelles to reverse MDR and enhance the anti-tumour effect of DTX. The micelles had a high drug loading content and showed an obvious reduction-sensitive release property for both DTX and VRP. In addition, an in vitro anti-tumour assay revealed that the micelles markedly inhibited the efflux activity of p-gp and accelerated cell apoptosis, resulting in the improvement of anti-tumour activity and reversal of MDR. The PP-SS-DTX micelles markedly enhanced the in vivo circulation time and increased the drug accumulation in tumour tissues. Therefore, the PP-SS-DTX/VRP micelle is a desirable drug delivery system for multi-drug resistance therapy of DTX and is very promising for clinical usage. Copyright © 2016 Elsevier B.V. All rights reserved.

Diamond-like carbon (DLC) thin film bioelectrodes: effect of thermal post-treatments and the use of Ti adhesion layer.

PubMed

Laurila, Tomi; Rautiainen, Antti; Sintonen, Sakari; Jiang, Hua; Kaivosoja, Emilia; Koskinen, Jari

2014-01-01

The effect of thermal post-treatments and the use of Ti adhesion layer on the performance of thin film diamond like carbon bioelectrodes (DLC) have been investigated in this work. The following results were obtained: (i) The microstructure of the DLC layer after the deposition was amorphous and thermal annealing had no marked effect on the structure, (ii) formation of oxygen containing SiOx and Ti[O,C] layers were detected at the Si/Ti and Ti/DLC interfaces with the help of transmission electron microscope (TEM), (iii) thermal post-treatments increased the polar fraction of the surface energy, (iv) cyclic voltammetry (CV) measurements showed that the DLC films had wide water windows and were stable in contact with dilute sulphuric acid and phosphate buffered saline (PBS) solutions, (v) use of Ti interlayer between Pt(Ir) microwire and DLC layer was crucial for the electrodes to survive the electrochemical measurements without the loss of adhesion of the DLC layer, (vi) DLC electrodes with small exposed Pt areas were an order of magnitude more sensitive towards dopamine than Pt electrodes and (vii) thermal post-treatments did not markedly change the electrochemical behavior of the electrodes despite the significant increase in the polar nature of the surfaces. It can be concluded that thin DLC bioelectrodes are stable under physiological conditions and can detect dopamine in micro molar range, but their sensitivity must be further improved. © 2013 Elsevier B.V. All rights reserved.

Self-motion perception in autism is compromised by visual noise but integrated optimally across multiple senses

PubMed Central

Zaidel, Adam; Goin-Kochel, Robin P.; Angelaki, Dora E.

2015-01-01

Perceptual processing in autism spectrum disorder (ASD) is marked by superior low-level task performance and inferior complex-task performance. This observation has led to theories of defective integration in ASD of local parts into a global percept. Despite mixed experimental results, this notion maintains widespread influence and has also motivated recent theories of defective multisensory integration in ASD. Impaired ASD performance in tasks involving classic random dot visual motion stimuli, corrupted by noise as a means to manipulate task difficulty, is frequently interpreted to support this notion of global integration deficits. By manipulating task difficulty independently of visual stimulus noise, here we test the hypothesis that heightened sensitivity to noise, rather than integration deficits, may characterize ASD. We found that although perception of visual motion through a cloud of dots was unimpaired without noise, the addition of stimulus noise significantly affected adolescents with ASD, more than controls. Strikingly, individuals with ASD demonstrated intact multisensory (visual–vestibular) integration, even in the presence of noise. Additionally, when vestibular motion was paired with pure visual noise, individuals with ASD demonstrated a different strategy than controls, marked by reduced flexibility. This result could be simulated by using attenuated (less reliable) and inflexible (not experience-dependent) Bayesian priors in ASD. These findings question widespread theories of impaired global and multisensory integration in ASD. Rather, they implicate increased sensitivity to sensory noise and less use of prior knowledge in ASD, suggesting increased reliance on incoming sensory information. PMID:25941373

Changes of intracellular milieu with fatigue or hypoxia depress contraction of skinned rabbit skeletal and cardiac muscle.

PubMed Central

Godt, R E; Nosek, T M

1989-01-01

1. Maximal calcium-activated force (Fmax) and calcium sensitivity were markedly decreased in detergent-skinned fibres from skeletal and cardiac muscle by solutions that mimicked the total milieu changes associated with fatigue and hypoxia. Further experiments determined the relative contribution of each of the individual changes in milieu. 2. Both Ca2+ sensitivity and Fmax of skeletal and cardiac fibres were decreased with increased [H+] or inorganic phosphate (Pi). These effects were greater in cardiac muscle. 3. Decreasing MgATP over the range observed with fatigue and hypoxia (6.8-4.7 mM) had no effect on Fmax or Ca2+ sensitivity of either muscle type. 4. Decreasing phosphocreatine (PCr: 15-1 mM) increased Fmax but had little effect on Ca2+ sensitivity in both muscle types. In cardiac fibres, the effect on Fmax could be mimicked by inhibition of endogenous creatine kinase. 5. ADP (0.7 mM) increased Fmax and Ca2+ sensitivity, while AMP (0.06 mM) slightly increased Fmax but had no effect on Ca2+ sensitivity of either skeletal or cardiac fibres. 6. Creatine (25 mM) had no significant effect on either Ca2+ sensitivity or Fmax of skeletal and cardiac muscle fibres. At higher levels (50 mM), however, creatine depressed Fmax and slightly altered Ca2+ sensitivity. 7. Thiophosphorylation of myosin P light chains (phosphorylatable light chains of myosin) in rabbit psoas fibres had no effect on Ca2+ sensitivity, yet slightly but significantly increased Fmax under fatigue conditions. 8. Reducing the affinity for ATP hydrolysis (by adding ADP, AMP and creatine) over the range calculated for fatigue/hypoxia (60-45 kJ/mol) produced the enhancement in Fmax expected from added ADP and AMP in cardiac but not skeletal muscle, indicating that changes in affinity influence Fmax of skeletal muscle. Reducing affinity produced little change in Ca2+ sensitivity of skeletal muscle. In contrast, the change produced in cardiac muscle was greater than that expected from addition of ADP and AMP; i.e. decreasing affinity increases calcium sensitivity of the heart. 9. Simple summation of all significant changes expected from each constituent altered by fatigue/hypoxia adequately predicted the observed changes in Fmax and Ca2+ sensitivity in both cardiac and skeletal muscle fibres with but one exception (the change in Ca2+ sensitivity of skeletal muscle at pH 7 was slightly overestimated). PMID:2600830

20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice.

PubMed

Cooper, Philip R; Mesaros, A Clementina; Zhang, Jie; Christmas, Peter; Stark, Christopher M; Douaidy, Karim; Mittelman, Michael A; Soberman, Roy J; Blair, Ian A; Panettieri, Reynold A

2010-04-20

Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways. Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 microm thickness) containing an intrapulmonary airway ( approximately 0.01 mm(2) lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC(50) and E(max) values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment. These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays a pivotal role in mediating acute ozone-induced AHR.

Identification of a sensitive urinary biomarker, selenium-binding protein 1, for early detection of acute kidney injury.

PubMed

Kim, Kyeong Seok; Yang, Hun Yong; Song, Hosup; Kang, Ye Rim; Kwon, JiHoon; An, JiHye; Son, Ji Yeon; Kwack, Seung Jun; Kim, Young-Mi; Bae, Ok-Nam; Ahn, Mee-Young; Lee, Jaewon; Yoon, Sungpil; Lee, Byung Mu; Kim, Hyung Sik

2017-01-01

Acute kidney injury (AKI) is associated with increased mortality rate in patients but clinically available biomarkers for disease detection are currently not available. Recently, a new biomarker, selenium-binding protein 1 (SBP1), was identified for detection of nephrotoxicity using proteomic analysis. The aim of this study was to assess the sensitivity of urinary SBP1 levels as an early detection of AKI using animal models such as cisplatin or ischemia/reperfusion (I/R). Sprague-Dawley rats were injected with cisplatin (6 mg/kg, once i.p.) and sacrificed at 1, 3, or 5 days after treatment. Ischemia was achieved by bilaterally occluding both kidneys with a microvascular clamp for 45 min and verified visually by a change in tissue color. After post-reperfusion, urine samples were collected at 9, 24, and 48 hr intervals. Urinary excretion of protein-based biomarkers was measured by Western blot analysis. In cisplatin-treated rats, mild histopathologic alterations were noted at day 1 which became severe at day 3. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at day 3. Levels of urinary excretion of SBP1, neutrophil gelatinase-associated lipocalin (NGAL), and a tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly elevated at day 3 and 5 following drug treatment. In the vehicle-treated I/R group, serum levels of BUN and SCr and AST activity were significantly increased compared to sham. Urinary excretion of SBP1 and NGAL rose markedly following I/R. The urinary levels of SBP1, NGAL, TIMP-1, and KIM-1 proteins excreted by AKI patients and normal subjects were compared. Among these proteins, a marked rise in SBP1 was observed in urine of patients with AKI compared to normal subjects. Based upon receiver-operator curves (ROC), SBP1 displayed a higher area under the curve (AUC) scores than levels of SCr, BUN, total protein, and glucose. In particular, SBP1 protein was readily detected in small amounts of urine without purification. Data thus indicate that urinary excretion of SBP1 may be useful as a reliable biomarker for early diagnosis of AKI in patients.

Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice.

PubMed

Oka, Saori; Wakui, Junichi; Ikeda, Shinobu; Yanagimoto, Shin; Kishimoto, Seishi; Gokoh, Maiko; Nasui, Miwako; Sugiura, Takayuki

2006-12-15

The possible involvement of 2-arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors (CB1 and CB2), in contact dermatitis in mouse ear was investigated. We found that the level of 2-AG was markedly elevated in the ear following a challenge with oxazolone in sensitized mice. Of note, the swelling following the challenge was suppressed by either the administration of SR144528, a CB2 receptor antagonist, immediately after sensitization, or the administration of SR144528 upon the challenge. The effect of AM251, a CB1 receptor antagonist, was marginal in either case. It seems apparent, therefore, that the CB2 receptor and its endogenous ligand 2-AG are closely involved in both the sensitization phase and the elicitation phase of oxazolone-induced contact dermatitis. In line with this, we found that Langerhans cells (MHC class II(+)) contain a substantial amount of CB2 receptor mRNA, whereas keratinocytes (MHC class II(-)) do not. We also obtained evidence that the expression of mRNAs for proinflammatory cytokines following a challenge with oxazolone was markedly suppressed by treatment with SR144528. We next examined whether the CB2 receptor and 2-AG participate in chronic contact dermatitis accompanied by the infiltration of tissues by eosinophils. The amount of 2-AG in mouse ear dramatically increased following repeated challenge with oxazolone. Importantly, treatment with SR144528 attenuated both the recruitment of eosinophils and ear swelling in chronic contact dermatitis induced by repeated challenge with oxazolone. These results strongly suggest that the CB2 receptor and 2-AG play important stimulative roles in the sensitization, elicitation, and exacerbation of allergic inflammation.

Reducing false positives of microcalcification detection systems by removal of breast arterial calcifications.

PubMed

Mordang, Jan-Jurre; Gubern-Mérida, Albert; den Heeten, Gerard; Karssemeijer, Nico

2016-04-01

In the past decades, computer-aided detection (CADe) systems have been developed to aid screening radiologists in the detection of malignant microcalcifications. These systems are useful to avoid perceptual oversights and can increase the radiologists' detection rate. However, due to the high number of false positives marked by these CADe systems, they are not yet suitable as an independent reader. Breast arterial calcifications (BACs) are one of the most frequent false positives marked by CADe systems. In this study, a method is proposed for the elimination of BACs as positive findings. Removal of these false positives will increase the performance of the CADe system in finding malignant microcalcifications. A multistage method is proposed for the removal of BAC findings. The first stage consists of a microcalcification candidate selection, segmentation and grouping of the microcalcifications, and classification to remove obvious false positives. In the second stage, a case-based selection is applied where cases are selected which contain BACs. In the final stage, BACs are removed from the selected cases. The BACs removal stage consists of a GentleBoost classifier trained on microcalcification features describing their shape, topology, and texture. Additionally, novel features are introduced to discriminate BACs from other positive findings. The CADe system was evaluated with and without BACs removal. Here, both systems were applied on a validation set containing 1088 cases of which 95 cases contained malignant microcalcifications. After bootstrapping, free-response receiver operating characteristics and receiver operating characteristics analyses were carried out. Performance between the two systems was compared at 0.98 and 0.95 specificity. At a specificity of 0.98, the sensitivity increased from 37% to 52% and the sensitivity increased from 62% up to 76% at a specificity of 0.95. Partial areas under the curve in the specificity range of 0.8-1.0 were significantly different between the system without BACs removal and the system with BACs removal, 0.129 ± 0.009 versus 0.144 ± 0.008 (p<0.05), respectively. Additionally, the sensitivity at one false positive per 50 cases and one false positive per 25 cases increased as well, 37% versus 51% (p<0.05) and 58% versus 67% (p<0.05) sensitivity, respectively. Additionally, the CADe system with BACs removal reduces the number of false positives per case by 29% on average. The same sensitivity at one false positive per 50 cases in the CADe system without BACs removal can be achieved at one false positive per 80 cases in the CADe system with BACs removal. By using dedicated algorithms to detect and remove breast arterial calcifications, the performance of CADe systems can be improved, in particular, at false positive rates representative for operating points used in screening.

Evaluation of insulin secretion and action in New World camelids.

PubMed

Firshman, Anna M; Cebra, Christopher K; Schanbacher, Barbara J; Seaquist, Elizabeth R

2013-01-01

To measure and compare insulin secretion and sensitivity in healthy alpacas and llamas via glucose clamping techniques. 8 llamas and 8 alpacas. Hyperinsulinemic euglycemic clamping (HEC) and hyperglycemic clamping (HGC) were performed on each camelid in a crossover design with a minimum 48-hour washout period between clamping procedures. The HEC technique was performed to measure insulin sensitivity. Insulin was infused IV at 6 mU/min/kg for 4 hours, and an IV infusion of glucose was adjusted to maintain blood glucose concentration at 150 mg/dL. Concentrations of blood glucose and plasma insulin were determined throughout. The HGC technique was performed to assess insulin secretion in response to exogenous glucose infusion. An IV infusion of glucose was administered to maintain blood glucose concentration at 320 mg/dL for 3 hours, and concentrations of blood glucose and plasma insulin were determined throughout. Alpacas and llamas were not significantly different with respect to whole-body insulin sensitivity during HEC or in pancreatic β-cell response during HGC. Alpacas and llamas had markedly lower insulin sensitivity during HEC and markedly lower pancreatic β-cell response during HGC, in comparison with many other species. New World camelids had lower glucose-induced insulin secretion and marked insulin resistance in comparison with other species. This likely contributes to the disorders of fat and glucose metabolism that are common to camelids.

Different sensitivities of rat skeletal muscles and brain to novel anti-cholinesterase agents, alkylammonium derivatives of 6-methyluracil (ADEMS)

PubMed Central

Petrov, Konstantin A; Yagodina, Lilia O; Valeeva, Guzel R; Lannik, Natalya I; Nikitashina, Alexandra D; Rizvanov, Albert A; Zobov, Vladimir V; Bukharaeva, Ellya A; Reznik, Vladimir S; Nikolsky, Eugeny E; Vyskočil, František

2011-01-01

BACKGROUND AND PURPOSE The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACH Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTS The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONS Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools. PMID:21232040

Cough and expiration reflexes elicited by inhaled irritant gases are intensified in ovalbumin-sensitized mice.

PubMed

Zhang, Cheng; Lin, Ruei-Lung; Hong, Jeff; Khosravi, Mehdi; Lee, Lu-Yuan

2017-05-01

This study was designed to determine the effect of active sensitization with ovalbumin (Ova) on cough responses to inhaled irritant gases in mice. Conscious mice moved freely in a recording chamber, while the pressure change in the chamber and audio and video signals of the mouse movements were recorded simultaneously to measure the frequencies of cough reflex (CR) and expiration reflex (ER). To further verify the accuracy of cough analysis, the intrapleural pressure was also recorded by a telemetry sensor surgically implanted in the intrapleural space in a subgroup of mice. During the irritant gas inhalation challenge, sulfur dioxide (SO 2 ; 200 and 400 ppm) or ammonia (NH 3 ; 0.1% and 0.2%) was drawn into the chamber at a constant flow rate for 8 min. Ova sensitization and sham sensitization with vehicle (Veh) were performed over a 25-day period in separate groups of mice. Our results showed that 1 ) both SO 2 and NH 3 inhalation challenges increased CR and ER frequencies in a concentration-dependent manner before Ova sensitization; 2 ) the baseline CR frequency was significantly elevated after Ova sensitization, accompanied by pronounced airway inflammation; and 3 ) Ova sensitization also markedly augmented the responses of CR and ER to both SO 2 and NH 3 inhalation challenges; in sharp contrast, the cough responses did not change after sham sensitization in the Veh group. In conclusion, Ova sensitization caused distinct and lingering increases in baseline cough frequency, and also intensified both CR and ER responses to inhaled irritant gases, which probably resulted from an allergic inflammation-induced hypersensitivity of airway sensory nerves. Copyright © 2017 the American Physiological Society.

The S201 far-ultraviolet imaging survey - A summary of results and implications for future surveys

NASA Technical Reports Server (NTRS)

Carruthers, G. R.; Page, T.

1984-01-01

The results from all-sky surveys with the S201 FUV camera/spectrograph from the moon during the Apollo 16 mission are summarized with respect to implications for future UV all-sky surveys. The scans provided imagery of 10 fields, each 20 deg in diameter, in the wavelength ranges 1050-1600 A and 1250-1600 A. Best detection thresholds were obtained with 10 and 30 min exposures at 1400 A. Only 7 percent sky coverage was recorded, and then only down to 11th mag. A Mark II camera may be flown on the Shuttle on the Spartan 3 mission, as may be an all-reflector Schmidt telescope. An additional 20 percent of the sky will be mapped and microchannel intensification will increase the diffuse source sensitivity by two orders of magnitude. Several objects sighted with the S201 will be reviewed with the Mark II.

Overlay accuracy fundamentals

NASA Astrophysics Data System (ADS)

Kandel, Daniel; Levinski, Vladimir; Sapiens, Noam; Cohen, Guy; Amit, Eran; Klein, Dana; Vakshtein, Irina

2012-03-01

Currently, the performance of overlay metrology is evaluated mainly based on random error contributions such as precision and TIS variability. With the expected shrinkage of the overlay metrology budget to < 0.5nm, it becomes crucial to include also systematic error contributions which affect the accuracy of the metrology. Here we discuss fundamental aspects of overlay accuracy and a methodology to improve accuracy significantly. We identify overlay mark imperfections and their interaction with the metrology technology, as the main source of overlay inaccuracy. The most important type of mark imperfection is mark asymmetry. Overlay mark asymmetry leads to a geometrical ambiguity in the definition of overlay, which can be ~1nm or less. It is shown theoretically and in simulations that the metrology may enhance the effect of overlay mark asymmetry significantly and lead to metrology inaccuracy ~10nm, much larger than the geometrical ambiguity. The analysis is carried out for two different overlay metrology technologies: Imaging overlay and DBO (1st order diffraction based overlay). It is demonstrated that the sensitivity of DBO to overlay mark asymmetry is larger than the sensitivity of imaging overlay. Finally, we show that a recently developed measurement quality metric serves as a valuable tool for improving overlay metrology accuracy. Simulation results demonstrate that the accuracy of imaging overlay can be improved significantly by recipe setup optimized using the quality metric. We conclude that imaging overlay metrology, complemented by appropriate use of measurement quality metric, results in optimal overlay accuracy.

Sensitive resettable odometer aids roadside census of red-winged blackbirds

USGS Publications Warehouse

Harke, D.T.; Stickley, A.R.

1968-01-01

A sensitive resettable odometer reading to 0.01 mile facilitated censusing breeding male redwinged blackbirds (Agelaius phoeniceus) from a vehicle. Territorial males along roadsides were 'marked' with recorded mileage readings rather than with landmarks of the types employed by Hewitt for censuses based on the Lincoln index principle. Sensitive odometers that can be reset have many potential uses in wildlife investigations.

Nile Delta vegetation response to Holocene climate variability

USGS Publications Warehouse

Bernhardt, Christopher E.; Horton, Benjamin P.; Stanley, Jean-Daniel

2012-01-01

A 7000 yr palynologic record from Burullus Lagoon, Nile Delta, Egypt, is assessed to investigate changes in terrestrial vegetation in response to Nile flow. Previous studies in this region have shown that sea-level rise in the early to mid-Holocene, and markedly increased human land use during the past several centuries, altered vegetation in and around the lagoon. The pollen record from this study documents changes in delta vegetation that likely reflect variations in Nile flow. We suggest that Cyperaceae pollen is a sensitive marker of precipitation over the Nile headwaters and the resultant Nile flow. Decreases in Cyperaceae pollen, interpreted as a marker for diminished Nile flow, as well as the increase in relative abundance of microscopic charcoal, occurred at ca. 6000–5500, ca. 5000, ca. 4200, and ca. 3000 cal. yr B.P. (calibrated years before present). These correspond to extreme regional and global aridity events associated with a more southerly mean position of the Intertropical Convergence Zone. These changes, also recorded by other proxy studies, indicate that several marked regional drought events affected the Nile Delta region and impacted ancient Egyptian and Middle Eastern civilizations.

ENHANCING TEST SENSITIVITY IN TOXICITY TESTING BY USING A STATISTICAL PERFORMANCE STANDARD

EPA Science Inventory

Previous reports have shown that within-test sensitivity can vary markedly among laboratories. Experts have advocated an empirical approach to controlling test variability based on the MSD, control means, and other test acceptability criteria. (The MSD represents the smallest dif...

75 FR 29763 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-27

... commercialization of results of federally-funded research and development. Foreign patent applications are filed on... patent applications. Simple, Quantitative and Highly Specific Antibody Detection of Lyme Disease... markedly out-performed the C6 ELISA test (currently the most sensitive test available, with 76% sensitivity...

18 CFR 3a.31 - Classification markings and special notations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Confidential will be stamped in red ink, printed, or written in letters considerably larger than those used in... disclosure subject to criminal sanctions. (4) Sensitive intelligence information. For classified information or material relating to sensitive intelligence sources and methods, the following warning notice...

The dependence of binocular contrast sensitivities on binocular single vision in normal and amblyopic human subjects

PubMed Central

Hood, A S; Morrison, J D

2002-01-01

We have measured monocular and binocular contrast sensitivities in response to medium to high spatial frequencies of vertical sinusoidal grating patterns in normal subjects, anisometropic amblyopes, strabismic amblyopes and non-amblyopic esotropes. On binocular viewing, contrast sensitivities were slightly but significantly increased in normal subjects, markedly increased in anisometropes and esotropes with anomalous binocular single vision (BSV) and significantly reduced in esotropes and exotropes without BSV. Application of a prismatic correction to the strabismic eye in order to achieve bifoveal stimulation resulted in a significant reduction in contrast sensitivity in esotropes with and without anomalous BSV, in exotropes and in non-amblyopic esotropes. Control experiments in normal subjects with monocular viewing showed that degradative effects of the prism occurred only with high prism powers and at high spatial frequencies, thus establishing that the reduced contrast sensitivities were the consequence of bifoveal stimulation rather than optical degradation. Displacement of the image of the grating pattern by 2 deg in normal subjects and anisometropes by a dichoptic method to simulate a small angle esotropia had no effect on the contrast sensitivities recorded through the companion eye. By contrast, esotropes showed similar reductions in contrast sensitivity to those obtained with the prism experiments, confirming a fundamental difference between subjects with normal and abnormal ocular alignments. The results have thus established a suppressive action of the fovea of the amblyopic eye acting on the companion, non-amblyopic eye and indicate that correction of ocular misalignments in adult esotropes may be disadvantageous to binocular visual performance. PMID:11956347

Health impacts of the July 2010 heat wave in Québec, Canada.

PubMed

Bustinza, Ray; Lebel, Germain; Gosselin, Pierre; Bélanger, Diane; Chebana, Fateh

2013-01-21

One of the consequences of climate change is the increased frequency and intensity of heat waves which can cause serious health impacts. In Québec, July 2010 was marked by an unprecedented heat wave in recent history. The purpose of this study is to estimate certain health impacts of this heat wave. The crude daily death and emergency department admission rates during the heat wave were analyzed in relation to comparison periods using 95% confidence intervals. During the heat wave, the crude daily rates showed a significant increase of 33% for deaths and 4% for emergency department admissions in relation to comparison periods. No displacement of mortality was observed over a 60-day horizon. The all-cause death indicator seems to be sufficiently sensitive and specific for surveillance of exceedences of critical temperature thresholds, which makes it useful for a heat health-watch system. Many public health actions combined with the increased use of air conditioning in recent decades have contributed to a marked reduction in mortality during heat waves. However, an important residual risk remains, which needs to be more vigorously addressed by public health authorities in light of the expected increase in the frequency and severity of heat waves and the aging of the population.

Sickle red cell dehydration: mechanisms and interventions.

PubMed

Bookchin, Robert M; Lew, Virgilio L

2002-03-01

A critical link between the single molecular defect in sickle cell anemia and the extensive pathology of this disease is the reversible increase in red cell membrane permeability generated by hemoglobin S polymers in the deoxygenated state. This permeability, usually described as P (sickle), triggers a chain of events in which two constitutive transporters of the red cell membrane become activated-the recently cloned intermediate conductance, Ca 2+ -sensitive K channel, and the electroneutral K:Cl cotransporter-leading to sickle cell dehydration. This article reviews knowledge of the dehydration mechanism, stressing the marked heterogeneity of dehydration rates in sickle cell populations, and discusses recent contributions to understanding of the function and regulation of P (sickle), Ca 2+ -sensitive K channel, and K:Cl cotransporter, and of therapies targeted at these transporters.

Cold hypersensitivity increases with age in mice with sickle cell disease.

PubMed

Zappia, Katherine J; Garrison, Sheldon R; Hillery, Cheryl A; Stucky, Cheryl L

2014-12-01

Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. In addition, both humans and mice with SCD experience heightened cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization or its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Furthermore, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the transient receptor potential melastatin 8 (Trpm8) and transient receptor potential ankyrin 1 (Trpa1) channels, as well as the 2-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk10), and TRAAK (Kcnk4). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes, and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Detection of drug-resistance mechanism of Pseudomonas aeruginosa developing from a sensitive strain to a persister during carbapenem treatment.

PubMed

Shen, J L; Fang, Y P

2015-06-18

We explored the mechanism of the development from sensitivity to resistance to carbapenem in Pseudomonas aeruginosa. Two P. aeruginosa strains were collected during treatment with carbapenem. Strain homology was investigated using pulsed-field gel electrophoresis. Porin oprD2 expression was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The minimum inhibitory concentrations (MICs) of imipenem and meropenem with or without MC207110 were determined using the agar dilution method. The expression level of efflux pump mRNA was tested using real-time polymerase chain reaction. Metallo-lactamases (MBLs) were screened using the EDTA-disk synergy test. Genes encoding MBLs were amplified and then analyzed by DNA sequencing. The two treated strains belonged to the same pulsed-field gel electrophoresis type. The SDS-PAGE profile of the P. aeruginosa strains revealed that the 46-kDa membrane protein OprD2 of IMP(R)MEM(R) type strains was lost, whereas OprD2 of 1 IMP(S)MEM(S) strain was normal. With or without MC207110 treatment, the MIC of carbapenem-resistant P. aeruginosa decreased by 4-fold, while the MIC of carbapenem-sensitive P. aeruginosa did not. Compared with the carbapenem-sensitive strain, MexX mRNA expression in the carbapenem-resistant strain increased by 102.5-fold, while the mRNA expression of other efflux pumps did not markedly increase. Neither carbapenem-resistant nor carbapenem-sensitive P. aeruginosa produced MBL. The mechanism of development from sensitivity to resistance of P. aeruginosa to carbapenem during carbapenem treatment is due to porin oprD2 loss and an increased expression level of MexXY-OprM.

Computer-aided detection of pulmonary embolism at CT pulmonary angiography: can it improve performance of inexperienced readers?

PubMed

Blackmon, Kevin N; Florin, Charles; Bogoni, Luca; McCain, Joshua W; Koonce, James D; Lee, Heon; Bastarrika, Gorka; Thilo, Christian; Costello, Philip; Salganicoff, Marcos; Joseph Schoepf, U

2011-06-01

To evaluate the effect of a computer-aided detection (CAD) algorithm on the performance of novice readers for detection of pulmonary embolism (PE) at CT pulmonary angiography (CTPA). We included CTPA examinations of 79 patients (50 female, 52 ± 18 years). Studies were evaluated by two independent inexperienced readers who marked all vessels containing PE. After 3 months all studies were reevaluated by the same two readers, this time aided by CAD prototype. A consensus read by three expert radiologists served as the reference standard. Statistical analysis used χ(2) and McNemar testing. Expert consensus revealed 119 PEs in 32 studies. For PE detection, the sensitivity of CAD alone was 78%. Inexperienced readers' initial interpretations had an average per-PE sensitivity of 50%, which improved to 71% (p < 0.001) with CAD as a second reader. False positives increased from 0.18 to 0.25 per study (p = 0.03). Per-study, the readers initially detected 27/32 positive studies (84%); with CAD this number increased to 29.5 studies (92%; p = 0.125). Our results suggest that CAD significantly improves the sensitivity of PE detection for inexperienced readers with a small but appreciable increase in the rate of false positives.

The use of centrifugation to study early Drosophila embryogenesis

NASA Technical Reports Server (NTRS)

Abbott, M. K.; Spooner, B. S. (Principal Investigator)

1993-01-01

By the end of 10th nuclear cycle, the somatic nuclei of the Drosophila embryo have migrated to the periphery of the egg. Centrifugation of embryos did not result in the displacement of these nuclei, since cytoskeletal elements anchor them to the cortex. But, mild centrifugal forces displace the centrally located, nascent yolk nuclei. If this increased sensitivity to hypergravity occurs before the beginning of nuclear differentiation during cycle 8, when the nascent yolk and somatic nuclei physically separate, then it would mark the earliest functional difference between these two lineages.

Enrichment of heavy nuclei in the 17 April 1972 solar flare.

NASA Technical Reports Server (NTRS)

Fleischer, R. L.; Hart, H. R., Jr.

1973-01-01

Polycarbonate and glass detectors exposed on Apollo 16 to the Apr. 17, 1972, solar flare were used to measure the spectrum of iron-group cosmic-ray nuclei down to about 0.02 MeV/nucleon. The enrichment of iron relative to lighter nuclei previously seen at higher energies increases markedly in this new, very-low-energy region. The energy spectrum of carbon and heavier nuclei inferred from sensitized Lexan polycarbonate reveals the enrichment of iron relative to carbon and heavier nuclei down to about 0.03 MeV/nucleon.

Stress-enhanced gelation: a dynamic nonlinearity of elasticity.

PubMed

Yao, Norman Y; Broedersz, Chase P; Depken, Martin; Becker, Daniel J; Pollak, Martin R; Mackintosh, Frederick C; Weitz, David A

2013-01-04

A hallmark of biopolymer networks is their sensitivity to stress, reflected by pronounced nonlinear elastic stiffening. Here, we demonstrate a distinct dynamical nonlinearity in biopolymer networks consisting of filamentous actin cross-linked by α-actinin-4. Applied stress delays the onset of relaxation and flow, markedly enhancing gelation and extending the regime of solidlike behavior to much lower frequencies. We show that this macroscopic network response can be accounted for at the single molecule level by the increased binding affinity of the cross-linker under load, characteristic of catch-bond-like behavior.

Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease.

PubMed

Giannoni, Alberto; Aimo, Alberto; Mancuso, Michelangelo; Piepoli, Massimo Francesco; Orsucci, Daniele; Aquaro, Giovanni Donato; Barison, Andrea; De Marchi, Daniele; Taddei, Claudia; Cameli, Matteo; Raglianti, Valentina; Siciliano, Gabriele; Passino, Claudio; Emdin, Michele

2017-12-01

Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement. Twenty-five MD patients (aged 46 ± 3 years, 32% male) with skeletal myopathy but without known cardiac disease, underwent a thorough evaluation including BNPs, galectin-3, soluble suppression of tumorigenesis 2 (sST2), high sensitivity troponin T/I, catecholamines, ECG, 24-h ECG recording, cardiopulmonary exercise testing, echocardiography, cardiac/muscle magnetic resonance (C/MMR), and ergoreflex assessment. Thirteen age- and sex-matched healthy controls were chosen. Among these myopathic patients, subclinical cardiac damage was detected in up to 80%, with 44% showing fibrosis at CMR. Ergoreflex sensitivity was markedly higher in patients than in controls (64% vs. 37%, P < 0.001), and correlated with muscle fat to water ratio and extracellular volume at MMR (both P < 0.05). Among patients, ergoreflex sensitivity was higher in those with cardiac involvement (P = 0.034). Patients showed a lower peak oxygen consumption (VO 2 /kg) than controls (P < 0.001), as well as ventilatory inefficiency (P = 0.024). Ergoreflex sensitivity correlated with reduced workload and peak VO 2 /kg (both P < 0.001), and several indicators of autonomic imbalance (P < 0.05). Plasma norepinephrine was the unique predictor of myocardial fibrosis at univariate analysis (P < 0.05). Skeletal myopathy in MD is characterized by enhanced ergoreflex sensitivity, which is associated with a higher incidence of cardiac involvement, exercise intolerance, and sympathetic activation. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

[Tuberculin sensitivity in infants and preschool children].

PubMed

Guseva, E M; Efimova, E P; Stepankina, T T; Chernyshova, L V

2001-01-01

Marked fluctuations in sensitivity to tuberculin related to the time of nonspecific vaccinations were found in children aged 1 to 7 years vaccinated with BCG within the first week of life in annual Mantoux test (2 tuberculin units). At the age of 3 and 7 years vaccinations raise sensitivity to tuberculin causing a rise in positive reactions to tuberculin. This indicates changes in postvaccination allergy to BCG.

Contrasting influences of Drosophila white/mini-white on ethanol sensitivity in two different behavioral assays.

PubMed

Chan, Robin F; Lewellyn, Lara; DeLoyht, Jacqueline M; Sennett, Kristyn; Coffman, Scarlett; Hewitt, Matthew; Bettinger, Jill C; Warrick, John M; Grotewiel, Mike

2014-06-01

The fruit fly Drosophila melanogaster has been used extensively to investigate genetic mechanisms of ethanol (EtOH)-related behaviors. Many past studies in flies, including studies from our laboratory, have manipulated gene expression using transposons carrying the genetic-phenotypic marker mini-white(mini-w), a derivative of the endogenous gene white(w). Whether the mini-w transgenic marker or the endogenous w gene influences behavioral responses to acute EtOH exposure in flies has not been systematically investigated. We manipulated mini-w and w expression via (i) transposons marked with mini-w, (ii) RNAi against mini-w and w, and (iii) a null allele of w. We assessed EtOH sensitivity and tolerance using a previously described eRING assay (based on climbing in the presence of EtOH) and an assay based on EtOH-induced sedation. In eRING assays, EtOH-induced impairment of climbing correlated inversely with expression of the mini-w marker from a series of transposon insertions. Additionally, flies harboring a null allele of w or flies with RNAi-mediated knockdown of mini-w were significantly more sensitive to EtOH in eRING assays than controls expressing endogenous w or the mini-w marker. In contrast, EtOH sensitivity and rapid tolerance measured in the EtOH sedation assay were not affected by decreased expression of mini-w or endogenous w in flies. EtOH sensitivity measured in the eRING assay is noticeably influenced by w and mini-w, making eRING problematic for studies on EtOH-related behavior in Drosophila using transgenes marked with mini-w. In contrast, the EtOH sensitivity assay described here is a suitable behavioral paradigm for studies on EtOH sensitivity and rapid tolerance in Drosophila including those that use widely available transgenes marked with mini-w. Copyright © 2014 by the Research Society on Alcoholism.

Improved Cell Sensitivity and Longevity in a Rapid Impedance-based Toxicity Sensor

DTIC Science & Technology

2009-01-06

sensitivity and longevity in a rapid impedance-based toxicity sensor† Improved cell sensitivity and longevityTheresa M. Curtis,a** Joel Tabb,a Lori...Romeo,a Steven J. Schwager,b Mark W. Widderc* and William H. van der Schaliec ABSTRACT: A number of toxicity sensors for testing field water using a...range of eukaryotic cell types have been proposed, but it has been difficult to identify sensors with both appropriate sensitivity to toxicants and the

Evaluation of the Utility of von Willebrand Factor Propeptide in the Differential Diagnosis of von Willebrand Disease and Acquired von Willebrand Syndrome.

PubMed

Stufano, Francesca; Boscarino, Marco; Bucciarelli, Paolo; Baronciani, Luciano; Maino, Alberto; Cozzi, Giovanna; Peyvandi, Flora

2018-06-18

An increased von Willebrand factor propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) indicates an enhanced clearance of VWF. This finding has been described in von Willebrand disease (VWD) and in acquired von Willebrand syndrome (AVWS). A distinction between these two diseases, one congenital and the other acquired, is primarily based on family and personal history of bleeding. However, if this information is scanty, the diagnosis might be challenging due to the lack of an effective diagnostic biomarker. In this cross-sectional study, we assessed the ability of VWFpp/VWF:Ag for the differential diagnosis between VWD and AVWS. VWFpp/VWF:Ag was measured in a group of 153 patients (125 with VWD and 28 with AVWS). Most patients with AVWS and VWD showed an increased VWFpp/VWF:Ag, although to variable degrees. A marked increase of VWFpp/VWF:Ag was mainly associated with the diagnosis of AVWS and VWD type 1 Vicenza. A receiver operating characteristic curve was used to identify the optimal cutoff of VWFpp/VWF:Ag for discrimination of patients with a modestly increased (most VWD cases) versus those with a markedly increased clearance (AVWS and VWD type 1 Vicenza), and this cutoff was identified at the value of 3.9 (sensitivity: 0.70, specificity: 0.97). The ROC curve sorting from a logistic model containing VWFpp/VWF:Ag, age, and sex had an area under the curve (AUC) of 0.88 (95% confidence interval: 0.80-0.95). A subsequent molecular evaluation discriminated VWD type 1 Vicenza from AVWS. In conclusion, VWFpp/VWF:Ag appears helpful to discriminate patients with a markedly increase VWF clearance (AVWS or VWD type 1 Vicenza) from those with a modestly increased clearance (most VWD patients). Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Loss of Par-1a/MARK3/C-TAK1 Kinase Leads to Reduced Adiposity, Resistance to Hepatic Steatosis, and Defective Gluconeogenesis ▿

PubMed Central

Lennerz, Jochen K.; Hurov, Jonathan B.; White, Lynn S.; Lewandowski, Katherine T.; Prior, Julie L.; Planer, G. James; Gereau, Robert W.; Piwnica-Worms, David; Schmidt, Robert E.; Piwnica-Worms, Helen

2010-01-01

Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a−/− but not in control or Par-1b−/− mice. The intercrossing of Par-1a−/− with Par-1b−/− mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a−/− mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b−/− mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice. PMID:20733003

Cardiorespiratory interactions to external stimuli.

PubMed

Bernardi, L; Porta, C; Spicuzza, L; Sleight, P

2005-09-01

Respiration is a powerful modulator of heart rate variability, and of baro- or chemo-reflex sensitivity. This occurs via a mechanical effect of breathing that synchronizes all cardiovascular variables at the respiratory rhythm, particularly when this occurs at a particular slow rate coincident with the Mayer waves in arterial pressure (approximately 6 cycles/min). Recitation of the rosary prayer (or of most mantras), induces a marked enhancement of these slow rhythms, whereas random verbalization or random breathing does not. This phenomenon in turn increases baroreflex sensitivity and reduces chemoreflex sensitivity, leading to increases in parasympathetic and reductions in sympathetic activity. The opposite can be seen during either verbalization or mental stress tests. Qualitatively similar effects can be obtained even by passive listening to more or less rhythmic auditory stimuli, such as music, and the speed of the rhythm (rather than the style) appears to be one of the main determinants of the cardiovascular and respiratory responses. These findings have clinical relevance. Appropriate modulation of breathing, can improve/restore autonomic control of cardiovascular and respiratory systems in relevant diseases such as hypertension and heart failure, and might therefore help improving exercise tolerance, quality of life, and ultimately, survival.

P21-activated kinase 2 (PAK2) regulates glucose uptake and insulin sensitivity in neuronal cells.

PubMed

Varshney, Pallavi; Dey, Chinmoy Sankar

2016-07-05

P21-activated kinases (PAKs) are recently reported as important players of insulin signaling and glucose homeostasis in tissues like muscle, pancreas and liver. However, their role in neuronal insulin signaling is still unknown. Present study reports the involvement of PAK2 in neuronal insulin signaling, glucose uptake and insulin resistance. Irrespective of insulin sensitivity, insulin stimulation decreased PAK2 activity. PAK2 downregulation displayed marked enhancement of GLUT4 translocation with increase in glucose uptake whereas PAK2 over-expression showed its reduction. Treatment with Akti-1/2 and wortmannin suggested that Akt and PI3K are mediators of insulin effect on PAK2 and glucose uptake. Rac1 inhibition demonstrated decreased PAK2 activity while inhibition of PP2A resulted in increased PAK2 activity, with corresponding changes in glucose uptake. Taken together, present study demonstrates an inhibitory role of insulin signaling (via PI3K-Akt) and PP2A on PAK2 activity and establishes PAK2 as a Rac1-dependent negative regulator of neuronal glucose uptake and insulin sensitivity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Reduced baroreflex sensitivity with volume loading in conscious dogs

NASA Technical Reports Server (NTRS)

Vatner, S. F.; Boettcher, D. H.; Heyndrickx, G. R.; Mcritchie, R. J.

1975-01-01

Results of studies of the Bainbridge reflex in intact conscious dogs are presented. They indicate that arterial baroreflex sensitivity is reduced progressively as atrial pressure is raised by volume loading; this observation explains how heart rate can rise markedly in the presence of an elevated arterial blood pressure.

A Simulation Study of Acoustic-Assisted Tracking of Whales for Mark-Recapture Surveys

PubMed Central

Peel, David; Miller, Brian S.; Kelly, Natalie; Dawson, Steve; Slooten, Elisabeth; Double, Michael C.

2014-01-01

Collecting enough data to obtain reasonable abundance estimates of whales is often difficult, particularly when studying rare species. Passive acoustics can be used to detect whale sounds and are increasingly used to estimate whale abundance. Much of the existing effort centres on the use of acoustics to estimate abundance directly, e.g. analysing detections in a distance sampling framework. Here, we focus on acoustics as a tool incorporated within mark-recapture surveys. In this context, acoustic tools are used to detect and track whales, which are then photographed or biopsied to provide data for mark-recapture analyses. The purpose of incorporating acoustics is to increase the encounter rate beyond using visual searching only. While this general approach is not new, its utility is rarely quantified. This paper predicts the “acoustically-assisted” encounter rate using a discrete-time individual-based simulation of whales and survey vessel. We validate the simulation framework using existing data from studies of sperm whales. We then use the framework to predict potential encounter rates in a study of Antarctic blue whales. We also investigate the effects of a number of the key parameters on encounter rate. Mean encounter rates from the simulation of sperm whales matched well with empirical data. Variance of encounter rate, however, was underestimated. The simulation of Antarctic blue whales found that passive acoustics should provide a 1.7–3.0 fold increase in encounter rate over visual-only methods. Encounter rate was most sensitive to acoustic detection range, followed by vocalisation rate. During survey planning and design, some indication of the relationship between expected sample size and effort is paramount; this simulation framework can be used to predict encounter rates and establish this relationship. For a case in point, the simulation framework indicates unequivocally that real-time acoustic tracking should be considered for quantifying the abundance of Antarctic blue whales via mark-recapture methods. PMID:24827919

A simulation study of acoustic-assisted tracking of whales for mark-recapture surveys.

PubMed

Peel, David; Miller, Brian S; Kelly, Natalie; Dawson, Steve; Slooten, Elisabeth; Double, Michael C

2014-01-01

Collecting enough data to obtain reasonable abundance estimates of whales is often difficult, particularly when studying rare species. Passive acoustics can be used to detect whale sounds and are increasingly used to estimate whale abundance. Much of the existing effort centres on the use of acoustics to estimate abundance directly, e.g. analysing detections in a distance sampling framework. Here, we focus on acoustics as a tool incorporated within mark-recapture surveys. In this context, acoustic tools are used to detect and track whales, which are then photographed or biopsied to provide data for mark-recapture analyses. The purpose of incorporating acoustics is to increase the encounter rate beyond using visual searching only. While this general approach is not new, its utility is rarely quantified. This paper predicts the "acoustically-assisted" encounter rate using a discrete-time individual-based simulation of whales and survey vessel. We validate the simulation framework using existing data from studies of sperm whales. We then use the framework to predict potential encounter rates in a study of Antarctic blue whales. We also investigate the effects of a number of the key parameters on encounter rate. Mean encounter rates from the simulation of sperm whales matched well with empirical data. Variance of encounter rate, however, was underestimated. The simulation of Antarctic blue whales found that passive acoustics should provide a 1.7-3.0 fold increase in encounter rate over visual-only methods. Encounter rate was most sensitive to acoustic detection range, followed by vocalisation rate. During survey planning and design, some indication of the relationship between expected sample size and effort is paramount; this simulation framework can be used to predict encounter rates and establish this relationship. For a case in point, the simulation framework indicates unequivocally that real-time acoustic tracking should be considered for quantifying the abundance of Antarctic blue whales via mark-recapture methods.

Stress modification of the toxicity of antimotion sickness drugs and Aspirin

NASA Technical Reports Server (NTRS)

Shields, D.; Marra, C.; Goodwin, A.; Vernikos-Danellis, J.

1975-01-01

The effect of environmental temperature on the toxicity of cyclizine, trimethobenzamide, and Aspirin were studied in mice. LD-50s were compared at 30 C, 22 C, and 15 C. At 30 C the toxicity of all three drugs increased, with that to Aspirin being affected most. Cooling decreased the toxicity of cyclizine and had no significant effect on that of trimethobenzamide or aspirin. These findings indicate that alterations in environmental temperature markedly affect drug toxicity. They emphasize that such alterations, and particularly increases in temperature, do not have to be particularly drastic, but that 'mild' variations in the environment are effective in altering an animal's sensitivity to a drug.

The effect of pertussis vaccine on the immune response of mice to sheep red blood cells

PubMed Central

Dresser, D. W.; Wortis, H. H.; Anderson, Hilary R.

1970-01-01

Bordetella pertussis is an adjuvant when given to mice immunized with sheep RBC. The adjuvant activity of pertussis is reflected in an increase in the number of cells producing antibody as measured by the localized haemolysis in gel technique. γG-PFC have a more marked response to pertussis than do γM-PFC, and in general γG-PFC are more sensitive than γM to variations in dose or injection schedule of pertussis organisms. Pertussis increases the response to doses of antigen which previously were considered to be maximal. The distribution of PFC between spleen, blood and lymph nodes is altered by pertussis injections. PMID:4924108

The Ca2+ sensitizer CK‐2066260 increases myofibrillar Ca2+ sensitivity and submaximal force selectively in fast skeletal muscle

PubMed Central

Cheng, Arthur J.; Hartman, James J.; Hinken, Aaron C.; Lee, Ken; Durham, Nickie; Russell, Alan J.; Malik, Fady I.; Westerblad, Håkan; Jasper, Jeffrey R.

2017-01-01

Key points We report that the small molecule CK‐2066260 selectively slows the off‐rate of Ca2 + from fast skeletal muscle troponin, leading to increased myofibrillar Ca2 + sensitivity in fast skeletal muscle.Rodents dosed with CK‐2066260 show increased hindlimb muscle force and power in response to submaximal rates of nerve stimulation in situ.CK‐2066260 has no effect on free cytosolic [Ca2 +] during contractions of isolated muscle fibres.We conclude that fast skeletal muscle troponin sensitizers constitute a potential therapy to address an unmet need of improving muscle function in conditions of weakness and premature muscle fatigue. Abstract Skeletal muscle dysfunction occurs in many diseases and can lead to muscle weakness and premature muscle fatigue. Here we show that the fast skeletal troponin activator, CK‐2066260, counteracts muscle weakness by increasing troponin Ca2+ affinity, thereby increasing myofibrillar Ca2+ sensitivity. Exposure to CK‐2066260 resulted in a concentration‐dependent increase in the Ca2+ sensitivity of ATPase activity in isolated myofibrils and reconstituted hybrid sarcomeres containing fast skeletal muscle troponin C. Stopped‐flow experiments revealed a ∼2.7‐fold decrease in the Ca2+ off‐rate of isolated troponin complexes in the presence of CK‐2066260 (6 vs. 17 s−1 under control conditions). Isolated mouse flexor digitorum brevis fibres showed a rapidly developing, reversible and concentration‐dependent force increase at submaximal stimulation frequencies. This force increase was not accompanied by any changes in the free cytosolic [Ca2+] or its kinetics. CK‐2066260 induced a slowing of relaxation, which was markedly larger at 26°C than at 31°C and could be linked to the decreased Ca2+ off‐rate of troponin C. Rats dosed with CK‐2066260 showed increased hindlimb isometric and isokinetic force in response to submaximal rates of nerve stimulation in situ producing significantly higher absolute forces at low isokinetic velocities, whereas there was no difference in force at the highest velocities. Overall muscle power was increased and the findings are consistent with a lack of effect on crossbridge kinetics. In conclusion, CK‐2066260 acts as a fast skeletal troponin activator that may be used to increase muscle force and power in conditions of muscle weakness. PMID:27869319

Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation.

PubMed

Cho, Josalyn L; Ling, Morris F; Adams, David C; Faustino, Lucas; Islam, Sabina A; Afshar, Roshi; Griffith, Jason W; Harris, Robert S; Ng, Aylwin; Radicioni, Giorgia; Ford, Amina A; Han, Andre K; Xavier, Ramnik; Kwok, William W; Boucher, Richard; Moon, James J; Hamilos, Daniel L; Kesimer, Mehmet; Suter, Melissa J; Medoff, Benjamin D; Luster, Andrew D

2016-10-05

Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4 + T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4 + T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation. Copyright © 2016, American Association for the Advancement of Science.

Enhanced expression of IL-8 in normal human keratinocytes and human keratinocyte cell line HaCaT in vitro after stimulation with contact sensitizers, tolerogens and irritants.

PubMed

Mohamadzadeh, M; Müller, M; Hultsch, T; Enk, A; Saloga, J; Knop, J

1994-12-01

To investigate the interleukin-8 production of keratinocytes after stimulation in vitro we have used various agents: (i) contact sensitizer (2,4-dinitrofluorobenzene, 3-n-pentadecylcatechol); (ii) tolerogen (5-methyl-3-n-pentadecylcatechol); (iii) irritant (sodium lauryl sulfate). Interleukin-8 gene expression was assessed by northern blot hybridization of the total cytoplasmic RNA extracted from subconfluent normal human keratinocyte cultures and the keratinocyte cell line HaCaT using a radiolabeled DNA probe specific for human interleukin-8. Interleukin-8 gene expression was markedly increased upon in vitro stimulation after 1-6 h with contact sensitizers, tolerogen and the irritant. In contrast, interleukin-8 production was not detectable in unstimulated normal human keratinocytes or the HaCaT keratinocyte cell line. These results suggest that the induction and production of interleukin-8 is a response to nonspecific stimuli and may play a critical role in the early response to immunogenic or inflammatory signals in man.

Effect of an ozone injury retardant chemical on isozyme profiles from alfalfa callus in vitro

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

Rier, J.P. Jr.; Sood, V.K.; Whitaker, A.

1983-01-01

Plant ozone injury retardant N-(2-(2-oxo-1-imidazolidinyl)-ethyl)-N'-phenylurea (EDU or ethylenediurea) at 1.0 ppm inhibited growth of callus of alfalfa cultivars Williamsburg (ozone-sensitive) and MSB-CW5An2 (ozone-insensitive) germplasm of Medicago sativa. The presence of EDU (0.1 ppm)in the growth medium increased the number of protein and peroxidase isozyme bands in alfalfa cultivar Williamsburg stem callus and ozone modified their intensities. Protein profiles of MSB stem callus from media containing EDU or exposed to ozone were unchanged. Marked differences were observed between the peroxidase profiles of ozonated and control ozone-insensitive stem callus from media containing EDU. Protein profiles of ozonated ozone-sensitive leaf callus differed slightlymore » from controls. The peroxidase profile of ozonated ozone-sensitive leaf callus was not altered when its growth medium contained EDU, but when it was absent, changes were observed in these profiles.« less

Finding knowledge translation articles in CINAHL.

PubMed

Lokker, Cynthia; McKibbon, K Ann; Wilczynski, Nancy L; Haynes, R Brian; Ciliska, Donna; Dobbins, Maureen; Davis, David A; Straus, Sharon E

2010-01-01

The process of moving research into practice has a number of names including knowledge translation (KT). Researchers and decision makers need to be able to readily access the literature on KT for the field to grow and to evaluate the existing evidence. To develop and validate search filters for finding KT articles in the database Cumulative Index to Nursing and Allied Health (CINAHL). A gold standard database was constructed by hand searching and classifying articles from 12 journals as KT Content, KT Applications and KT Theory. Sensitivity, specificity, precision, and accuracy of the search filters. Optimized search filters had fairly low sensitivity and specificity for KT Content (58.4% and 64.9% respectively), while sensitivity and specificity increased for retrieving KT Application (67.5% and 70.2%) and KT Theory articles (70.4% and 77.8%). Search filter performance was suboptimal marking the broad base of disciplines and vocabularies used by KT researchers. Such diversity makes retrieval of KT studies in CINAHL difficult.

Usefulness of pressure-sensitive adhesives as a pretreatment material before application of topical drug formulations and a peeling tape for excess stratum corneum layers.

PubMed

Kikuchi, Keisuke; Todo, Hiroaki; Sugibayashi, Kenji

2014-01-01

Two unique pressure-sensitive adhesive (PSA) tapes (PSA-A, -B) with different adhesive properties of commercial PSAs were prepared and evaluated for their usefulness as a pretreatment material prior to the application of transdermal therapeutic systems or topical drug formulations and also as a peeling agent against excess layers of the stratum corneum. In the present study, in vitro permeation experiments were conducted using vertical type diffusion cells and excised hairless rat or porcine skin from which the stratum corneum had been stripped several times with PSAs. The results obtained revealed that PSA-A and -B had higher stripping or peeling effects than those of the marketed PSAs. Marked changes were observed in skin barrier function before and after stripping using PSAs, and the enhancement effect on the skin permeation of drugs achieved by stripping the stratum corneum was markedly different between the PSAs. PSA-A, in particular, markedly improved skin permeation and the skin concentration of topically applied chemical compounds because it removed many layers of the stratum corneum when skin was stripped only a few times. In contrast, when PSA-B was used to pretreat the skin surface, the extent of skin permeation and concentration of drugs was safely increased because only a few layers of the stratum corneum were removed, even with repeated stripping. The enhancement effect achieved by PSA-B was not as high as that by PSA-A. Thus, stripping with PSA-A can be used as a penetration enhancement tool, whereas PSA-B can be used as a peeling material against excess layers of the stratum corneum.

Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection.

PubMed

Funata, Sayaka; Matsusaka, Keisuke; Yamanaka, Ryota; Yamamoto, Shogo; Okabe, Atsushi; Fukuyo, Masaki; Aburatani, Hiroyuki; Fukayama, Masashi; Kaneda, Atsushi

2017-08-15

Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were "DNA methylation-sensitive" genes, which acquired DNA methylation in the whole promoter regions and thus were repressed. These included anti-oncogenic genes, e.g. CDKN2A . The other half were "DNA methylation-resistant" genes, where DNA methylation is acquired in the surrounding of promoter regions, but unmethylated status is protected in the vicinity of transcription start site. These genes thereby retained gene expression, and included DNA repair genes. Histone modification was altered dynamically and coordinately with DNA methylation alteration. DNA methylation-sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks, H3K4me3 and H3K27ac. Apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes. Genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Our data show that orchestrated epigenetic alterations are important in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at transcription start site.

Rigorous electromagnetic simulation applied to alignment systems

NASA Astrophysics Data System (ADS)

Deng, Yunfei; Pistor, Thomas V.; Neureuther, Andrew R.

2001-09-01

Rigorous electromagnetic simulation with TEMPEST is used to provide benchmark data and understanding of key parameters in the design of topographical features of alignment marks. Periodic large silicon trenches are analyzed as a function of wavelength (530-800 nm), duty cycle, depth, slope and angle of incidence. The signals are well behaved except when the trench width becomes about 1 micrometers or smaller. Segmentation of the trenches to form 3D marks shows that a segmentation period of 2-5 wavelengths makes the diffraction in the (1,1) direction about 1/3 to 1/2 of that in the main first order (1,0). Transmission alignment marks nanoimprint lithography using the difference between the +1 and -1 reflected orders showed a sensitivity of the difference signal to misalignment of 0.7%/nm for rigorous simulation and 0.5%/nm for simple ray-tracing. The sensitivity to a slanted substrate indentation was 10 nm off-set per degree of tilt from horizontal.

Increasing Protein Charge State When Using Laser Electrospray Mass Spectrometry

NASA Astrophysics Data System (ADS)

Karki, Santosh; Flanigan, Paul M.; Perez, Johnny J.; Archer, Jieutonne J.; Levis, Robert J.

2015-05-01

Femtosecond (fs) laser vaporization is used to transfer cytochrome c, myoglobin, lysozyme, and ubiquitin from the condensed phase into an electrospray (ES) plume consisting of a mixture of a supercharging reagent, m-nitrobenzyl alcohol ( m-NBA), and trifluoroacetic acid (TFA), acetic acid (AA), or formic acid (FA). Interaction of acid-sensitive proteins like cytochrome c and myoglobin with the highly charged ES droplets resulted in a shift to higher charge states in comparison with acid-stable proteins like lysozyme and ubiquitin. Laser electrospray mass spectrometry (LEMS) measurements showed an increase in both the average charge states (Zavg) and the charge state with maximum intensity (Zmode) for acid-sensitive proteins compared with conventional electrospray ionization mass spectrometry (ESI-MS) under equivalent solvent conditions. A marked increase in ion abundance of higher charge states was observed for LEMS in comparison with conventional electrospray for cytochrome c (ranging from 19+ to 21+ versus 13+ to 16+) and myoglobin (ranging from 19+ to 26+ versus 18+ to 21+) using an ES solution containing m-NBA and TFA. LEMS measurements as a function of electrospray flow rate yielded increasing charge states with decreasing flow rates for cytochrome c and myoglobin.

Ultrasonographic Differentiation Between Nodular Hyperplasia and Neoplastic Follicular-Patterned Lesions of the Thyroid Gland.

PubMed

Song, Yong Sub; Kim, Ji-Hoon; Na, Dong Gyu; Min, Hye Sook; Won, Jae-Kyung; Yun, Tae Jin; Choi, Seung Hong; Sohn, Chul-Ho

2016-08-01

We evaluate the gray-scale ultrasonographic characteristics that differentiate between nodular hyperplasia (NH) and neoplastic follicular-patterned lesions (NFPLs) of the thyroid gland. Ultrasonographic features of 750 patients with 832 thyroid nodules (NH, n = 361; or NFPLs, follicular adenoma, n = 123; follicular carcinoma, n = 159; and follicular variant papillary carcinoma, n = 189) were analyzed. Except for echogenicity, over two-thirds of the cases of NH and NFPLs share the ultrasonographic characteristics of solid internal content, a well-defined smooth margin and round-to-ovoid shape. Independent predictors for NH were non-solid internal content (sensitivity 27.1%, specificity 90.2%), isoechogenicity (sensitivity 69.5%, specificity 63.5%) and an ill-defined margin (sensitivity 18.8%, specificity 94.5%). Independent predictors for NFPLs were hypoechogenicity (sensitivity 60.5%, specificity 70.4%), marked hypoechogenicity (sensitivity 2.8%, specificity 99.4%) and taller-than-wide shape (sensitivity 6.6%, specificity 98.1%). Although NH and NFPLs commonly share ultrasonographic characteristics, non-solid internal content and ill-defined margin are specific to NH and marked hypoechogenicity and taller-than-wide shape are specific to NFPLs. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Contrasting influences of Drosophila white/mini-white on ethanol sensitivity in two different behavioral assays

PubMed Central

Chan, Robin F.; Lewellyn, Lara; DeLoyht, Jacqueline M.; Sennett, Kristyn; Coffman, Scarlett; Hewitt, Matthew; Bettinger, Jill C.; Warrick, John M.; Grotewiel, Mike

2014-01-01

Background The fruit fly Drosophila melanogaster has been used extensively to investigate genetic mechanisms of ethanol-related behaviors. Many past studies in flies, including studies from our laboratory, have manipulated gene expression using transposons carrying the genetic-phenotypic marker mini-white, a derivative of the endogenous gene white. Whether the mini-white transgenic marker or the endogenous white gene influence behavioral responses to acute ethanol exposure in flies has not been systematically investigated. Methods We manipulated mini-white and white expression via (i) transposons marked with mini-white, (ii) RNAi against mini-white and white and (iii) a null allele of white. We assessed ethanol sensitivity and tolerance using a previously described eRING assay (based on climbing in the presence of ethanol) and an assay based on ethanol-induced sedation. Results In eRING assays, ethanol-induced impairment of climbing correlated inversely with expression of the mini-white marker from a series of transposon insertions. Additionally, flies harboring a null allele of white or flies with RNAi-mediated knockdown of mini-white were significantly more sensitive to ethanol in eRING assays than controls expressing endogenous white or the mini-white marker. In contrast, ethanol sensitivity and rapid tolerance measured in the ethanol sedation assay were not affected by decreased expression of mini-white or endogenous white in flies. Conclusions Ethanol sensitivity measured in the eRING assay is noticeably influenced by white and mini-white, making eRING problematic for studies on ethanol-related behavior in Drosophila using transgenes marked with mini-white. In contrast, the ethanol sedation assay described here is a suitable behavioral paradigm for studies on ethanol sedation and rapid tolerance in Drosophila including those that use widely available transgenes marked with mini-white. PMID:24890118

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

Danysz, A.; Proniewski, H.; Wisniewski, K.

< ; < > 8 ; 9 8 8 ; < ; 8 : to dogs (400 r), cats (400 r), gninea pigs (450 r), and mice (180-200 r). The course of radiation illness was estimated on the basis of leukocyte count. During radiation sickness the changes in pharmacologic action and toxicity of various drugs affecting the autonomic nervous system were investigated. By tests on the reactivity of mouse intestine in situ it was shown that at the peak of acute radiation sickness the toxicity of parasympathicotonics (pilocarpine, prostigmine), especially of acetylcholine, sympathicolytics (Priscol), and ganglioplegics (nicotine) decreased. The toxicitymore » of parasympathicolytic drugs (atropine) was higher. No changes of toxicity of sympathicotonics (adrenaline, iproniazid) were found, except for ephedrine, whose toxicity after irradiation significantly increased. Mouse intestinal motility tests showed a reduction 3--6 days postirradiation in the pharmacologic effects of parasympathicotonics (acetylcholine, prostigmine), especially of pilocarpine and ganglioplegics (nicotine, hexamethonium). At the same time the effects of sympathicotonic drugs (adrenaline, Sympatol) increased; on the contrary the monamine oxidase (MAO) inhibitor (iproniazid) showed a marked decrease in effect. With sympathicotonic drugs, pressor effects, changes of ECG, vasoconstrictive and mydriatic effects, and the contractive action on the nictitating membrane of cat were investigated. The pressor effects of adrenaline in dogs rose in the course of radiation sickness. No changes of pressor effects of noradrenaline and ephedrine were found, but the time of post-ephedrine hypertension was prolonged. In the acute stage of the illness, catecholamines evoked more significant changes in the ECG in dogs. During radiation sickness in cats, phasic changes in reactivity of the blood vessels in an isolated limb to catecholamines were observed: in the first phase, diminution; however, at the peak of the disease an increase in vasoconstrictory effects was seen. The action of iproniazid was insignificantly diminished. The mydriatic effect of catecholamines increased at the peak of radiation sickness. The reactivity of the nictitating membrane of cat did not change after smaller doses of adrenaline. In tests of parasympathicotonic drugs, the sensitivity of isolated guinea pig organs (intestine, uterus) to acetylcholine, pilocarpine, and prostigmine at the peak of radiation sickness was markedly diminished, but the sensitivity of intestinal smooth muscle to histamine remained unchanged. With parasympathicolnic drugs, an increase of mydriatic effect of atropine in irradiated mice was observed. Thus in most cases there were increased pharmacologic effects of directacting adrenergic drugs and decreased effects, but increased toxicity, of MAO inhibitors. The diminished pharmacologic effects and toxicity of parasympathicolytic drugs was also shown. The effects and toxicity of ganglioplegic drugs and toxicity of sympathicolytic drugs showed a marked decrease. The results indicrte increased susceptibility of adrenergic receptors and diminished susceptibility of cholinergic receptors on the peak of radiation sickness. It is suggested that these changes may arise from the characteristic disturbances in functional state of the vegetative nervous system, and particularly on the neurohormonal basis. To verify this, catecholamine level in the adrenals and cholinesterase activity was determined. Crtecholamine levels in the adrenals of irradiated mice varied phasically. In the first phase of radiation sickness (1--7 days) this level diminished to approximates 50% of the initial value. In the second phase it showed an increase of nearly 10 times. During radiation sickness a marked fall of acetylcholinesterase activity in the uterus, intestine, and brain of the gninea pigs was found. This supports the postulated parasympathicotonia at the peak of radiation sickness. The influence of increased acetylcholine level after prostigmine on the antiperistaltic action of adrenaline and on the toxicity« less

RADIATION EFFECTS ON IMMUNE MECHANISMS

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

Stoner, R.D.; Hale, W.M.

1963-03-01

Experiments were performed on pathogen-free Swiss albino mice to determine the repressive effect of ionizing radiation on immune mechanisms. In animals given sublethal doses of Co/sup 60/ gamma radiation by acute short-term exposure or by chronic long-term exposure at a low dose rate, ability to produce antibody was inhibited or abolished, and natural resistance and active and passive immunity to pneumococcal and Trichinella infections were severely depressed. It appears that the repression resulted from damage to the cellular defensive mechanisms of the host. Active immunity and natural resistance to influenza virus infections were not altered significantly by radiation. Exposure tomore » radiation enhanced the severity of anaphylactic shock markedly in mice previously sensitized to tetanus toxoid and challenged with tetanus toxoid after radiation. Chronic exposure to radiation caused immediate increased sensitivity to fatal anaphylaxis. (auth)« less

[Study of mixed dry binders in directly compressible lactoses and microcrystalline cellulose].

PubMed

Muzíková, J; Vinklarová, S

2004-09-01

The paper evaluated the compressibility of dry binders prepared in the ratios of 3:1, 1:1, and 1:3 from Pharmatosa DCL 15 and DCL 21 and Avicel PH 200, and the sensitivity of the mixtures to an addition of the lubricant magnesium stearate from the standpoint of the effect on the strength of tablets. Mixtures of lactoses with Avicel PH -200 in a ratio of 3:1 proved to be most advantageous. The strengths of tablets made of these mixtures oscillated in the optimal range and they showed the least sensitivity to the added lubricant. An increase in stearate concentration did not result in a marked decrease in the strength of compacts. Pharmatosa DCL 21 in a mixture with Avicel PH 200 yielded stronger compacts at lower compression force than Pharmatosa DCL 15.

Fascaplysin sensitizes cells to TRAIL-induced apoptosis through upregulating DR5 expression

NASA Astrophysics Data System (ADS)

Wang, Feng; Chen, Haimin; Yan, Xiaojun; Zheng, Yanling

2013-05-01

This study investigated the molecular mechanism of anti-tumor effect of fascaplysin, a nitrogenous red pigment firstly isolated from a marine sponge. Microarray analysis show that the TNF and TNF receptor superfamily in human umbilical vein endothelial cells (HUVEC) and human hepatocarcinoma cells (BEL-7402) were significantly regulated by fascaplysin. Western Blot results reveal that fascaplysin increased the expression of cleaved caspase-9, active caspase-3, and decreased the level of procaspase-8 and Bid. Flow cytometry and cytotoxicity tests indicate that fascaplysin sensitized cells to tumor necrosis-related apoptosisinducing ligand-(TRAIL) induced apoptosis, which was markedly blocked by TRAIL R2/Fc chimera, a dominant negative form of TRAIL receptor DR5. Therefore, our results demonstrate that fascaplysin promotes apoptosis through the activation of TRAIL signaling pathway by upregulating DR5 expression.

Far ultraviolet wide field imaging and photometry - Spartan-202 Mark II Far Ultraviolet Camera

NASA Technical Reports Server (NTRS)

Carruthers, George R.; Heckathorn, Harry M.; Opal, Chet B.; Witt, Adolf N.; Henize, Karl G.

1988-01-01

The U.S. Naval Research Laboratory' Mark II Far Ultraviolet Camera, which is expected to be a primary scientific instrument aboard the Spartan-202 Space Shuttle mission, is described. This camera is intended to obtain FUV wide-field imagery of stars and extended celestial objects, including diffuse nebulae and nearby galaxies. The observations will support the HST by providing FUV photometry of calibration objects. The Mark II camera is an electrographic Schmidt camera with an aperture of 15 cm, a focal length of 30.5 cm, and sensitivity in the 1230-1600 A wavelength range.

Complex Adaptive Systems, soil degradation and land sensitivity to desertification: A multivariate assessment of Italian agro-forest landscape.

PubMed

Salvati, Luca; Mavrakis, Anastasios; Colantoni, Andrea; Mancino, Giuseppe; Ferrara, Agostino

2015-07-15

Degradation of soils and sensitivity of land to desertification are intensified in last decades in the Mediterranean region producing heterogeneous spatial patterns determined by the interplay of factors such as climate, land-use changes, and human pressure. The present study hypothesizes that rising levels of soil degradation and land sensitivity to desertification are reflected into increasingly complex (and non-linear) relationships between environmental and socioeconomic variables. To verify this hypothesis, the Complex Adaptive Systems (CAS) framework was used to explore the spatiotemporal dynamics of eleven indicators derived from a standard assessment of soil degradation and land sensitivity to desertification in Italy. Indicators were made available on a detailed spatial scale (773 agricultural districts) for various years (1960, 1990, 2000 and 2010) and analyzed through a multi-dimensional exploratory data analysis. Our results indicate that the number of significant pair-wise correlations observed between indicators increased with the level of soil and land degradation, although with marked differences between northern and southern Italy. 'Fast' and 'slow' factors underlying soil and land degradation, and 'rapidly-evolving' or 'locked' agricultural districts were identified according to the rapidity of change estimated for each of the indicators studied. In southern Italy, 'rapidly-evolving' districts show a high level of soil degradation and land sensitivity to desertification during the whole period of investigation. On the contrary, those districts in northern Italy are those experiencing a moderate soil degradation and land sensitivity to desertification with the highest increase in the level of sensitivity over time. The study framework contributes to the assessment of complex local systems' dynamics in affluent but divided countries. Results may inform thematic strategies for the mitigation of land and soil degradation in the framework of action plans to combat desertification. Copyright © 2015 Elsevier B.V. All rights reserved.

Difference-Sensitive Communities, Networked Learning, and Higher Education: Potentialities and Risks

ERIC Educational Resources Information Center

Papastephanou, Marianna

2005-01-01

Recent emphases on prospects for difference-sensitive virtual communities rely implicity or explicity on some optimist accounts of cyberspace and globalization. It is expected that hybridity, diaspora and fluidity, marking new understandings of spatiality and temporality in a globalized postmodern era, will create new forms of belonging that will…

Dance Marking Diplomacy: Rehearsing Intercultural Exchange

ERIC Educational Resources Information Center

Warburton, Edward C.

2017-01-01

Diplomacy is the art of relationships: the ability to work with individual to international-level concerns in a sensitive way. Like the diplomat, dance artists and educators know that success requires sensitivity to rapidly changing situational demands. A growing body of research suggests that the nonverbal art form of dance can be an effective…

Behavioral characteristics of capsaicin mediated cutaneous, myogenic, and arthrogenic orofacial nociception in rats.

PubMed

Rohrs, Eric L; Neubert, John K; Caudle, Robert M; Allen, Kyle D

2018-04-30

To assess changes in orofacial tactile sensitivity and gnawing related to capsaicin-mediated cutaneous, myogenic, and arthrogenic nociception in the rat. After recovery from anesthesia, orofacial tactile sensitivity and gnawing were assessed using operant testing methods following capsaicin application. Twenty female CD-Hairless rats were tested with bilateral capsaicin cream application to the cheek or with isoflurane anesthesia alone. Following several weeks of recovery, animals (n = 20) received either 10 μL unilateral masseter injections of vehicle, or phosphate buffered saline (PBS) to assess injection sensitization. After several weeks, masseter capsaicin (1.0%) injections (10 μL) were assessed compared to vehicle and PBS (n = 13). Weeks later capsaicin TMJ injections were evaluated. Animals (n = 11) received either 10 μL unilateral TMJ injections of capsaicin solution (1%) or vehicle. Capsaicin cream to the skin significantly altered gnawing activity (increased puncture time by 248 s (p = 0.0002)) and tactile sensitivity (decreased tolerated bottle distance by 0.980 cm compared to isoflurane only (p = 0.0001)). Similarly, capsaicin masseter injection increased puncture time (339.6 s, p = 0.07) and decreased tolerated bottle distance (1.04 cm, p = 0.005) compared to vehicle. However, intra-articular capsaicin in the TMJ only modified gnawing (increased puncture time by 133 s), with no changes found in tactile sensitivity compared to vehicle. Application of capsaicin to the skin and masseter had similar behavioral effects; however, intra-articular injections to the TMJ only affected gnawing. These data indicate the behavioral changes in rodent models of myogenic and cutaneous pain may be markedly different than models of arthrogenic pain originating from the TMJ. Copyright © 2018. Published by Elsevier Ltd.

Reducing false positives of microcalcification detection systems by removal of breast arterial calcifications

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

Mordang, Jan-Jurre, E-mail: Jan-Jurre.Mordang@radboudumc.nl; Gubern-Mérida, Albert; Karssemeijer, Nico

Purpose: In the past decades, computer-aided detection (CADe) systems have been developed to aid screening radiologists in the detection of malignant microcalcifications. These systems are useful to avoid perceptual oversights and can increase the radiologists’ detection rate. However, due to the high number of false positives marked by these CADe systems, they are not yet suitable as an independent reader. Breast arterial calcifications (BACs) are one of the most frequent false positives marked by CADe systems. In this study, a method is proposed for the elimination of BACs as positive findings. Removal of these false positives will increase the performancemore » of the CADe system in finding malignant microcalcifications. Methods: A multistage method is proposed for the removal of BAC findings. The first stage consists of a microcalcification candidate selection, segmentation and grouping of the microcalcifications, and classification to remove obvious false positives. In the second stage, a case-based selection is applied where cases are selected which contain BACs. In the final stage, BACs are removed from the selected cases. The BACs removal stage consists of a GentleBoost classifier trained on microcalcification features describing their shape, topology, and texture. Additionally, novel features are introduced to discriminate BACs from other positive findings. Results: The CADe system was evaluated with and without BACs removal. Here, both systems were applied on a validation set containing 1088 cases of which 95 cases contained malignant microcalcifications. After bootstrapping, free-response receiver operating characteristics and receiver operating characteristics analyses were carried out. Performance between the two systems was compared at 0.98 and 0.95 specificity. At a specificity of 0.98, the sensitivity increased from 37% to 52% and the sensitivity increased from 62% up to 76% at a specificity of 0.95. Partial areas under the curve in the specificity range of 0.8–1.0 were significantly different between the system without BACs removal and the system with BACs removal, 0.129 ± 0.009 versus 0.144 ± 0.008 (p<0.05), respectively. Additionally, the sensitivity at one false positive per 50 cases and one false positive per 25 cases increased as well, 37% versus 51% (p<0.05) and 58% versus 67% (p<0.05) sensitivity, respectively. Additionally, the CADe system with BACs removal reduces the number of false positives per case by 29% on average. The same sensitivity at one false positive per 50 cases in the CADe system without BACs removal can be achieved at one false positive per 80 cases in the CADe system with BACs removal. Conclusions: By using dedicated algorithms to detect and remove breast arterial calcifications, the performance of CADe systems can be improved, in particular, at false positive rates representative for operating points used in screening.« less

Sex and age-specific differences in ultraviolet reflectance of scent marks of bank voles (Clethrionomys glareolus).

PubMed

Koivula, M; Koskela, E; Viitala, J

1999-12-01

Scent markings of voles are visible via their ultraviolet reflection. Kestrels, and possibly other diurnal raptors, may use this property when hunting. We performed a laboratory study on bank voles to determine whether UV-reflectance of scent marks differs in relation to sex, age and social status. When reflectance spectra of scent marks were measured with a spectro-radiometer, we found UV reflectance to be strongest in mature males. There were no differences between mature females and immature juveniles, nor between sexes in juveniles or mature and immature individuals in females. Moreover, we did not find any difference in UV reflectance between dominant and subordinate mature males. The results of this study support earlier findings that UV sensitive predators may use UV reflectance of scent marks as a prey cue. Consequently, studies on differing vulnerability of voles to avian predators should take into account not only their space use and behaviour but also the UV reflectance of their scent marks.

Investigation of Meniscus Region Behavior and Oscillation Mark Formation in Steel Continuous Casting Using a Transient Thermo-Fluid Model

NASA Astrophysics Data System (ADS)

Blaes, Carly

In the continuous casting of steel, many complex phenomena in the meniscus region of the mold are responsible for the formation of oscillation marks. Oscillation marks are depressions found around the perimeter of continuously cast steel slabs, which if too large can lead to cracking in steel slabs. Therefore, knowledge on how to minimize the size of oscillation marks is very valuable. A computational model was created of the meniscus region, which includes transient multiphase fluid flow of slag and steel, with low-Reynolds turbulence, heat transfer in the mold, slag, and steel, steel shell solidification, mold oscillation, and temperature-dependent properties. This model was first validated using previous experimental and plant data. The model was then used to study the impact of varying casting parameters, including oscillation frequency, stroke, modification ratio, casting speed, molten steel level fluctuations, and temperature-dependent slag properties and surface tension on the oscillation mark shape, and other aspects of thermal-flow behavior during each oscillation cycle, including heat flux profile, slag consumption and mold friction. The first half of oscillation marks were formed during negative strip time as the slag rim pushed molten steel away from the mold wall and that the second half of oscillation marks were formed during positive strip time as the molten steel is drawn near the mold wall due to the upstroke of the mold. Oscillation mark depth was found to decrease with increasing frequency, modification ratio, casting speed, and slag viscosity, while oscillation mark depth was found to increase with increasing stroke. Oscillation mark width was only found to increase due to increases in pitch, which can be contributed to decreasing frequency or increasing casting speed. While many observations were made in this study, in general, oscillation mark depth and total slag consumption increase with increasing negative strip time, while the average heat flux and average mold friction decrease with increasing negative strip time.

Determination of Betaines by Fast Atom Bombardment Mass Spectrometry 1

PubMed Central

Rhodes, David; Rich, Patrick J.; Myers, Ann C.; Reuter, Carol C.; Jamieson, Gene C.

1987-01-01

A rapid, sensitive, and selective method for the determination of betaines is described and discussed. The method entails derivatizing the quaternary ammonium compounds to increase their sensitivity to detection by fast atom bombardment mass spectrometry. Sensitivity of detection increases markedly as the length of the carbon chain of the alcohol used to esterify the betaine carboxylic acid group is increased (C4 > C3 > C2 > C1 > C0). The lower limit of detection of glycine betaine as the n-propyl ester is 0.05 nanomole per microliter of glycerol. Betaine aldehyde can be readily derivatized to the di-n-butyl or di-n-propyl acetal derivatives which exhibit lower limits of detection of about 5 picomoles and 10 picomoles per microliter of glycerol, respectively. Accurate quantification of these compounds is accomplished by the use of deuterium labeled internal standards or quaternary ammonium compound homologs of distinct mass. Methods for the synthesis of these internal standards are reported. Some applications of these methods are illustrated with stable isotope tracer studies on the kinetics of metabolism of choline to betaine aldehyde and glycine betaine in spinach leaf discs, and the identification of several Zea mays genotypes which appear deficient in glycine betaine. Tracer studies with deuterium labeled betaine aldehyde suggest that the deficiency of glycine betaine in one sweet corn hybrid is probably not due to a deficiency in the capacity to oxidize betaine aldehyde. PMID:16665522

Is Reliance on Mitochondrial Respiration a “Chink in the Armor” of Therapy-Resistant Cancer?

PubMed Central

Wolf, Dieter A.

2016-01-01

Summary A series of recent reports has suggested PGC1α-driven upregulation of mitochondrial oxidative phosphorylation as a selective vulnerability of drug-resistant cancers. Accordingly, chemical inhibitors of respiration led to selective eradication of such cancer cells due to their preferential sensitivity to mitochondrial production of reactive oxygen species. These novel insights create a timely opportunity for a biomarker guided application of already existing and newly emerging mitochondrial inhibitors in recurrent drug resistant cancer, including lymphomas, melanomas, and other malignant diseases marked by increased mitochondrial respiration. PMID:25490445

Separation of paralytic shellfish poisoning toxins on Chromarods-SIII by thin-layer chromatography with the Iatroscan (mark 5) and flame thermionic detection.

PubMed

Indrasena, W M; Ackman, R G; Gill, T A

1999-09-10

Thin-layer chromatography (TLC) on Chromarods-SIII with the Iatroscan (Mark-5) and a flame thermionic detector (FTID) was used to develop a rapid method for the detection of paralytic shellfish poisoning (PSP) toxins. The effect of variation in hydrogen (H2) flow, air flow, scan time and detector current on the FTID peak response for both phosphatidylcholine (PC) and PSP were studied in order to define optimum detection conditions. A combination of hydrogen and air flow-rates of 50 ml/min and 1.5-2.0 l/min respectively, along with a scan time of 40 s/rod and detector current of 3.0 A (ampere) or above were found to yield the best results for the detection of PSP compounds. Increasing the detector current level to as high as 3.3 A gave about 130 times more FTID response than did flame ionization detection (FID), for PSP components. Quantities of standards as small as 1 ng neosaxitoxin (NEO), 5 ng saxitoxin (STX), 5 ng B1-toxins (B1), 2 ng gonyautoxin (GTX) 2/3, 6 ng GTX 1/4 and 6 ng C-toxins (C1/C2) could be detected with the FTID. The method detection limits for toxic shellfish tissues using the FTID were 0.4, 2.1, 0.8 and 2.5 micrograms per g tissue for GTX 2/3, STX, NEO and C toxins, respectively. The FTID response increased with increasing detector current and with increasing the scan time. Increasing hydrogen and air flow-rates resulted in decreasing sensitivity within defined limits. Numerous solvent systems were tested, and, solvent consisting of chloroform: methanol-water-acetic acid (30:50:8:2) could separate C toxins from GTX, which eluted ahead of NEO and STX. Accordingly, TLC/FTID with the Iatroscan (Mark-5) seems to be a promising, relatively inexpensive and rapid method of screening plant and animal tissues for PSP toxins.

Increased renal alpha-epithelial sodium channel (ENAC) protein and increased ENAC activity in normal pregnancy.

PubMed

West, Crystal; Zhang, Zheng; Ecker, Geoffrey; Masilamani, Shyama M E

2010-11-01

Pregnancy-mediated sodium (Na) retention is required to provide an increase in plasma volume for the growing fetus. The mechanisms responsible for this Na retention are not clear. We first used a targeted proteomics approach and found that there were no changes in the protein abundance compared with virgin rats of the β or γ ENaC, type 3 Na(+)/H(+) exchanger (NHE3), bumetanide-sensitive cotransporter (NKCC2), or NaCl cotransporter (NCC) in mid- or late pregnancy. In contrast, we observed marked increases in the abundance of the α-ENaC subunit. The plasma volume increased progressively during pregnancy with the greatest plasma volume being evident in late pregnancy. ENaC inhibition abolished the difference in plasma volume status between virgin and pregnant rats. To determine the in vivo activity of ENaC, we conducted in vivo studies of rats in late pregnancy (days 18-20) and virgin rats to measure the natriuretic response to ENaC blockade (with benzamil). The in vivo activity of ENaC (U(Na)V postbenzamil-U(Na)V postvehicle) was markedly increased in late pregnancy, and this difference was abolished by pretreatment with the mineralocorticoid receptor antagonist, eplerenone. These findings demonstrate that the increased α-ENaC subunit of pregnancy is associated with an mineralocorticoid-dependent increase in ENaC activity. Further, we show that ENaC activity is a major contributor of plasma volume status in late pregnancy. These changes are likely to contribute to the renal sodium retention and plasma volume expansion required for an optimal pregnancy.

Interdecadal changes in the community, population and individual levels of the fish fauna of an extensively modified estuary.

PubMed

Valesini, F J; Cottingham, A; Hallett, C S; Clarke, K R

2017-05-01

This study examined inter-period changes over two to three decades in the fish fauna of an urbanized estuary experiencing rapid population growth and a drying climate (Swan-Canning Estuary, Western Australia). Responses were compared at the fish community level (species composition; 1978-2009 in the shallows and 1993-2009 in deeper waters) and at the population and individual levels of an estuarine indicator species, black bream Acanthopagrus butcheri (biomass-abundance and per capita mass at age, respectively; 1993-2009). All three levels showed distinct shifts from earlier to later periods, but their patterns, sensitivity and breadth differed. Community composition changed markedly in the shallows of the lower-middle estuary between the late 1970s and all later periods and moderately between more disparate periods from 1995 to 2009. Several species trends could be linked to the increasing salinity of the estuary or declining dissolved oxygen levels in its middle-upper reaches. Community changes were, however, small or insignificant in the shallow and deeper waters of the upper estuary and deeper waters of the middle estuary, where environmental perturbations are often most pronounced. This may reflect the resilience of the limited suite of species that typify those reaches and thus their lack of sensitivity in reflecting longer-term change at the coarser level of mean abundance. One such species, the selected indicator, A. butcheri, did, however, show marked temporal changes at both the population and individual levels. Biomass decreased markedly in deeper waters while increasing in the shallows from earlier to later periods, presumably reflecting an onshore movement of fish, and per capita body mass in the 2+, 3+ and 4+ year classes fell steadily over time. Such changes probably indicate deteriorating habitat quality in the deeper waters. The study outcomes provide support for a multifaceted approach to the biomonitoring of estuaries using fishes and highlight the need for complementary monitoring of relevant stressors to better disentangle cause-effect pathways. © 2017 The Fisheries Society of the British Isles.

Ferrocene-cinchona hybrids with triazolyl-chalcone linkers act as pro-oxidants and sensitize human cancer cell lines to paclitaxel.

PubMed

Podolski-Renić, Ana; Bősze, Szilvia; Dinić, Jelena; Kocsis, László; Hudecz, Ferenc; Csámpai, Antal; Pešić, Milica

2017-08-16

Recently, we demonstrated that ferrocene-containing compounds with a cinchona moiety displayed marked anticancer activity. Here we report on the effects of the most promising isomers encompassing quinine- (compounds 4 and 5) and quinidine-epimers (compounds 6 and 7) - synthesized using improved methods providing controlled diastereoselectivity - in three different human multidrug resistant (MDR) cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCI-H460/R/NCI-H460, colorectal carcinoma DLD1-TxR/DLD1 and glioblastoma U87-TxR/U87). We observed that the presence of the MDR phenotype did not diminish the activity of the compounds suggesting that ferrocene quinine- and quinidine-epimers are not substrates for P-glycoprotein, which has been indicated as a major mechanism of MDR in the cell lines used. Considering that metal-based anticancer agents mainly act by increasing ROS production, we investigated the potential of ferrocene-quinidine epimers to generate ROS. We found that 6 and 7 more readily increased ROS production and induced mitochondrial damage in MDR cancer cells. According to cell death analysis, 6 and 7 were more active against MDR cancer cells showing collateral sensitivity. In addition, our data suggest that these compounds could act as inhibitors of autophagy. Importantly, simultaneous treatments of 6 and 7 with paclitaxel (PTX) increased the sensitivity of MDR cancer cells to PTX. In conclusion, the ferrocene-quinidine epimers, besides being selective towards MDR cancer cells, could also possess potential to overcome PTX resistance.

Striatal hyper-sensitivity during stress in remitted individuals with recurrent depression

PubMed Central

Admon, Roee; Holsen, Laura M.; Aizley, Harlyn; Remington, Anne; Whitfield-Gabrieli, Susan; Goldstein, Jill M.; Pizzagalli, Diego A.

2014-01-01

Background Increased sensitivity to stress and dysfunctional reward processing are two primary characteristics of Major Depressive Disorder (MDD) that may persist following remission. Preclinical work has established the pivotal role of the striatum in mediating both stress and reward responses. Human neuroimaging studies have corroborated these preclinical findings and highlighted striatal dysfunction in MDD in response to reward, but have yet to investigate striatal function during stress, in particular in individuals with recurrent depression. Methods Thirty three remitted individuals with a history of recurrent MDD (rMDD) and 35 matched healthy controls underwent a validated mild psychological stress task involving viewing of negative stimuli during fMRI. Cortisol and anxiety levels were assessed throughout scanning. Stress-related activation was investigated in three striatal regions: caudate, nucleus accumbens (Nacc), and putamen. Psychophysiological interaction (PPI) analyses probed connectivity of those regions with central structures of the neural stress circuitry, the amygdala and hippocampus. Results The task increased cortisol and anxiety levels, although to a greater extent in rMDD than healthy controls. In response to the negative stimuli, rMDD individuals, but not controls, also exhibited significantly potentiated caudate, Nacc, and putamen activations, as well as increased caudate-amygdala and caudate-hippocampus connectivity. Conclusions Findings highlight striatal hyper-sensitivity in response to a mild psychological stress in rMDD, as manifested by hyper-activation and hyper-connectivity with the amygdala and hippocampus. Striatal hyper-sensitivity during stress might thus constitute a trait mark of depression, providing a potential neural substrate for the interaction between stress and reward dysfunction in MDD. PMID:25483401

Lymphocyte sensitization to nervous tissues and muscle in patients with the Guillain-Barré syndrome

PubMed Central

Caspary, E. A.; Currie, S.; Walton, J. N.; Field, E. J.

1971-01-01

By means of an electrophoretic method lymphocytes from patients with the Guillain-Barré syndrome (`acute idiopathic polyneuritis') have been shown to be sensitized to both encephalitogenic factor (EF) and a similar basic protein prepared from human sciatic nerve (SNBP). Sensitization was more marked in the acute stage of the disorder during which there also appeared to be a degree of sensitization to muscle. The results are consistent with the view that lymphocytic infiltration of peripheral nerves in the condition is of pathogenetic significance. PMID:5106345

Theoretical aspects of the acceptance of new technologies on the smartphone market

NASA Astrophysics Data System (ADS)

Barkoczi, N.; Lobontiu, G.

2017-05-01

Adoption of new technologies on mobile phone market in the past 30 years has transformed the industry and had a large impact on the global economy. Technological progress, as the main factor in the adoption of new technologies, has enabled reduce costs and increase equipment performance. The smartphone is perceived by consumers as a sustainable element, to which the price sensitivity is less important. Consumers are willing to pay more in exchange for better quality and features of the product. Smartphones have changed the way people communicate with others, find information and manage their daily life. In addition, recent developments of new operating systems, abundant applications and competition between suppliers have facilitated a marked increase of the users' number.

Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib.

PubMed

Kirane, Amanda; Toombs, Jason E; Larsen, Jill E; Ostapoff, Katherine T; Meshaw, Kathryn R; Zaknoen, Sara; Brekken, Rolf A; Burrows, Francis J

2012-09-01

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 µM and remained sufficient to completely inhibit prostaglandin E(2) production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.

Reminder effects: the molecular cascade following a reminder in young chicks does not recapitulate that following training on a passive avoidance task.

PubMed

Salinska, Elzbieta; Bourne, Rachel C; Rose, Steven P R

2004-06-01

Memory traces, once established, are no longer sensitive to disruption by metabolic inhibitors. However, memories reactivated by reminder are once again vulnerable, in a time-dependent manner, to amnestic treatment. To determine whether the metabolic events following a reminder recapitulate those following initial training we examined the temporal dynamics of amnesia induced by the protein synthesis inhibitor anisomycin and the glycosylation inhibitor 2-deoxygalactose. The effects of both were transient and dependent on time of reminder post-training and time of injection relative to reminder, and differed from those following initial training. 2-[(14)C]-deoxyglucose uptake increased in two brain regions, the intermediate medial hyperstriatum ventrale (IMHV) and lobus parolfactorius (LPO) following reminder as it did following training, but the increase was bilateral rather than confined to the left hemisphere and was more marked in LPO than IMHV. C-fos expression after reminder was increased only in the LPO, the chick brain region associated with a late phase of memory processing and recall. Thus although, like initial consolidation, memory processing after reminder is sensitive to inhibitors of protein synthesis and glycosylation, the temporal and pharmacological dynamics indicate differences between these two processes.

Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone

PubMed Central

Wilson-Fritch, Leanne; Nicoloro, Sarah; Chouinard, My; Lazar, Mitchell A.; Chui, Patricia C.; Leszyk, John; Straubhaar, Juerg; Czech, Michael P.; Corvera, Silvia

2004-01-01

Adipose tissue plays a central role in the control of energy homeostasis through the storage and turnover of triglycerides and through the secretion of factors that affect satiety and fuel utilization. Agents that enhance insulin sensitivity, such as rosiglitazone, appear to exert their therapeutic effect through adipose tissue, but the precise mechanisms of their actions are unclear. Rosiglitazone changes the morphological features and protein profiles of mitochondria in 3T3-L1 adipocytes. To examine the relevance of these effects in vivo, we studied white adipocytes from ob/ob mice during the development of obesity and after treatment with rosiglitazone. The levels of approximately 50% of gene transcripts encoding mitochondrial proteins were decreased with the onset of obesity. About half of those genes were upregulated after treatment with rosiglitazone, and this was accompanied by an increase in mitochondrial mass and changes in mitochondrial structure. Functionally, adipocytes from rosiglitazone-treated mice displayed markedly enhanced oxygen consumption and significantly increased palmitate oxidation. These data reveal mitochondrial remodeling and increased energy expenditure in white fat in response to rosiglitazone treatment in vivo and suggest that enhanced lipid utilization in this tissue may affect whole-body energy homeostasis and insulin sensitivity. PMID:15520860

microRNA-137 modulates pancreatic cancer cells tumor growth, invasion and sensitivity to chemotherapy

PubMed Central

Xiao, Jie; Peng, Feng; Yu, Chao; Wang, Min; Li, Xu; Li, Zhipeng; Jiang, Jianxin; Sun, Chengyi

2014-01-01

Background: We intended to investigate the role of microRNA 137 (miR-137) in regulating pancreatic cancer cells’ growth in vitro and tumor development in vivo. Methods: QTR-PCR was used to examine the expression of miR-137 in pancreatic cancer cell lines and tumor cells from human patients. Lentivirual vector containing miR-137 mimic was used to overexpress miR-137 in PANC-1 and MIA PaCa-2 cells. The effects of overexpressing miR-137 on pancreatic cancer cell invasion and chemo-sensitivity to 5-fluorouracil (5-FU) were examined by cell migration and survival essays in vitro. The molecular target of miR-137, pleiotropic growth factor (PTN), was down-regulated by siRNA to examine its effects on cancer cell invasion. MIA PaCa-2 cells with endogenously overexpressed miR-137 were transplanted into null mice to examine tumor growth in vivo. Results: We found miR-137 was markedly underexpressed in both pancreatic cancer cell lines and tumor cells from patients. In cancer cells, transfection of lentivirus containing miR-137 mimic was able to markedly upregulate endogenous expression of miR-137, inhibited cancer cell invasion and increased sensitivities to chemotherapy reagent 5-FU. PTN was significantly down-regulated by overexpressing miR-137 in pancreatic cancer cells, and knocking down PTN was effective to rescue the reduced cancer cell invasion ability caused by miR-137 overexpression. More importantly, overexpressing miR-137 led to significant inhibition on tumor formation, including reductions in tumor weight and tumor size in vivo. Conclusion: Our study demonstrated that miR-137 played an important role in pancreatic cancer development. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer. PMID:25550779

Role of Prefrontal Serotonergic and Dopaminergic Systems in Encounter-Induced Hyperactivity in Methamphetamine-Sensitized Mice.

PubMed

Tanaka, Tatsunori; Ago, Yukio; Umehara, Chiaki; Imoto, Emina; Hasebe, Shigeru; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio

2017-05-01

Isolation-reared mice show social encounter-induced hyperactivity with activation of prefrontal serotonergic and dopaminergic systems, but it is not known whether this stress response is observed in other pathological conditions. Here we examined whether the social encounter stimulation induces abnormal behavior during withdrawal in chronic methamphetamine-treated mice. To induce methamphetamine-induced behavioral sensitization, male mice were injected with methamphetamine (1 mg/kg) once daily for 7 days. The encounter with an intruder elicited hyperactivity 24 h after the last injection of methamphetamine in methamphetamine-sensitized mice. This response was observed even as long as 2 weeks after withdrawal of methamphetamine. The encounter increased c-Fos expression in the prefrontal cortex, dorsal raphe nucleus and ventral tegmental area in methamphetamine-sensitized mice, while it did not in control mice. Furthermore, the encounter increased extracellular serotonin (5-HT) and dopamine, but not noradrenaline, levels in the prefrontal cortex in methamphetamine-sensitized mice. Local injection of 5,7-dihydroxytryptamine and 6-hydroxydopamine into the prefrontal cortex attenuated encounter-induced hyperactivity in methamphetamine-sensitized mice and it markedly decreased prefrontal 5-HT and dopamine levels, respectively. Pharmacological analysis showed that the encounter-induced hyperactivity is mediated by dopamine D1 receptors and 5-HT2A receptors and attenuated by anxiolytics and antidepressants such as diazepam, osemozotan and selective 5-HT reuptake inhibitors. The effect of paroxetine was blocked by the 5-HT3 receptor antagonist azasetron. The present study shows that psychological stress elicits hyperactivity with activation of prefrontal 5-HT and dopamine systems in methamphetamine-dependent mice and suggests that the abnormal behavior is associated with anxiety and depression. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Paired emitter-detector diode detection with dual wavelength monitoring for enhanced sensitivity to transition metals in ion chromatography with post-column reaction.

PubMed

O' Toole, Martina; Barron, Leon; Shepherd, Roderick; Paull, Brett; Nesterenko, Pavel; Diamond, Dermot

2009-01-01

The combination of post-column derivatisation and visible detection are regularly employed in ion chromatography (IC) to detect poorly absorbing species. Although this mode is often highly sensitive, one disadvantage is the increase in repeating baseline artifacts associated with out-of-sync pumping systems. The work presented here will demonstrate the use of a second generation design paired emitter-detector diode (PEDD-II) detection mode offering enhanced sensitivity to transition metals in IC by markedly reducing this problem and also by improving signal noise. First generation designs demonstrated the use of a single integrated PEDD detector cell as a simple, small (15 x 5 mm), highly sensitive, low cost photometric detector for the detection of metals in IC. The basic principle of this detection mode lies in the employment of two linear light emitting diodes (LEDs), one operating in normal mode as a light source and the other in reverse bias serving as a light detector. The second generation PEDD-II design showed increased sensitivity for Mn(II)- and Co(II)-2-(pyridylazo)resorcinol (PAR) complexes as a result of two simultaneously acquiring detection cells--one analytical PEDD cell and one reference PEDD cell. Therefore, the PEDD-II employs two wavelengths whereby one monitors the analyte reaction product and the second monitors a wavelength close to the isosbestic point. The optimum LED wavelength to be used for the analytical cell was investigated to maximise peak response. The fabrication process for both the analytical and reference PEDD cells was validated by determining the reproducibility of detectors within a batch. The reproducibility and sensitivity of the PEDD-II detector was then investigated using signals obtained from both intra- and inter-day chromatograms.

Pichia anomala DBVPG 3003 Secretes a Ubiquitin-Like Protein That Has Antimicrobial Activity▿

PubMed Central

De Ingeniis, Jessica; Raffaelli, Nadia; Ciani, Maurizio; Mannazzu, Ilaria

2009-01-01

The yeast strain Pichia anomala DBVPG 3003 secretes a killer toxin (Pikt) that has antifungal activity against Brettanomyces/Dekkera sp. yeasts. Pikt interacts with β-1,6-glucan, consistent with binding to the cell wall of sensitive targets. In contrast to that of toxin K1, secreted by Saccharomyces cerevisiae, Pikt killer activity is not mediated by an increase in membrane permeability. Purification of the toxin yielded a homogeneous protein of about 8 kDa, which showed a marked similarity to ubiquitin in terms of molecular mass and N-terminal sequences. Pikt is also specifically recognized by anti-bovine ubiquitin antibodies and, similar to ubiquitin-like peptides, is not absorbed by DEAE-cellulose. However, Pikt differs from ubiquitin in its sensitivity to proteolytic enzymes. Therefore, Pikt appears to be a novel ubiquitin-like peptide that has killer activity. PMID:19114528

Sulfuric acid induces airway hyperresponsiveness to substance P in the guinea pig.

PubMed

Stengel, P W; Bendele, A M; Cockerham, S L; Silbaugh, S A

1993-01-01

We investigated whether sulfuric acid inhalation would cause hyperresponsiveness to substance P. Guinea pigs became dyspneic during a 1 h sulfuric acid exposure, but recovered by 24 h when they were challenged with substance P or histamine aerosols. Eight minutes after the start of challenge, animals were killed and excised lung gas volumes measured. Sulfuric acid slightly increased histamine responsiveness compared to controls. However, sulfuric acid caused a much more pronounced leftward shift in the dose response to substance P. Coadministration of the neutral endopeptidase (NEP) inhibitor, thiorphan, did not reduce sulfuric acid-related hyperresponsiveness to substance P. By 72 h, sensitization to substance P was absent. Histological evaluation of sulfuric acid-treated lungs revealed mild alveolitis at 24 h, but not at 72 h. We conclude that sulfuric acid produces a marked sensitization to substance P. Inactivation of NEP does not appear to account for this effect.

Magnetic particles as powerful purification tool for high sensitive mass spectrometric screening procedures.

PubMed

Peter, Jochen F; Otto, Angela M

2010-02-01

The effective isolation and purification of proteins from biological fluids is the most crucial step for a successful protein analysis when only minute amounts are available. While conventional purification methods such as dialysis, ultrafiltration or protein precipitation often lead to a marked loss of protein, SPE with small-sized particles is a powerful alternative. The implementation of particles with superparamagnetic cores facilitates the handling of those particles and allows the application of particles in the nanometer to low micrometer range. Due to the small diameters, magnetic particles are advantageous for increasing sensitivity when using subsequent MS analysis or gel electrophoresis. In the last years, different types of magnetic particles were developed for specific protein purification purposes followed by analysis or screening procedures using MS or SDS gel electrophoresis. In this review, the use of magnetic particles for different applications, such as, the extraction and analysis of DNA/RNA, peptides and proteins, is described.

Switching from high-fat to low-fat diet normalizes glucose metabolism and improves glucose-stimulated insulin secretion and insulin sensitivity but not body weight in C57BL/6J mice.

PubMed

Agardh, Carl-David; Ahrén, Bo

2012-03-01

Environmental factors such as a high-fat diet contribute to type 2 diabetes and obesity. This study examined glycemia, insulin sensitivity, and β-cell function after switching from a high-fat diet to a low-fat diet in mice. C57BL/6J mice were fed a high-fat diet or low-fat diet for 18 months, after which mice on the high-fat diet either maintained this diet or switched to a low-fat diet for 4 weeks. Body weight and glucose and insulin responses to intraperitoneal glucose were determined. Insulin secretion (insulinogenic index: the 10-minute insulin response divided by the 10-minute glucose level) and insulin sensitivity (1 divided by basal insulin) were determined. After 18 months on a high-fat diet, mice had glucose intolerance, marked hyperinsulinemia, and increased body weight compared to mice on a low-fat diet (P < 0.001). Switching from a high-fat diet to low-fat diet normalized glucose tolerance, reduced but not normalized body weight (P < 0.001), increased insulin secretion (248 ± 39 vs 141 ± 46 pmol/mmol; P = 0.028) and improved but not normalized insulin sensitivity (3.2 ± 0.1 vs 1.0 ± 0.1 [pmol/L]; P = 0.012). Switching from a high-fat diet to low-fat diet normalizes glucose tolerance and improves but not normalizes insulin secretion and insulin sensitivity. These effects are more pronounced than the reduced body weight.

Evaluation of high throughput gene expression platforms using a genomic biomarker signature for prediction of skin sensitization.

PubMed

Forreryd, Andy; Johansson, Henrik; Albrekt, Ann-Sofie; Lindstedt, Malin

2014-05-16

Allergic contact dermatitis (ACD) develops upon exposure to certain chemical compounds termed skin sensitizers. To reduce the occurrence of skin sensitizers, chemicals are regularly screened for their capacity to induce sensitization. The recently developed Genomic Allergen Rapid Detection (GARD) assay is an in vitro alternative to animal testing for identification of skin sensitizers, classifying chemicals by evaluating transcriptional levels of a genomic biomarker signature. During assay development and biomarker identification, genome-wide expression analysis was applied using microarrays covering approximately 30,000 transcripts. However, the microarray platform suffers from drawbacks in terms of low sample throughput, high cost per sample and time consuming protocols and is a limiting factor for adaption of GARD into a routine assay for screening of potential sensitizers. With the purpose to simplify assay procedures, improve technical parameters and increase sample throughput, we assessed the performance of three high throughput gene expression platforms--nCounter®, BioMark HD™ and OpenArray®--and correlated their performance metrics against our previously generated microarray data. We measured the levels of 30 transcripts from the GARD biomarker signature across 48 samples. Detection sensitivity, reproducibility, correlations and overall structure of gene expression measurements were compared across platforms. Gene expression data from all of the evaluated platforms could be used to classify most of the sensitizers from non-sensitizers in the GARD assay. Results also showed high data quality and acceptable reproducibility for all platforms but only medium to poor correlations of expression measurements across platforms. In addition, evaluated platforms were superior to the microarray platform in terms of cost efficiency, simplicity of protocols and sample throughput. We evaluated the performance of three non-array based platforms using a limited set of transcripts from the GARD biomarker signature. We demonstrated that it was possible to achieve acceptable discriminatory power in terms of separation between sensitizers and non-sensitizers in the GARD assay while reducing assay costs, simplify assay procedures and increase sample throughput by using an alternative platform, providing a first step towards the goal to prepare GARD for formal validation and adaption of the assay for industrial screening of potential sensitizers.

Homosexuality as a consequence of epigenetically canalized sexual development.

PubMed

Rice, William R; Friberg, Urban; Gavrilets, Sergey

2012-12-01

Male and female homosexuality have substantial prevalence in humans. Pedigree and twin studies indicate that homosexuality has substantial heritability in both sexes, yet concordance between identical twins is low and molecular studies have failed to find associated DNA makers. This paradoxical pattern calls for an explanation. We use published data on fetal androgen signaling and gene regulation via nongenetic changes in DNA packaging (epigenetics) to develop a new model for homosexuality. It is well established that fetal androgen signaling strongly influences sexual development. We show that an unappreciated feature of this process is reduced androgen sensitivity in XX fetuses and enhanced sensitivity in XY fetuses, and that this difference is most feasibly mused by numerous sex-specific epigenetic modifications ("epi-marks") originating in embryonic stem cells. These epi-marks buffer XX fetuses from masculinization due to excess fetal androgen exposure and similarly buffer XY fetuses from androgen underexposure. Extant data indicates that individual epi-marks influence some but not other sexually dimorphic traits, vary in strength across individuals, and are produced during ontogeny and erased between generations. Those that escape erasure will steer development of the sexual phenotypes they influence in a gonad-discordant direction in opposite sex offspring, mosaically feminizing XY offspring and masculinizing XX offspring. Such sex-specific epi-marks are sexually antagonistic (SA-epi-marks) because they canalize sexual development in the parent that produced them, but contribute to gonad-trait discordances in opposite-sex offspring when unerased. In this model, homosexuality occurs when stronger-than-average SA-epi-marks (influencing sexual preference) from an opposite-sex parent escape erasure and are then paired with a weaker-than-average de novo sex-specific epi-marks produced in opposite-sex offspring. Our model predicts that homosexuality is part of a wider phenomenon in which recently evolved androgen-influenced traits commonly display gonad-trait discordances at substantial frequency, and that the molecular feature underlying most homosexuality is not DNA polymorphism(s), but epi-marks that evolved to canalize sexual dimorphic development that sometimes carryover across generations and contribute to gonad-trait discordances in opposite-sex descendants.

Dehydration Effects on Imbibitional Leakage from Desiccation-Sensitive Seeds 1

PubMed Central

Becwar, Michael R.; Stanwood, Phillip C.; Roos, Eric E.

1982-01-01

Changes in electrolyte leakage and viability in response to dehydration stress were examined in two species of seeds that do not survive desiccation. Leakage from silver maple (Acer saccharinum L.) seeds increased markedly as seed moisture contents decreased from 45 to 35% (fresh weight basis) and germination decreased from 97 to 5%, coincidentally. Time course curves of imbibitional leakage from areca palm (Chrysalido-carpus lutescens [Bory] Wendl.) embryos showed an increase in both initial leakage and steady-state leakage rates in response to dehydration from an original moisture content of 84 to as low as 53%. Absorbance at 530 nanometers of extracts from triphenyl tetrazolium chloride stained embryos of areca palm was used as a measure of viability. Absorbance decreased significantly in response to dehydration as embryo moisture content decreased from 80 to 30%. Collectively, the data suggest that membranes in the desiccation-sensitive seed tissues studied are damaged by dehydration below a critical moisture content, 40% in silver maple seed and 55% in areca palm embryos, and that the membrane damage contributes to loss of viability. PMID:16662357

Development and use of a real-time polymerase chain reaction assay for the detection of Ophidiomyces ophiodiicola in snakes.

PubMed

Allender, Matthew C; Bunick, David; Dzhaman, Elena; Burrus, Lucienne; Maddox, Carol

2015-03-01

Fungal pathogens threatening the conservation of wildlife are becoming increasingly common. Since 2008, free-ranging snakes across North America have been experiencing a marked increase in the prevalence of snake fungal disease associated with Ophidiomyces ophiodiicola. Diagnosis has historically relied on histology, microbiology, and conventional polymerase chain reaction (PCR). More sensitive methods are needed to adequately characterize the epidemiology. The current study describes the development of a real-time PCR (qPCR) assay for detecting a segment of the internal transcribed spacer 1 region between the 18S and 5.8S ribosomal RNA gene. The assay was able to detect as few as 1.05 × 10(1) gene copies per reaction. An additional 4 positive cases were detected when comparing a conventional PCR (n = 3) and the qPCR (n = 7) when used on swab samples from 47 eastern massasauga rattlesnakes. The newly developed assay is a sensitive and specific tool for surveillance and monitoring in the conservation of free-ranging snakes. © 2015 The Author(s).

Gender-Based Differences on the Association between Salt-Sensitive Genes and Obesity in Korean Children Aged between 8 and 9 Years

PubMed Central

Kim, Seon-Mee; Park, Hyesoon; Park, Chang gyu; Park, Hye Kyung

2015-01-01

Background High sodium intake is associated with the development of chronic diseases such as obesity. Although its role in obesity remains controversial, there may be a correlation between salt sensitivity and the early onset of chronic diseases in obese children. Methods In all, 2,163 Korean children (1,106 boys and 1,057 girls) aged 8–9 years were recruited from seven elementary schools in Seoul. To evaluate whether obesity risk was modulated by the salt sensitivity, 11 SNPs related to salt sensitive genes (SSG) became the target of sodium intakes in obese children. Results BP, HOMA-IR, LDLc, TG, and the girls’ sodium intake significantly increased, but HDLc significantly decreased with increase in BMI. Regardless of sex, the obesity risk was 5.27-fold (CI; 1.320–27.560) higher in the Q2 to Q5 of sodium intake adjusted by energy (4044.9–5058.9 mg/day) than in the lowest Q1 level (2287.6 mg/day) in obese children. BP was sensitively dependent on insulin resistance and lipid accumulation in all subjects; however, sodium intake may be an independent risk factor of obesity without increasing BP in girls. GRK4 A486V mutant homozygote was highly distributed in the obese group, but other SNPs had no impact. The obesity risk increased 7.06, 16.8, and 46.09-fold more in boys with GRK4 A486V, ACE, and SLC12A3 mutants as sodium intake increased. Among girls, the obesity risk increased in GRK4 A486V heterozygote and CYP11β-2 mutant homozygote although sodium intake was relatively lower, implying that ACE, SLC12A, CYP11β-2, and GRK4 A486V polymorphisms showed gender-based differences with regard to interaction between sodium intake and obesity. Conclusion A high sodium intake markedly increased the obesity risk in variants of GRK4 A486V regardless of sex. The obesity risk increased with GRK4 A486V, ACE, and SLC12A3 variants in boys, whereas it increased with GRK4 A486V and CYP11B2 variants in girls as sodium intake increased. Obese children with the specific gene variants are recommended to reduce their sodium intake. PMID:25768006

Gender-based differences on the association between salt-sensitive genes and obesity in Korean children aged between 8 and 9 years.

PubMed

Lee, Myoungsook; Kim, Mi Kyung; Kim, Seon-Mee; Park, Hyesoon; Park, Chang Gyu; Park, Hye Kyung

2015-01-01

High sodium intake is associated with the development of chronic diseases such as obesity. Although its role in obesity remains controversial, there may be a correlation between salt sensitivity and the early onset of chronic diseases in obese children. In all, 2,163 Korean children (1,106 boys and 1,057 girls) aged 8-9 years were recruited from seven elementary schools in Seoul. To evaluate whether obesity risk was modulated by the salt sensitivity, 11 SNPs related to salt sensitive genes (SSG) became the target of sodium intakes in obese children. BP, HOMA-IR, LDLc, TG, and the girls' sodium intake significantly increased, but HDLc significantly decreased with increase in BMI. Regardless of sex, the obesity risk was 5.27-fold (CI; 1.320-27.560) higher in the Q2 to Q5 of sodium intake adjusted by energy (4044.9-5058.9 mg/day) than in the lowest Q1 level (2287.6 mg/day) in obese children. BP was sensitively dependent on insulin resistance and lipid accumulation in all subjects; however, sodium intake may be an independent risk factor of obesity without increasing BP in girls. GRK4 A486V mutant homozygote was highly distributed in the obese group, but other SNPs had no impact. The obesity risk increased 7.06, 16.8, and 46.09-fold more in boys with GRK4 A486V, ACE, and SLC12A3 mutants as sodium intake increased. Among girls, the obesity risk increased in GRK4 A486V heterozygote and CYP11β-2 mutant homozygote although sodium intake was relatively lower, implying that ACE, SLC12A, CYP11β-2, and GRK4 A486V polymorphisms showed gender-based differences with regard to interaction between sodium intake and obesity. A high sodium intake markedly increased the obesity risk in variants of GRK4 A486V regardless of sex. The obesity risk increased with GRK4 A486V, ACE, and SLC12A3 variants in boys, whereas it increased with GRK4 A486V and CYP11B2 variants in girls as sodium intake increased. Obese children with the specific gene variants are recommended to reduce their sodium intake.

Antibody mechanisms implicated in digestive disturbances following ingestion of soya protein in calves and piglets.

PubMed Central

Barratt, M E; Strachan, P J; Porter, P

1978-01-01

Serum antibody responses to ingested aqueous alcohol-extracted soya proteins were studied in thirty-six pre-ruminant calves. Characterization of this antibody showed it to be predominantly a complement-fixing IgG1 preciptin. No evidence of tolerance was seen; previously sensitized calves responded to reintroduction of a soya diet with marked increases in antibody levels. The soya antigen was shown to be resistant to proteolysis and, to a lesser degree, to the microbial action of rumen fluid. Biopsy studies showed that the feeding of soya protein resulted in morphological disturbances to the villi and lamina propria of the intestine. Physiological studies by Thirty-Vella loop perfusion in the pig showed that soya protein solutions resulted in significant inhibition of flow rates. The effect was only observed after previous sensitization with the soya antigen. This study shows the necessity of applying immunological criteria to the quality control of soya bean processing in order to ensure that the sensitizing agent is eliminated and the nutritional qualities of soya protein concentrates are optimized. Images FIG. 2a FIG. 2b PMID:565686

A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells

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

Kojima, Keitaro; Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, 1-1 Naka-fudogaoka, Kakamigahara, Gifu 504-0838; Ohhashi, Riyako

2008-08-29

SIRT1, which belongs to the family of type III histone deacetylase, is implicated in diverse cellular processes. We have determined the expression levels of SIRT1 in human prostate cancer cell lines and have examined the roles of SIRT1 in cell growth and chemoresistance. SIRT1 expression was markedly up-regulated in androgen-refractory PC3 and DU145 cells compared with androgen-sensitive LNCaP cells and its expression level was correlated with cell growth in PC3 cells. Treatment with a SIRT1 inhibitor, sirtinol, inhibited cell growth and increased sensitivity to camptothecin and cisplatin. Silencing of SIRT1 expression by siRNA also suppressed cell proliferation and reduced camptothecinmore » resistance in PC3 cells, mimicking the chemosensitizing effect caused by sirtinol. Also in DU145 cells, sirtinol treatment enhanced sensitivity to camptothecin and cisplatin. These results suggest that up-regulation of SIRT1 expression may play an important role in promoting cell growth and chemoresistance in androgen-refractory PC3 and DU145 cells.« less

Influences of Phonological Context on Tense Marking in Spanish–English Dual Language Learners

PubMed Central

Barlow, Jessica A.; Potapova, Irina; Pruitt-Lord, Sonja

2017-01-01

Purpose The emergence of tense-morpheme marking during language acquisition is highly variable, which confounds the use of tense marking as a diagnostic indicator of language impairment in linguistically diverse populations. In this study, we seek to better understand tense-marking patterns in young bilingual children by comparing phonological influences on marking of 2 word-final tense morphemes. Method In spontaneous connected speech samples from 10 Spanish–English dual language learners aged 56–66 months (M = 61.7, SD = 3.4), we examined marking rates of past tense -ed and third person singular -s morphemes in different environments, using multiple measures of phonological context. Results Both morphemes were found to exhibit notably contrastive marking patterns in some contexts. Each was most sensitive to a different combination of phonological influences in the verb stem and the following word. Conclusions These findings extend existing evidence from monolingual speakers for the influence of word-final phonological context on morpheme production to a bilingual population. Further, novel findings not yet attested in previous research support an expanded consideration of phonological context in clinical decision making and future research related to word-final morphology. PMID:28750415

GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.

PubMed

Barton, James C; Chen, Wen-Pin; Emond, Mary J; Phatak, Pradyumna D; Subramaniam, V Nathan; Adams, Paul C; Gurrin, Lyle C; Anderson, Gregory J; Ramm, Grant A; Powell, Lawrie W; Allen, Katrina J; Phillips, John D; Parker, Charles J; McLaren, Gordon D; McLaren, Christine E

2017-03-01

GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300μg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). The mean age of 56 participants (94.6% men) was 55±10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p=0.0126). GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. Copyright © 2016 Elsevier Inc. All rights reserved.

Forster's tern chick survival in response to a managed relocation of predatory California gulls

USGS Publications Warehouse

Ackerman, Joshua T.; Herzog, Mark P.; Hartman, C. Alex; Herring, Garth

2014-01-01

Gull populations can severely limit the productivity of waterbirds. Relocating gull colonies may reduce their effects on nearby breeding waterbirds, but there are few examples of this management strategy. We examined gull predation and survival of Forster's tern (Sterna forsteri) chicks before (2010) and after (2011) the managed relocation of the largest California gull (Larus californicus) colony (24,000 adults) in San Francisco Bay, California. Overall, survival of radio-marked Forster's tern chicks from hatching to fledging was 0.22 ± 0.03 (mean ± SE), and daily survival rates increased with age. Gulls were the predominant predator of tern chicks, potentially causing 54% of chick deaths. Prior to the gull colony relocation, 56% of radio-marked and 20% of banded tern chicks from the nearest tern colony were recovered dead in the gull colony, compared to only 15% of radio-marked and 4% of banded chicks recovered dead from all other tern colonies. The managed relocation of the gull colony substantially increased tern chick survival (by 900%) in the nearby (3.8 km) reference tern colony (0.29 ± 0.10 in 2010 and 0.25 ± 0.09 in 2011). Among 19 tern nesting islands, fledging success was higher when gull abundance was lower at nearby colonies and when gull colonies were farther from the tern colony. Our results indicate that the managed relocation of gull colonies away from preferred nesting areas of sensitive waterbirds can improve local reproductive success, but this conservation strategy may shift gull predation pressure to other areas or species.

The interplay of attention economics and computer-aided detection marks in screening mammography

NASA Astrophysics Data System (ADS)

Schwartz, Tayler M.; Sridharan, Radhika; Wei, Wei; Lukyanchenko, Olga; Geiser, William; Whitman, Gary J.; Haygood, Tamara Miner

2016-03-01

Introduction: According to attention economists, overabundant information leads to decreased attention for individual pieces of information. Computer-aided detection (CAD) alerts radiologists to findings potentially associated with breast cancer but is notorious for creating an abundance of false-positive marks. We suspected that increased CAD marks do not lengthen mammogram interpretation time, as radiologists will selectively disregard these marks when present in larger numbers. We explore the relevance of attention economics in mammography by examining how the number of CAD marks affects interpretation time. Methods: We performed a retrospective review of bilateral digital screening mammograms obtained between January 1, 2011 and February 28, 2014, using only weekend interpretations to decrease distractions and the likelihood of trainee participation. We stratified data according to reader and used ANOVA to assess the relationship between number of CAD marks and interpretation time. Results: Ten radiologists, with median experience after residency of 12.5 years (range 6 to 24,) interpreted 1849 mammograms. When accounting for number of images, Breast Imaging Reporting and Data System category, and breast density, increasing numbers of CAD marks was correlated with longer interpretation time only for the three radiologists with the fewest years of experience (median 7 years.) Conclusion: For the 7 most experienced readers, increasing CAD marks did not lengthen interpretation time. We surmise that as CAD marks increase, the attention given to individual marks decreases. Experienced radiologists may rapidly dismiss larger numbers of CAD marks as false-positive, having learned that devoting extra attention to such marks does not improve clinical detection.

Risky decision making from childhood through adulthood: Contributions of learning and sensitivity to negative feedback.

PubMed

Humphreys, Kathryn L; Telzer, Eva H; Flannery, Jessica; Goff, Bonnie; Gabard-Durnam, Laurel; Gee, Dylan G; Lee, Steve S; Tottenham, Nim

2016-02-01

Decision making in the context of risk is a complex and dynamic process that changes across development. Here, we assessed the influence of sensitivity to negative feedback (e.g., loss) and learning on age-related changes in risky decision making, both of which show unique developmental trajectories. In the present study, we examined risky decision making in 216 individuals, ranging in age from 3-26 years, using the balloon emotional learning task (BELT), a computerized task in which participants pump up a series of virtual balloons to earn points, but risk balloon explosion on each trial, which results in no points. It is important to note that there were 3 balloon conditions, signified by different balloon colors, ranging from quick- to slow-to-explode, and participants could learn the color-condition pairings through task experience. Overall, we found age-related increases in pumps made and points earned. However, in the quick-to-explode condition, there was a nonlinear adolescent peak for points earned. Follow-up analyses indicated that this adolescent phenotype occurred at the developmental intersection of linear age-related increases in learning and decreases in sensitivity to negative feedback. Adolescence was marked by intermediate values on both these processes. These findings show that a combination of linearly changing processes can result in nonlinear changes in risky decision making, the adolescent-specific nature of which is associated with developmental improvements in learning and reduced sensitivity to negative feedback. (c) 2016 APA, all rights reserved).

Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism

PubMed Central

Cornford, Andrea S.; Hinko, Alexander; Nelson, Rachael K.; Barkan, Ariel L.; Horowitz, Jeffrey F.

2014-01-01

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ~4000 kcals·day−1 (70 kcal·kg−1 fat free mass·day−1). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser312, Akt-Ser473, and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg−1 wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg−1 wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ~35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating. PMID:23668758

Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism.

PubMed

Cornford, Andrea S; Hinko, Alexander; Nelson, Rachael K; Barkan, Ariel L; Horowitz, Jeffrey F

2013-05-01

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day(-1) (70 kcal·kg(-1) fat free mass·day(-1)). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser(312), Akt-Ser(473), and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg(-1) wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg(-1) wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

Improved Heart Rate Recovery After Marked Weight Loss Induced by Gastric Bypass Surgery: 2 Year Follow Up in the Utah Obesity Study

PubMed Central

Wasmund, Stephen L.; Yanowitz, Frank G.; Adams, Ted D.; Hunt, Steven C.; Hamdan, Mohamed H.; Litwin, Sheldon E.

2010-01-01

Background Obesity is associated with significantly increased cardiovascular mortality that has been attributed, in part, to sympathetic activation. Gastric bypass surgery (GBS) appears to increase long-term survival in the severely obese, but mechanisms responsible for this increase are still being sought. Heart rate (HR) recovery after exercise reflects the balance of cardiac autonomic input from the sympathetic and parasympathetic systems. Blunted HR recovery is a very powerful predictor of increased mortality while enhanced HR recovery portends a good prognosis. Objectives To evaluate the effect of marked weight loss achieved via GBS on HR recovery. Methods Severely obese patients underwent submaximal exercise testing (80% predicted maximum HR) at baseline and 2 years after GBS (n=153) or nonsurgical treatment (n=188). Results Patients in the GBS group lost an average of 100±37 lbs compared to 3±22 lbs in the nonsurgical group (p<0.001, GBS vs. nonsurgical). Resting HR decreased from 73 beats/minute (bpm) to 60 bpm in the GBS group and from 74 bpm to 68 bpm in nonsurgical patients (p<0.001). Heart rate recovery improved by 13 bpm in the GBS group and did not change in the nonsurgical group (p<0.001 GBS vs. nonsurgical). In multivariable analysis, the independent correlates of HR recovery at the 2-year time point were resting HR, treadmill time, age, body mass index and HOMA-IR. Conclusion Marked weight loss 2 years after GBS resulted in a significant decrease in resting HR and an enhancement in HR recovery after exercise. These changes are likely attributable to improvement in insulin sensitivity and cardiac autonomic balance. Whether and to what extent this contributes to a reduction in cardiovascular mortality with GBS remains to be determined. PMID:20970524

Epidemic 2014 enterovirus D68 cross-reacts with human rhinovirus on a respiratory molecular diagnostic platform.

PubMed

McAllister, Shane C; Schleiss, Mark R; Arbefeville, Sophie; Steiner, Marie E; Hanson, Ryan S; Pollock, Catherine; Ferrieri, Patricia

2015-01-01

Enterovirus D68 (EV-D68) is an emerging virus known to cause sporadic disease and occasional epidemics of severe lower respiratory tract infection. However, the true prevalence of infection with EV-D68 is unknown, due in part to the lack of a rapid and specific nucleic acid amplification test as well as the infrequency with which respiratory samples are analyzed by enterovirus surveillance programs. During the 2014 EV-D68 epidemic in the United States, we noted an increased frequency of "low-positive" results for human rhinovirus (HRV) detected in respiratory tract samples using the GenMark Diagnostics eSensor respiratory viral panel, a multiplex PCR assay able to detect 14 known respiratory viruses but not enteroviruses. We simultaneously noted markedly increased admissions to our Pediatric Intensive Care Unit for severe lower respiratory tract infections in patients both with and without a history of reactive airway disease. Accordingly, we hypothesized that these "low-positive" RVP results were due to EV-D68 rather than rhinovirus infection. Sequencing of the picornavirus 5' untranslated region (5'-UTR) of 49 samples positive for HRV by the GenMark RVP revealed that 33 (67.3%) were in fact EV-D68. Notably, the mean intensity of the HRV RVP result was significantly lower in the sequence-identified EV-D68 samples (20.3 nA) compared to HRV (129.7 nA). Using a cut-off of 40 nA for the differentiation of EV-D68 from HRV resulted in 94% sensitivity and 88% specificity. The robust diagnostic characteristics of our data suggest that the cross-reactivity of EV-D68 and HRV on the GenMark Diagnostics eSensor RVP platform may be an important factor to consider in making accurate molecular diagnosis of EV-D68 at institutions utilizing this system or other molecular respiratory platforms that may also cross-react.

Partial lesion of the serotonergic system by a single dose of MDMA results in behavioural disinhibition and enhances acute MDMA-induced social behaviour on the social interaction test.

PubMed

Ando, Romeo D; Benko, Anita; Ferrington, Linda; Kirilly, Eszter; Kelly, Paul A T; Bagdy, Gyorgy

2006-06-01

The acute effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) on anxiety-related behaviours were studied using indices of social interaction in Dark Agouti (DA) both drug naive rats and those pretreated with MDMA (15 mg/kg i.p.) 3 weeks earlier. The functional neuroanatomy of these MDMA effects was visualised using 2-deoxyglucose imaging of local cerebral glucose use (LCMRglu), whilst MDMA-induced serotonergic neurotoxicity was measured by radioligand binding with [3H]paroxetine. Acute MDMA alone markedly decreased most typical elements of social interaction but increased adjacent lying, a behaviour that also contains social elements. In animals pre-exposed to MDMA, decreased [3H]paroxetine binding indicated serotonergic terminal depletion, and in these animals significant increases in locomotor activity, exploratory behaviour and aggressive behaviour were found. Both behavioural effects and also the metabolic activation induced by acute MDMA were potentiated in rats previously exposed to the drug. In conclusion, a single dose of MDMA caused marked changes in social behaviour acutely that might be interpreted either as a decrease or increase in anxiety. Three weeks after MDMA a behavioural disinhibition similar to psychomotor agitation, a symptom connected to depression or mania, and a sensitization to the acute effects of MDMA are apparent in both the behavioural and brain metabolic effects of the drug.

Trace gas concentrations, intertropical convergence, atmospheric fronts, and ocean currents in the tropical Pacific

NASA Technical Reports Server (NTRS)

Wilkniss, P. E.; Rodgers, E. B.; Swinnerton, J. W.; Larson, R. E.; Lamontagne, R. A.

1979-01-01

Descriptions of the intertropical convergence zones (ITCZ) in the tropical Pacific have been obtained from shipboard measurements of Rn-222, CO, and CH4 in combination with conventional meteorological data and satellite images. The intertropical convergence zone is marked by light shifting waves near an area of heavy cloud cover and precipitation, and appears to be located north and south of the south equatorial current. A 'second' ITCZ with the same atmospheric features was encountered just north of the south equatorial current in the Southern Hemisphere. Atmospheric Rn-222 increases north of the ITCZ and serves as a sensitive indicator for this atmospheric boundary.

Increased androgenic sensitivity in the hind limb muscular system marks the evolution of a derived gestural display.

PubMed

Mangiamele, Lisa A; Fuxjager, Matthew J; Schuppe, Eric R; Taylor, Rebecca S; Hödl, Walter; Preininger, Doris

2016-05-17

Physical gestures are prominent features of many species' multimodal displays, yet how evolution incorporates body and leg movements into animal signaling repertoires is unclear. Androgenic hormones modulate the production of reproductive signals and sexual motor skills in many vertebrates; therefore, one possibility is that selection for physical signals drives the evolution of androgenic sensitivity in select neuromotor pathways. We examined this issue in the Bornean rock frog (Staurois parvus, family: Ranidae). Males court females and compete with rivals by performing both vocalizations and hind limb gestural signals, called "foot flags." Foot flagging is a derived display that emerged in the ranids after vocal signaling. Here, we show that administration of testosterone (T) increases foot flagging behavior under seminatural conditions. Moreover, using quantitative PCR, we also find that adult male S. parvus maintain a unique androgenic phenotype, in which androgen receptor (AR) in the hind limb musculature is expressed at levels ∼10× greater than in two other anuran species, which do not produce foot flags (Rana pipiens and Xenopus laevis). Finally, because males of all three of these species solicit mates with calls, we accordingly detect no differences in AR expression in the vocal apparatus (larynx) among taxa. The results show that foot flagging is an androgen-dependent gestural signal, and its emergence is associated with increased androgenic sensitivity within the hind limb musculature. Selection for this novel gestural signal may therefore drive the evolution of increased AR expression in key muscles that control signal production to support adaptive motor performance.

Increased androgenic sensitivity in the hind limb muscular system marks the evolution of a derived gestural display

PubMed Central

Mangiamele, Lisa A.; Fuxjager, Matthew J.; Schuppe, Eric R.; Taylor, Rebecca S.; Hödl, Walter; Preininger, Doris

2016-01-01

Physical gestures are prominent features of many species’ multimodal displays, yet how evolution incorporates body and leg movements into animal signaling repertoires is unclear. Androgenic hormones modulate the production of reproductive signals and sexual motor skills in many vertebrates; therefore, one possibility is that selection for physical signals drives the evolution of androgenic sensitivity in select neuromotor pathways. We examined this issue in the Bornean rock frog (Staurois parvus, family: Ranidae). Males court females and compete with rivals by performing both vocalizations and hind limb gestural signals, called “foot flags.” Foot flagging is a derived display that emerged in the ranids after vocal signaling. Here, we show that administration of testosterone (T) increases foot flagging behavior under seminatural conditions. Moreover, using quantitative PCR, we also find that adult male S. parvus maintain a unique androgenic phenotype, in which androgen receptor (AR) in the hind limb musculature is expressed at levels ∼10× greater than in two other anuran species, which do not produce foot flags (Rana pipiens and Xenopus laevis). Finally, because males of all three of these species solicit mates with calls, we accordingly detect no differences in AR expression in the vocal apparatus (larynx) among taxa. The results show that foot flagging is an androgen-dependent gestural signal, and its emergence is associated with increased androgenic sensitivity within the hind limb musculature. Selection for this novel gestural signal may therefore drive the evolution of increased AR expression in key muscles that control signal production to support adaptive motor performance. PMID:27143723

The clinical relevance of birch pollen profilin cross-reactivity in sensitized patients.

PubMed

Wölbing, F; Kunz, J; Kempf, W E; Grimmel, C; Fischer, J; Biedermann, T

2017-04-01

Overlapping seasons and cross-reactivity, especially to grass pollen profilin, can hamper the diagnosis of birch pollen allergy. To identify the primary sensitizing allergen and the clinical relevance of cross-sensitization, we correlated sensitization profiles with in vitro and in vivo tests, symptom scores, and pollen counts. A total of 433 patients with positive skin prick test (SPT) to birch pollen were analyzed regarding IgE to major birch and grass pollen allergens Bet v 1 and Phl p 1/p 5 and the profilins Bet v 2 and Phl p 12. Subgroups were analyzed by basophil activation test (BAT) and CAP-FEIA-based cross- and self-inhibition tests. A total of 349 patients were sensitized to Bet v 1, 44 patients to both Bet v 1 and Bet v 2, and 15 patients to Bet v 2 only. From Bet v 2-sensitized patients, 40 were also sensitized to Phl p 12. Ex vivo, Bet v 2 and Phl p 12 induced dose-dependent activation in basophils of these patients. Cross- and self-inhibition tests with both allergens confirmed cross-reactivity. However, semiquantitative analysis of SPTs demonstrated markedly increased reactivity to grass compared to birch pollen extract in Bet v 2 only sensitized patients. Accordingly, in most of those patients, clinical symptoms precisely correlated with grass pollen counts. Identification of the clinically relevant and sensitizing allergen needs correlation of actual pollen counts with clinical symptoms and sensitization status to major allergens. Semiquantitative analysis of SPT or BAT and determining profilin-specific IgE can contribute to making the diagnosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of metabolic and respiratory acidosis on intracellular calcium in osteoblasts

PubMed Central

Bushinsky, David A.

2010-01-01

In vivo, metabolic acidosis {decreased pH from decreased bicarbonate concentration ([HCO3−])} increases urine calcium (Ca) without increased intestinal Ca absorption, resulting in a loss of bone Ca. Conversely, respiratory acidosis [decreased pH from increased partial pressure of carbon dioxide (Pco2)] does not appreciably alter Ca homeostasis. In cultured bone, chronic metabolic acidosis (Met) significantly increases cell-mediated net Ca efflux while isohydric respiratory acidosis (Resp) does not. The proton receptor, OGR1, appears critical for cell-mediated, metabolic acid-induced bone resorption. Perfusion of primary bone cells or OGR1-transfected Chinese hamster ovary (CHO) cells with Met induces transient peaks of intracellular Ca (Cai). To determine whether Resp increases Cai, as does Met, we imaged Cai in primary cultures of bone cells. pH for Met = 7.07 ([HCO3−] = 11.8 mM) and for Resp = 7.13 (Pco2 = 88.4 mmHg) were similar and lower than neutral (7.41). Both Met and Resp induced a marked, transient increase in Cai in individual bone cells; however, Met stimulated Cai to a greater extent than Resp. We used OGR1-transfected CHO cells to determine whether OGR1 was responsible for the greater increase in Cai in Met than Resp. Both Met and Resp induced a marked, transient increase in Cai in OGR1-transfected CHO cells; however, in these cells Met was not different than Resp. Thus, the greater induction of Cai by Met in primary bone cells is not a function of OGR1 alone, but must involve H+ receptors other than OGR1, or pathways sensitive to Pco2, HCO3−, or total CO2 that modify the effect of H+ in primary bone cells. PMID:20504884

Effect of metabolic and respiratory acidosis on intracellular calcium in osteoblasts.

PubMed

Frick, Kevin K; Bushinsky, David A

2010-08-01

In vivo, metabolic acidosis {decreased pH from decreased bicarbonate concentration ([HCO(3)(-)])} increases urine calcium (Ca) without increased intestinal Ca absorption, resulting in a loss of bone Ca. Conversely, respiratory acidosis [decreased pH from increased partial pressure of carbon dioxide (Pco(2))] does not appreciably alter Ca homeostasis. In cultured bone, chronic metabolic acidosis (Met) significantly increases cell-mediated net Ca efflux while isohydric respiratory acidosis (Resp) does not. The proton receptor, OGR1, appears critical for cell-mediated, metabolic acid-induced bone resorption. Perfusion of primary bone cells or OGR1-transfected Chinese hamster ovary (CHO) cells with Met induces transient peaks of intracellular Ca (Ca(i)). To determine whether Resp increases Ca(i), as does Met, we imaged Ca(i) in primary cultures of bone cells. pH for Met = 7.07 ([HCO(3)(-)] = 11.8 mM) and for Resp = 7.13 (Pco(2) = 88.4 mmHg) were similar and lower than neutral (7.41). Both Met and Resp induced a marked, transient increase in Ca(i) in individual bone cells; however, Met stimulated Ca(i) to a greater extent than Resp. We used OGR1-transfected CHO cells to determine whether OGR1 was responsible for the greater increase in Ca(i) in Met than Resp. Both Met and Resp induced a marked, transient increase in Ca(i) in OGR1-transfected CHO cells; however, in these cells Met was not different than Resp. Thus, the greater induction of Ca(i) by Met in primary bone cells is not a function of OGR1 alone, but must involve H(+) receptors other than OGR1, or pathways sensitive to Pco(2), HCO(3)(-), or total CO(2) that modify the effect of H(+) in primary bone cells.

Development of a Micro-Fabricated Total-Field Magnetometer

DTIC Science & Technology

2011-03-01

are made with fluxgate technologies. Fluxgates have lower sensitivity than Cs magnetometers , yet they continue to be used in small wands simply...extraction process by providing the sensitivity of a Cs magnetometer with the convenience and low cost of a fluxgate wand. Extremely small and low cost...FINAL REPORT Development of a Micro-Fabricated Total-Field Magnetometer SERDP Project MR-1512 MARCH 2011 Mark Prouty Geometrics, Inc

Suprathreshold Contrast Sensitivity Vision Test Chart

DTIC Science & Technology

1991-07-14

with data collected on patients having amblyopia , glaucoma and macular degeneration showed that the SCTS may be effectively used as an initial...dramatically in certain cases of abnormal vision, such as amblyopia (Ginsburg, 1978, 1981; Hess, Bradley and Piotrowski, 1983; Loshin and Levi, 1983). The...combination of frequencies. Amblyopia results in marked losses of contrast sensitivity particularly at high spatial frequencies, but may also result in

Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator–Activated Receptor-γ Agonism

PubMed Central

Dallaire, Patrice; Bellmann, Kerstin; Laplante, Mathieu; Gélinas, Stéphanie; Centeno-Baez, Carolina; Penfornis, Patrice; Peyot, Marie-Line; Latour, Martin G.; Lamontagne, Julien; Trujillo, Maria E.; Scherer, Philipp E.; Prentki, Marc; Deshaies, Yves; Marette, André

2008-01-01

OBJECTIVE—Synthetic ligands for peroxisome proliferator–activated receptor-γ (PPAR-γ) improve insulin sensitivity in obesity, but it is still unclear whether inflammatory signals modulate their metabolic actions. In this study, we tested whether targeted disruption of inducible nitric oxide (NO) synthase (iNOS), a key inflammatory mediator in obesity, modulates the metabolic effects of rosiglitazone in obese mice. RESEARCH DESIGN AND METHODS—iNOS−/− and iNOS+/+ were subjected to a high-fat diet or standard diet for 18 weeks and were then treated with rosiglitazone for 2 weeks. Whole-body insulin sensitivity and glucose tolerance were determined and metabolic tissues harvested to assess activation of insulin and AMP-activated protein kinase (AMPK) signaling pathways and the levels of inflammatory mediators. RESULTS—Rosiglitazone was found to similarly improve whole-body insulin sensitivity and insulin signaling to Akt/PKB in skeletal muscle of obese iNOS−/− and obese iNOS+/+ mice. However, rosiglitazone further improved glucose tolerance and liver insulin signaling only in obese mice lacking iNOS. This genotype-specific effect of rosiglitazone on glucose tolerance was linked to a markedly increased ability of the drug to raise plasma adiponectin levels. Accordingly, rosiglitazone increased AMPK activation in muscle and liver only in obese iNOS−/− mice. PPAR-γ transcriptional activity was increased in adipose tissue of iNOS−/− mice. Conversely, treatment of 3T3-L1 adipocytes with a NO donor blunted PPAR-γ activity. CONCLUSIONS—Our results identify the iNOS/NO pathway as a critical modulator of PPAR-γ activation and circulating adiponectin levels and show that invalidation of this key inflammatory mediator improves the efficacy of PPAR-γ agonism in an animal model of obesity and insulin resistance. PMID:18458147

Diffusion-weighted and T2-weighted MR imaging for colorectal liver metastases detection in a rat model at 7 T: a comparative study using histological examination as reference.

PubMed

Wagner, Mathilde; Maggiori, Léon; Ronot, Maxime; Paradis, Valérie; Vilgrain, Valérie; Panis, Yves; Van Beers, Bernard E

2013-08-01

To compare diffusion-weighted (DW) and T2-weighted MR imaging in detecting colorectal liver metastases in a rat model, using histological examination as a reference method. Eighteen rats had four liver injections of colon cancer cells. MR examinations at 7 T included FSE-T2-weighted imaging and SE-DW MR imaging (b = 0, 20 and 150 s/mm(2)) and were analysed by two independent readers. Histological examination was performed on 0.4-mm slices. McNemar's test was used to compare the sensitivities and the Wilcoxon matched pairs test to compare the average number of false-positives per rat. One hundred and sixty-six liver metastases were identified on histological examination. The sensitivity in detecting liver metastases was significantly higher on DW MR than on T2-weighted images (99/166 (60 %) (reader 1) and 92/166 (55 %) (reader 2) versus 77/166 (46 %), P ≤ 0.001), without an increase in false-positives per rat (P = 0.773/P = 0.850). After stratification according to metastasis diameter, DW MR imaging had a significantly higher sensitivity than T2-weighted imaging only for metastases with a diameter (0.6-1.2 mm) similar to that of the spatial resolution of MR imaging in the current study. This MR study with histological correlations shows the higher sensitivity of DW relative to T2-weighted imaging at 7 T for detecting liver metastases, especially small ones. • Diffusion weighted (DW) sequences are increasingly used in magnetic resonance imaging (MRI). • DW has higher sensitivity for liver metastases than T2-weighted imaging at 7 T. • This increase in sensitivity is especially marked for small liver metastasis detection. • This higher sensitivity is confirmed in an animal model with histological correlation. • DW imaging has the potential for earlier diagnosis of small liver metastases.

Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

PubMed Central

2011-01-01

Background We and others have demonstrated previously that ghrelin receptor (GhrR) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. Results Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. Conclusions These results indicate that improved glucose homeostasis of GhrR KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge. PMID:21211044

SNAP-23 regulates phagosome formation and maturation in macrophages

PubMed Central

Sakurai, Chiye; Hashimoto, Hitoshi; Nakanishi, Hideki; Arai, Seisuke; Wada, Yoh; Sun-Wada, Ge-Hong; Wada, Ikuo; Hatsuzawa, Kiyotaka

2012-01-01

Synaptosomal associated protein of 23 kDa (SNAP-23), a plasma membrane–localized soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE), has been implicated in phagocytosis by macrophages. For elucidation of its precise role in this process, a macrophage line overexpressing monomeric Venus–tagged SNAP-23 was established. These cells showed enhanced Fc receptor–mediated phagocytosis. Detailed analyses of each process of phagocytosis revealed a marked increase in the production of reactive oxygen species within phagosomes. Also, enhanced accumulation of a lysotropic dye, as well as augmented quenching of a pH-sensitive fluorophore were observed. Analyses of isolated phagosomes indicated the critical role of SNAP-23 in the functional recruitment of the NADPH oxidase complex and vacuolar-type H+-ATPase to phagosomes. The data from the overexpression experiments were confirmed by SNAP-23 knockdown, which demonstrated a significant delay in phagosome maturation and a reduction in uptake activity. Finally, for analyzing whether phagosomal SNAP-23 entails a structural change in the protein, an intramolecular Förster resonance energy transfer (FRET) probe was constructed, in which the distance within a TagGFP2-TagRFP was altered upon close approximation of the N-termini of its two SNARE motifs. FRET efficiency on phagosomes was markedly enhanced only when VAMP7, a lysosomal SNARE, was coexpressed. Taken together, our results strongly suggest the involvement of SNAP-23 in both phagosome formation and maturation in macrophages, presumably by mediating SNARE-based membrane traffic. PMID:23087210

Hydroclimatic trends in simulations over the CORDEX North America region

NASA Astrophysics Data System (ADS)

Arritt, Raymond; Groisman, Pavel; Daniel, Ariele; Schillerberg, Tayler

2015-04-01

An increase in the occurrence of heavy precipitation has been one of the most pronounced climate change signals for the central United States. We study this trend by using the RegCM4 regional climate model to dynamically downscale CMIP5 global projections for 1950-2099 over the CORDEX North America domain. We examine the robustness of the results by driving the regional model with two different global models, by performing simulations at both 50 km and 25 km grid spacing, and by using different convective parameterizations in RegCM4. The global models sample the range of climate sensitivity in CMIP5: HadGEM2-ES has the highest equilibrium climate sensitivity of the CMIP5 models, while GFDL-ESM2M has one of the lowest sensitivities. RegCM4 results show increases in heavy precipitation (> 50 mm/day) over the central United States for the period 1951-2005 similar to observed trends. This trend is predicted to accelerate so that by the end of the 21st century incidence of heavy precipitation increases by a factor of 2 to 3. The trend is robust in that it is produced regardless of the driving global model or the configuration of the regional model. Results also show a modest increase in the number of dry days and a marked increase in the number of long runs of dry days (16 or more consecutive dry days). The combination of heavier events and longer runs of dry days has implications for sectors such as agriculture and water quality. This research was sponsored by USDA NIFA under the Earth System Modeling program and as part of a regional collaborative project.

Repeatability of automated perimetry: a comparison between standard automated perimetry with stimulus size III and V, matrix, and motion perimetry.

PubMed

Wall, Michael; Woodward, Kimberly R; Doyle, Carrie K; Artes, Paul H

2009-02-01

Standard automated perimetry (SAP) shows a marked increase in variability in damaged areas of the visual field. This study was conducted to test the hypothesis that larger stimuli are associated with more uniform variability, by investigating the retest variability of four perimetry tests: standard automated perimetry size III (SAP III), with the SITA standard strategy; SAP size V (SAP V), with the full-threshold strategy; Matrix (FDT II), and Motion perimetry. One eye each of 120 patients with glaucoma was examined on the same day with these four perimetric tests and retested 1 to 8 weeks later. The decibel scales were adjusted to make the test's scales numerically similar. Retest variability was examined by establishing the distributions of retest threshold estimates, for each threshold level observed at the first test. The 5th and 95th percentiles of the retest distribution were used as point-wise limits of retest variability. Regression analyses were performed to quantify the relationship between visual field sensitivity and variability. With SAP III, the retest variability increased substantially with reducing sensitivity. Corresponding increases with SAP V, Matrix, and Motion perimetry were considerably smaller or absent. With SAP III, sensitivity explained 22% of the retest variability (r(2)), whereas corresponding data for SAP V, Matrix, and Motion perimetry were 12%, 2%, and 2%, respectively. Variability of Matrix and Motion perimetry does not increase as substantially as that of SAP III in damaged areas of the visual field. Increased sampling with the larger stimuli of these techniques is the likely explanation for this finding. These properties may make these stimuli excellent candidates for early detection of visual field progression.

Flooding of the root system in soybean: biochemical and molecular aspects of N metabolism in the nodule during stress and recovery.

PubMed

Souza, Sarah C R; Mazzafera, Paulo; Sodek, Ladaslav

2016-05-01

Nitrogen fixation of the nodule of soybean is highly sensitive to oxygen deficiency such as provoked by waterlogging of the root system. This study aimed to evaluate the effects of flooding on N metabolism in nodules of soybean. Flooding resulted in a marked decrease of asparagine (the most abundant amino acid) and a concomitant accumulation of γ-aminobutyric acid (GABA). Flooding also resulted in a strong reduction of the incorporation of (15)N2 in amino acids. Nodule amino acids labelled before flooding rapidly lost (15)N during flooding, except for GABA, which initially increased and declined slowly thereafter. Both nitrogenase activity and the expression of nifH and nifD genes were strongly decreased on flooding. Expression of the asparagine synthetase genes SAS1 and SAS2 was reduced, especially the former. Expression of genes encoding the enzyme glutamic acid decarboxylase (GAD1, GAD4, GAD5) was also strongly suppressed except for GAD2 which increased. Almost all changes observed during flooding were reversible after draining. Possible changes in asparagine and GABA metabolism that may explain the marked fluctuations of these amino acids during flooding are discussed. It is suggested that the accumulation of GABA has a storage role during flooding stress.

Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis.

PubMed

Sun, Der-Shan; Chang, Yao-Wen; Kau, Jyh-Hwa; Huang, Hsin-Hsien; Ho, Pei-Hsun; Tzeng, Yin-Jeh; Chang, Hsin-Hou

2017-10-03

As one of the virulence factors of Bacillus anthracis, lethal toxin (LT) induces various pathogenic responses including the suppression of the coagulation system. In this study, we observed that LT markedly increased the circulating soluble P-selectin (sP-sel) levels and microparticle (MP) count in wild-type but not P-selectin (P-sel, Selp -/- ) or P-sel ligand-1 (PSGL-1, Selplg -/- ) knockout mice. Because sP-sel induces a hypercoagulable state through PSGL-1 pathway to generate tissue factor-positive MPs, we hypothesized that the increase in plasma sP-sel levels can be a self-rescue response in hosts against the LT-mediated suppression of the coagulation system. In agreement with our hypothesis, our results indicated that compared with wild-type mice, Selp -/- and Selplg -/- mice were more sensitive to LT. In addition, the recombinant sP-sel treatment markedly ameliorated LT-mediated pathogenesis and reduced mortality. As a result, elicitation of circulating sP-sel is potentially a self-rescue response, which is beneficial to host recovery from an LT-induced hypocoagulation state. These results suggest that the administration of sP-sel is likely to be useful in the development of a new strategy to treat anthrax.

[Diabetes insipidus].

PubMed

Krysiak, Robert; Handzlik-Orlik, Gabriela; Okopień, Bogusław

2014-01-01

Diabetes insipidus is an uncommon disorder of water-electrolyte balance characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The disease may result from the insufficient production of vasopressin, its increased degradation, an impaired response of kidneys to vasopressin, or may be secondary to excessive water intake. Patients with severe and uncompensated symptoms may develop marked dehydration, neurologic symptoms and encephalopathy, and therefore diabetes insipidus can be a life-threatening condition if not properly diagnosed and managed. Patients with diabetes insipidus require treatment with desmopressin or drugs increasing sensitivity of the distal nephron to vasopressin, but this treatment may be confusing because of the disorder's variable pathophysiology and side-effects of pharmacotherapy. This review summarizes the current knowledge on different aspects of the pathophysiology, classification, clinical presentation, diagnosis, and management of diabetes insipidus. The reader is also provided with some practical recommendations on dealing with patients suffering from this disease.

Plumbing noise in multifamily dwellings: 50 years and counting

NASA Astrophysics Data System (ADS)

Loverde, John J.; Dong, David W.

2005-09-01

Historically, plumbing sound was only of concern in luxury buildings and plumbing noise was rarely addressed explicitly in building codes or design guidelines. The last couple of decades have seen marked increases in population density, occupant expectations and sensitivity to noise, and the number of noise-related lawsuits. These demographic factors have considerably increased the importance of adequately addressing plumbing noise in multifamily projects, as shown by the increasing number of published guidelines (such as in the latest ASHRAE Handbook). Over the course of our firm's history, we have attempted to determine the relationship between the sound level from plumbing systems and the acceptability to the occupants. Our current criteria for plumbing noise and the reasoning behind them is discussed, including test cases and lawsuits, as well as the materials and methods available to meet those criteria, and their impact on the design of multifamily projects.

Clues on the origin of post-2000 earthquakes at Campi Flegrei caldera (Italy).

PubMed

Chiodini, G; Selva, J; Del Pezzo, E; Marsan, D; De Siena, L; D'Auria, L; Bianco, F; Caliro, S; De Martino, P; Ricciolino, P; Petrillo, Z

2017-06-30

The inter-arrival times of the post 2000 seismicity at Campi Flegrei caldera are statistically distributed into different populations. The low inter-arrival times population represents swarm events, while the high inter-arrival times population marks background seismicity. Here, we show that the background seismicity is increasing at the same rate of (1) the ground uplift and (2) the concentration of the fumarolic gas specie more sensitive to temperature. The seismic temporal increase is strongly correlated with the results of recent simulations, modelling injection of magmatic fluids in the Campi Flegrei hydrothermal system. These concurrent variations point to a unique process of temperature-pressure increase of the hydrothermal system controlling geophysical and geochemical signals at the caldera. Our results thus show that the occurrence of background seismicity is an excellent parameter to monitor the current unrest of the caldera.

Solid-phase microextraction coupled to gas chromatography for the determination of 2,3-dimethyl-2,3-dinitrobutane as a marking agent for explosives.

PubMed

Li, Xiujuan; Zeng, Zhaorui; Zeng, Yi

2007-06-15

This paper investigates the detection of 2,3-dimethyl-2,3-dinitrobutane (DMNB), a marking agent in explosives, by gas chromatography (GC) with electron capture detection using solid-phase microextraction (SPME) as a sample preparation technique. The 25,27-dihydroxy-26,28-oxy (2',7'-dioxo-3',6'-diazaoctyl) oxy-p-tert-butylcalix[4]arene/hydroxy-terminated silicone oil coated fiber was highly sensitive to trap DMNB from ammonium nitrate matrix. The analysis was performed by extracting 2g of explosives for 30s at room temperature and then immediately introducing into the heated GC injector for 1min of thermal desorption. The method showed good linearity in the range from 0.01 to 1.0mug/g. The relative standard deviations for these extractions were <8%. The calculated limit of detection for DMNB (S/N=3) was 4.43x10(-4)mug/g, which illustrates that the proposed systems are suitable for explosive detection at trace level. This is the first report of an SPME-GC system shown to extract marking agent in explosives for subsequent detection in a simple, rapid, sensitive, and inexpensive manner.

Minnesota Local Agency Pavement Marking : Mining Existing Data

DOT National Transportation Integrated Search

2017-11-01

Pavement marking is important for safety. Maximizing pavement marking performance in terms of increased retroreflectivity, within limited budget constraints, allows agencies to make better decisions toward providing more effective pavement marking pe...

Random mutagenesis screening indicates the absence of a separate H(+)-sensor in the pH-sensitive Kir channels.

PubMed

Paynter, Jennifer J; Shang, Lijun; Bollepalli, Murali K; Baukrowitz, Thomas; Tucker, Stephen J

2010-01-01

Several inwardly-rectifying (Kir) potassium channels (Kir1.1, Kir4.1 and Kir4.2) are characterised by their sensitivity to inhibition by intracellular H(+) within the physiological range. The mechanism by which these channels are regulated by intracellular pH has been the subject of intense scrutiny for over a decade, yet the molecular identity of the titratable pH-sensor remains elusive. In this study we have taken advantage of the acidic intracellular environment of S. cerevisiae and used a K(+) -auxotrophic strain to screen for mutants of Kir1.1 with impaired pH-sensitivity. In addition to the previously identified K80M mutation, this unbiased screening approach identified a novel mutation (S172T) in the second transmembrane domain (TM2) that also produces a marked reduction in pH-sensitivity through destabilization of the closed-state. However, despite this extensive mutagenic approach, no mutations could be identified which removed channel pH-sensitivity or which were likely to act as a separate H(+) -sensor unique to the pH-sensitive Kir channels. In order to explain these results we propose a model in which the pH-sensing mechanism is part of an intrinsic gating mechanism common to all Kir channels, not just the pH-sensitive Kir channels. In this model, mutations which disrupt this pH-sensor would result in an increase, not reduction, in pH-sensitivity. This has major implications for any future studies of Kir channel pH-sensitivity and explains why formal identification of these pH-sensing residues still represents a major challenge.

Influence of the axial rotation angle on tool mark striations.

PubMed

Garcia, Derrel Louis; Pieterman, René; Baiker, Martin

2017-10-01

A tool's axial rotation influences the geometric properties of a tool mark. The larger the axial rotation angle, the larger the compression of structural details like striations. This complicates comparing tool marks at different axial rotations. Using chisels, tool marks were made from 0° to 75° axial rotation and compared using an automated approach Baiker et al. [10]. In addition, a 3D topographic surface of a chisel was obtained to generate virtual tool marks and to test whether the axial rotation angle of a mark could be predicted. After examination of the tool mark and chisel data-sets it was observed that marks lose information with increasing rotation due to the change in relative distance between geometrical details on the tool and the disappearance of smaller details. The similarity and repeatability were high for comparisons between marks with no difference in axial rotation, but decreasing with increased rotation angle from 0° to 75°. With an increasing difference in the rotation angles, the tool marks had to be corrected to account for the different compression factors between them. For compression up to 7.5%, this was obtained automatically by the tool mark alignment method. For larger compression, manually re-sizing the marks to the uncompressed widths at 0° rotation before the alignment was found suitable for successfully comparing even large differences in axial rotation. The similarity and repeatability were decreasing however, with increasing degree of re-sizing. The quality was assessed by determining the similarity at different detail levels within a tool mark. With an axial rotation up to 75°, tool marks were found to reliably represent structural details down to 100μm. The similarity of structural details below 100μm was dependent on the angle, with the highest similarity at small rotation angles and the lowest similarity at large rotation angles. Filtering to remove the details below 100μm lead to consistently higher similarity between tool marks at all angles and allowed for a comparison of marks up to 75° axial rotation. Finally, generated virtual tool mark profiles with an axial rotation were compared to experimental tool marks. The similarity between virtual and experimental tool marks remained high up to 60° rotation after which it decreased due to the loss in quality in both marks. Predicting the rotation angle is possible under certain conditions up to 45° rotation with an accuracy of 2.667±0.577° rotation. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel signal amplification technology for ELISA based on catalyzed reporter deposition. Demonstration of its applicability for measuring aflatoxin B(1).

PubMed

Bhattacharya, D; Bhattacharya, R; Dhar, T K

1999-11-19

In an earlier communication we have described a novel signal amplification technology termed Super-CARD, which is able to significantly improve antigen detection sensitivity in conventional Dot-ELISA by approximately 10(5)-fold. The method utilizes hitherto unreported synthesized electron rich proteins containing multiple phenolic groups which, when immobilized over a solid phase as blocking agent, markedly increases the signal amplification capability of the existing CARD method (Bhattacharya, R., Bhattacharya, D., Dhar, T.K., 1999. A novel signal amplification technology based on catalyzed reporter deposition and its application in a Dot-ELISA with ultra high sensitivity. J. Immunol. Methods 227, 31.). In this paper we describe the utilization of this Super-CARD amplification technique in ELISA and its applicability for the rapid determination of aflatoxin B(1) (AFB(1)) in infected seeds. Using this method under identical conditions, the increase in absorbance over the CARD method was approximately 400%. The limit of detection of AFB(1) by this method was 0.1 pg/well, the sensitivity enhancement being 5-fold over the optimized CARD ELISA. Furthermore, the total incubation time was reduced to 16 min compared to 50 min for the CARD method. Assay specificity was not adversely affected and the amount of AFB(1) measured in seed extracts correlated well with the values obtained by conventional ELISA.

A review of 241 subjects who were patch tested twice: could fragrance mix I cause active sensitization?

PubMed

White, J M L; McFadden, J P; White, I R

2008-03-01

Active patch test sensitization is an uncommon phenomenon which may have undesirable consequences for those undergoing this gold-standard investigation for contact allergy. To perform a retrospective analysis of the results of 241 subjects who were patch tested twice in a monocentre evaluating approximately 1500 subjects per year. Positivity to 11 common allergens in the recommended Baseline Series of contact allergens (European) was analysed: nickel sulphate; Myroxylon pereirae; fragrance mix I; para-phenylenediamine; colophonium; epoxy resin; neomycin; quaternium-15; thiuram mix; sesquiterpene lactone mix; and para-tert-butylphenol resin. Only fragrance mix I gave a statistically significant, increased rate of positivity on the second reading compared with the first (P=0.011). This trend was maintained when separately analysing a subgroup of 42 subjects who had been repeat patch tested within 1 year; this analysis was done to minimize the potential confounding factor of increased usage of fragrances with a wide interval between both tests. To reduce the confounding effect of age on our data, we calculated expected frequencies of positivity to fragrance mix I based on previously published data from our centre. This showed a marked excess of observed cases over predicted ones, particularly in women in the age range 40-60 years. We suspect that active sensitization to fragrance mix I may occur. Similar published analysis from another large group using standard methodology supports our data.

A comparison of 2 techniques for estimating deer density

USGS Publications Warehouse

Storm, G.L.; Cottam, D.F.; Yahner, R.H.; Nichols, J.D.

1977-01-01

We applied mark-resight and area-conversion methods to estimate deer abundance at a 2,862-ha area in and surrounding the Gettysburg National Military Park and Eisenhower National Historic Site during 1987-1991. One observer in each of 11 compartments counted marked and unmarked deer during 65-75 minutes at dusk during 3 counts in each of April and November. Use of radio-collars and vinyl collars provided a complete inventory of marked deer in the population prior to the counts. We sighted 54% of the marked deer during April 1987 and 1988, and 43% of the marked deer during November 1987 and 1988. Mean number of deer counted increased from 427 in April 1987 to 582 in April 1991, and increased from 467 in November 1987 to 662 in November 1990. Herd size during April, based on the mark-resight method, increased from approximately 700-1,400 from 1987-1991, whereas the estimates for November indicated an increase from 983 for 1987 to 1,592 for 1990. Given the large proportion of open area and the extensive road system throughout the study area, we concluded that the sighting probability for marked and unmarked deer was fairly similar. We believe that the mark-resight method was better suited to our study than the area-conversion method because deer were not evenly distributed between areas suitable and unsuitable for sighting within open and forested areas. The assumption of equal distribution is required by the area-conversion method. Deer marked for the mark-resight method also helped reduce double counting during the dusk surveys.

UroMark-a urinary biomarker assay for the detection of bladder cancer.

PubMed

Feber, Andrew; Dhami, Pawan; Dong, Liqin; de Winter, Patricia; Tan, Wei Shen; Martínez-Fernández, Mónica; Paul, Dirk S; Hynes-Allen, Antony; Rezaee, Sheida; Gurung, Pratik; Rodney, Simon; Mehmood, Ahmed; Villacampa, Felipe; de la Rosa, Federico; Jameson, Charles; Cheng, Kar Keung; Zeegers, Maurice P; Bryan, Richard T; James, Nicholas D; Paramio, Jesus M; Freeman, Alex; Beck, Stephan; Kelly, John D

2017-01-01

Bladder cancer (BC) is one of the most common cancers in the western world and ranks as the most expensive to manage, due to the need for cystoscopic examination. BC shows frequent changes in DNA methylation, and several studies have shown the potential utility of urinary biomarkers by detecting epigenetic alterations in voided urine. The aim of this study is to develop a targeted bisulfite next-generation sequencing assay to diagnose BC from urine with high sensitivity and specificity. We defined a 150 CpG loci biomarker panel from a cohort of 86 muscle-invasive bladder cancers and 30 normal urothelium. Based on this panel, we developed the UroMark assay, a next-generation bisulphite sequencing assay and analysis pipeline for the detection of bladder cancer from urinary sediment DNA. The 150 loci UroMark assay was validated in an independent cohort ( n  = 274, non-cancer ( n  = 167) and bladder cancer ( n  = 107)) voided urine samples with an AUC of 97%. The UroMark classifier sensitivity of 98%, specificity of 97% and NPV of 97% for the detection of primary BC was compared to non-BC urine. Epigenetic urinary biomarkers for detection of BC have the potential to revolutionise the management of this disease. In this proof of concept study, we show the development and utility of a novel high-throughput, next-generation sequencing-based biomarker for the detection of BC-specific epigenetic alterations in urine.

A Closer Look at Solar Wind Sputtering of Lunar Surface Materials

NASA Technical Reports Server (NTRS)

Barghouty, A. F.; Adams, J. H., Jr.; Meyer, F.; Mansur, L.; Reinhold, C.

2008-01-01

Solar-wind induced potential sputtering of the lunar surface may be a more efficient erosive mechanism than the "standard" kinetic (or physical) sputtering. This is partly based on new but limited laboratory measurements which show marked enhancements in the sputter yields of slow-moving, highly-charged ions impacting oxides. The enhancements seen in the laboratory can be orders of magnitude for some surfaces and highly charged incident ions, but seem to depend very sensitively on the properties of the impacted surface in addition to the fluence, energy and charge of the impacting ion. For oxides, potential sputtering yields are markedly enhanced and sputtered species, especially hydrogen and light ions, show marked dependence on both charge and dose.

Increasing The Electric Field For An Improved Search For Time-Reversal Violation Using Radium-225

NASA Astrophysics Data System (ADS)

Powers, Adam

2017-09-01

Radium-225 atoms, because of their unusual pear-shaped nuclei, have an enhanced sensitivity to the violation of time reversal symmetry. A breakdown of this fundamental symmetry could help explain the apparent scarcity of antimatter in the Universe. Our goal is to improve the statistical sensitivity of an ongoing experiment that precisely measures the EDM of Radium-225. This can be done by increasing the electric field acting on the Radium atoms. We do this by increasing the voltage that can be reliably applied between two electrodes, and narrowing the gap between them. We use a varying high voltage system to condition the electrodes using incremental voltage ramp tests to achieve higher voltage potential differences. Using an adjustable gap mount to change the distance between the electrodes, specific metals for their composition, and a clean room procedure to keep particulates out of the system, we produce a higher and more stable electric field. Progress is marked by measurements of the leakage current between the electrodes during our incremental voltage ramp tests or emulated tests of the actual experiment, with low and constant current showing stability of the field. This project is supported by Michigan State University, and the US DOE, Office of Science, Office of Nuclear Physics, under Contract DE-AC02-06CH11357.

The new horizon in 2D electrophoresis: new technology to increase resolution and sensitivity.

PubMed

Moche, Martin; Albrecht, Dirk; Maaß, Sandra; Hecker, Michael; Westermeier, Reiner; Büttner, Knut

2013-06-01

A principally new type of an electrophoresis setup for the second dimension of 2DE named HPE (high performance electrophoresis) has recently become available that provides excellent reproducibility much superior to traditional 2DE. It takes up ideas from early beginnings of 2DE which could not be satisfactory realized at that time. The new HPE system is in contrast to all other established systems a horizontal electrophoresis that employs a new type of precast polyacrylamide gels on film-backing and runs on a multilevel flatbed electrophoresis apparatus. In a systematic approach we compared its features to traditional 2DE for the cytosolic proteome of Bacillus subtilis. Not only the reproducibility is enhanced, but also nearly all qualitative parameters as resolution, sensitivity, the number of protein spots (25% more), and the number of different proteins (also additional 25%) are markedly increased. More than 200 proteins were exclusively found in HPE. This new electrophoresis system does not use buffer tanks. No glass plates are needed. Therefore handling of gels is greatly facilitated and very simple to use even for personnel with low technical skills. The new HPE system is technically at the beginnings and further development with increased performance can be expected. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sensitization by subcutaneous route is superior to intraperitoneal route in induction of asthma by house dust mite in a murine mode

PubMed Central

Aun, Marcelo Vivolo; Saraiva-Romanholo, Beatriz Mangueira; de Almeida, Francine Maria; Brüggemann, Thayse Regina; Kalil, Jorge; Martins, Milton de Arruda; Arantes-Costa, Fernanda Magalhães; Giavina-Bianchi, Pedro

2015-01-01

ABSTRACT Objective To develop a new experimental model of chronic allergic pulmonary disease induced by house dust mite, with marked production of specific immunoglobulin E (IgE), eosinophilic inflammatory infiltrate in the airways and remodeling, comparing two different routes of sensitization. Methods The protocol lasted 30 days. BALB/c mice were divided into six groups and were sensitized subcutaneously or intraperitoneally with saline (negative control), Dermatophagoides pteronyssinus (Der p) 50 or 500mcg in three injections. Subsequently they underwent intranasal challenge with Der p or saline for 7 days and were sacrificed 24 hours after the last challenge. We evaluated the titration of specific IgE anti-Der p, eosinophilic density in peribronchovascular space and airway remodeling. Results Both animals sensitized intraperitoneally and subcutaneously produced specific IgE anti-Der p. Peribronchovascular eosinophilia increased only in mice receiving lower doses of Der p. However, only the group sensitized with Der p 50mcg through subcutaneously route showed significant airway remodeling. Conclusion In this murine model of asthma, both pathways of sensitization led to the production of specific IgE and eosinophilia in the airways. However, only the subcutaneously route was able to induce remodeling. Furthermore, lower doses of Der p used in sensitization were better than higher ones, suggesting immune tolerance. Further studies are required to evaluate the efficacy of this model in the development of bronchial hyperresponsiveness, but it can already be replicated in experiments to create new therapeutic drugs or immunotherapeutic strategies. PMID:26761554

Evidence for Non-Opponent Coding of Colour Information in Human Visual Cortex: Selective Loss of "Green" Sensitivity in a Subject with Damaged Ventral Occipito-Temporal Cortex.

PubMed

Rauscher, Franziska G; Plant, Gordon T; James-Galton, Merle; Barbur, John L

2011-01-01

Damage to ventral occipito-temporal extrastriate visual cortex leads to the syndrome of prosopagnosia often with coexisting cerebral achromatopsia. A patient with this syndrome resulting in a left upper homonymous quadrantanopia, prosopagnosia, and incomplete achromatopsia is described. Chromatic sensitivity was assessed at a number of locations in the intact visual field using a dynamic luminance contrast masking technique that isolates the use of colour signals. In normal subjects chromatic detection thresholds form an elliptical contour when plotted in the Commission Internationale d'Eclairage, (x-y), chromaticity diagram. Because the extraction of colour signals in early visual processing involves opponent mechanisms, subjects with Daltonism (congenital red/green loss of sensitivity) show symmetric increase in thresholds towards the long wavelength ("red") and middle wavelength ("green") regions of the spectrum locus. This is also the case with acquired loss of chromatic sensitivity as a result of retinal or optic nerve disease. Our patient's results were an exception to this rule. Whilst his chromatic sensitivity in the central region of the visual field was reduced symmetrically for both "red/green" and "yellow/blue" directions in colour space, the subject's lower left quadrant showed a marked asymmetry in "red/green" thresholds with the greatest loss of sensitivity towards the "green" region of the spectrum locus. This spatially localized asymmetric loss of "green" but not "red" sensitivity has not been reported previously in human vision. Such loss is consistent with selective damage of neural substrates in the visual cortex that process colour information, but are spectrally non-opponent.

The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines.

PubMed

Stanley, Joanna L; Lincoln, Rachael J; Brown, Terry A; McDonald, Louise M; Dawson, Gerard R; Reynolds, David S

2005-05-01

The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.

HIF1α regulated expression of XPA contributes to cisplatin resistance in lung cancer

PubMed Central

Liu, Yanbin; Bernauer, Amanda M.; Yingling, Christin M.; Belinsky, Steven A.

2012-01-01

Factors regulating nucleotide excision repair probably contribute to the heterogenous response of advanced stage lung cancer patients to drugs such as cisplatin. Studies to identify the genes in the nucleotide excision repair pathway most closely associated with resistance to cisplatin have not been conclusive. We hypothesized that Xeroderma pigmentosum complementation group A (XPA), because of its dual role in sensing and recruiting other DNA repair proteins to the damaged template, would be critical in defining sensitivity to cisplatin. Studies were conducted to identify factors regulating transcription of XPA, to assess its role in modulating sensitivity to cisplatin and its expression in primary lung tumors. Hypoxia-inducible factor 1 alpha (HIF1α) subunit was found to bind with strong affinity to a hypoxia response element sequence in the promoter of XPA. Modulating expression of HIF1α by small interfering RNA or cobalt chloride markedly reduced or increased transcription of XPA in lung cancer cell lines, respectively. Protein levels of XPA were strongly correlated with sensitivity to cisplatin (r = 0.88; P < 0.001) in cell lines and sensitivity could be increased by small interfering RNA depletion of XPA. Expression of XPA determined in 54 primary lung tumors was elevated on average 5.2-fold when compared with normal bronchial epithelial cells and correlated with levels of HIF1α (r = 0.58; P < 0.01). Together, these studies identify XPA as a novel target for regulation by HIF1α whose modulation could impact lung cancer therapy. PMID:22467238

The influence of social and endocrine factors on urine-marking by captive wolves (Canis lupus)

USGS Publications Warehouse

Asa, C.S.; Mech, L.D.; Seal, U.S.; Plotka, E.D.

1990-01-01

Although serum hormones varied seasonally in all adult animals, only dominant male and female wolves urine-marked. Serum testosterone and urine-marking rates, which increased during the fall/winter breeding season, were positively correlated in both male and female dominant wolves. Estradiol, which increased in conjunction with proestrus and estrus, was not correlated with female urine-marking. These findings suggest that hormonal influence on urine-marking in the wolf is modulated by social factors and contrast with those for both domestic dogs and coyotes, two other members of the genus Canis.

32 CFR 149.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... access to classified national security information, restricted data, and/or sensitive but unclassified... ON TECHNICAL SURVEILLANCE COUNTERMEASURES § 149.3 Definitions. Classified National Security... is marked to indicate its classified status when in documentary form. Restricted Data (RD). All data...

Effect of Hydroxyurea on Staphylococcus epidermidis and Micrococcus lysodeikticus: Thickening of the Cell Wall

PubMed Central

Feiner, Rose R.; Coward, Joe E.; Rosenkranz, Herbert S.

1973-01-01

Hydroxyurea-sensitive strains of Staphylococcus epidermidis and Micrococcus lysodeikticus showed marked thickening of cell walls and reduction in deoxyribonucleic acid synthesis when grown in the presence of hydroxyurea. Images PMID:4790602

Protect sensitive data with lightweight memory encryption

NASA Astrophysics Data System (ADS)

Zhou, Hongwei; Yuan, Jinhui; Xiao, Rui; Zhang, Kai; Sun, Jingyao

2018-04-01

Since current commercial processor is not able to deal with the data in the cipher text, the sensitive data have to be exposed in the memory. It leaves a window for the adversary. To protect the sensitive data, a direct idea is to encrypt the data when the processor does not access them. On the observation, we have developed a lightweight memory encryption, called LeMe, to protect the sensitive data in the application. LeMe marks the sensitive data in the memory with the page table entry, and encrypts the data in their free time. LeMe is built on the Linux with a 3.17.6 kernel, and provides four user interfaces as dynamic link library. Our evaluations show LeMe is effective to protect the sensitive data and incurs an acceptable performance overhead.

Balancing data sharing requirements for analyses with data sensitivity

USGS Publications Warehouse

Jarnevich, C.S.; Graham, J.J.; Newman, G.J.; Crall, A.W.; Stohlgren, T.J.

2007-01-01

Data sensitivity can pose a formidable barrier to data sharing. Knowledge of species current distributions from data sharing is critical for the creation of watch lists and an early warning/rapid response system and for model generation for the spread of invasive species. We have created an on-line system to synthesize disparate datasets of non-native species locations that includes a mechanism to account for data sensitivity. Data contributors are able to mark their data as sensitive. This data is then 'fuzzed' in mapping applications and downloaded files to quarter-quadrangle grid cells, but the actual locations are available for analyses. We propose that this system overcomes the hurdles to data sharing posed by sensitive data. ?? 2006 Springer Science+Business Media B.V.

Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity.

PubMed

Broussard, Josiane L; Nelson, Michael D; Kolka, Cathryn M; Bediako, Isaac Asare; Paszkiewicz, Rebecca L; Smith, Laura; Szczepaniak, Edward W; Stefanovski, Darko; Szczepaniak, Lidia S; Bergman, Richard N

2016-01-01

The worldwide incidence of obesity and diabetes continues to rise at an alarming rate. A major cause of the morbidity and mortality associated with obesity and diabetes is heart disease, yet the mechanisms that lead to cardiovascular complications remain unclear. We performed cardiac MRI to assess left ventricular morphology and function during the development of moderate obesity and insulin resistance in a well-established canine model (n = 26). To assess the influence of dietary fat composition, we randomised animals to a traditional lard diet (rich in saturated and monounsaturated fat; n = 12), a salmon oil diet (rich in polyunsaturated fat; n = 8) or a control diet (n = 6). High-fat feeding with lard increased body weight and fasting insulin and markedly reduced insulin sensitivity. Lard feeding also significantly reduced left ventricular function, evidenced by a worsening of circumferential strain and impairment in left ventricular torsion. High-fat feeding with salmon oil increased body weight; however, salmon oil feeding did not impair insulin sensitivity or cardiac function. These data emphasise the importance of dietary fat composition on both metabolic and cardiac function, and have important implications for the relationship between diet and health.

Genes involved in nonpermissive temperature-induced cell differentiation in Sertoli TTE3 cells bearing temperature-sensitive simian virus 40 large T-antigen

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

Tabuchi, Yoshiaki; Kondo, Takashi; Suzuki, Yoshihisa

2005-04-15

Sertoli TTE3 cells, derived from transgenic mice bearing temperature-sensitive simian virus 40 large T (tsSV40LT)-antigen, proliferated continuously at a permissive temperature (33 deg C) whereas inactivation of the large T-antigen by a nonpermissive temperature (39 deg C) led to differentiation as judged by elevation of transferrin. To clarify the detailed mechanisms of differentiation, we investigated the time course of changes in gene expression using cDNA microarrays. Of the 865 genes analyzed, 14 genes showed increased levels of expression. Real-time quantitative PCR revealed that the mRNA levels of p21{sup waf1}, milk fat globule membrane protein E8, heat-responsive protein 12, and selenoproteinmore » P were markedly elevated. Moreover, the differentiated condition induced by the nonpermissive temperature significantly increased mRNA levels of these four genes in several cell lines from the transgenic mice bearing the oncogene. The present results regarding changes in gene expression will provide a basis for a further understanding of molecular mechanisms of differentiation in both Sertoli cells and cell lines transformed by tsSV40LT-antigen.« less

Metabolic Responses to Low Temperature of Three Peach Fruit Cultivars Differently Sensitive to Cold Storage

PubMed Central

Brizzolara, Stefano; Hertog, Maarten; Tosetti, Roberta; Nicolai, Bart; Tonutti, Pietro

2018-01-01

Refrigerated storage is widely applied in order to maintain peach quality but it can also induce chilling injuries (CIs) such as flesh browning and bleeding, and mealiness. Peach fruit from three cultivars (‘Red Haven’, RH, ‘Regina di Londa’, RL, and ‘Flaminia’, FL) were stored for 4 weeks under low temperatures (0.5 and 5.5°C). GC-MS was employed to study changes in both metabolome and volatilome induced by cold storage in the mesocarp. CIs were assessed both at the end of each week of storage and after subsequent shelf-life (SL) at 20°C. Flesh browning and mealiness appeared to be more related to 5.5°C storage, while flesh bleeding revealed high incidence following 0.5°C storage. Compared to RL and FL, RH showed a marked lower incidence of CIs. Multivariate statistical analyses indicate that RH peaches indeed differ from RL and FL in particular when considering data from samples collected at the end of the cold storage. Common and divergent responses have been identified in terms of metabolic responses to the applied low temperatures. In all three cultivars raffinose, glucose-6P, fucose, xylose, sorbitol, GABA, epicatechin, catechin, and putrescine markedly increased during cold storage, while citramalic, glucuronic, mucic and shikimic acids decreased. Among volatile organic compounds (VOCs), aldehydes and alcohols generally accumulated more under low temperature conditions while esters and lactones evolved during subsequent SL. The main cultivar differences developed after cold storage during SL although some common responses (e.g., an increased production of ethyl acetate) were observed. The lower levels of flesh browning and bleeding displayed by RH peaches were related to compounds with antioxidant activity, or acting as osmotic protectants and membrane stabilizer. Indeed, RH showed higher levels of amino acids and urea, together with a marked increase in putrescine, sorbitol, maltitol, myoinositol and sucrose detected during storage and SL. PMID:29892309

Metabolic Responses to Low Temperature of Three Peach Fruit Cultivars Differently Sensitive to Cold Storage.

PubMed

Brizzolara, Stefano; Hertog, Maarten; Tosetti, Roberta; Nicolai, Bart; Tonutti, Pietro

2018-01-01

Refrigerated storage is widely applied in order to maintain peach quality but it can also induce chilling injuries (CIs) such as flesh browning and bleeding, and mealiness. Peach fruit from three cultivars ('Red Haven', RH, 'Regina di Londa', RL, and 'Flaminia', FL) were stored for 4 weeks under low temperatures (0.5 and 5.5°C). GC-MS was employed to study changes in both metabolome and volatilome induced by cold storage in the mesocarp. CIs were assessed both at the end of each week of storage and after subsequent shelf-life (SL) at 20°C. Flesh browning and mealiness appeared to be more related to 5.5°C storage, while flesh bleeding revealed high incidence following 0.5°C storage. Compared to RL and FL, RH showed a marked lower incidence of CIs. Multivariate statistical analyses indicate that RH peaches indeed differ from RL and FL in particular when considering data from samples collected at the end of the cold storage. Common and divergent responses have been identified in terms of metabolic responses to the applied low temperatures. In all three cultivars raffinose, glucose-6P, fucose, xylose, sorbitol, GABA, epicatechin, catechin, and putrescine markedly increased during cold storage, while citramalic, glucuronic, mucic and shikimic acids decreased. Among volatile organic compounds (VOCs), aldehydes and alcohols generally accumulated more under low temperature conditions while esters and lactones evolved during subsequent SL. The main cultivar differences developed after cold storage during SL although some common responses (e.g., an increased production of ethyl acetate) were observed. The lower levels of flesh browning and bleeding displayed by RH peaches were related to compounds with antioxidant activity, or acting as osmotic protectants and membrane stabilizer. Indeed, RH showed higher levels of amino acids and urea, together with a marked increase in putrescine, sorbitol, maltitol, myoinositol and sucrose detected during storage and SL.

Paralysis and pernicious anemia in a young woman.

PubMed

Matrana, Marc R; Gauthier, Carl; Lafaye, Kristina M

2009-01-01

Vitamin B12 is important for normal nervous system functioning, and deficiencies are associated with various neurological abnormalities. We present a case of an 18-year-old woman who presented with significant neurological sequelae, but only mild hematologic abnormalities and normal vitamin B12 levels. She was found to have a moderately increased mean corpuscular volume, a markedly elevated homocysteine level, and a greatly increased methylmalonic acid level. In symptomatic patients it is important for physicians to maintain a high index of suspicion for B12 deficiency despite normal serum levels. The measurement of MMA and homocysteine levels provides much more sensitive tests, but even these tests do not completely rule out a deficiency. Although, the traditional treatment for vitamin B12 deficiency has been intramuscular cobalamin injections, recent studies have shown that oral cobalamin may be as efficacious.

Disgust Sensitivity and the Neurophysiology of Left-Right Political Orientations

PubMed Central

Smith, Kevin B.; Oxley, Douglas; Hibbing, Matthew V.; Alford, John R.; Hibbing, John R.

2011-01-01

Disgust has been described as the most primitive and central of emotions. Thus, it is not surprising that it shapes behaviors in a variety of organisms and in a variety of contexts—including homo sapien politics. People who believe they would be bothered by a range of hypothetical disgusting situations display an increased likelihood of displaying right-of-center rather than left-of-center political orientations. Given its primal nature and essential value in avoiding pathogens disgust likely has an effect even without registering in conscious beliefs. In this article, we demonstrate that individuals with marked involuntary physiological responses to disgusting images, such as of a man eating a large mouthful of writhing worms, are more likely to self-identify as conservative and, especially, to oppose gay marriage than are individuals with more muted physiological responses to the same images. This relationship holds even when controlling for the degree to which respondents believe themselves to be disgust sensitive and suggests that people's physiological predispositions help to shape their political orientations. PMID:22039415

Investigating relativity using lunar laser ranging - Geodetic precession and the Nordtvedt effect

NASA Technical Reports Server (NTRS)

Dickey, J. O.; Newhall, X. X.; Williams, J. G.

1989-01-01

The emplacement of retroreflectors on the moon by Apollo astronauts and the Russian Lunakhod spacecraft marked the inception of lunar laser ranging (LLR) and provided a natural laboratory for the study of general relativity. Continuing acquisition of increasingly accurate LLR data has provided enhanced sensitivity to general relativity parameters. Two relativistic effects are investigated in this paper: (1) the Nordtvedt effect, yielding a test of the strong equivalence principle, would appear as a distortion of the geocentric lunar orbit in the direction of the sun. The inclusion of recent LLR data limits the size of any such effect to 3 + or - 4 cm. The sensitivities to the various PPN quantities are also highlighted. (2) the geodetic precession of the lunar perigee is predicted by general relativity as a consequence of the motion of the earth-moon system about the sun; its theoretical magnitude is 19.2 mas/yr. Analysis presented here confirms this value and determines this quality to a 2 percent level.

Prenatal nicotinic exposure augments cardiorespiratory responses to activation of bronchopulmonary C-fibers

PubMed Central

Zhuang, Jianguo; Zhao, Lei; Zang, Na

2015-01-01

Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 μg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia. PMID:25747962

Selenium-binding protein 1: a sensitive urinary biomarker to detect heavy metal-induced nephrotoxicity.

PubMed

Lee, Eui Kyung; Shin, Young-Jun; Park, Eun Young; Kim, Nam Deuk; Moon, Aree; Kwack, Seung Jun; Son, Ji Yeon; Kacew, Sam; Lee, Byung Mu; Bae, Ok-Nam; Kim, Hyung Sik

2017-04-01

Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl 2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl 2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl 2 -treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and β-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl 2 -exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl 2 , CdCl 2 , or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.

Effect of an ozone injury-retardant chemical on isozyme profiles from alfalfa callus in vitro

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

Rier, J.P.; Sood, V.K.; Whitaker, A.

1983-01-01

Plant ozone injury retardant (EDU or ethylenediurea) at 1.0 ppm inhibited growth of callus of alfalfa cultivars Williamsburg (ozone-sensitive) and MSB-CW5An2(ozone-insensitive) germplasm of Medicago sative. The presence of EDU(0.1 ppm) in growth medium increased the number of protein and peroxidase isozyme bands in alfalfa cultivar stem callus and ozone modified their intensities. Protein profiles of MSB stem callus from media containing EDU or exposed to ozone were unchanged. Marked differences were observed between the peroxidase profiles of ozonated and control ozone-insensitive stem callus from media containing EDU. Protein profiles of ozonated ozone-insensitive leaf callus differed slightly from controls.

Documenting a decline in boreal spring rainfall over the Congo Basin and eastern Africa

NASA Astrophysics Data System (ADS)

Nicholson, S. E.

2016-12-01

The Africa rain forest is one of the continent's greatest resources. Unfortunately, evidence shows that a serious decline in photosynthetic activity has occurred in widespread parts of this environmental sensitive region. An extended period of drought appears to be a major factor in this decline. This paper presents an analysis of rainfall conditions in the region over the last half century. Commencing in the 1980s April-May-June rainfall decreased markedly over the eastern Congo Basin, as well as throughout much of eastern Africa. Ironically, in areas with the greatest decline, October-November-December rainfall increased at the same time. Possible meteorological reasons for these changes are examined.

Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia

PubMed Central

Chen, Jeng-Haur; Stoltz, David A.; Karp, Philip H.; Ernst, Sarah E.; Pezzulo, Alejandro A.; Moninger, Thomas O.; Rector, Michael V.; Reznikov, Leah R.; Launspach, Janice L.; Chaloner, Kathryn; Zabner, Joseph; Welsh, Michael J.

2011-01-01

SUMMARY Defective transepithelial electrolyte transport is thought to initiate cystic fibrosis (CF) lung disease. Yet, how loss of CFTR affects electrolyte transport remains uncertain. CFTR−/− pigs spontaneously develop lung disease resembling human CF. At birth, their airways exhibit a bacterial host defense defect, but are not inflamed. Therefore, we studied ion transport in newborn nasal and tracheal/bronchial epithelia in tissue, cultures, and in vivo. CFTR−/− epithelia showed markedly reduced Cl− and HCO3− transport. However, in contrast to a widely held view, lack of CFTR did not increase transepithelial Na+ or liquid absorption or reduce periciliary liquid depth. Like human CF, CFTR−/− pigs showed increased amiloride-sensitive voltage and current, but lack of apical Cl− conductance caused the change, not increased Na+ transport. These results indicate that CFTR provides the predominant transcellular pathway for Cl− and HCO3− in porcine airway epithelia, and reduced anion permeability may initiate CF airway disease. PMID:21145458

The effect of a histone deacetylase inhibitor - valproic acid - on nucleoli in human leukaemic myeloblasts.

PubMed

Smetana, K; Zápotocký, M

2010-01-01

The present study was undertaken to provide more information on nucleolar changes induced by a histone deacetylase inhibitor such as valproic acid in leukaemic myeloblasts at the single-cell level. For this study, RNA in nucleoli was visualized by a simple but sensitive cytochemical procedure in unfixed cytospins of short-term bone marrow cultures from patients suffering from acute myeloid leukaemia. Valproic acid in leukaemic myeloblasts markedly reduced the nucleolar size and also produced significant transformation of "active" to "resting" and "inactive" nucleoli that reflected the alteration of the nucleolar transcription in sensitive myeloblasts. On this occasion it should be added that valproic acid significantly increased the incidence of altered myeloblasts that changed to apoptotic cells or apoptotic bodies and cell ghosts. In contrast to the above-mentioned decreased nucleolar size, the nucleolar RNA concentration, expressed by computerassisted RNA image densitometry in valproic acidtreated myeloblasts, was not significantly changed. The results of the present study clearly indicated that the nucleolar size and transformation of "active" to "sleeping" or "inactive" nucleoli are convenient markers of the sensitivity and alteration of leukaemic myeloblasts produced by a histone deacetylase inhibitor, valproic acid, at the single-cell level.

Prospective assessment of Platelia Aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients.

PubMed

Husain, Shahid; Kwak, Eun Jeong; Obman, Asia; Wagener, Marilyn M; Kusne, Shimon; Stout, Janet E; McCurry, Kenneth R; Singh, Nina

2004-05-01

The clinical utility of Platelia trade mark Aspergillus galactomannan antigen for the early diagnosis of invasive aspergillosis was prospectively assessed in 70 consecutive lung transplant recipients. Sera were collected twice weekly and tested for galactomannan. Invasive aspergillosis was documented in 17.1% (12/70) of the patients. Using the generalized estimating equation model, at the cutoff value of >or= 0.5, the sensitivity of the test was 30%, specificity 93% with positive and negative likelihood ratios of 4.2 and 0.75, respectively. Increasing the cutoff value to >or= 0.66 yielded a sensitivity of 30%, specificity of 95%, and positive and negative likelihood ratios of 5.5 and 0.74. A total of 14 patients had false-positive tests, including nine who had cystic fibrosis or chronic obstructive pulmonary disease. False-positive tests occurred within 3 days of transplantation in 43% (6/14) of the patients, and within 7 days in 64% (9/14). Thus, the test demonstrated excellent specificity, but a low sensitivity for the diagnosis of aspergillosis in this patient population. Patients with cystic fibrosis or chronic obstructive pulmonary disease may transiently have a positive test in the early post-transplant period.

Sensitivity Profile for Orientation Selectivity in the Visual Cortex of Goggle-Reared Mice

PubMed Central

Yoshida, Takamasa; Ozawa, Katsuya; Tanaka, Shigeru

2012-01-01

It has been widely accepted that ocular dominance in the responses of visual cortical neurons can change depending on visual experience in a postnatal period. However, experience-dependent plasticity for orientation selectivity, which is another important response property of visual cortical neurons, is not yet fully understood. To address this issue, using intrinsic signal imaging and two-photon calcium imaging we attempted to observe the alteration of orientation selectivity in the visual cortex of juvenile and adult mice reared with head-mounted goggles, through which animals can experience only the vertical orientation. After one week of goggle rearing, the density of neurons optimally responding to the exposed orientation increased, while that responding to unexposed orientations decreased. These changes can be interpreted as a reallocation of preferred orientations among visually responsive neurons. Our obtained sensitivity profile for orientation selectivity showed a marked peak at 5 weeks and sustained elevation at 12 weeks and later. These features indicate the existence of a critical period between 4 and 7 weeks and residual orientation plasticity in adult mice. The presence of a dip in the sensitivity profile at 10 weeks suggests that different mechanisms are involved in orientation plasticity in childhood and adulthood. PMID:22792390

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

PubMed Central

Piekarski, David J.; Johnson, Carolyn; Boivin, Josiah R.; Thomas, A. Wren; Lin, Wan Chen; Delevich, Kristen; Galarce, Ezequiel; Wilbrecht, Linda

2016-01-01

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential. PMID:27590721

Asymmetric dimethylarginine may mediate increased heat pain threshold in experimental chronic kidney disease.

PubMed

Kielstein, Jan T; Suntharalingam, Mayuren; Perthel, Ronny; Rong, Song; Martens-Lobenhoffer, Jens; Jäger, Kristin; Bode-Böger, Stefanie M; Nave, Heike

2012-03-01

Thermal sensitivity in uraemia is decreased. Non-selective synthetic nitric oxide synthase (NOS) inhibitors significantly attenuate thermal hyperalgesia in preclinical models. The aim of our study was to evaluate the effect of experimental uraemia, which is associated with an increase of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), on thermal sensitivity in rats. Furthermore, we intended to study the effect of chronic ADMA infusion alone on thermal sensitivity. Male Sprague-Dawley rats (n = 54), 10 weeks old, weight 370-430 g, were randomly assigned to three groups receiving either (i) isotonic saline or (ii) ADMA via osmotic mini pumps or (iii) underwent 5/6 nephrectomy (Nx). After 14 days, 50% of all animals from all groups underwent thermal sensitivity testing and terminal blood draw. After 28 days, the remaining animals underwent the same procedures. Thermal sensitivity examination was performed by the hot-plate test, measuring time from heat exposition to first paw licking or jumping of the animal. While the median [interquartile range] latency time between heat exposition to first paw licking or jumping of the animal in the NaCl infusion group remained unchanged between Day 14 (8.4 [6.75-11.50] s) and Day 28 (7.35 [6.10-7.90] s) both, ADMA infusion and 5/6 nephrectomy tended to increase the thermal pain threshold at Day 14 (9.25 [6.55-12.18] s) and (9.50 [5.8 ± 11.0] s), respectively, compared to NaCl on Day 14 (8.4 [6.75-11.50] s). This difference became statistical significant at Day 28 where the median latency time in the ADMA group (13.10 [11.85-15.95] s) and in the 5/6 Nx group (13.50 [10.85-17.55] s) were significantly higher than in the NaCl group (7.35 [6.10-7.90] s). Induction of progressive renal failure in rats by 5/6 nephrectomy, which is accompanied by a marked increase of the serum levels of the endogenous NOS inhibitor ADMA, leads to a significantly increased heat pain threshold at 28 days. The sole infusion of ADMA into healthy rats leads to the same increase in heat pain threshold.

Thermal and hydrologic responses to climate change predict marked alterations in boreal stream invertebrate assemblages.

PubMed

Mustonen, Kaisa-Riikka; Mykrä, Heikki; Marttila, Hannu; Sarremejane, Romain; Veijalainen, Noora; Sippel, Kalle; Muotka, Timo; Hawkins, Charles P

2018-06-01

Air temperature at the northernmost latitudes is predicted to increase steeply and precipitation to become more variable by the end of the 21st century, resulting in altered thermal and hydrological regimes. We applied five climate scenarios to predict the future (2070-2100) benthic macroinvertebrate assemblages at 239 near-pristine sites across Finland (ca. 1200 km latitudinal span). We used a multitaxon distribution model with air temperature and modeled daily flow as predictors. As expected, projected air temperature increased the most in northernmost Finland. Predicted taxonomic richness also increased the most in northern Finland, congruent with the predicted northwards shift of many species' distributions. Compositional changes were predicted to be high even without changes in richness, suggesting that species replacement may be the main mechanism causing climate-induced changes in macroinvertebrate assemblages. Northern streams were predicted to lose much of the seasonality of their flow regimes, causing potentially marked changes in stream benthic assemblages. Sites with the highest loss of seasonality were predicted to support future assemblages that deviate most in compositional similarity from the present-day assemblages. Macroinvertebrate assemblages were also predicted to change more in headwaters than in larger streams, as headwaters were particularly sensitive to changes in flow patterns. Our results emphasize the importance of focusing protection and mitigation on headwater streams with high-flow seasonality because of their vulnerability to climate change. © 2018 John Wiley & Sons Ltd.

Near-infrared fluorescence glucose sensing based on glucose/galactose-binding protein coupled to 651-Blue Oxazine

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

Khan, Faaizah; Pickup, John C., E-mail: john.pickup@kcl.ac.uk

Highlights: •We showed that the NIR fluorophore, 651-Blue Oxazine, is solvatochromic (polarity sensitive). •Blue Oxazine was covalently attached to mutants of glucose/galactose-binding protein (GBP). •Fluorescence intensity of GBP-Blue Oxazine increased with addition of glucose. •Fluorescence from bead-immobilised GBP-Blue Oxazine was detectable through skin in vitro. •This shows proof-of-concept for non-invasive glucose sensing using GBP-Blue Oxazine. -- Abstract: Near-infrared (NIR) fluorescent dyes that are environmentally sensitive or solvatochromic are useful tools for protein labelling in in vivo biosensor applications such as glucose monitoring in diabetes since their spectral properties are mostly independent of tissue autofluorescence and light scattering, and they offermore » potential for non-invasive analyte sensing. We showed that the fluorophore 651-Blue Oxazine is polarity-sensitive, with a marked reduction in NIR fluorescence on increasing solvent polarity. Mutants of glucose/galactose-binding protein (GBP) used as the glucose receptor were site-specifically and covalently labelled with Blue Oxazine using click chemistry. Mutants H152C/A213R and H152C/A213R/L238S showed fluorescence increases of 15% and 21% on addition of saturating glucose concentrations and binding constants of 6 and 25 mM respectively. Fluorescence responses to glucose were preserved when GBP-Blue Oxazine was immobilised to agarose beads, and the beads were excited by NIR light through a mouse skin preparation studied in vitro. We conclude GBP-Blue Oxazine shows proof-of-concept as a non-invasive continuous glucose sensing system.« less

Inquiline roach responds to trail-marking substance of leaf-cutting ants

Treesearch

John C. Moser

1964-01-01

Nymphs and females of the roach inquiline, Attaphila fungicola W. M. Wheeler, respond to odor-trail substances of Atta texana (Buckley) and Trachymyrmex septentrionalis (McCook).The ants are more sensitive than roaches to the pheromone.

Effects of short-term very low-calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects.

PubMed

Lara-Castro, Cristina; Newcomer, Bradley R; Rowell, Jennifer; Wallace, Penny; Shaughnessy, Sara M; Munoz, A Julian; Shiflett, Alanna M; Rigsby, Dana Y; Lawrence, Jeannine C; Bohning, Daryl E; Buchthal, Steven; Garvey, W Timothy

2008-01-01

The study aimed to analyze the effects of a short-term very low-calorie diet (VLCD) on intramyocellular lipid (IMCL), total body fat, and insulin sensitivity in a group of obese nondiabetic and type 2 diabetic subjects. Seven untreated type 2 diabetic and 5 obese nondiabetic individuals were studied before and after a 6-day VLCD using proton magnetic resonance spectroscopy to quantify IMCL, dual-energy x-ray absorptiometry to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity. In both groups, decrements in total body fat mass and body mass index were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared with baseline values in nondiabetic subjects (56% decrease) and type 2 diabetic subjects (40% decrease) (P < .05), and this was accompanied by an overall 9.3% increase in maximally stimulated glucose disposal rate (P < .01). Intramyocellular lipid was significantly correlated with insulin sensitivity (r = -0.69, P < .01) and waist circumference (r = 0.72 and 0.83, baseline and postdiet, respectively; both P < .01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as body mass index, percentage of body fat, or total body fat (P = not significant). In conclusion, short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in nondiabetic and type 2 diabetic subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL both in nondiabetic and type 2 diabetic subjects in the absence of substantial changes in total body fat. These observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than to body fat per se.

Effects of Short-Term Very Low Calorie Diet on Intramyocellular Lipid and Insulin Sensitivity in Non-diabetics and Type 2 Diabetic Patients

PubMed Central

Lara-Castro, Cristina; Newcomer, Bradley R; Rowell, Jennifer; Wallace, Penny; Shaughnessy, Sara M; Munoz, A Julian; Shiflett, Alanna M; Rigsby, Dana Y; Lawrence, Jeannine C; Bohning, Daryl E; Buchthal, Steven; Garvey, W Timothy

2008-01-01

Objective To study the effects of a short-term very-low calorie diet (VLCD) on intramyocellular lipid (IMCL), total body fat, and insulin sensitivity in a group of obese non-diabetic and Type 2 Diabetic (T2DM) patients. Research Methods and Procedures Seven untreated T2DM and 5 obese non-diabetic individuals were studied before and after a 6-day VLCD using proton-magnetic resonance spectroscopy to quantify IMCL, DXA to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity. Results In both groups, decrements in total body fat mass and BMI were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared to baseline values in non-diabetics (56% decrease) and T2DM (40% decrease), P<0.05, and this was accompanied by an overall 9.3% increase in maximally-stimulated glucose disposal rate (P<0.01). IMCL was significantly correlated with insulin sensitivity, (r=−0.69; P<0.01) and waist circumference (r = 0.72 and 0.83, baseline and post-diet respectively, both P < 0.01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as BMI, % body fat, or total body fat (P=NS). Conclusions Short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in non-diabetic and T2DM subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL in both non-diabetics and in T2DM in the absence of substantial changes in total body fat. These observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than body fat per se. PMID:18078853

Estimating parasitic sea lamprey abundance in Lake Huron from heterogenous data sources

USGS Publications Warehouse

Young, Robert J.; Jones, Michael L.; Bence, James R.; McDonald, Rodney B.; Mullett, Katherine M.; Bergstedt, Roger A.

2003-01-01

The Great Lakes Fishery Commission uses time series of transformer, parasitic, and spawning population estimates to evaluate the effectiveness of its sea lamprey (Petromyzon marinus) control program. This study used an inverse variance weighting method to integrate Lake Huron sea lamprey population estimates derived from two estimation procedures: 1) prediction of the lake-wide spawning population from a regression model based on stream size and, 2) whole-lake mark and recapture estimates. In addition, we used a re-sampling procedure to evaluate the effect of trading off sampling effort between the regression and mark-recapture models. Population estimates derived from the regression model ranged from 132,000 to 377,000 while mark-recapture estimates of marked recently metamorphosed juveniles and parasitic sea lampreys ranged from 536,000 to 634,000 and 484,000 to 1,608,000, respectively. The precision of the estimates varied greatly among estimation procedures and years. The integrated estimate of the mark-recapture and spawner regression procedures ranged from 252,000 to 702,000 transformers. The re-sampling procedure indicated that the regression model is more sensitive to reduction in sampling effort than the mark-recapture model. Reliance on either the regression or mark-recapture model alone could produce misleading estimates of abundance of sea lampreys and the effect of the control program on sea lamprey abundance. These analyses indicate that the precision of the lakewide population estimate can be maximized by re-allocating sampling effort from marking sea lampreys to trapping additional streams.

Cytosolic increased labile Zn2+ contributes to arrhythmogenic action potentials in left ventricular cardiomyocytes through protein thiol oxidation and cellular ATP depletion.

PubMed

Degirmenci, Sinan; Olgar, Yusuf; Durak, Aysegul; Tuncay, Erkan; Turan, Belma

2018-07-01

Intracellular labile (free) Zn 2+ -level ([Zn 2+ ] i ) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn 2+ ] i is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn 2+ ] i on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction. High-[Zn 2+ ] i induced significant changes in action potential (AP) parameters, including depolarization in resting membrane-potential and prolongations in AP-repolarizing phases. We detected also the time-dependent effects such as induction of spontaneous APs at the time of ≥ 3 min following [Zn 2+ ] i increases, a manner of cellular ATP dependent and reversible with disulfide-reducing agent dithiothreitol, DTT. High-[Zn 2+ ] i induced inhibitions in voltage-dependent K + -channel currents, such as transient outward K + -currents, I to , steady-state currents, I ss and inward-rectifier K + -currents, I K1 , reversible with DTT seemed to be responsible from the prolongations in APs. We, for the first time, demonstrated that lowering cellular ATP level induced significant decreaeses in both I ss and I K1 , while no effect on I to . However, the increased-[Zn 2+ ] i could induce marked activation in ATP-sensitive K + -channel currents, I KATP , depending on low cellular ATP and thiol-oxidation levels of these channels. The mRNA levels of Kv4.3, Kv1.4 and Kv2.1 were depressed markedly with increased-[Zn 2+ ] i with no change in mRNA level of Kv4.2, while the mRNA level of I KATP subunit, SUR2A was increased significantly with increased-[Zn 2+ ] i , being reversible with DTT. Overall we demonstrated that high-[Zn 2+ ] i, even if nanomolar levels, alters cardiac function via prolonged APs of cardiomyocytes, at most, due to inhibitions in voltage-dependent K + -currents, although activation of I KATP is playing cardioprotective role, through some biochemical changes in cellular ATP- and thiol-oxidation levels. It seems, a well-controlled [Zn 2+ ] i can be novel therapeutic target for cardiac complications under pathological conditions including oxidative stress. Copyright © 2018 Elsevier GmbH. All rights reserved.

Character-marked furniture: potential for lumber yield increase in rip-first rough mills

Treesearch

Urs Buehlmann; Janice K. Wiedenbeck; D. Earl Kline; D. Earl Kline

1998-01-01

The inclusion of character marks in furniture parts increases part yield at least as much as previously estimated by industrial practitioners and scientists specializing in yield efficiency. However, character-marked furniture is uncommon in the more popular North American furniture species and designs. Opportunities for extending the hardwood resource associated with...

Character-marked furniture: potential for lumber yield increase in crosscut-first rough mills

Treesearch

Urs Buehlmann; Janice K. Wiedenbeck; E. Earl Kline; E. Earl Kline

1999-01-01

Including character marks in dimension parts of the furniture, cabinet, and dimension industries offers an opportunity to increase lumber yield substantially. However, little quantitative knowledge exists as to how the incorporation of character marks in parts influences yield when processing lumber in a crosscut-first rough mill. Using computer simulation, this study...

Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet-Induced Obesity

PubMed Central

Zhao, Ding; McCully, Belinda H.

2012-01-01

Obesity decreases baroreflex gain (BRG); however, the mechanisms are unknown. We tested the hypothesis that impaired BRG is related to the concurrent insulin resistance, and, therefore, BRG would be improved after treatment with the insulin-sensitizing drug rosiglitazone. Male rats fed a high-fat diet diverged into obesity-prone (OP) and obesity-resistant (OR) groups after 2 weeks. Then, OP and OR rats, as well as control (CON) rats fed a standard diet, were treated daily for 2 to 3 weeks with rosiglitazone (3 or 6 mg/kg) or its vehicle by gavage. Compared with OR and CON rats, conscious OP rats exhibited reductions in BRG (OP, 2.9 ± 0.1 bpm/mm Hg; OR, 4.0 ± 0.2 bpm/mm Hg; CON, 3.9 ± 0.2 bpm/mm Hg; P < 0.05) and insulin sensitivity (hyperinsulinemic euglycemic clamp; OP, 6.8 ± 0.9 mg/kg · min; OR, 22.2 ± 1.2 mg/kg · min; CON, 17.7 ± 0.8 mg/kg · min; P < 0.05), which were well correlated (r2 = 0.49; P < 0.01). In OP rats, rosiglitazone dose-dependently improved (P < 0.05) insulin sensitivity (12.8 ± 0.6 mg/kg · min at 3 mg/kg; 16.0 ± 1.5 mg/kg · min at 6 mg/kg) and BRG (3.8 ± 0.4 bpm/mm Hg at 3 mg/kg; 5.3 ± 0.7 bpm/mm Hg at 6 mg/kg). However, 6 mg/kg rosiglitazone also increased BRG in OR rats without increasing insulin sensitivity, disrupted the correlation between BRG and insulin sensitivity (r2 = 0.08), and, in OP and OR rats, elevated BRG relative to insulin sensitivity (analysis of covariance; P < 0.05). Moreover, in OP rats, stimulation of the aortic depressor nerve, to activate central baroreflex pathways, elicited markedly reduced decreases in heart rate and arterial pressure, but these responses were not improved by rosiglitazone. In conclusion, diet-induced obesity impairs BRG via a central mechanism that is related to the concurrent insulin resistance. Rosiglitazone normalizes BRG, but not by improving brain baroreflex processing or insulin sensitivity. PMID:22815534

Otolith marking of juvenile shortnose gar by immersion in oxytetracycline

USGS Publications Warehouse

Snow, Richard A.; Long, James M.

2017-01-01

Oxytetracycline (OTC) has been used to mark a variety of fish species at multiple developmental stages; however, there is little information on batch-marking Lepisosteidae. Juvenile Shortnose Gar Lepisosteus platostomus (53 ± 3 mm TL) were seined from an Oklahoma State University research pond and transported to the Oklahoma Fishery Research Lab. Juvenile Shortnose Gar were exposed to a range of OTC concentrations—0, 500, 600, and 700 mg/L—for 4, 5, or 6 h. Lapillus and sagitta otoliths were examined 14 d postexposure for mark presence and evaluation using fluorescent microscopy. Overall, 93.3% of otoliths exposed to OTC exhibited a mark. Concentration of OTC affected the mean mark quality, whereas duration and otolith type examined did not. However, as concentration increased, so did mortality, suggesting a balance is needed to achieve marking goals. Based on our findings, batch marking of Shortnose Gar can be successful at OTC concentrations from 500 to 700 mg/L for 4–6 h, although mark quality may vary and mortality rates increase at the higher concentrations and longer durations.

Up-regulation of 5-lipoxygenase by inhibition of cathepsin G enhances TRAIL-induced apoptosis through down-regulation of survivin

PubMed Central

Woo, Seon Min; Min, Kyoung-Jin; Seo, Seung Un; Kim, Shin; Park, Jong-Wook; Song, Dae Kyu; Lee, Hyun-Shik; Kim, Sang Hyun; Kwon, Taeg Kyu

2017-01-01

Cathepsin G is a serine protease secreted from activated neutrophils, it has important roles in inflammation and immune response. Moreover, cathepsin G promotes tumor cell-cell adhesion and migration in cancer cells. In this study, we investigated whether inhibition of cathepsin G could sensitize TRAIL-mediated apoptosis in cancer cells. An inhibitor of cathepsin G [Cathepsin G inhibitor I (Cat GI); CAS 429676-93-7] markedly induced TRAIL-mediated apoptosis in human renal carcinoma (Caki, ACHN, and A498), lung cancer (A549) and cervical cancer (Hela) cells. In contrast, combined treatment with Cat GI and TRAIL had no effect on apoptosis in normal cells [mesangial cell (MC) and human skin fibroblast (HSF)]. Cat GI induced down-regulation of survivin expression at the post-translational level, and overexpression of survivin markedly blocked apoptosis induced by combined treatment with Cat GI plus TRAIL. Interestingly, Cat GI induced down-regulation of survivin via 5-lipoxygenase (5-LOX)-mediated reactive oxygen species (ROS) production. Inhibition of 5-LOX by gene silencing (siRNA) or a pharmacological inhibitor of 5-LOX (zileuton) markedly attenuated combined treatment-induced apoptosis. Taken together, our results indicate that inhibition of cathepsin G sensitizes TRAIL-induced apoptosis through 5-LOX-mediated down-regulation of survivin expression. PMID:29290980

Long-term changes in aluminum fractions of drainage waters in two forest catchments with contrasting lithology.

PubMed

Krám, Pavel; Hruska, Jakub; Driscoll, Charles T; Johnson, Chris E; Oulehle, Filip

2009-11-01

Aluminum (Al) chemistry was studied in soils and waters of two catchments covered by spruce (Picea abies) monocultures in the Czech Republic that represent geochemical end-members of terrestrial and aquatic sensitivity to acidic deposition. The acid-sensitive Lysina catchment, underlain by granite, was compared to the acid-resistant Pluhův Bor catchment on serpentine. Organically-bound Al was the largest pool of reactive soil Al at both sites. Very high median total Al (Alt) concentrations (40 micromol L(-1)) and inorganic monomeric Al (Ali) concentrations (27 micromol L(-1)) were observed in acidic (pH 4.0) stream water at Lysina in the 1990s and these concentrations decreased to 32 micromol L(-1) (Alt) and 13 micromol L(-1) (Ali) in the 2000s. The potentially toxic Ali fraction decreased in response to long-term decreases in acidic deposition, but Ali remained the largest fraction. However, the organic monomeric (Alo) and particulate (Alp) fractions increased in the 2000s at Lysina. In contrast to Lysina, marked increases of Alt concentrations in circum-neutral waters at Pluhův Bor were observed in the 2000s in comparison with the 1990s. These increases were entirely due to the Alp fraction, which increased more than 3-fold in stream water and up to 8-fold in soil water in the A horizon. Increase of Alp coincided with dissolved organic carbon (DOC) increases. Acidification recovery may have increased the content of colloidal Al though the coagulation of monomeric Al.

Short-lived high-amplitude cooling on Svalbard during the Dark Ages

NASA Astrophysics Data System (ADS)

van der Bilt, Willem; D`Andrea, William; Bakke, Jostein; Balascio, Nicholas; Werner, Johannes; Hoek, Wim

2016-04-01

As the paradigm of a stable Holocene climate has shifted, an increasing number of high-resolution proxy timeseries reveal dynamic conditions, characterized by high-amplitude climate shifts. Some of these events occurred during historical times and allow us to study the interaction between environmental and cultural change, providing valuable lessons for the near future. These include the Dark Ages Cold Period (DACP) between 300 and 800 AD, a period marked by political upheaval and climate instability that remains poorly investigated. Here, we present two temperature reconstructions from the High Arctic Svalbard Archipelago. To this end, we applied the established alkenone-based UK37 paleothermometer on sediments from two lakes on western Spitsbergen, Lake Hajeren and Lake Hakluyt. The Arctic is presently warming twice as fast as the global average and proxy data as well as model simulations suggest that this amplified response is characteristic for regional climate. The Arctic therefore provides a uniquely sensitive environment to study relatively modest climate shifts, like the DACP, that may not be adequately captured at lower-latitude sites. Owing to undisturbed sediments, a high sampling resolution and robust chronological control, the presented reconstructions resolve the attendant sub-centennial-scale climate shifts. Our findings suggest that the DACP marks a cold spell within the cool Neoglacial period, which started some 4 ka BP on Svalbard. Close investigation reveals a distinct temperature minimum around 500 AD that is reproduced in another alkenone-based temperature reconstruction from a nearby lake. At ± 1.75 °C, cooling underlines the sensitivity of Arctic climate as well as the magnitude of the DACP.

Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure.

PubMed

Leonis, Mike A; Toney-Earley, Kenya; Degen, Sandra J F; Waltz, Susan E

2002-11-01

The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK(-/-) mice display marked protection compared with control Ron TK(+/+) mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK(-/-) mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK(-/-) mice. Paradoxically, treatment of Ron TK(-/-) mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) alpha, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-alpha production) and interferon (IFN)-gamma (a TNF-alpha sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-alpha. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.

Effects of onion extract on endogenous vascular H2S and adrenomedulin in rat atherosclerosis.

PubMed

Li, Wei; Tang, Chaoshu; Jin, Hongfang; Du, Junbao

2011-09-01

This study aimed to explore the effect of onion extract on endogenous hydrogen sulfide (H2S) and adrenomedulin (ADM) and on atherosclerotic progression in rats with atherosclerosis (AS). Male Sprague-Dawley rats were randomly divided into control, AS and AS+onion groups. Ultrastructure of aorta and atherosclerotic lesions both in aorta and in coronary artery were detected. Plasma and aortic H2S were detected by using a sulfide- sensitive electrode. Plasma and aortic ADM was determined with radioimmunoassay. Cystathionine-γ-lyase (CSE), calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP1, RAMP2 and RAMP3) mRNA expressions were analysed. Glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and NO synthase (NOS) contents in plasma, SOD1, SOD2 and ICAM-1 expressions in aorta were detected. Rats in the AS group showed marked atherosclerotic lesions both in aorta and in coronary artery but decreased aortic H2S production. Decreased plasma and aortic ADM content, but increased levels of aortic CRLR, RAMP2 and RAMP3 mRNAs were observed. Plasma GSH-PX and SOD were reduced but MDA elevated. Plasma ICAM-1 and NO contents and iNOS activity were increased. Onion extract, however, lessened atherosclerotic lesions and increased endogenous aortic H2S production, but decreased plasma ADM content, aortic ADM content and aortic CRLR, RAMP2 and RAMP3 mRNAs. In addition, it increased plasma GSH-PX level and SOD activities but reduced MDA; it decreased inflammatory response but increased plasma eNOS activity and NO content. Onion extract exerted a marked antiatherogenic effect in association with the up-regulation of the endogenous CSE/H2S pathway but down-regulation of the ADM/CRLR family in atherosclerotic rats.

Short-Course Treatment With Gefitinib Enhances Curative Potential of Radiation Therapy in a Mouse Model of Human Non-Small Cell Lung Cancer

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

Bokobza, Sivan M.; Jiang, Yanyan; Weber, Anika M.

2014-03-15

Purpose: To evaluate the combination of radiation and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in preclinical models of human non-small cell lung cancer. Methods and Materials: Sensitivity to an EGFR TKI (gefitinib) or radiation was assessed using proliferation assays and clonogenic survival assays. Effects on receptor signal transduction pathways (pEGFR, pAKT, pMAPK) and apoptosis (percentage of cleaved PARP Poly (ADP-ribose) polymerase (PARP)) were assessed by Western blotting. Radiation-induced DNA damage was assessed by γH2AX immunofluorescence. Established (≥100 mm{sup 3}) EGFR-mutated (HCC287) or EGFR wild-type (A549) subcutaneous xenografts were treated with radiation (10 Gy, day 1) or gefitinib (50 mg/kg,more » orally, on days 1-3) or both. Results: In non-small cell lung cancer (NSCLC) cell lines with activating EGFR mutations (PC9 or HCC827), gefitinib treatment markedly reduced pEGFR, pAKT, and pMAPK levels and was associated with an increase in cleaved PARP but not in γH2AX foci. Radiation treatment increased the mean number of γH2AX foci per cell but did not significantly affect EGFR signaling. In contrast, NSCLC cell lines with EGFR T790M (H1975) or wild-type EGFR (A549) were insensitive to gefitinib treatment. The combination of gefitinib and radiation treatment in cell culture produced additive cell killing with no evidence of synergy. In xenograft models, a short course of gefitinib (3 days) did not significantly increase the activity of radiation treatment in wild-type EGFR (A549) tumors (P=.27), whereas this combination markedly increased the activity of radiation (P<.001) or gefitinib alone (P=.002) in EGFR-mutated HCC827 tumors, producing sustained tumor regressions. Conclusions: Gefitinib treatment increases clonogenic cell killing by radiation but only in cell lines sensitive to gefitinib alone. Our data suggest additive rather than synergistic interactions between gefitinib and radiation and that a combination of short-course gefitinib and high-dose/-fraction radiation may have the greatest potential against the subsets of lung cancers harboring activating mutations in the EGFR gene.« less

Four-quadrant gratings moiré fringe alignment measurement in proximity lithography.

PubMed

Zhu, Jiangping; Hu, Song; Yu, Junsheng; Zhou, Shaolin; Tang, Yan; Zhong, Min; Zhao, Lixin; Chen, Minyong; Li, Lanlan; He, Yu; Jiang, Wei

2013-02-11

This paper aims to deal with a four-quadrant gratings alignment method benefiting from phase demodulation for proximity lithography, which combines the advantages of interferometry with image processing. Both the mask alignment mark and the wafer alignment mark consist of four sets of gratings, which bring the convenience and simplification of realization for coarse alignment and fine alignment. Four sets of moiré fringes created by superposing the mask alignment mark and the wafer alignment mark are highly sensitive to the misalignment between them. And the misalignment can be easily determined through demodulating the phase of moiré fringe without any external reference. Especially, the period and phase distribution of moiré fringes are unaffected by the gap between the mask and the wafer, not excepting the wavelength of alignment illumination. Disturbance from the illumination can also be negligible, which enhances the technological adaptability. The experimental results bear out the feasibility and rationality of our designed approach.

Diffraction-based overlay measurement on dedicated mark using rigorous modeling method

NASA Astrophysics Data System (ADS)

Lu, Hailiang; Wang, Fan; Zhang, Qingyun; Chen, Yonghui; Zhou, Chang

2012-03-01

Diffraction Based Overlay (DBO) is widely evaluated by numerous authors, results show DBO can provide better performance than Imaging Based Overlay (IBO). However, DBO has its own problems. As well known, Modeling based DBO (mDBO) faces challenges of low measurement sensitivity and crosstalk between various structure parameters, which may result in poor accuracy and precision. Meanwhile, main obstacle encountered by empirical DBO (eDBO) is that a few pads must be employed to gain sufficient information on overlay-induced diffraction signature variations, which consumes more wafer space and costs more measuring time. Also, eDBO may suffer from mark profile asymmetry caused by processes. In this paper, we propose an alternative DBO technology that employs a dedicated overlay mark and takes a rigorous modeling approach. This technology needs only two or three pads for each direction, which is economic and time saving. While overlay measurement error induced by mark profile asymmetry being reduced, this technology is expected to be as accurate and precise as scatterometry technologies.

Synthesis and Characterization of High Energy Sheet Materials Based on HMX / RDX and Hydroxyl Terminated Polybutadiene

NASA Astrophysics Data System (ADS)

Elsharkawy, Karim; Guo, Lin; Taha, Elhussein; Fouda, Hany

2017-07-01

In this paper three types of thin sheets of highly energetic materials were prepared and characterized. The first based on 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX). The second type based on 1,3,5-trinitro-1,3,5-triazinane (RDX). Both types contain polyurethane (PU), formulated by hydroxyl terminated polybutadiene (HTPB) and Isophorondiisocyanate (IPDI). The third type based on (RDX) and polyisoprene (PI) as high elastomeric material. The first and second types of thin sheets were prepared by applying the casting technique while the third type was prepared by slurry technique then followed by rolling of the prepared beads of the RDX coated by PI. These high energy sheet materials were cured in oven at 60°C. The measured explosive properties of the prepared sheets were discussed and showed that the sensitivity to impact and friction of the prepared sheets explosives materials were markedly decreased when compared to pure HMX or pure RDX, but the sensitivity to heat was close to that of pure RDX. In spite of the markedly decrease in the sensitivity of these sheets, the explosive characteristics were nearly not affected the sheets have very good stress-strain values.

A Culture-Sensitive Agent in Kirman's Ant Model

NASA Astrophysics Data System (ADS)

Chen, Shu-Heng; Liou, Wen-Ching; Chen, Ting-Yu

The global financial crisis brought a serious collapse involving a "systemic" meltdown. Internet technology and globalization have increased the chances for interaction between countries and people. The global economy has become more complex than ever before. Mark Buchanan [12] indicated that agent-based computer models will prevent another financial crisis and has been particularly influential in contributing insights. There are two reasons why culture-sensitive agent on the financial market has become so important. Therefore, the aim of this article is to establish a culture-sensitive agent and forecast the process of change regarding herding behavior in the financial market. We based our study on the Kirman's Ant Model[4,5] and Hofstede's Natational Culture[11] to establish our culture-sensitive agent based model. Kirman's Ant Model is quite famous and describes financial market herding behavior from the expectations of the future of financial investors. Hofstede's cultural consequence used the staff of IBM in 72 different countries to understand the cultural difference. As a result, this paper focuses on one of the five dimensions of culture from Hofstede: individualism versus collectivism and creates a culture-sensitive agent and predicts the process of change regarding herding behavior in the financial market. To conclude, this study will be of importance in explaining the herding behavior with cultural factors, as well as in providing researchers with a clearer understanding of how herding beliefs of people about different cultures relate to their finance market strategies.

Unified Model Deformation and Flow Transition Measurements

NASA Technical Reports Server (NTRS)

Burner, Alpheus W.; Liu, Tianshu; Garg, Sanjay; Bell, James H.; Morgan, Daniel G.

1999-01-01

The number of optical techniques that may potentially be used during a given wind tunnel test is continually growing. These include parameter sensitive paints that are sensitive to temperature or pressure, several different types of off-body and on-body flow visualization techniques, optical angle-of-attack (AoA), optical measurement of model deformation, optical techniques for determining density or velocity, and spectroscopic techniques for determining various flow field parameters. Often in the past the various optical techniques were developed independently of each other, with little or no consideration for other techniques that might also be used during a given test. Recently two optical techniques have been increasingly requested for production measurements in NASA wind tunnels. These are the video photogrammetric (or videogrammetric) technique for measuring model deformation known as the video model deformation (VMD) technique, and the parameter sensitive paints for making global pressure and temperature measurements. Considerations for, and initial attempts at, simultaneous measurements with the pressure sensitive paint (PSP) and the videogrammetric techniques have been implemented. Temperature sensitive paint (TSP) has been found to be useful for boundary-layer transition detection since turbulent boundary layers convect heat at higher rates than laminar boundary layers of comparable thickness. Transition is marked by a characteristic surface temperature change wherever there is a difference between model and flow temperatures. Recently, additional capabilities have been implemented in the target-tracking videogrammetric measurement system. These capabilities have permitted practical simultaneous measurements using parameter sensitive paint and video model deformation measurements that led to the first successful unified test with TSP for transition detection in a large production wind tunnel.

A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma[S

PubMed Central

Jiang, Xuntian; Sidhu, Rohini; Porter, Forbes D.; Yanjanin, Nicole M.; Speak, Anneliese O.; te Vruchte, Danielle Taylor; Platt, Frances M.; Fujiwara, Hideji; Scherrer, David E.; Zhang, Jessie; Dietzen, Dennis J.; Schaffer, Jean E.; Ory, Daniel S.

2011-01-01

Niemann-Pick type C1 (NPC1) disease is a rare, progressively fatal neurodegenerative disease for which there are no FDA-approved therapies. A major barrier to developing new therapies for this disorder has been the lack of a sensitive and noninvasive diagnostic test. Recently, we demonstrated that two cholesterol oxidation products, specifically cholestane-3β,5α,6β-triol (3β,5α,6β-triol) and 7-ketocholesterol (7-KC), were markedly increased in the plasma of human NPC1 subjects, suggesting a role for these oxysterols in diagnosis of NPC1 disease and evaluation of therapeutics in clinical trials. In the present study, we describe the development of a sensitive and specific LC-MS/MS method for quantifying 3β,5α,6β-triol and 7-KC human plasma after derivatization with N,N-dimethylglycine. We show that dimethylglycine derivatization successfully enhanced the ionization and fragmentation of 3β,5α,6β-triol and 7-KC for mass spectrometric detection of the oxysterol species in human plasma. The oxysterol dimethylglycinates were resolved with high sensitivity and selectivity, and enabled accurate quantification of 3β,5α,6β-triol and 7-KC concentrations in human plasma. The LC-MS/MS assay was able to discriminate with high sensitivity and specificity between control and NPC1 subjects, and offers for the first time a noninvasive, rapid, and highly sensitive method for diagnosis of NPC1 disease. PMID:21518695

Effect of background parenchymal enhancement on breast cancer detection with magnetic resonance imaging.

PubMed

Telegrafo, M; Rella, L; Stabile Ianora, A A; Angelelli, G; Moschetta, M

2016-03-01

To investigate whether background parenchymal enhancement (BPE) may influence the sensitivity of dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging in breast cancer detection. A total of 180 consecutive women with 194 breast cancers underwent MR imaging examination. Women were assigned to two different groups depending on the degree of BPE. Group 1 consisted of women with minimal or mild BPE and group 2 of women with moderate or marked BPE. The distributions of histotypes of tumors within the two groups were compared using the χ(2) test. Difference in sensitivities of DCE-MR imaging for tumor detection between the two groups was searched for using the Student t-test. No differences in terms of distributions of histotypes of tumors between the two groups of women were found (P=0.5). The 11% difference in sensitivity of DCE-MR imaging for tumor detection between group 1 (91/92; 99%; 95% CI: 94-100%) and group 2 (90/102; 88%; 95% CI: 80-94%) was statistically significant (P=0.0058). The sensitivity of DCE-MR imaging is significantly lower in women with moderate and marked BPE as compared with women with minimal and mild BPE regardless of cancer histotype. BPE could represent a limitation for breast MR imaging interpretation and should be indicated in MR imaging reports. Copyright © 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Acute and long-term administration of palmitoylcarnitine induces muscle-specific insulin resistance in mice.

PubMed

Liepinsh, Edgars; Makrecka-Kuka, Marina; Makarova, Elina; Volska, Kristine; Vilks, Karlis; Sevostjanovs, Eduards; Antone, Unigunde; Kuka, Janis; Vilskersts, Reinis; Lola, Daina; Loza, Einars; Grinberga, Solveiga; Dambrova, Maija

2017-09-10

Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of diet-induced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity. © 2017 BioFactors, 43(5):718-730, 2017. © 2017 The Authors BioFactors published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology.

Surfing parameter hyperspaces under climate change scenarios to design future rice ideotypes.

PubMed

Paleari, Livia; Movedi, Ermes; Cappelli, Giovanni; Wilson, Lloyd T; Confalonieri, Roberto

2017-11-01

Growing food crops to meet global demand and the search for more sustainable cropping systems are increasing the need for new cultivars in key production areas. This study presents the identification of rice traits putatively producing the largest yield benefits in five areas that markedly differ in terms of environmental conditions in the Philippines, India, China, Japan and Italy. The ecophysiological model WARM and sensitivity analysis techniques were used to evaluate phenotypic traits involved with light interception, photosynthetic efficiency, tolerance to abiotic stressors, resistance to fungal pathogens and grain quality. The analysis involved only model parameters that have a close relationship with phenotypic traits breeders are working on, to increase the in vivo feasibility of selected ideotypes. Current climate and future projections were considered, in the light of the resources required by breeding programs and of the role of weather variables in the identification of promising traits. Results suggest that breeding for traits involved with disease resistance, and tolerance to cold- and heat-induced spikelet sterility could provide benefits similar to those obtained from the improvement of traits involved with canopy structure and photosynthetic efficiency. In contrast, potential benefits deriving from improved grain quality traits are restricted by weather variability and markedly affected by G × E interactions. For this reason, district-specific ideotypes were identified using a new index accounting for both their productivity and feasibility. © 2017 John Wiley & Sons Ltd.

A marked proportional rise in IVC aldosterone following cosyntropin administration during AVS is a signal to the presence of adrenal hyperplasia in primary aldosteronism.

PubMed

Kline, G A; Pasieka, J L; Harvey, A; So, B; Dias, V C

2014-05-01

We hypothesized aldosteronoma responsiveness to cosyntropin may be a characterizing feature that could be determined in addition to standard adrenal vein sampling (AVS) data. We reviewed an AVS database from June 2005 to October 2011 including 65 patients with confirmed primary aldosteronism (PA) who underwent AVS and, if applicable, unilateral adrenalectomy. Patients were divided into confirmed lateralized and non-lateralized groups and subgrouped by histology. Plasma aldosterone in inferior vena cava (IVC) pre- and post-cosyntropin infusion during AVS was measured. Peak aldosterone and proportional change was compared between groups. Baseline and peak IVC aldosterone was higher in lateralized patients but incremental aldosterone rise was much greater in subjects with bilateral hyperplasia. From receiver operator characteristics (ROC) analysis, the optimized diagnostic cut point of peak IVC aldosterone of >649 pmol l(-1) would have a sensitivity of 94% for surgical disease although specificity of just 59%. A 250% increase in IVC aldosterone following cosyntropin would be specific enough to exclude 87% of surgical/lateralized disease. These diagnostic capabilities are similar to other results with non-AVS tests performed for diagnosis of lateralization. Although not specific enough to replace standard AVS interpretation, a marked IVC aldosterone increase after cosyntropin during AVS is a useful additional test to diagnose non-lateralizing forms of PA. Such a calculation requires no additional expense or tests.

Bilateral six-hydroxydopamine administration to PFC prevents the expression of behavioral sensitization to methylphenidate.

PubMed

Wanchoo, S J; Lee, M J; Swann, A C; Dafny, N

2010-02-02

Psychostimulants like amphetamine and methylphenidate (MPD) are used to treat attention deficit hyperactivity disorder (ADHD), which is marked by developmentally inappropriate inattention, hyperactivity, and impulsivity. Neuropsychological analyses indicate that ADHD patients are impaired on tasks of behavioral inhibition, reward reversal, and working memory, which are functions of the prefrontal cortex (PFC) and are modulated by the mesocortical dopamine (DA) system. Non-specific electrical lesioning of PFC eliminated the expression of behavioral sensitization elicited by chronic MPD administration. Behavioral sensitization is the progressive augmentation of locomotor activity as a result of repetitive (chronic) exposure to the drug. It is believed that the sensitization to chronic drug treatment is caused due to an increase in DA in the mesocorticolimbic DA system, which includes the PFC. Therefore, this study investigated the role of PFC DA in mediating the behavioral sensitization to repeated administration of MPD in adult male Sprague-Dawley rats. On experimental day (ED) 1, the behavior was recorded post-saline injection. On ED 2, the rats were divided into three groups--control, sham and bilateral 6-OHDA treated group; and the sham and 6-OHDA treated groups underwent respective surgeries. After 5 days of rest following surgery, the post-surgery baseline was recorded on ED 8 following a saline injection. All three groups received 2.5 mg/kg MPD for 6 days (from ED 9 to ED 14), followed by a 3-day washout period (ED 15 to ED 18). On ED 19, a rechallenge injection of 2.5 mg/kg MPD was given and locomotor activity was recorded. It was found that the 6-OHDA lesion group failed to exhibit behavioral sensitization to MPD. The involvement of the dopaminergic afferents of PFC in behavioral sensitization to MPD is discussed. (c) 2009 Elsevier B.V. All rights reserved.

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.

PubMed

Henrich, C J; Brooks, A D; Erickson, K L; Thomas, C L; Bokesch, H R; Tewary, P; Thompson, C R; Pompei, R J; Gustafson, K R; McMahon, J B; Sayers, T J

2015-02-26

Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects.

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation

PubMed Central

Henrich, C J; Brooks, A D; Erickson, K L; Thomas, C L; Bokesch, H R; Tewary, P; Thompson, C R; Pompei, R J; Gustafson, K R; McMahon, J B; Sayers, T J

2015-01-01

Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects. PMID:25719250

Evidence for Non-Opponent Coding of Colour Information in Human Visual Cortex: Selective Loss of “Green” Sensitivity in a Subject with Damaged Ventral Occipito-Temporal Cortex

PubMed Central

Rauscher, Franziska G.; Plant, Gordon T.; James-Galton, Merle; Barbur, John L.

2011-01-01

Damage to ventral occipito-temporal extrastriate visual cortex leads to the syndrome of prosopagnosia often with coexisting cerebral achromatopsia. A patient with this syndrome resulting in a left upper homonymous quadrantanopia, prosopagnosia, and incomplete achromatopsia is described. Chromatic sensitivity was assessed at a number of locations in the intact visual field using a dynamic luminance contrast masking technique that isolates the use of colour signals. In normal subjects chromatic detection thresholds form an elliptical contour when plotted in the Commission Internationale d’Eclairage, (x-y), chromaticity diagram. Because the extraction of colour signals in early visual processing involves opponent mechanisms, subjects with Daltonism (congenital red/green loss of sensitivity) show symmetric increase in thresholds towards the long wavelength (“red”) and middle wavelength (“green”) regions of the spectrum locus. This is also the case with acquired loss of chromatic sensitivity as a result of retinal or optic nerve disease. Our patient’s results were an exception to this rule. Whilst his chromatic sensitivity in the central region of the visual field was reduced symmetrically for both “red/green” and “yellow/blue” directions in colour space, the subject’s lower left quadrant showed a marked asymmetry in “red/green” thresholds with the greatest loss of sensitivity towards the “green” region of the spectrum locus. This spatially localized asymmetric loss of “green” but not “red” sensitivity has not been reported previously in human vision. Such loss is consistent with selective damage of neural substrates in the visual cortex that process colour information, but are spectrally non-opponent. PMID:27956924

Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance

PubMed Central

Amati, Francesca; Dubé, John J.; Alvarez-Carnero, Elvis; Edreira, Martin M.; Chomentowski, Peter; Coen, Paul M.; Switzer, Galen E.; Bickel, Perry E.; Stefanovic-Racic, Maja; Toledo, Frederico G.S.; Goodpaster, Bret H.

2011-01-01

OBJECTIVE Chronic exercise and obesity both increase intramyocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercise-trained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite higher IMTGs and would account for its higher insulin sensitivity. We also hypothesized that the expression of key skeletal muscle proteins involved in lipid droplet hydrolysis, DAG formation, and fatty-acid partitioning and oxidation would be associated with the lipotoxic phenotype. RESEARCH DESIGN AND METHODS A total of 14 normal-weight, endurance-trained athletes (NWA group) and 7 normal-weight sedentary (NWS group) and 21 obese sedentary (OBS group) volunteers were studied. Insulin sensitivity was assessed by glucose clamps. IMTGs, DAGs, ceramides, and protein expression were measured in muscle biopsies. RESULTS DAG content in the NWA group was approximately twofold higher than in the OBS group and ~50% higher than in the NWS group, corresponding to higher insulin sensitivity. While certain DAG moieties clearly were associated with better insulin sensitivity, other species were not. Ceramide content was higher in insulin-resistant obese muscle. The expression of OXPAT/perilipin-5, adipose triglyceride lipase, and stearoyl-CoA desaturase protein was higher in the NWA group, corresponding to a higher mitochondrial content, proportion of type 1 myocytes, IMTGs, DAGs, and insulin sensitivity. CONCLUSIONS Total myocellular DAGs were markedly higher in highly trained athletes, corresponding with higher insulin sensitivity, and suggest a more complex role for DAGs in insulin action. Our data also provide additional evidence in humans linking ceramides to insulin resistance. Finally, this study provides novel evidence supporting a role for specific skeletal muscle proteins involved in intramyocellular lipids, mitochondrial oxidative capacity, and insulin resistance. PMID:21873552

High dynamic range vision sensor for automotive applications

NASA Astrophysics Data System (ADS)

Grenet, Eric; Gyger, Steve; Heim, Pascal; Heitger, Friedrich; Kaess, Francois; Nussbaum, Pascal; Ruedi, Pierre-Francois

2005-02-01

A 128 x 128 pixels, 120 dB vision sensor extracting at the pixel level the contrast magnitude and direction of local image features is used to implement a lane tracking system. The contrast representation (relative change of illumination) delivered by the sensor is independent of the illumination level. Together with the high dynamic range of the sensor, it ensures a very stable image feature representation even with high spatial and temporal inhomogeneities of the illumination. Dispatching off chip image feature is done according to the contrast magnitude, prioritizing features with high contrast magnitude. This allows to reduce drastically the amount of data transmitted out of the chip, hence the processing power required for subsequent processing stages. To compensate for the low fill factor (9%) of the sensor, micro-lenses have been deposited which increase the sensitivity by a factor of 5, corresponding to an equivalent of 2000 ASA. An algorithm exploiting the contrast representation output by the vision sensor has been developed to estimate the position of a vehicle relative to the road markings. The algorithm first detects the road markings based on the contrast direction map. Then, it performs quadratic fits on selected kernel of 3 by 3 pixels to achieve sub-pixel accuracy on the estimation of the lane marking positions. The resulting precision on the estimation of the vehicle lateral position is 1 cm. The algorithm performs efficiently under a wide variety of environmental conditions, including night and rainy conditions.

Chloroplast avoidance movement as a sensitive indicator of relative water content during leaf desiccation in the dark.

PubMed

Nauš, Jan; Šmecko, Slavomír; Špundová, Martina

2016-08-01

In the context of global climate change, drought is one of the major stress factors with negative effect on photosynthesis and plant productivity. Currently, chlorophyll fluorescence parameters are widely used as indicators of plant stress, mainly owing to the rapid, non-destructive and simple measurements this technique allows. However, these parameters have been shown to have limited sensitivity for the monitoring of water deficit as leaf desiccation has relatively small effect on photosystem II photochemistry. In this study, we found that blue light-induced increase in leaf transmittance reflecting chloroplast avoidance movement was much more sensitive to a decrease in relative water content (RWC) than chlorophyll fluorescence parameters in dark-desiccating leaves of tobacco (Nicotiana tabacum L.) and barley (Hordeum vulgare L.). Whereas the inhibition of chloroplast avoidance movement was detectable in leaves even with a small RWC decrease, the chlorophyll fluorescence parameters (F V/F M, V J, Ф PSII, NPQ) changed markedly only when RWC dropped below 70 %. For this reason, we propose light-induced chloroplast avoidance movement as a sensitive indicator of the decrease in leaf RWC. As our measurement of chloroplast movement using collimated transmittance is simple and non-destructive, it may be more suitable in some cases for the detection of plant stresses including water deficit than the conventionally used chlorophyll fluorescence methods.

Hepatocellular carcinoma repression by TNFα‐mediated synergistic lethal effect of mitosis defect‐induced senescence and cell death sensitization

PubMed Central

Li, Dan; Fu, Jing; Du, Min; Zhang, Haibin; Li, Lu; Cen, Jin; Li, Weiyun; Chen, Xiaotao; Lin, Yunfei; Conway, Edward M.; Pikarsky, Eli; Wang, Hongyan; Pan, Guoyu

2016-01-01

Hepatocellular carcinoma (HCC) is a cancer lacking effective therapies. Several measures have been proposed to treat HCCs, such as senescence induction, mitotic inhibition, and cell death promotion. However, data from other cancers suggest that single use of these approaches may not be effective. Here, by genetic targeting of Survivin, an inhibitor of apoptosis protein (IAP) that plays dual roles in mitosis and cell survival, we identified a tumor necrosis factor alpha (TNFα)‐mediated synergistic lethal effect between senescence and apoptosis sensitization in malignant HCCs. Survivin deficiency results in mitosis defect‐associated senescence in HCC cells, which triggers local inflammation and increased TNFα. Survivin inactivation also sensitizes HCC cells to TNFα‐triggered cell death, which leads to marked HCC regression. Based on these findings, we designed a combination treatment using mitosis inhibitor and proapoptosis compounds. This treatment recapitulates the therapeutic effect of Survivin deletion and effectively eliminates HCCs, thus representing a potential strategy for HCC therapy. Conclusion: Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence‐associated TNFα and sensitizing HCC cells to TNFα‐induced cell death. Combined use of mitotic inhibitor and second mitochondrial‐derived activator of caspases mimetic can induce senescence‐associated TNFα and enhance TNFα‐induced cell death and synergistically eliminate HCC. (Hepatology 2016;64:1105‐1120) PMID:27177758

Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR.

PubMed

Iwama, Eiji; Takayama, Koichi; Harada, Taishi; Okamoto, Isamu; Ookubo, Fumihiko; Kishimoto, Junji; Baba, Eishi; Oda, Yoshinao; Nakanishi, Yoichi

2015-08-21

The mutation of T790M in EGFR is a major mechanism of resistance to treatment with EGFR-TKIs. Only qualitative detection (presence or absence) of T790M has been described to date, however. Digital PCR (dPCR) analysis has recently been applied to the quantitative detection of target molecules in cancer with high sensitivity. In the present study, 25 tumor samples (13 obtained before and 12 after EGFR-TKI treatment) from 18 NSCLC patients with activating EGFR mutations were evaluated for T790M with dPCR. The ratio of the number of T790M alleles to that of activating mutation alleles (T/A) was determined. dPCR detected T790M in all 25 samples. Although T790M was present in all pre-TKI samples from 13 patients, 10 of these patients had a low T/A ratio and manifested substantial tumor shrinkage during treatment with EGFR-TKIs. In six of seven patients for whom both pre- and post-TKI samples were available, the T/A ratio increased markedly during EGFR-TKI treatment. Highly sensitive dPCR thus detected T790M in all NSCLC patients harboring activating EGFR mutations whether or not they had received EGFR-TKI treatment. Not only highly sensitive but also quantitative detection of T790M is important for evaluation of the contribution of T790M to EGFR-TKI resistance.

Efficiency enhancement of hybridized solar cells through co-sensitization and fast charge extraction by up-converted polyethylene glycol modified carbon quantum dots

NASA Astrophysics Data System (ADS)

Zhu, Wanlu; Duan, Jialong; Duan, Yanyan; Zhao, Yuanyuan; Tang, Qunwei

2017-11-01

Photovoltaics are promising solutions to energy crisis and environmental pollution problems. The dye-sensitized solar cells with mesoscopic structures have attracted growing interests because of zero emissions, easy fabrication, scalable materials and techniques, etc. However, the state-of-the-art dye-sensitized solar cells have narrow spectral absorption for photoelectric conversion and high electron-hole recombination rate under sunlight illumination. Therefore, it is a persistent object to make wide-spectral absorption and fast charge extraction solar cells for energy harvest in both solar and dark-light conditions. To address this issue, we present here experimental realization of a category of solar cells converting visible and near-infrared light into electricity by co-sensitizing photoanode with N719 dye and polyethylene glycol (PEG) modified carbon quantum dots (PEG-m-CQDs), arising from up-conversion and hole-transporting behaviors of PEG-m-CQDs as well as photofluorescence of green-emitting long persistence phosphors. The optimized solar cell yields maximized photoelectric conversion efficiencies of 9.89% and 25.81% under simulated sunlight (air mass 1.5, 100 mW cm-2) illumination and dark conditions, respectively. This work is far from optimization, but the physical proof-of-concept hybridized solar cell may markedly increase electricity generation time and total power output of photovoltaic platforms.

CELLULAR REACTIONS TO REINJECTION OF ANTIGEN

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

Speirs, R.S.; Speirs, E.E.

1963-01-01

Studies in mice showed that an injection of tritiated antigen resulted in an incorporation of radioactivity in neutrophils, eosinophils, and macrophages at different times during the inflammatory cycle. Necrosis of labeled cells was frequently observed, and the incorporated radioactive material was passed from cell to cell by phagocytosis. As the inflammation subsided, there was a marked decrease in the number of labeled cells in the exudate, and a concomitant appearance and persistence of labeled cells in lymph nodes, spleen, and bone marrow. The fate of these labeled cells was followed after re-exposure to antigen, using autoradiographic procedures. An intraperitoneal injectionmore » of tetanus or diphtheria toxoid at 10, 30, or 60 days after sensitization produced an increase in the total number of mononuclear cells and an increase in the mononuclear cells containing radioactive material. The labeled cells were found in all animals autopsied within 70 days of sensitization and in several animals autopsied approximately 270 days after sensitization. The labeled cells were macrophages or large lymphoid cells. Approximately 12% of these cells were multinucleated, usually binucleated. An attempt was made to develop a concept of antibody formation on a molecular level. It is postulated that lymphocytes, macrophages, and plasma cells act as carriers for the necessary template RNA and associated microsomes, whereas the eosinophiles, and possibly the neutrophiles, supply a means of transporting antigen and specific enzymatic material to the reacting cells, thereby initiating changes leading to hypersensitivity and antibody formation. (C.H.)« less

Scalable fabrication of SnO2 thin films sensitized with CuO islands for enhanced H2S gas sensing performance

NASA Astrophysics Data System (ADS)

Van Toan, Nguyen; Chien, Nguyen Viet; Van Duy, Nguyen; Vuong, Dang Duc; Lam, Nguyen Huu; Hoa, Nguyen Duc; Van Hieu, Nguyen; Chien, Nguyen Duc

2015-01-01

The detection of H2S, an important gaseous molecule that has been recently marked as a highly toxic environmental pollutant, has attracted increasing attention. We fabricate a wafer-scale SnO2 thin film sensitized with CuO islands using microelectronic technology for the improved detection of the highly toxic H2S gas. The SnO2-CuO island sensor exhibits significantly enhanced H2S gas response and reduced operating temperature. The thickness of CuO islands strongly influences H2S sensing characteristics, and the highest H2S gas response is observed with 20 nm-thick CuO islands. The response value (Ra/Rg) of the SnO2-CuO island sensor to 5 ppm H2S is as high as 128 at 200 °C and increases nearly 55-fold compared with that of the bare SnO2 thin film sensor. Meanwhile, the response of the SnO2-CuO island sensor to H2 (250 ppm), NH3 (250 ppm), CO (250 ppm), and LPG (1000 ppm) are low (1.3-2.5). The enhanced gas response and selectivity of the SnO2-CuO island sensor to H2S gas is explained by the sensitizing effect of CuO islands and the extension of electron depletion regions because of the formation of p-n junctions.

THE MUSCARINIC ANTAGONIST SCOPOLAMINE ATTENUATES CHLORPYRIFOS INDUCED HYPOTHERMIA IN THE DEVELOPING RAT.

EPA Science Inventory

Chlorpyrifos (CHP), an anticholinesterase organophosphate (OP) pesticide, induces acute hypothermia in adult and developing rats. Previously we demonstrated that thermoregulation in preweanling pups is markedly more sensitive to the neurotoxic effects of CHP than in adults. The c...

Responses of female rock lizards to multiple scent marks of males: effects of male age, male density and scent over-marking.

PubMed

Martín, José; López, Pilar

2013-03-01

Scent-marked substrates may inform conspecifics on the characteristics of territorial males. Scent-marks of male Carpetan rock lizards (Iberolacerta cyreni) affect space use of females, which by selecting an area may increase the probability of mating with the male that has scent-marked that area. However, males do not hold exclusive territories, and scent-marks of different individual males are often together. This may provide complex information from multiple sources on the social structure. Here, we examined female preference in response to scent marks of various males and combinations in a laboratory experiment. Females preferred areas scent-marked by territorial old males against those scent-marked by young satellite-sneaker males. This reflected the known preference of females for mating with old males. In a second experiment, females preferred areas scent-marked by two males to areas of similar size marked by a single male. This may increase the probability of obtaining multiple copulations with different males, which may favour sperm competition and cryptic female choice, or may be a way to avoid infertile males. Finally, when we experimentally over-marked the scent-marks of an old male with scent-marks of a young male, females did not avoid, nor prefer, the over-marked area, suggesting that the quality of the old male may override the presence of a satellite male. We suggest that, irrespective of the causes underlying why a female selects a scent-marked area, this strategy may affect her reproductive success, which may have the same evolutionary consequences that "direct" mate choice decisions of other animals. Copyright © 2013 Elsevier B.V. All rights reserved.

Sensitivity of tropical carbon to climate change constrained by carbon dioxide variability.

PubMed

Cox, Peter M; Pearson, David; Booth, Ben B; Friedlingstein, Pierre; Huntingford, Chris; Jones, Chris D; Luke, Catherine M

2013-02-21

The release of carbon from tropical forests may exacerbate future climate change, but the magnitude of the effect in climate models remains uncertain. Coupled climate-carbon-cycle models generally agree that carbon storage on land will increase as a result of the simultaneous enhancement of plant photosynthesis and water use efficiency under higher atmospheric CO(2) concentrations, but will decrease owing to higher soil and plant respiration rates associated with warming temperatures. At present, the balance between these effects varies markedly among coupled climate-carbon-cycle models, leading to a range of 330 gigatonnes in the projected change in the amount of carbon stored on tropical land by 2100. Explanations for this large uncertainty include differences in the predicted change in rainfall in Amazonia and variations in the responses of alternative vegetation models to warming. Here we identify an emergent linear relationship, across an ensemble of models, between the sensitivity of tropical land carbon storage to warming and the sensitivity of the annual growth rate of atmospheric CO(2) to tropical temperature anomalies. Combined with contemporary observations of atmospheric CO(2) concentration and tropical temperature, this relationship provides a tight constraint on the sensitivity of tropical land carbon to climate change. We estimate that over tropical land from latitude 30° north to 30° south, warming alone will release 53 ± 17 gigatonnes of carbon per kelvin. Compared with the unconstrained ensemble of climate-carbon-cycle projections, this indicates a much lower risk of Amazon forest dieback under CO(2)-induced climate change if CO(2) fertilization effects are as large as suggested by current models. Our study, however, also implies greater certainty that carbon will be lost from tropical land if warming arises from reductions in aerosols or increases in other greenhouse gases.

Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age.

PubMed

Morrison, Christopher D; White, Christy L; Wang, Zhong; Lee, Seung-Yub; Lawrence, David S; Cefalu, William T; Zhang, Zhong-Yin; Gettys, Thomas W

2007-01-01

Animals at advanced ages exhibit a reduction in central leptin sensitivity. However, changes in growth, metabolism, and obesity risk occur much earlier in life, particularly during the transition from youth to middle age. To determine when initial decreases in central leptin sensitivity occur, leptin-dependent suppression of food intake was tested in 8-, 12-, and 20-wk-old male, chow-fed Sprague Dawley rats. Intracerebroventricular leptin injection (3 microg) suppressed 24-h food intake in 8- and 12-wk-old rats (P < 0.05) but not 20-wk-old rats. To identify potential cellular mediators of this resistance, we focused on protein tyrosine phosphatase 1B (PTP1B), a recently described inhibitor of leptin signaling. PTP1B protein levels, as determined by Western blot, were significantly higher in mediobasal hypothalamic punches collected from 20-wk-old rats, compared with 8-wk-old rats (P < 0.05). When 20-wk-old rats were fasted for 24 h, levels of hypothalamic PTP1B decreased (P < 0.05), coincident with a restoration of leptin sensitivity. To directly test whether inhibition of PTP1B restores leptin sensitivity, 20-wk-old chow-fed rats were pretreated with a pharmacological PTP1B inhibitor 1 h before leptin, and 24-h food intake was recorded. As expected, leptin alone produced a small but nonsignificant reduction in food intake. However, pretreatment with the PTP1B inhibitor resulted in a marked improvement in leptin-dependent suppression of food intake (P < 0.05). These data are consistent with the hypothesis that increases in PTP1B contribute to hypothalamic leptin resistance as rats transition into middle age.

The tumor suppressor gene TUSC2 (FUS1) sensitizes NSCLC to the AKT inhibitor MK2206 in LKB1-dependent manner.

PubMed

Meng, Jieru; Majidi, Mourad; Fang, Bingliang; Ji, Lin; Bekele, B Nebiyou; Minna, John D; Roth, Jack A

2013-01-01

TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.

Insulin sensitivity, fat distribution, and adipocytokine response to different diets in lean and obese cats before and after weight loss.

PubMed

Hoenig, M; Thomaseth, K; Waldron, M; Ferguson, D C

2007-01-01

Obesity is a major health problem in cats and a risk factor for diabetes. It has been postulated that cats are always gluconeogenic and that the rise in obesity might be related to high dietary carbohydrates. We examined the effect of a high-carbohydrate/low-protein (HC) and a high-protein/low-carbohydrate (HP) diet on glucose and fat metabolism during euglycemic hyperinsulinemic clamp, adipocytokines, and fat distribution in 12 lean and 16 obese cats before and after weight loss. Feeding diet HP led to greater heat production in lean but not in obese cats. Regardless of diet, obese cats had markedly decreased glucose effectiveness and insulin resistance, but greater suppression of nonesterified fatty acids during the euglycemic hyperinsulinemic clamp was seen in obese cats on diet HC compared with lean cats on either diet or obese cats on diet HP. In contrast to humans, obese cats had abdominal fat equally distributed subcutaneously and intra-abdominally. Weight loss normalized insulin sensitivity; however, increased nonesterified fatty acid suppression was maintained and fat loss was less in cats on diet HC. Adiponectin was negatively and leptin positively correlated with fat mass. Lean cats and cats during weight loss, but not obese cats, adapted to the varying dietary carbohydrate/protein content with changes in substrate oxidation. We conclude that diet HP is beneficial through maintenance of normal insulin sensitivity of fat metabolism in obese cats, facilitating the loss of fat during weight loss, and increasing heat production in lean cats. These data also show that insulin sensitivity of glucose and fat metabolism can be differentially regulated in cats.

Three methionine residues located within the regulator of conductance for K+ (RCK) domains confer oxidative sensitivity to large-conductance Ca2+-activated K+ channels.

PubMed

Santarelli, Lindsey Ciali; Wassef, Ramez; Heinemann, Stefan H; Hoshi, Toshinori

2006-03-01

Methionine-directed oxidation of the human Slo1 potassium channel (hSlo1) shifts the half-activation voltage by -30 mV and markedly slows channel deactivation at low concentrations of intracellular Ca2+ ([Ca2+]i). We demonstrate here that the contemporaneous mutation of M536, M712 and M739 to leucine renders the channel functionally insensitive to methionine oxidation caused by the oxidant chloramine-T (Ch-T) without altering other functional characteristics. Coexpression with the auxiliary beta1 subunit fails to restore the full oxidative sensitivity to this triple mutant channel. The Ch-T effect is mediated specifically by M536, M712 and M739 because even small changes in this residue combination interfere with the ability to remove the oxidant sensitivity following mutation. Replacement of M712 or M739, but not M536, with the hydrophilic residue glutamate largely mimics oxidation of the channel and essentially removes the Ch-T sensitivity, suggesting that M712 and M739 may be part of a hydrophobic pocket disrupted by oxidation of non-polar methionine to the more hydrophilic methionine sulfoxide. The increase in wild-type hSlo1 open probability caused by methionine oxidation disappears at high [Ca2+]i and biophysical modelling of the Ch-T effect on steady-state activation implicates a decrease in the allosteric coupling between Ca2+ binding and the pore. The dramatic increase in open probability at low [Ca2+]i especially within the physiological voltage range suggests that oxidation of M536, M712 or M739 may enhance the Slo1 BK activity during conditions of oxidative stress, such as those associated with ischaemia-reperfusion and neurodegenerative disease, or in response to metabolic cues.

Sensitive Determination of Onco-metabolites of D- and L-2-hydroxyglutarate Enantiomers by Chiral Derivatization Combined with Liquid Chromatography/Mass Spectrometry Analysis

PubMed Central

Cheng, Qing-Yun; Xiong, Jun; Huang, Wei; Ma, Qin; Ci, Weimin; Feng, Yu-Qi; Yuan, Bi-Feng

2015-01-01

2-hydroxyglutarate (2HG) is a potent competitor of α-ketoglutarate (α-KG) and can inhibit multiple α-KG dependent dioxygenases that function on the epigenetic modifications. The accumulation of 2HG contributes to elevated risk of malignant tumors. 2HG carries an asymmetric carbon atom in its carbon backbone and differentiation between D-2-hydroxyglutarate (D-2HG) and L-2-hydroxyglutarate (L-2HG) is crucially important for accurate diagnosis of 2HG related diseases. Here we developed a strategy by chiral derivatization combined with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis for highly sensitive determination of D-2HG and L-2HG enantiomers. N-(p-toluenesulfonyl)-L-phenylalanyl chloride (TSPC) was used to derivatize 2HG. The formed diastereomers by TSPC labeling can efficiently improve the chromatographic separation of D-2HG and L-2HG. And derivatization by TSPC could also markedly increase the detection sensitivities by 291 and 346 folds for D-2HG and L-2HG, respectively. Using the developed method, we measured the contents of D-2HG and L-2HG in clear cell renal cell carcinoma (ccRCC) tissues. We observed 12.9 and 29.8 folds increase of D-2HG and L-2HG, respectively, in human ccRCC tissues compared to adjacent normal tissues. The developed chiral derivatization combined with LC-ESI-MS/MS analysis offers sensitive determination of D-2HG and L-2HG enantiomers, which benefits the precise diagnosis of 2HG related metabolic diseases. PMID:26458332

Effect of Increasing Glutathione With Cysteine and Glycine Supplementation on Mitochondrial Fuel Oxidation, Insulin Sensitivity, and Body Composition in Older HIV-Infected Patients

PubMed Central

Nguyen, Dan; Hsu, Jean W.; Jahoor, Farook

2014-01-01

Background: HIV-infected patients are reported to have impaired oxidation of fatty acids despite increased availability, suggesting a mitochondrial defect. We investigated whether diminished levels of a key mitochondrial antioxidant, glutathione (GSH), was contributing to defective fatty acid oxidation in older HIV-infected patients, and if so, the metabolic mechanisms contributing to GSH deficiency in these patients. Methods: In an open-label design, 8 older GSH-deficient HIV-infected males were studied before and after 14 days of oral supplementation with the GSH precursors cysteine and glycine. A combination of stable-isotope tracers, calorimetry, hyperinsulinemic-euglycemic clamp, and dynamometry were used to measure GSH synthesis, fasted and insulin-stimulated (fed) mitochondrial fuel oxidation, insulin sensitivity, body composition, anthropometry, forearm-muscle strength, and lipid profiles. Results: Impaired synthesis contributed to GSH deficiency in the patients and was restored with cysteine plus glycine supplementation. GSH improvement was accompanied by marked improvements in fasted and fed mitochondrial fuel oxidation. Associated benefits included improvements in insulin sensitivity, body composition, anthropometry, muscle strength, and dyslipidemia. Conclusions: This work identifies 2 novel findings in older HIV-infected patients: 1) diminished synthesis due to decreased availability of cysteine and glycine contributes to GSH deficiency and can be rapidly corrected by dietary supplementation of these precursors and 2) correction of GSH deficiency is associated with improvement of mitochondrial fat and carbohydrate oxidation in both fasted and fed states and with improvements in insulin sensitivity, body composition, and muscle strength. The role of GSH on ameliorating metabolic complications in older HIV-infected patients warrants further investigation. PMID:24081740

Potentiation by Tumor Necrosis Factor of Mitoxantrone Cytotoxicity to Human Ovarian Cancer Cell Lines

PubMed Central

Parodi, Silvio; Billi, Giovanna; Oliva, Cristina; Venturing, Marco; Noviello, Elvira; Conte, PierFranco

1992-01-01

The cytotoxic activity of human recombinant tumor necrosis factor (rHuTNF) (from 0.01 to 10000 U/ml) was assayed on six human ovarian cancer cell lines and one human cervical carcinoma cell line using a crystal violet assay. rHuTNF was cytotoxic to four cell lines (A2780, A2774, SW626, PAD, while 3 cell lines (IGROV1, SKOV3, Mel80) were marginally sensitive to its activity. However, under the same experimental conditions rHuTNF markedly enhanced the cytotoxicity of mitoxantrone, a chemotherapeutic drug targeted at DNA topoisomerase II, in six cell lines. The potentiation of mitoxantrone cytotoxicity was not caused by increased drug accumulation after rHuTNF treatment. No significant increase in cytotoxicity to Me180 cell line was seen when rHuTNF was added to mitoxantrone. PMID:1517145

Heat-resistant variants of the Chinese hamster ovary cell: alteration of cellular structure and expression of vimentin.

PubMed

Lee, Y J; Hou, Z Z; Curetty, L; Armour, E P; al-Saadi, A; Bernstein, J; Corry, P M

1992-04-01

Three heat-resistant mutant cell lines (78-1, 78-2, 78-3) were previously selected from Chinese hamster ovary cells. In this study, we investigated whether the differences in intrinsic thermal sensitivity result from alteration of stress protein levels or cellular structural changes. Although there was no significant difference in the levels of stress proteins, i.e., constitutive HSP70 in wild type and three heat-resistant mutant strains, there were marked differences in the amounts of vimentin among the cell lines. Two-dimensional gel electrophoresis and Western blot showed a 2.3-2.9-fold increase in the level of vimentin in the mutant cells under normal growth conditions. Northern blot also revealed higher amounts of vimentin mRNA in the mutant cells. Electron microscopy and immunofluorescence suggest that increased amounts of the vimentin-containing intermediate filaments are correlated with the heat-resistant phenotypes.

PRRT2 Is a Key Component of the Ca2+-Dependent Neurotransmitter Release Machinery

PubMed Central

Valente, Pierluigi; Castroflorio, Enrico; Rossi, Pia; Fadda, Manuela; Sterlini, Bruno; Cervigni, Romina Ines; Prestigio, Cosimo; Giovedì, Silvia; Onofri, Franco; Mura, Elisa; Guarnieri, Fabrizia C.; Marte, Antonella; Orlando, Marta; Zara, Federico; Fassio, Anna; Valtorta, Flavia; Baldelli, Pietro; Corradi, Anna; Benfenati, Fabio

2016-01-01

Summary Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release. PMID:27052163

Rapid Evolution of Culture-Impaired Bacteria During Adaptation to Biofilm Growth

PubMed Central

Penterman, Jon; Nguyen, Dao; Anderson, Erin; Staudinger, Benjamin J.; Greenberg, Everett P.; Lam, Joseph S.; Singh, Pradeep K.

2014-01-01

Summary Biofilm growth increases the fitness of bacteria in harsh conditions. However, bacteria from clinical and environmental biofilms can exhibit impaired growth in culture, even when the species involved are readily cultureable, and permissive conditions are used. Here we show that culture-impaired variants of Pseudomonas aeruginosa rapidly and abundantly evolve in laboratory biofilms. The culture-impaired phenotype is caused by mutations that alter the outer-membrane lipopolysaccharide structure. Within biofilms, the lipopolysaccharide mutations markedly increase bacterial fitness. However, outside the protected biofilm environment, the mutations sensitize the variants to killing by a self-produced antimicrobial agent. Thus, a biofilm-mediated adaptation produces a stark fitness trade off that compromises bacterial survival in culture. Trade offs like this could limit the ability of bacteria to transition between biofilm growth and the free-living state, and produce bacterial populations that escape detection by culture-based sampling. PMID:24412364

Pain, sensory function, and neurogenic inflammatory response in young women with low mood.

PubMed

Lehoux, Cory P; Abbott, Frances V

2011-03-01

To determine the relationship of mood status to pain complaints, sensory function, neurogenic inflammatory response, and general health in young women. Ninety-three women aged 18-29 participated in the study and were categorized by SCL-90-R depression score into low-mood (n=21) and normal-mood (n=72) groups. All subjects were below the threshold for possible clinical depression. Low mood was associated with decreased tactile sensitivity, reduced response to topical capsaicin, and increased complaints of back, joint, muscle, and visceral pain, but not headache, when compared to normal mood controls. Low mood was also associated with reported poorer health and physical functioning, increased psychopathology, and family history of mood problems. These data show that even subclinical low mood is associated with marked alterations in health and psychophysiological function. Copyright © 2011 Elsevier Inc. All rights reserved.

Increased ethanol consumption after interruption of fat bingeing.

PubMed

Blanco-Gandía, M Carmen; Miñarro, José; Aguilar, Maria Asuncion; Rodríguez-Arias, Marta

2018-01-01

There is a marked comorbidity between alcohol abuse and eating disorders, especially in the young population. We have previously reported that bingeing on fat during adolescence increases the rewarding effects of ethanol (EtOH). The aim of the present work was to study if vulnerability to EtOH persists after cessation of binge eating. OF1 mice binged on fat (HFB: high-fat binge) during adolescence (PND 25-43) and were tested for 15 days after the last access to HFB (on PND 59) using the self-administration paradigm, the conditioned place preference (CPP) and locomotor sensitization to ethanol. Our results showed that after 15 days of cessation of fat ingestion, mice increased their consumption of ethanol and showed greater motivation to obtain ethanol. On the other hand, no effects were observed in the CPP, while an increased locomotor response to ethanol was detected. The present results confirm and extend our previous study demonstrating that the compulsive intake of fat induces long-lasting effects on the reward system that lead to an increased consumption of EtOH.

Increased ethanol consumption after interruption of fat bingeing

PubMed Central

Blanco-Gandía, M. Carmen; Miñarro, José; Aguilar, Maria Asuncion

2018-01-01

There is a marked comorbidity between alcohol abuse and eating disorders, especially in the young population. We have previously reported that bingeing on fat during adolescence increases the rewarding effects of ethanol (EtOH). The aim of the present work was to study if vulnerability to EtOH persists after cessation of binge eating. OF1 mice binged on fat (HFB: high-fat binge) during adolescence (PND 25–43) and were tested for 15 days after the last access to HFB (on PND 59) using the self-administration paradigm, the conditioned place preference (CPP) and locomotor sensitization to ethanol. Our results showed that after 15 days of cessation of fat ingestion, mice increased their consumption of ethanol and showed greater motivation to obtain ethanol. On the other hand, no effects were observed in the CPP, while an increased locomotor response to ethanol was detected. The present results confirm and extend our previous study demonstrating that the compulsive intake of fat induces long-lasting effects on the reward system that lead to an increased consumption of EtOH. PMID:29590149

Computer-aided mass detection in mammography: False positive reduction via gray-scale invariant ranklet texture features

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

Masotti, Matteo; Lanconelli, Nico; Campanini, Renato

In this work, gray-scale invariant ranklet texture features are proposed for false positive reduction (FPR) in computer-aided detection (CAD) of breast masses. Two main considerations are at the basis of this proposal. First, false positive (FP) marks surviving our previous CAD system seem to be characterized by specific texture properties that can be used to discriminate them from masses. Second, our previous CAD system achieves invariance to linear/nonlinear monotonic gray-scale transformations by encoding regions of interest into ranklet images through the ranklet transform, an image transformation similar to the wavelet transform, yet dealing with pixels' ranks rather than with theirmore » gray-scale values. Therefore, the new FPR approach proposed herein defines a set of texture features which are calculated directly from the ranklet images corresponding to the regions of interest surviving our previous CAD system, hence, ranklet texture features; then, a support vector machine (SVM) classifier is used for discrimination. As a result of this approach, texture-based information is used to discriminate FP marks surviving our previous CAD system; at the same time, invariance to linear/nonlinear monotonic gray-scale transformations of the new CAD system is guaranteed, as ranklet texture features are calculated from ranklet images that have this property themselves by construction. To emphasize the gray-scale invariance of both the previous and new CAD systems, training and testing are carried out without any in-between parameters' adjustment on mammograms having different gray-scale dynamics; in particular, training is carried out on analog digitized mammograms taken from a publicly available digital database, whereas testing is performed on full-field digital mammograms taken from an in-house database. Free-response receiver operating characteristic (FROC) curve analysis of the two CAD systems demonstrates that the new approach achieves a higher reduction of FP marks when compared to the previous one. Specifically, at 60%, 65%, and 70% per-mammogram sensitivity, the new CAD system achieves 0.50, 0.68, and 0.92 FP marks per mammogram, whereas at 70%, 75%, and 80% per-case sensitivity it achieves 0.37, 0.48, and 0.71 FP marks per mammogram, respectively. Conversely, at the same sensitivities, the previous CAD system reached 0.71, 0.87, and 1.15 FP marks per mammogram, and 0.57, 0.73, and 0.92 FPs per mammogram. Also, statistical significance of the difference between the two per-mammogram and per-case FROC curves is demonstrated by the p-value<0.001 returned by jackknife FROC analysis performed on the two CAD systems.« less

What happens to your brain on the way to Mars.

PubMed

Parihar, Vipan K; Allen, Barrett; Tran, Katherine K; Macaraeg, Trisha G; Chu, Esther M; Kwok, Stephanie F; Chmielewski, Nicole N; Craver, Brianna M; Baulch, Janet E; Acharya, Munjal M; Cucinotta, Francis A; Limoli, Charles L

2015-05-01

As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae.

Temperature Sensitivity of Soil Respiration to Nitrogen Fertilization: Varying Effects between Growing and Non-Growing Seasons

PubMed Central

Liu, Qingfang; Wang, Rui; Li, Rujian; Hu, Yaxian; Guo, Shengli

2016-01-01

Nitrogen (N) fertilization has a considerable effect on food production and carbon cycling in agro-ecosystems. However, the impacts of N fertilization rates on the temperature sensitivity of soil respiration (Q10) were controversial. Five N rates (N0, N45, N90, N135, and N180) were applied to a continuous winter wheat (Triticum aestivum L.) crop on the semi-arid Loess Plateau, and the in situ soil respiration was monitored during five consecutive years from 2008 to 2013. During the growing season, the mean soil respiration rates increased with increasing N fertilization rates, peaking at 1.53 μmol m−2s−1 in the N135 treatment. A similar dynamic pattern was observed during the non-growing season, yet on average with 7.3% greater soil respiration rates than the growing season. In general for all the N fertilization treatments, the mean Q10 value during the non-growing season was significantly greater than that during the growing season. As N fertilization rates increased, the Q10 values did not change significantly in the growing season but significantly decreased in the non-growing season. Overall, N fertilization markedly influenced soil respirations and Q10 values, in particular posing distinct effects on the Q10 values between the growing and non-growing seasons. PMID:27992576

Effect of phenazine methosulphate on K+ transport in human red cells.

PubMed

Gibson, John S; Muzyamba, Morris C; Ellory, Clive J

2003-01-01

The effect of phenazine methosulphate (PMS; 1 mM) on (86Rb+) K+ transport in human red cells was investigated to ascertain its action on the K+-Cl- cotransporter (KCC; defined as the Cl- dependent component of K+ flux measured in the presence of ouabain and bumetanide) and the Ca2+-activated K+ channel (Gardos channel; defined as the clotrimazole, 5 microM, -sensitive K+ flux). In the presence of Ca2+, both transport pathways were stimulated but effects were markedly greater under deoxygenated conditions (5-fold for KCC; 20-fold for the Gardos channel). KCC activation was inhibited by prior treatment with calyculin A (100 nM), implying action via protein dephosphorylation. Activation of the Gardos channel correlated with 28 +/- 3% inhibition of the plasma membrane Ca2+ pump, with maximal activity reduced from 7.7 +/- 1.1 to 2.7 +/- 0.7 micromol.(l cells.h)(-1) (all means +/- S.E.M. for n = 3), and a 3-fold increase in sensitivity of the channel to Ca2+ (EC50 reduced from 437 +/- 156 to 152 +/- 57 nM). Increased availability of NADH in deoxygenated conditions, resulting in increased free radical generation by PMS, may be responsible. We speculate that the similarity of the K+ transport phenotype produced by PMS to that seen in deoxygenated sickle cells is relevant to the pathophysiology of sickle cell disease. Copyright 2003 S. Karger AG, Basel

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

PubMed

Piekarski, David J; Johnson, Carolyn M; Boivin, Josiah R; Thomas, A Wren; Lin, Wan Chen; Delevich, Kristen; M Galarce, Ezequiel; Wilbrecht, Linda

2017-01-01

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

Rhabdomyolysis and Artifactual Increase in Plasma Bicarbonate Concentration in an Amazon Parrot (Amazona species).

PubMed

Leissinger, Mary K; Johnson, James G; Tully, Thomas N; Gaunt, Stephen D

2017-09-01

A 7-year-old male Amazon parrot housed outdoors presented with acute collapse, marked lethargy, and open-mouth breathing. The patient had stiffness of the pectoral muscles, and petechiation and ecchymosis noted around the eyes and beneath the mandible. Laboratory data revealed markedly increased aspartate aminotransferase, creatine kinase, and lactate dehydrogenase activity consistent with rhabdomyolysis, as well as markedly increased plasma bicarbonate concentration. Marked clinical improvement and resolution of laboratory abnormalities occurred with fluid therapy, administration of a nonsteroidal anti-inflammatory medication, and husbandry modifications, including indoor housing and dietary alteration. A spurious increase in bicarbonate measurement as documented in equine and bovine cases of rhabdomyolysis also occurred in this avian patient and must be considered for accurate interpretation of acid-base status in exotic species presenting with consistent clinical signs.

Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes: a longitudinal analysis from the Whitehall II cohort study.

PubMed

Hulman, Adam; Simmons, Rebecca K; Brunner, Eric J; Witte, Daniel R; Færch, Kristine; Vistisen, Dorte; Ikehara, Satoyo; Kivimaki, Mika; Tabák, Adam G

2017-07-01

South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age suggest that impaired insulin secretion is a particular feature of diabetes development among South Asians. We therefore aimed to examine ethnic differences in early changes in glucose metabolism prior to incident type 2 diabetes. In a prospective British occupational cohort, subject to 5 yearly clinical examinations, we examined ethnic differences in trajectories of fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI 0,120 ) among 120 South Asian and 867 white participants who developed diabetes during follow-up (1991-2013). We fitted cubic mixed-effects models to longitudinal data with adjustment for a wide range of covariates. Compared with white individuals, South Asians had a faster increase in FPG before diagnosis (slope difference 0.22 mmol/l per decade; 95% CI 0.02, 0.42; p = 0.03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p < 0.001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI 0,120 declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2hPG trajectories. We observed different trajectories of plasma glucose, insulin sensitivity and secretion prior to diabetes diagnosis in South Asian and white individuals. This might be due to ethnic differences in the natural history of diabetes. South Asian individuals experienced a more rapid decrease in insulin sensitivity and faster increases in FPG compared with white individuals. These findings suggest more marked disturbance in beta cell compensation prior to diabetes diagnosis in South Asian individuals.

Oxygen induces mutation in a strict anaerobe, Prevotella melaninogenica.

PubMed

Takumi, Shota; Komatsu, Masaharu; Aoyama, Kohji; Watanabe, Kunitomo; Takeuchi, Toru

2008-05-15

Strict anaerobes are highly sensitive to oxygen, but the mutagenicity of oxygen in strict anaerobes has not been well understood. Prevotella melaninogenica, a strict anaerobe, is susceptible to oxygen and shows an increase in oxidative DNA damage upon exposure to oxygen. In this study, we have investigated the mutagenicity of oxygen and the types of mutations induced by oxygen. Exposure to oxygen decreased cell survival and increased the levels of 8-oxo-deoxyguanosine (8-oxodG). The frequency of rifampicin-resistant mutants was markedly increased after exposure to oxygen. After sequencing a 254-bp fragment of the rpoB gene, which encodes the beta subunit of bacterial RNA polymerase, a target molecule of rifampicin, we found that most mutants induced by oxygen had GC to TA transversions, a signature of 8-oxodG. In addition, all detected single-nucleotide changes would lead to amino acid changes that confer rifampicin resistance. These results indicate that oxygen is mutagenic in a strict anaerobe, P. melaninogenica, and its mutagenic characteristics could be analyzed with this experimental system.

Effects of Terrestrial Buffer Zones on Amphibians on Golf Courses

PubMed Central

Puglis, Holly J.; Boone, Michelle D.

2012-01-01

A major cause of amphibian declines worldwide is habitat destruction or alteration. Public green spaces, such as golf courses and parks, could serve as safe havens to curb the effects of habitat loss if managed in ways to bolster local amphibian communities. We reared larval Blanchard's cricket frogs (Acris blanchardi) and green frogs (Rana clamitans) in golf course ponds with and without 1 m terrestrial buffer zones, and released marked cricket frog metamorphs at the golf course ponds they were reared in. Larval survival of both species was affected by the presence of a buffer zone, with increased survival for cricket frogs and decreased survival for green frogs when reared in ponds with buffer zones. No marked cricket frog juveniles were recovered at any golf course pond in the following year, suggesting that most animals died or migrated. In a separate study, we released cricket frogs in a terrestrial pen and allowed them to choose between mown and unmown grass. Cricket frogs had a greater probability of using unmown versus mown grass. Our results suggest that incorporating buffer zones around ponds can offer suitable habitat for some amphibian species and can improve the quality of the aquatic environment for some sensitive local amphibians. PMID:22761833

Moxonidine improves glycaemic control in mildly hypertensive, overweight patients: a comparison with metformin.

PubMed

Chazova, Irina; Almazov, Vladimir A; Shlyakhto, Evgeny

2006-07-01

To compare the effects of moxonidine and metformin on glycaemic control in patients with impaired glucose tolerance and signs of the metabolic syndrome. A multicentre, prospective, randomized, open-label study design was adopted with blinded endpoint evaluation. Patients > or =40 years old, with impaired glucose tolerance (or diabetes mellitus treated with diet alone) and a body mass index (BMI) of at least 27 kg/m2 were treated twice daily with moxonidine 0.2 mg or metformin 500 mg for 16 weeks. Oral glucose tolerance test (OGTT) was performed at baseline and end-of-study; plasma insulin and plasma glucose levels were measured at 0, 60, 120 and 180 min after administration. With regard to effects on insulin [mean area under the curve (AUC) for insulin], the primary efficacy endpoint of the study, both drugs did not show equivalence. On the contrary, in the per protocol (PP) population, moxonidine statistically significantly (p = 0.025) decreased the AUC for insulin from baseline in the PP population; for metformin, the treatment effect on insulin was a small, net increase resulting in a statistically significant between-group difference of 16.2% (95% CI = 0.1-35.0). The change in mean insulin AUC was most marked in the subgroup of patients with higher sympathetic activity (heart rate >80 bpm). Mean fasting plasma glucose (FPG) levels and HbA1c levels were largely unchanged by moxonidine treatment but significantly decreased by metformin treatment. The difference between the groups was 14.7% (p = 0.0523) in the intent-to-treat (ITT) sample. By study end, both treatments had significantly increased the Matsuda Insulin Sensitivity Index (ISI) from baseline to a comparable extent: moxonidine by reducing plasma insulin after a glucose challenge, metformin by reducing FPG. BMI fell significantly in both groups and blood pressure normalized; both drugs were well tolerated. Moxonidine improved insulin sensitivity in response to glucose challenge in patients with evidence of metabolic syndrome. This improvement resulted from a reduction in plasma insulin levels and was most marked in patients with high sympathetic drive at baseline. By enhancing insulin sensitivity, moxonidine treatment may help prevent the development of diabetes and thereby ameliorate the risk for cardiovascular disease.

Turbulence intensity measurements using particle image velocimetry in diseased carotid artery models: effect of stenosis severity, plaque eccentricity, and ulceration.

PubMed

Kefayati, Sarah; Holdsworth, David W; Poepping, Tamie L

2014-01-03

Clinical decision-making for the treatment of patients with diseased carotid artery is mainly based on the severity of the stenosis. However, stenosis severity alone is not a sensitive indicator, and other local factors for the assessment of stroke risk are required. Flow disturbance is of particular interest due to its proven association with increased thromboembolic activities. The objective of this study was to investigate the level of turbulence intensity (TI) with regards to certain geometrical features of the plaque - namely stenosis severity, eccentricity, and ulceration. A family of eight carotid-artery bifurcation models was examined using particle image velocimetry. Results showed a marked difference in turbulence intensity among these models; increasing degree of stenosis severity resulted in increased turbulence intensity, going from 0.12 m/s for mild stenosis to 0.37 m/s for severe stenosis (with concentric geometry). Moreover, independent of stenosis severity, eccentricity led to further elevations in turbulence intensity, increasing TI by 0.05-0.10 m/s over the counterpart concentric plaque. The presence of ulceration (in a 50% eccentric plaque) produced a larger portion of moderate turbulence intensity (~0.10 m/s) compared to the non-ulcerated model, more proximal to the bifurcation apex in the post-stenotic recirculation zone. The effect of plaque eccentricity and ulceration in enhancing the downstream turbulence has potential clinical implications for a more sensitive assessment of stroke risk beyond stenosis severity alone. © 2013 Elsevier Ltd. All rights reserved.

Characteristics of Dysphagia in Infants with Microcephaly Caused by Congenital Zika Virus Infection, Brazil, 2015.

PubMed

Leal, Mariana C; van der Linden, Vanessa; Bezerra, Thiago P; de Valois, Luciana; Borges, Adriana C G; Antunes, Margarida M C; Brandt, Kátia G; Moura, Catharina X; Rodrigues, Laura C; Ximenes, Coeli R

2017-08-01

We summarize the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection. The Schedule for Oral Motor Assessment, fiberoptic endoscopic evaluation of swallowing, and the videofluoroscopic swallowing study were used as noninstrumental and instrumental assessments. All infants had a degree of neurologic damage and showed abnormalities in the oral phase. Of the 9 infants, 8 lacked oral and upper respiratory tract sensitivity, leading to delays in initiation of the pharyngeal phase of swallowing. Those delays, combined with marked oral dysfunction, increased the risk for aspiration of food, particularly liquid foods. Dysphagia resulting from congenital Zika virus syndrome microcephaly can develop in infants >3 months of age and is severe.

Characteristics of Dysphagia in Infants with Microcephaly Caused by Congenital Zika Virus Infection, Brazil, 2015

PubMed Central

van der Linden, Vanessa; Bezerra, Thiago P.; de Valois, Luciana; Borges, Adriana C.G.; Antunes, Margarida M.C.; Brandt, Kátia G.; Moura, Catharina X.; Rodrigues, Laura C.; Ximenes, Coeli R.

2017-01-01

We summarize the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection. The Schedule for Oral Motor Assessment, fiberoptic endoscopic evaluation of swallowing, and the videofluoroscopic swallowing study were used as noninstrumental and instrumental assessments. All infants had a degree of neurologic damage and showed abnormalities in the oral phase. Of the 9 infants, 8 lacked oral and upper respiratory tract sensitivity, leading to delays in initiation of the pharyngeal phase of swallowing. Those delays, combined with marked oral dysfunction, increased the risk for aspiration of food, particularly liquid foods. Dysphagia resulting from congenital Zika virus syndrome microcephaly can develop in infants >3 months of age and is severe. PMID:28604336

From the Cover: Adipose tissue mass can be regulated through the vasculature

NASA Astrophysics Data System (ADS)

Rupnick, Maria A.; Panigrahy, Dipak; Zhang, Chen-Yu; Dallabrida, Susan M.; Lowell, Bradford B.; Langer, Robert; Judah Folkman, M.

2002-08-01

Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

High-level dietary cadmium exposure is associated with global DNA hypermethylation in the gastropod hepatopancreas

PubMed Central

Popescu, Cristina; Draghici, George A.; Andrica, Florina-Maria; Privistirescu, Ionela A.; Gergen, Iosif I.; Stöger, Reinhard

2017-01-01

5-methylcytosine (5mC) is a key epigenetic mark which influences gene expression and phenotype. In vertebrates, this epigenetic mark is sensitive to Cd exposure, but there is no information linking such an event with changes in global 5mC levels in terrestrial gastropods despite their importance as excellentecotoxicological bioindicators of metal contamination. Therefore, we first evaluated total 5mC content in DNA of the hepatopancreas of adult Cantareus aspersus with the aim to determine whether this epigenetic mark is responsive to Cd exposure. The experiment was conducted under laboratory conditions and involved a continuous exposure, multiple dose- and time-point (14, 28, and 56 days) study design. Hepatopancreas cadmium levels were measured using Flame Atomic Absorption Spectrometry and the percentage of 5-mC in samples using an ELISA-based colorimetric assay. Snail death rates were also assessed. Our results, for the first time, reveal the presence of 5mC in C. aspersus and provide evidence for Cd-induced changes in global 5mC levels in DNA of gastropods and mollusks. Although less sensitive than tissue accumulation, DNA methylation levels responded in a dose- and time-dependent manner to dietary cadmium, with exposure dose having a much stronger effect than exposure duration. An obvious trend of increasing 5mC levels was observed starting at 28 days of exposure to the second highest dose and this trend persisted at the two highest treatments for close to one month, when the experiment was terminated after 56 days. Moreover, a strong association was identified between Cd concentrations in the hepatopancreas and DNA methylation levels in this organ. These data indicate an overall trend towards DNA hypermethylation with elevated Cd exposure. No consistent lethal effect was observed, irrespective of time point and Cd-dosage. Overall, our findings suggest that the total 5mC content in DNA of the hepatopancreas of land snails is responsive to sublethal Cd exposure and give new insights into invertebrate environmental epigenetics. PMID:28877233

AGE-RELATED EFFECTS OF CHLORPYRIFOS ON ACETYLCHOLINE RELEASE IN RAT BRAIN. (R825811)

EPA Science Inventory

Chlorpyrifos (CPF) is an organophosphorus insecticide that elicits toxicity through inhibition of acetylcholinesterase (AChE). Young animals are markedly more sensitive than adults to the acute toxicity of CPF. We evaluated acetylcholine (ACh) release and its muscarinic recept...

Grammaticality Judgements in Adolescents with and without Language Impairment

ERIC Educational Resources Information Center

Miller, Carol; Leonard, Laurence; Finneran, Denise

2008-01-01

Background: Existing evidence suggests that young children with specific language impairment have unusual difficulty in detecting omissions of obligatory tense-marking morphemes, but little is known about adolescents' sensitivity to such violations. Aims: The study investigated whether limitations in receptive morphosyntax (as measured by…

Silver-Zinc Redox-Coupled Electroceutical Wound Dressing Disrupts Bacterial Biofilm

PubMed Central

Roy, Sashwati; Khanna, Savita; Hemann, Craig; Deng, Binbin; Das, Amitava; Zweier, Jay L.; Wozniak, Daniel; Sen, Chandan K.

2015-01-01

Pseudomonas aeruginosa biofilm is commonly associated with chronic wound infection. A FDA approved wireless electroceutical dressing (WED), which in the presence of conductive wound exudate gets activated to generate electric field (0.3–0.9V), was investigated for its anti-biofilm properties. Growth of pathogenic P. aeruginosa strain PAO1 in LB media was markedly arrested in the presence of the WED. Scanning electron microscopy demonstrated that WED markedly disrupted biofilm integrity in a setting where silver dressing was ineffective. Biofilm thickness and number of live bacterial cells were decreased in the presence of WED. Quorum sensing genes lasR and rhlR and activity of electric field sensitive enzyme, glycerol-3-phosphate dehydrogenase was also repressed by WED. This work provides first electron paramagnetic resonance spectroscopy evidence demonstrating that WED serves as a spontaneous source of reactive oxygen species. Redox-sensitive multidrug efflux systems mexAB and mexEF were repressed by WED. Taken together, these observations provide first evidence supporting the anti-biofilm properties of WED. PMID:25803639

Identification of e6a2 BCR-ABL fusion in a Philadelphia-positive CML with marked basophilia: implications for treatment strategy.

PubMed

Rohon, Peter; Divoka, Martina; Calabkova, Lenka; Mojzikova, Renata; Katrincsakova, Beata; Rusinakova, Zuzana; Lapcikova, Anna; Raida, Ludek; Faber, Edgar; Jarosova, Marie; Divoky, Vladimir; Indrak, Karel

2011-06-01

This is a case report of a 51 year old male with marked splenomegaly, basophilia, severe thrombocytopenia, anemia and high SFKL phosphorylation downstream of Bcr-Abl, investigated for association of the e6a2 BCR-ABL fusion gene and marked basophilia. The treatment strategy implications in patients with Philadelphia positive CML are described. RT-PCR and sequencing were carried out on the peripheral blood leukocytes to detect the type of BCR-ABL transcript. The BCR-ABL mutational status was assessed using sequencing of the RT-PCR products. The in vitro test of sensitivity to TKIs was based on detecting inhibited phosphorylation of the Crkl and Phospho-Src family kinases (SFK, Tyr416) using immunodetection. The cytogenetics revealed 90% of Ph+ (Philadelphia) cells in the bone marrow aspirate with no additional clonal chromosomal abnormalities at diagnosis. This correlated with an accelerated phase of the CML. Sequencing analysis of reverse transcribed and PCR amplified BCR-ABL transcript revealed a rare e6a2 fusion, with no evidence for Bcr-Abl kinase domain mutation. Western blot analysis showed high phosphorylation (activation) of Crkl and the Src family of kinases (P-SFK). In vitro test of sensitivity of the patients' leukemic cells to imatinib demonstrated sensitivity of Bcr-Abl tyrosine kinase to imatinib, as assessed by a decrease in phosphorylated Crkl and the disappearance of P-SFK, suggesting that P-Src reflects only the Bcr-Abl-dependent Src activity. The initial treatment strategy was reduced imatinib and search for an unrelated hematopoietic stem cell donor (according to the ELN recommendations). The patient was allografted with peripheral stem cells from an HLA- identical male donor but on day +70 graft failure occurred. He was allografted again with the peripheral stem cells from an HLA-identical female donor, engrafted on day +15 and showed 100% donor chimerism with no evidence of the e6a2 BCR-ABL fusion transcript on day +30. The clinical disease course in patients with the rare e6a2 BCR-ABL transcript variant is aggressive. This may be the result of increased kinase activity due to partial loss of the guanine exchange factor/dbl-like domain which mediates the interaction with several Ras-like G-proteins involved in cell proliferation, signal transduction, and cytoskeletal organization. For the above reasons, these patients should receive stem cell transplant immediately after a short course of treatment with imatinib/ dual Src/Abl kinase inhibitor or they should be registered in clinical trials with experimental agents.

Selective Reversible Inhibition of Liver Carnitine Palmitoyl-Transferase 1 by Teglicar Reduces Gluconeogenesis and Improves Glucose Homeostasis

PubMed Central

Conti, Roberto; Mannucci, Edoardo; Pessotto, Pompeo; Tassoni, Emanuela; Carminati, Paolo; Giannessi, Fabio; Arduini, Arduino

2011-01-01

OBJECTIVE We have developed a new antihyperglycemic agent (teglicar) through the selective and reversible inhibition of the liver isoform of carnitine palmitoyl-transferase 1 (L-CPT1). RESEARCH DESIGN AND METHODS Glucose production was investigated in isolated hepatocytes and during pancreatic clamps in healthy rats. Chronic treatments on C57BL/6J, db/db, high-fat fed mice, and rats were performed to understand glucose metabolism and insulin sensitivity. RESULTS In isolated hepatocytes, teglicar concentration dependently reduced ketone bodies and glucose production up to 72 and 50%, respectively. In rats, teglicar reduced the endogenous glucose production (−62%) without affecting peripheral glucose utilization. Heart 2-[3H]deoxyglucose uptake in mice was also not affected, confirming in vivo the drug selectivity toward L-CPT1. Chronic treatment in db/db mice (50 mg/kg/bid; 45 days) reduced postabsorptive glycemia (−38%), water consumption (−31%), and fructosamine (−30%). Such antidiabetic activity was associated with an improved insulin sensitivity assessed by the insulin tolerance test. A significant 50% increase in hepatic triglyceride content (HTGC) was found, although plasma alanineaminotransferase was not altered. In addition, long-term teglicar administration to high-fat fed C57BL/6J mice normalized glycemia (−19%) and insulinemia (−53%). Long-term teglicar administration (30 days, 80 mg/kg) in healthy overnight-fasted rats slightly reduced basal glycemia (−20%, ns), reduced basal insulin levels by 60%, doubled triglycerides, and increased free-fatty acids (+53%). HTGC was markedly increased, but liver and peripheral insulin sensitivity assessed by hyperinsulinemiceuglycemic clamp were not affected. CONCLUSIONS Teglicar, in vitro and in animal models, reduces gluconeogenesis and improves glucose homeostasis, refreshing the interest in selective and reversible L-CPT1 inhibition as a potential antihyperglycemic approach. PMID:21270274

Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

PubMed

Lane, E L; Cheetham, S C; Jenner, P

2005-01-01

BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

Effect of mouse strain in a model of chemical-induced respiratory allergy.

PubMed

Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

2014-01-01

The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical-related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical-related respiratory allergens by using a long-term sensitization-challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences in respiratory allergic reactions to the well-known chemical respiratory allergen glutaraldehyde (GA). According to our protocol, BALB/c, NC/Nga, C3H/HeN, C57BL/6N, and CBA/J mice were sensitized dermally with GA for 3 weeks and then challenged with intratracheal or inhaled GA at 2 weeks after the last sensitization. The day after the final challenge, all mice were euthanized, and total serum IgE levels were assayed. In addition, immunocyte counts, cytokine production, and chemokine levels in the hilar lymph nodes (LNs) and bronchoalveolar lavage fluids (BALF) were also assessed. In conclusion, BALB/c and NC/Nga mice demonstrated markedly increased IgE reactions. Inflammatory cell counts in BALF were increased in the treated groups of all strains, especially BALB/c, NC/Nga, and CBA/J strains. Cytokine levels in LNs were increased in all treated groups except for C3H/HeN and were particularly high in BALB/c and NC/Nga mice. According to our results, we suggest that BALB/c and NC/Nga are highly susceptible to respiratory allergic responses and therefore are good candidates for use in our model for detecting environmental chemical respiratory allergens.

Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin

PubMed Central

Prueksaritanont, Thomayant; Chu, Xiaoyan; Evers, Raymond; Klopfer, Stephanie O; Caro, Luzelena; Kothare, Prajakti A; Dempsey, Cynthia; Rasmussen, Scott; Houle, Robert; Chan, Grace; Cai, Xiaoxin; Valesky, Robert; Fraser, Iain P; Stoch, S Aubrey

2014-01-01

Aims Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. Methods The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. Results Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration–time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. Conclusions The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose. PMID:24617605

Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers

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

M'kacher, Radhia; Bennaceur-Griscelli, Annelise; Girinsky, Theodore

Purpose: To investigate a potential link between telomere length, chromosomal instability, and the advent of a second cancer (SC) in patients with Hodgkin's lymphoma (HL), who are known to be at risk for SCs. This study was premised on the finding that telomere dysfunction and DNA repair pathways were related to many pathologic conditions. Methods and Materials: Three cohorts of patients with HL were studied: 73 who were prospectively followed >5 years after diagnosis (prospective HL cohort), 28 who developed a SC (SC HL cohort), and 18 long-term survivors with no evidence of disease or complication since their initial treatmentmore » (NED HL cohort). Telomere length was analyzed by a telomeric restriction fragment assay in peripheral blood lymphocytes. Thirty healthy donors and 70 patients with a newly diagnosed solid tumor were the control population. Results: Compared with controls, patients from the prospective HL cohort, before any treatment, showed age-independent shorter telomeres (mean, 8.3 vs. 11.7 kb in healthy donors; <6 kb in 18% in HL patients), increased spontaneous chromosomal abnormalities, and increased in vitro radiation sensitivity (p < 10{sup -4} each). After treatment, telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations. Moreover, the two cases of SC in the prospective HL patients had short telomeres and CCR initially. In addition, the SC HL cohort was characterized by markedly short telomeres (6.6 vs. 9.7 kb in the NED HL cohort), the presence of complex chromosome rearrangements, and increased in vitro radiation sensitivity. Conclusions: An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients.« less

Effect of glutamate, aspartate and related derivatives on cerebellar Purkinje cell dendrites in the rat: an in vitro study

PubMed Central

Crepel, F.; Dhanjal, S. S.; Sears, T. A.

1982-01-01

1. The responses of Purkinje cells to short duration (pulse) ionophoretic applications of L-aspartate (L-asp), L-glutamate (L-glu), N-methyl DL-aspartate (NMDLA) and quisqualic acid in their dendritic fields were studied in vitro on sagittal slices of lobules IX and X of the adult rat cerebellum. 2. Pulse application of L-asp or L-glu evoked transient and dose-dependent increases in the firing rate of the simple spikes recorded extracellularly as single units. When the ionophoretic electrode was positioned in the dendritic field of the Purkinje cells, the lowest thresholds for L-glu and L-asp mediated excitations of the cells were as low as 25 and 35 pC respectively, with a latency for maximal responses as brief as 7 ms. 3. In intracellular recordings these excitatory responses consisted of depolarizations of up to 18 mV in amplitude and with depolarizing slopes up to 0·52 mV/ms. They were generally unaccompanied by changes in cell input resistance in contrast to the marked decrease which occurred in response to steady applications of large doses of L-asp and L-glu. 4. The spatial distribution of the excitatory sites confirmed that the dendritic sensitivity to L-glu was greater than that of the soma and showed that the same was true for L-asp. In 34% of cells the sensitivity for L-asp declined markedly in the upper region of the molecular layer, whereas it remained high for L-glu; no such differential sensitivity was detected in the remaining 66% of cells. 5. Inhibitory responses, antagonized by 10-5 M-bicuculline in the bath, were also induced in Purkinje cells by L-glu and L-asp when the ionophoretic electrode was withdrawn from the excitatory sites by as little as 8 μm and up to 40 μm upward or downward along the track of parallel fibres or positioned as far as 250 μm laterally. 6. Whenever it was applied in the molecular layer, the pulse application of NMDLA elicited no excitatory response in Purkinje cells recorded extra or intracellularly. However, slow depolarizations accompanied by a slight increase in cell input resistance were obtained with steady applications of 20-50 nA of the drug for 20-30 s. 7. In contrast, pulse application of quisqualic acid appeared to have the same type of fast excitatory effect on Purkinje cells as L-asp and L-glu, but its potency was greater and its action more prolonged. Furthermore, its steady application led to an abrupt and marked decrease in cell membrane resistance. 8. The excitatory effects of L-asp, L-glu and quisqualic acid were antagonized by L-glutamic acid diethyl ester more consistently than by D-α-aminoadipate, suggesting together with previous observations that L-asp and L-glu act on Purkinje cells via quisqualic acid rather than via NMDLA receptors. PMID:6754909

[Expression of AMPA receptors and related protein in immobilization stressed rats and effect of Xiaoyaosan].

PubMed

Yue, Guang-Xin; Wang, Zhu-Feng; Zhang, Qiao-Li; Zhao, Xin; Yue, Li-Feng; Ding, Jie; Chen, Jia-Xu

2008-05-01

To observe protein expression changes of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and related regulatory protein in the hippocampus and amygdala in chronic immobilization stressed rat and Xiaoyaosan's regulatory effect. Rats were tied 3 h per day to establish immobilization stress condition and treatment with Xiaoyaosan. After 7 days and 21 days stress, the protein expression of AMPA receptor subunit (GluR2/3), N-ethylmaleimide sensitive factor (NSF) and protein interacting with C-kinase 1 (PICK1) in hippocampus and amygdala were detected by using Western blot techniques. The expression of GluR2/3, NSF in dentate gyrus (DG) and amygdala were markedly attenuated (P < 0.05) and PICK1 in CA1 region were significantly increased (P < 0.05) in 7 d immobilization stressed rats while 7 days xiaoyaosan treatment showed an effective regulatory result to PICK1's changes. Under 21 days immobilization stressed condition, the expression of GluR2/3, NSF in CA1 region showed an increasing trend, and GluR2/3 showed a markedly increase (P < 0.01), but showed an significantly decreased trend in amygdala, Xiaoyaosan showed an effective result to such changes above (P < 0.05). The expression of PICK1 showed increasing trend in amygdala and xiaoyaosan could lower its expression (P < 0.05). There are different trends of the expression of AMPA receptor in repeat short-term stress versus chronic immobilization stress, and in hippocampal CA1 region versus amygdala. Xiaoyaosan has better regulation effect on the expression of AMPA receptors in the condition of chronic immobilization stress than those of repeat shortterm stress.

Effects of phosphoramidon on endothelin-1 and big endothelin-1 production in human aortic endothelial cells.

PubMed

Matsumura, Y; Tsukahara, Y; Kojima, T; Murata, S; Murakami, A; Takada, K; Takaoka, M; Morimoto, S

1995-03-01

Using cultured human aortic endothelial cells, we examined the effects of phosphoramidon, an endothelin converting enzyme (ECE) inhibitor, on the release of endogenous endothelin-1 (ET-1) and big endothelin-1 (big ET-1), and on the generation of ET-1 from exogenously applied big ET-1. Phosphoramidon, at concentrations of 10(-6) to 2 x 10(-4) M, caused a biphasic alteration of the ET-1 release, i.e., at lower concentrations of the drug, there were slight but unexpected increases of the release, whereas higher concentrations led to a decrease which is due to the drug-induced inhibition of ECE. The former effect appears to be based on the inhibition of ET-1 degradation by neutral endopeptidase 24.11 (NEP), since kelatorphan, a specific NEP inhibitor, produced a similar increasing effect on ET-1 release. Phosphoramidon enhanced the big ET-1 release from the cells in a concentration-dependent manner. When high concentrations of phosphoramidon were added, there was a dramatic increase in the release of big ET-1, which cannot be explained only by the drug-induced inhibition of ECE. This increase in big ET-1 release appeared to be partly due to a transient stimulation of the expression of prepro ET-1 mRNA. The amount of ET-1 generated from exogenously applied big ET-1 was markedly decreased by phosphoramidon in a concentration-dependent manner. In a similar fashion, phosphoramidon markedly inhibited ECE activity of the membrane fraction of cultured cells. Thus, ET-1 generation from exogenously applied big ET-1 reflects the functional phosphoramidon-sensitive ECE activities in human aortic endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitating silver-stained neurodegeneration: the neurotoxicity of trimethlytin (TMT) in aged rats.

PubMed

Scallet, A C; Pothuluri, N; Rountree, R L; Matthews, J C

2000-05-15

This report describes the development of a histoanalytical procedure to measure the degree of neurodegeneration produced by the organometal toxicant trimethyltin (TMT). Based on a previous, non-quantitated experiment we hypothesized that the same dose of TMT would produce greater damage in animals of increasing age. Male rats aged 6, 12, 18, or 24 months at the time of dosing were given either 4.5 mg/kg TMT or saline (i.p.). One month after dosing, rats were perfused and their brains removed and processed to selectively silver-impregnate degenerating cell bodies as well as axon terminals and dendrites. Neurodegeneration was most prominent in the hippocampi (especially CA1 stratum radiatum) of TMT-treated rats, but not in the controls. Computer-assisted counting of the silver grains marking damage indicated greater neurotoxicity from the same dose of TMT when given to the older animals. Thus the grain density in the 6-month-old TMT-treated rats was not significantly elevated from the 6-month-old controls (P>0.10). The 12-month-old TMT-treated rats had significantly increased grain densities compared to their controls (P<0.05), but still larger increases of grain counts were observed in the 18- and 24-month-old rats (both P-values<0.01). Our findings with TMT are similar to previous, but nonquantitative, reports that the neurotoxic effects of kainic acid and methionine sulfoximine were also greater in older rats. An increased sensitivity to neurotoxicants might help explain the apparently spontaneous degeneration of cortical neurons in aging and in the neurological diseases of old age. The method we report here for quantitation of silver grains marking neurodegeneration should be adaptable to a wide range of histologically-based neurotoxicology investigations.

Endothelial microparticles (EMP) bind and activate monocytes: elevated EMP-monocyte conjugates in multiple sclerosis.

PubMed

Jy, Wenche; Minagar, Alireza; Jimenez, Joaquin J; Sheremata, William A; Mauro, Lucia M; Horstman, Lawrence L; Bidot, Carlos; Ahn, Yeon S

2004-09-01

Elevated plasma endothelial microparticles (EMP) have been documented in MS during exacerbation. However, the role of EMP in pathogenesis of MS remains unclear. We investigated the formation of EMP-monocyte conjugates (EMP-MoC) and their potential role in transendothelial migration of inflammatory cells in MS. EMP-MoC were assayed in 30 MS patients in exacerbation, 20 in remission and in 35 controls. EMP-leukocyte conjugation was investigated flowcytometrically by employing alpha-CD54 or alpha-CD62E for EMP, and alpha-CD45 for leukocytes. EMP-MoC were characterized by identifying adhesion molecules involved and their effect on monocyte function. In vivo (clinical): EMP-MoC were markedly elevated in exacerbation vs. remission and controls, correlating with presence of GD+ MRI lesions. Free CD54+ EMP were not elevated but free CD62E+ EMP were. In vitro: EMP bound preferentially to monocytes, less to neutrophils, but little to lymphocytes. Bound EMP activated monocytes: CD11b expression increased 50% and migration through cerebral endothelial cell layer increased 2.6-fold. Blockade of CD54 reduced binding by 80%. Most CD54+ EMP bound to monocytes, leaving little free EMP, while CD62+ EMP were found both free and bound. These results demonstrated that phenotypic subsets of EMP interacted differently with monocytes. Based on our observations, EMP may enhance inflammation and increase transendothelial migration of monocytes in MS by binding to and activating monocytes through CD54. EMP-MoC were markedly increased in MS patients in exacerbation compared to remission and may serve as a sensitive marker of MS disease activity.

Statin-induced myotoxicity is exacerbated by aging: A biophysical and molecular biology study in rats treated with atorvastatin.

PubMed

Camerino, Giulia Maria; De Bellis, Michela; Conte, Elena; Liantonio, Antonella; Musaraj, Kejla; Cannone, Maria; Fonzino, Adriano; Giustino, Arcangela; De Luca, Annamaria; Romano, Rossella; Camerino, Claudia; Laghezza, Antonio; Loiodice, Fulvio; Desaphy, Jean-Francois; Conte Camerino, Diana; Pierno, Sabata

2016-09-01

Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4-5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expression of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly. Copyright © 2016 Elsevier Inc. All rights reserved.

The Impact on Stakeholder Confidence of Increased Transparency in the Examination Assessment Process

ERIC Educational Resources Information Center

Bamber, Matthew

2015-01-01

A group of postgraduate accounting and finance students were asked to participate in a three-phase exercise: sit an unseen past examination question; mark a fully anonymised previous student solution (exemplar); and then mark their own work. The marking process was facilitated by explaining and discussing the marking guide, assessment systems and…

Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice.

PubMed

Cattaruzza, Fiore; Johnson, Cali; Leggit, Alan; Grady, Eileen; Schenk, A Katrin; Cevikbas, Ferda; Cedron, Wendy; Bondada, Sandhya; Kirkwood, Rebekah; Malone, Brian; Steinhoff, Martin; Bunnett, Nigel; Kirkwood, Kimberly S

2013-06-01

Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1(+/+) and trpa1(-/-) mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1(-/-) mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.

Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men.

PubMed Central

Fried, S K; Russell, C D; Grauso, N L; Brolin, R E

1993-01-01

There are marked variations in the activity of lipoprotein lipase (LPL) among adipose depots, particularly in women. Consistent with data on LPL activity, the level of expression of LPL mRNA was lower in omental (OM) than subcutaneous (SQ) adipose tissue of women. To investigate the cellular basis of these differences, OM and SQ adipose tissues obtained at surgery from obese men and women were placed in organ culture for 7 d with varying concentrations of insulin and dexamethasone. Insulin increased levels of LPL mRNA and LPL activity in abdominal SQ but not OM adipose tissue. Dexamethasone also increased LPL mRNA and LPL activity, and these effects were more marked in the OM adipose tissue, particularly in men. When insulin and dexamethasone were added together, synergistic increases in LPL activity were seen in both depots, and this was in part explained at the level of LPL mRNA. The SQ depot was more sensitive to the effects of submaximal doses of dexamethasone in the presence of insulin. The maximum activity of LPL induced by insulin or insulin plus dexamethasone was higher in the SQ than in the OM depot of women, and this was associated with higher levels of LPL mRNA. Rates of LPL synthesis paralleled LPL mRNA levels. These data show that insulin and glucocorticoids influence human adipose tissue LPL activity at the level of LPL gene expression, as well as posttranslationally, and that responsiveness to these hormonal effects is dependent on adipose depot and gender. Images PMID:8227334

Seasonal changes in pancreatic B-cell function in euthermic yellow-bellied marmots.

PubMed

Florant, G L; Lawrence, A K; Williams, K; Bauman, W A

1985-08-01

Fasting plasma insulin (PI) and glucose (PG) concentrations were measured throughout the body weight cycle of marmots. Animals gained weight during summer, and in late fall body weight peaked, after which they ceased feeding. Each month euthermic animals were injected intra-arterially with either dextrose (500 mg/kg) or porcine insulin (0.1 U/kg), and blood samples were collected over the subsequent 2 h. During weight gain fasting PI concentration and pancreatic B-cell response to injected dextrose increased markedly. Maximal insulin release to a dextrose challenge was measured during peak body weight or when body weight initially began to decline. The PG concentration after exogenous insulin administration was slight (less than 10%) in the fall but increased approximately 25% in the spring after marmots lost weight. Basal PG levels were not significantly different throughout the year. Basal fasting PI concentrations were significantly higher during the fall (P less than 0.01). It is suggested that in the fall, when marmots are obese, hyperinsulinemia and peripheral insulin resistance appear. Furthermore, in two animals with an increase in body weight of approximately 30% or less over the summer, peripheral resistance was demonstrable, albeit not as marked as in animals that appropriately doubled their body weights when given food ad libitum. Thus we hypothesize that factors other than adiposity, i.e., food intake, central nervous system input to the pancreatic B-cell, and/or changes in B-cell sensitivity to PG, may contribute to the observed peripheral insulin resistance and may be involved in body weight regulation.

Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair.

PubMed

Li, Xiao-Qin; Ren, Jin; Chen, Ping; Chen, Yu-Jiao; Wu, Min; Wu, Yan; Chen, Kang; Li, Jian

2018-05-31

For the majority of patients with advanced non-small cell lung cancer (NSCLC), the standard of care remains platinum-based chemotherapy. However, cisplatin resistance is a big obstacle to the treatment, and elucidation of its mechanism is warranted. In this study, we showed that there was no difference in intracellular uptake of cisplatin or the removal of platinum-DNA adducts between a cisplatin-resistant NSCLC cell line (A549/DR) and a cisplatin-sensitive NSCLC cell line (A549). However, the capacity to repair DNA interstrand crosslinks (ICLs) and double-strand breaks (DSBs) was significantly enhanced in the A549/DR cell line compared to 3 cisplatin-sensitive cell lines. We found that the protein and mRNA expression levels of Pol η, a Y-family translesion synthesis (TLS) polymerase, were markedly increased upon cisplatin exposure in A549/DR cells compared with A549 cells. Furthermore, intracellular co-localization of Pol η and proliferation cell nuclear antigen (PCNA) induced by cisplatin or cisplatin plus gemcitabine treatment was inhibited by depleting ataxia telangiectasia mutated and Rad-3-related (ATR). Pol η depletion by siRNA sensitized A549/DR cells to cisplatin; co-depletion of Pol η and ATR further increased A549/DR cell death induced by cisplatin or cisplatin plus gemcitabine compared to depletion of Pol η or ATR alone, concomitant with inhibition of DNA ICL and DSB repair and accumulation of DNA damage. No additional sensitization effect of co-depleting Pol η and ATR was observed in A549 cells. These results demonstrate that co-inhibition of Pol η and ATR reverses the drug resistance of cisplatin-resistant NSCLC cells by blocking the repair of DNA ICLs and DSBs induced by cisplatin or cisplatin plus gemcitabine.

Characterization in vitro and in vivo of progressively adriamycin-resistant B16-BL6 mouse melanoma cells.

PubMed

Ganapathi, R; Grabowski, D; Schmidt, H; Bell, D; Melia, M

1987-07-01

Adriamycin (ADR)-resistant sublines of B16-BL6 mouse melanoma selected by exposure to increasing concentrations of ADR were characterized in vitro for growth properties and in vivo for tumorigenicity and pulmonary metastases. The progressively resistant sublines adapted to grow in the presence of 0.025, 0.05, 0.1, and 0.25 microgram/ml ADR in monolayer culture were found to be 5-, 10-, 20-, and 40-fold ADR-resistant, respectively, compared to the parental sensitive cells, using a soft-agar colony assay and continuous ADR treatment for 7 days. The doubling time in monolayer culture of the parent sensitive and progressively ADR-resistant sublines of B16-BL6 melanoma cells was approximately 16-18 h. Although the colony-forming efficiency in soft agar of parental sensitive cells was only 0.5-4%, the 5-, 10-, 20-, and 40-fold ADR-resistant sublines had colony-forming efficiencies of 15, 20, 30, and 77%, respectively. Tumorigenicity in C57BL/6 mice of progressively ADR-resistant sublines was similar to parental sensitive cells following s.c. and i.p. implantation of 10(5)-10(6) tumor cells. Experimental pulmonary metastases were significantly lower in ADR-resistant sublines with progressive resistance. Additionally, unlike the parental sensitive and 5-fold ADR-resistant B16-BL6 cells, the 10-, 20-, and 40-fold ADR-resistant sublines were spontaneously nonmetastatic. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunochemical detection of P-glycoprotein revealed the presence of a Mr 170,000 plasma membrane glycoprotein in the 40-fold ADR-resistant subline and its counterpart maintained for 1 year in ADR-free medium. Results from this study suggest that progressively ADR-resistant B16-BL6 mouse melanoma cells selected in vitro demonstrate a marked increase in colony formation in soft agar and a decrease in the ability to produce pulmonary metastases, without alterations in tumorigenicity.

Multienzyme-nanoparticles amplification for sensitive virus genotyping in microfluidic microbeads array using Au nanoparticle probes and quantum dots as labels.

PubMed

Zhang, He; Liu, Lian; Li, Cheuk-Wing; Fu, Huayang; Chen, Yao; Yang, Mengsu

2011-11-15

A novel microfluidic device with microbeads array was developed and sensitive genotyping of human papillomavirus was demonstrated using a multiple-enzyme labeled oligonucleotide-Au nanoparticle bioconjugate as the detection tool. This method utilizes microbeads as sensing platform that was functionalized with the capture probes and modified electron rich proteins, and uses the horseradish peroxidase (HRP)-functionalized gold nanoparticles as label with a secondary DNA probe. The functionalized microbeads were independently introduced into the arrayed chambers using the loading chip slab. A single channel was used to generate weir structures to confine the microbeads and make the beads array accessible by microfluidics. Through "sandwich" hybridization, the enzyme-functionalized Au nanoparticles labels were brought close to the surface of microbeads. The oxidation of biotin-tyramine by hydrogen peroxide resulted in the deposition of multiple biotin moieties onto the surface of beads. This deposition is markedly increased in the presence of immobilized electron rich proteins. Streptavidin-labeled quantum dots were then allowed to bind to the deposited biotin moieties and displayed the signal. Enhanced detection sensitivity was achieved where the large surface area of Au nanoparticle carriers increased the amount HRP bound per sandwiched hybridization. The on-chip genotyping method could discriminate as low as 1fmol/L (10zmol/chip, SNR>3) synthesized HPV oligonucleotides DNA. The chip-based signal enhancement of the amplified assay resulted in 1000 times higher sensitivity than that of off-chip test. In addition, this on-chip format could discriminate and genotype 10copies/μL HPV genomic DNA using the PCR products. These results demonstrated that this on-chip approach can achieve highly sensitive detection and genotyping of target DNA and can be further developed for detection of disease-related biomolecules at the lowest level at their earliest incidence. Copyright © 2011 Elsevier B.V. All rights reserved.

Responses of molluscan communities to centuries of human impact in the northern Adriatic Sea

PubMed Central

Haselmair, Alexandra; Tomašových, Adam; Stachowitsch, Michael; Zuschin, Martin

2017-01-01

In sediment cores spanning ~500 years of history in the Gulf of Trieste, down-core changes in molluscan community structure are characterized by marked shifts in species and functional composition. Between the 16th and 19th century, a strong heavy metal contamination of the sediments, most notably by Hg, together with the effects of natural climatic oscillations (increased sedimentation and organic enrichment) drive community changes. Since the early 20th century up to 2013, the combined impacts of cultural eutrophication, frequent hypoxic events and intensifying bottom trawling replace heavy metal contamination and climatic factors as the main drivers. The pollution-tolerant and opportunistic bivalve Corbula gibba and the scavenging gastropod Nassarius pygmaeus significantly increase in abundance during the 20th century, while species more sensitive to disturbances and hypoxia such as Turritella communis and Kurtiella bidentata become rare or absent. An infaunal life habit and scavenging emerge as the dominant life strategies during the late 20th century. Down-core shifts in the proportional abundances of molluscan species and functional groups represent a sensitive proxy for past ecological changes and reveal a century-long anthropogenic impact as the main driver behind these processes in the northern Adriatic Sea, offering also a unique perspective for other shallow marine ecosystems worldwide. PMID:28723935

Organic solvent and temperature-enhanced ion chromatography-high resolution mass spectrometry for the determination of low molecular weight organic and inorganic anions.

PubMed

Gilchrist, Elizabeth S; Nesterenko, Pavel N; Smith, Norman W; Barron, Leon P

2015-03-20

There has recently been increased interest in coupling ion chromatography (IC) to high resolution mass spectrometry (HRMS) to enable highly sensitive and selective analysis. Herein, the first comprehensive study focusing on the direct coupling of suppressed IC to HRMS without the need for post-suppressor organic solvent modification is presented. Chromatographic selectivity and added HRMS sensitivity offered by organic solvent-modified IC eluents on a modern hyper-crosslinked polymeric anion-exchange resin (IonPac AS18) are shown using isocratic eluents containing 5-50 mM hydroxide with 0-80% methanol or acetonitrile for a range of low molecular weight anions (<165 Da). Comprehensive experiments on IC thermodynamics over a temperature range between 20-45 °C with the eluent containing up to 60% of acetonitrile or methanol revealed markedly different retention behaviour and selectivity for the selected analytes on the same polymer based ion-exchange resin. Optimised sensitivity with HRMS was achieved with as low as 30-40% organic eluent content. Analytical performance characteristics are presented and compared with other IC-MS based works. This study also presents the first application of IC-HRMS to forensic detection of trace low-order anionic explosive residues in latent human fingermarks. Copyright © 2015 Elsevier B.V. All rights reserved.

Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice

PubMed Central

2011-01-01

Background The expanding set of genomics tools available for inbred mouse strains has renewed interest in phenotyping larger sets of strains. The present study aims to explore phenotypic variability among six commonly-used inbred mouse strains to both the rewarding and locomotor stimulating effects of cocaine in a place conditioning task, including several strains or substrains that have not yet been characterized for some or all of these behaviors. Methods C57BL/6J (B6), BALB/cJ (BALB), C3H/HeJ (C3H), DBA/2J (D2), FVB/NJ (FVB) and 129S1/SvImJ (129) mice were tested for conditioned place preference to 20 mg/kg cocaine. Results Place preference was observed in most strains with the exception of D2 and 129. All strains showed a marked increase in locomotor activity in response to cocaine. In BALB mice, however, locomotor activation was context-dependent. Locomotor sensitization to repeated exposure to cocaine was most significant in 129 and D2 mice but was absent in FVB mice. Conclusions Genetic correlations suggest that no significant correlation between conditioned place preference, acute locomotor activation, and locomotor sensitization exists among these strains indicating that separate mechanisms underlie the psychomotor and rewarding effects of cocaine. PMID:21806802

Assessing the Potential of Metal-Assisted Imaging Mass Spectrometry in Cancer Research.

PubMed

Dufresne, M; Patterson, N H; Lauzon, N; Chaurand, P

2017-01-01

In the last decade, imaging mass spectrometry (IMS) has been the primary tool for biomolecular imaging. While it is possible to map a wide range of biomolecules using matrix-assisted laser desorption/ionization IMS ranging from high-molecular-weight proteins to small metabolites, more often than not only the most abundant easily ionisable species are detected. To better understand complex diseases such as cancer more specific and sensitive methods need to be developed to enable the detection of lower abundance molecules but also molecules that have yet to be imaged by IMS. In recent years, a big shift has occurred in the imaging community from developing wide reaching methods to developing targeted ones which increases sensitivity through the use of more specific sample preparations. This has been primarily marked by the advent of solvent-free matrix deposition methods for polar lipids, chemical derivatization for hormones and metabolites, and the use of alternative ionization agents for neutral lipids. In this chapter, we discuss two of the latest sample preparations which exploit the use of alternative ionization agents to enable the detection of certain classes of neutral lipids along with free fatty acids by high-sensitivity IMS as demonstrated within our lab. © 2017 Elsevier Inc. All rights reserved.

Biological and genetic evolution of HIV type 1 in two siblings with different patterns of disease progression.

PubMed

Ripamonti, Chiara; Leitner, Thomas; Laurén, Anna; Karlsson, Ingrid; Pastore, Angela; Cavarelli, Mariangela; Antonsson, Liselotte; Plebani, Anna; Fenyö, Eva Maria; Scarlatti, Gabriella

2007-12-01

To investigate the immunological and virological factors that may lead to different patterns of disease progression characteristic of HIV-1-infected children, two HIV-1-infected siblings, a slow and a fast progressor, were followed prospectively before the onset of highly active antiretroviral therapy. Viral coreceptor usage, including the use of CCR5/CXCR4 chimeric receptors, macrophage tropism, and sensitivity to the CC-chemokine RANTES, has been studied. An autologous and heterologous neutralizing antibody response has been documented using peripheral blood mononuclear cells- and GHOST(3) cell line-based assays. Viral evolution was investigated by env C2-V3 region sequence analysis. Although both siblings were infected with HIV-1 of the R5 phenotype, their viruses showed important biological differences. In the fast progressor there was a higher RANTES sensitivity of the early virus, an increased trend to change the mode of CCR5 receptor use, and a larger genetic evolution. Both children developed an autologous neutralizing antibody response starting from the second year with evidence of the continuous emergence of resistant variants. A marked viral genetic and phenotypic evolution was documented in the fast progressor sibling, which is accompanied by a high viral RANTES sensitivity and persistent neutralizing antibodies.

32 CFR 806.16 - For official use only.

Code of Federal Regulations, 2014 CFR

2014-07-01

... FREEDOM OF INFORMATION ACT PROGRAM § 806.16 For official use only. (a) Markings. Record owners may also... approval of (owner's organization, office symbol, phone).)” (b) Dissemination and transmission. (1) When deciding whether to send FOUO records over facsimile equipment, balance the sensitivity of the records...

32 CFR 806.16 - For official use only.

Code of Federal Regulations, 2013 CFR

2013-07-01

... FREEDOM OF INFORMATION ACT PROGRAM § 806.16 For official use only. (a) Markings. Record owners may also... approval of (owner's organization, office symbol, phone).)” (b) Dissemination and transmission. (1) When deciding whether to send FOUO records over facsimile equipment, balance the sensitivity of the records...

32 CFR 806.16 - For official use only.

Code of Federal Regulations, 2012 CFR

2012-07-01

... FREEDOM OF INFORMATION ACT PROGRAM § 806.16 For official use only. (a) Markings. Record owners may also... approval of (owner's organization, office symbol, phone).)” (b) Dissemination and transmission. (1) When deciding whether to send FOUO records over facsimile equipment, balance the sensitivity of the records...

VARIATION IN RESPONSIVENESS TO CONTAMINANTS IN WILD POPULATIONS OF ESTUARINE FISH, FUNDULUS HETERCLITUS

EPA Science Inventory

Populations of the non-migratory estuarine fish species Fundulus heteroclitus indigenous to a PCB-contaminated Superfund site (New Bedford Harbor, MA, USA) are markedly less sensitive to the toxic effects of local contaminants than those from a reference site. We characterized th...

Regulation of breathing and body temperature of a burrowing rodent during hypoxic-hypercapnia.

PubMed

Barros, Renata C H; Abe, Augusto S; Cárnio, Evelin C; Branco, Luiz G S

2004-05-01

Burrowing mammals usually have low respiratory sensitivity to hypoxia and hypercapnia. However, the interaction between ventilation (V), metabolism and body temperature (Tb) during hypoxic-hypercapnia has never been addressed. We tested the hypothesis that Clyomys bishopi, a burrowing rodent of the Brazilian cerrado, shows a small ventilatory response to hypoxic-hypercapnia, accompanied by a marked drop in Tb and metabolism. V, Tb and O(2) consumption (V?O(2)) of C. bishopi were measured during exposure to air, hypoxia (10% and 7% O(2)), hypercapnia (3% and 5% CO(2)) and hypoxic-hypercapnia (10% O(2)+ 3% CO(2)). Hypoxia of 7% but not 10%, caused a significant increase in V, and a significant drop in Tb. Both hypoxic levels decreased V?O(2) and 7% O(2) significantly increased V/V?O(2). Hypercapnia of 5%, but not 3%, elicited a significant increase in V, although no significant change in Tb, V?O(2) or V/V?O(2) was detected. A combination of 10% O(2) and 3% CO(2) had minor effects on V and Tb, while V?O(2) decreased and V/V?O(2) tended to increase. We conclude that C. bishopi has a low sensitivity not only to hypoxia and hypercapnia, but also to hypoxic-hypercapnia, manifested by a biphasic ventilatory response, a drop in metabolism and a tendency to increase V/V?O(2). The effect of hypoxic-hypercapnia was the summation of the hypoxia and hypercapnia effects, with respiratory responses tending to have hypercapnic patterns while metabolic responses, hypoxic patterns.

The role of sugar-sweetened beverage consumption in adolescent obesity: a review of the literature.

PubMed

Harrington, Susan

2008-02-01

Soft drink consumption has increased by 300% in the past 20 years, and 56-85% of children in school consume at least one soft drink daily. The odds ratio of becoming obese among children increases 1.6 times for each additional can or glass of sugar-sweetened drink consumed beyond their usual daily intake of the beverage. Soft drinks currently constitute the leading source of added sugars in the diet and exceed the U.S. Department of Agriculture's recommended total sugar consumption for adolescents. With the increase in adolescent obesity and the concurrent increase in consumption of sugar-sweetened beverages (SSB), the assumption infers a relationship between the two variables. SSB, classified as high-glycemic index (GI) liquids, increase postprandial blood glucose levels and decrease insulin sensitivity. Additionally, high-GI drinks submit to a decreased satiety level and subsequent overeating. Low-GI beverages stimulate a delayed return of hunger, thereby prompting an increased flexibility in amounts and frequencies of servings. Single intervention manipulation, elimination, or marked reduction of SSB consumption may serve to decrease caloric intake, increase satiety levels, decrease tendencies towards insulin resistance, and simplify the process of weight management in this population.

Role of PDGFs/PDGFRs signaling pathway in myocardial fibrosis of DOCA/salt hypertensive rats

PubMed Central

Fan, Bin; Ma, Likun; Li, Qian; Wang, Lin; Zhou, Junling; Wu, Jiawei

2014-01-01

This study aimed to investigate the role of PDGF/PDGFR signaling pathway in myocardial fibrosis of desoxycorticosterone (DOCA) induced salt-sensitive hypertensive rats and explore the influence of PDGF/PDGFR signaling pathway on fibroblasts and myofibroblasts in the heart. 60 male SD rats underwent right nephrectomy and bred with 1% sodium chloride and 0.1% potassium chloride for 4 weeks, and then randomly divided into 3 groups (CON group, DOCA group and DOCA+IMA group). Results showed that: 1) 14 and 28 days after intervention, the SBP in DOCA and DOCA+IMA group was significantly higher than that in CON group. At days 28, the severity of myocardial fibrosis and PVCA/VA ratio in DOCA group were significantly increased when compared with CON group. The severity of myocardial fibrosis and PVCA/VA ratio in DOCA+IMA group were markedly lower than those in DOCA group although they were higher than those in CON group. 2) At days 14, the mRNA expressions of PDGFRα and PDGFRβ in DOCA group were significantly higher than CON and DOCA+IMA group. At days 28, the mRNA expressions of PDGFRβ, FSP-1, α-SMA, procollagen I and procollagen III in DOCA group were significantly higher than those in CON group. In addition, in a specific group, the PDGFRβ mRNA expression was higher than the PDGFRα mRNA expression. In DOCA+IMA group, the mRNA expressions of PDGFRβ, FSP-1, α-SMA, procollagen I and procollagen III were markedly reduced when compared with DOCA group. 3) At 14 days, the protein expressions of PDGFRα and PDGFRβ in DOCA group were significantly higher than those in CON group. The PDGFRα protein expression in DOCA+IMA group was markedly lower than that in DOCA group. At days 28, the protein expressions of PDGFRα and PDGFRβ in DOCA group were significantly increased when compared with CON group. The protein expressions of PDGFRα and PDGFRβ in DOCA+IMA group were significantly lower than those in DOCA group. At day 28, the cardiac interstitium mainly contained vimentin positive fibroblasts, and α-SMA positive cells were less identified in CON group. In DOCA group, α-SMA positive fibroblasts (spindle-shaped) increased significantly, but the myofibroblasts reduced significantly in DOCA+IMA group when compared with DOCA group. 4) PDGFRα protein expression was observed in fibroblasts and myofibroblasts, but not in VSMCs. PDGFRβ protein expression was noted in not only fibroblasts and myofibroblasts but also VSMCs. Thus, During myocardial fibrosis of DOCA induced salt-sensitive hypertensive rats, PDGFRα acts at early stage, but PDGFRβ functions in the whole process. PDGFRα and PDGFRβ expressions increase in fibroblasts and myofibroblasts, suggesting that PDGF/PDGFR signaling pathway is involved in the myocardial fibrosis via stimulating fibroblasts to proliferate and transform into myofibroblasts. PMID:24427322

c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury?

PubMed Central

Gao, Yong-Jing; Ji, Ru-Rong

2009-01-01

c-Fos, the protein of the protooncogene c-fos, has been extensively used as a marker for the activation of nociceptive neurons in the spinal cord for more than twenty years since Hunt et al. first reported that peripheral noxious stimulation to a hind paw of rats leads to a marked induction of c-Fos in superficial and deep dorsal horn neurons in 1987. In 1999, Ji et al. reported that phosphorylated extracellular signal-regulated kinase (pERK) is specifically induced by noxious stimulation in superficial dorsal horn neurons. Accumulating evidence indicates that pERK induction or ERK activation in dorsal horn neurons is essential for the development of central sensitization, increased sensitivity of dorsal horn neurons that is responsible for the generation of persistent pain. Further, molecular mechanisms underlying ERK-mediated central sensitization have been revealed. In contrast, direct evidence for c-Fos-mediated central sensitization is not sufficient. After a noxious stimulus (e.g., capsaicin injection) or tissue injury, c-Fos begins to be induced after 30-60 minutes, whereas pERK can be induced within a minute, which can correlate well with the development of pain hypersensitivity. While c-Fos is often induced in the nuclei of neurons, pERK can be induced in different subcellular structures of neurons such as nuclei, cytoplasma, axons, and dendrites. pERK can even be induced in spinal cord microglia and astrocytes after nerve injury. In summary, both c-Fos and pERK can be used as markers for neuronal activation following noxious stimulation and tissue injury, but pERK is much more dynamic and appears to be a better marker for central sensitization. PMID:19898681

Impact of Breast Reader Assessment Strategy on mammographic radiologists' test reading performance.

PubMed

Suleiman, Wasfi I; Rawashdeh, Mohammad A; Lewis, Sarah J; McEntee, Mark F; Lee, Warwick; Tapia, Kriscia; Brennan, Patrick C

2016-06-01

The detection of breast cancer is somewhat limited by human factors, and thus there is a need to improve reader performance. This study assesses whether radiologists who regularly undertake the education in the form of the Breast Reader Assessment Strategy (BREAST) demonstrate any changes in mammography interpretation performance over time. In 2011, 2012 and 2013, 14 radiologists independently assessed a year-specific BREAST mammographic test-set. Radiologists read a different single test-set once each year, with each comprising 60 digital mammogram cases. Radiologists marked the location of suspected lesions without computer-aided diagnosis (CAD) and assigned a confidence rating of 2 for benign and 3-5 for malignant lesions. The mean sensitivity, specificity, location sensitivity, JAFROC FOM and ROC AUC were calculated. A Kruskal-Wallis test was used to compare the readings for the 14 radiologists across the 3 years. Wilcoxon signed rank test was used to assess comparison between pairs of years. Relationships between changes in performance and radiologist characteristics were examined using a Spearman's test. Significant increases were noted in mean sensitivity (P = 0.01), specificity (P = 0.01), location sensitivity (P = 0.001) and JAFROC FOM (P = 0.001) between 2011 and 2012. Between 2012 and 2013, significant improvements were noted in mean sensitivity (P = 0.003), specificity (P = 0.002), location sensitivity (P = 0.02), JAFROC FOM (P = 0.005) and ROC AUC (P = 0.008). No statistically significant correlations were shown between the levels of improvement and radiologists' characteristics. Radiologists' who undertake the BREAST programme demonstrate significant improvements in test-set performance during a 3-year period, highlighting the value of ongoing education through the use of test-set. © 2016 The Royal Australian and New Zealand College of Radiologists.

Group in-course assessment promotes cooperative learning and increases performance.

PubMed

Pratten, Margaret K; Merrick, Deborah; Burr, Steven A

2014-01-01

The authors describe and evaluate a method to motivate medical students to maximize the effectiveness of dissection opportunities by using In-Course-Assessments (ICAs) to encourage teamwork. A student's final mark was derived by combining the group dissection mark, group mark for questions, and their individual question mark. An analysis of the impact of the ICA was performed by comparing end of module practical summative marks in student cohorts who had, or had not, participated in the ICAs. Summative marks were compared by two-way ANOVA followed by Dunnets test, or by repeated measures ANOVA, as appropriate. A cohort of medical students was selected that had experienced both practical classes without (year one) and with the new ICA structure (year two). Comparison of summative year one and year two marks illustrated an increased improvement in year two performance in this cohort. A significant increase was also noted when comparing this cohort with five preceding year two cohorts who had not experienced the ICAs (P <0.0001). To ensure that variation in the practical summative examination was not impacting on the data, a comparison was made between three cohorts who had performed the same summative examination. Results show that students who had undertook weekly ICAs showed significantly improved summative marks, compared with those who did not (P <0.0001). This approach to ICA promotes engagement with learning resources in an active, team-based, cooperative learning environment. © 2013 American Association of Anatomists.

The effects of slice thickness and radiation dose level variations on computer-aided diagnosis (CAD) nodule detection performance in pediatric chest CT scans

NASA Astrophysics Data System (ADS)

Emaminejad, Nastaran; Lo, Pechin; Ghahremani, Shahnaz; Kim, Grace H.; Brown, Matthew S.; McNitt-Gray, Michael F.

2017-03-01

For pediatric oncology patients, CT scans are performed to assess treatment response and disease progression. CAD may be used to detect lung nodules which would reflect metastatic disease. The purpose of this study was to investigate the effects of reducing radiation dose and varying slice thickness on CAD performance in the detection of solid lung nodules in pediatric patients. The dataset consisted of CT scans of 58 pediatric chest cases, from which 7 cases had lung nodules detected by radiologist, and a total of 28 nodules were marked. For each case, the original raw data (sinogram data) was collected and a noise addition model was used to simulate reduced-dose scans of 50%, 25% and 10% of the original dose. In addition, the original and reduced-dose raw data were reconstructed at slice thicknesses of 1.5 and 3 mm using a medium sharp (B45) kernel; the result was eight datasets (4 dose levels x 2 thicknesses) for each case An in-house CAD tool was applied on all reconstructed scans, and results were compared with the radiologist's markings. Patient level mean sensitivities at 3mm thickness were 24%, 26%, 25%, 27%, and at 1.5 mm thickness were 23%, 29%, 35%, 36% for 10%, 25%, 50%, and 100% dose level, respectively. Mean FP numbers were 1.5, 0.9, 0.8, 0.7 at 3 mm and 11.4, 3.5, 2.8, 2.8 at 1.5 mm thickness for 10%, 25%, 50%, and 100% dose level respectively. CAD sensitivity did not change with dose level for 3mm thickness, but did change with dose for 1.5 mm. False Positives increased at low dose levels where noise values were high.

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

Chen, Haiwen; Li, Hongliang, E-mail: honglianglity@sina.com; Chen, Qi

Docetaxel efficiency in the therapy of prostate cancer (PCa) patients is limited due to the development of chemoresistance. Recent studies have implied a role of INPP4B in tumor chemoresistance, while the effects of INPP4B on docetaxel resistance in PCa have not been elucidated. In the present study, the docetaxel-resistant human PCa cell lines PC3-DR and DU-145-DR were established from the parental cell lines PC3 and DU-145, and the expression and role of INPP4B in docetaxel-resistant PCa cells were investigated. The results demonstrated that INPP4B expression was significantly downregulated in docetaxel-resistant cells. Overexpression of INPP4B increased the sensitivity to docetaxel andmore » promoted cell apoptosis in PC3-DR and DU-145-DR cells. In addition, INPP4B overexpression downregulated the expression of the mesenchymal markers fibronectin, N-cadherin, and vimentin, and upregulated the expression level of the epithelial maker E-cadherin. Furthermore, INPP4B overexpression markedly inhibited the PI3K/Akt pathway. We also found that IGF-1, the inhibitor of PI3K/Akt, markedly blocked the change in EMT markers induced by overexpression of INPP4B, and reversed the resistance of PC3-DR and DU-145-DR cells to docetaxel, which is sensitized by Flag-INPP4B. In summary, the presented data indicate that INPP4B is crucial for docetaxel-resistant PCa cell survival, potentially by regulating EMT through the PI3K/Akt signaling pathway. - Highlights: • INPP4B is downregulated in docetaxel-resistant PCa cells. • INPP4B inhibits cell proliferation. • INPP4B induces cell apoptosis. • INPP4B inhibits PCa cell EMT.« less

Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats

PubMed Central

Thorn, David A; An, Xiao-Fei; Zhang, Yanan; Pigini, Maria; Li, Jun-Xu

2012-01-01

BACKGROUND AND PURPOSE Imidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist-induced hypothermia as a functional in vivo assay of I2 receptor agonism. EXPERIMENTAL APPROACH Different groups of rats were used to examine the effects of I2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2 receptor ligands and different antagonists. KEY RESULTS All the selective I2 receptor agonists examined (2-BFI, diphenyzoline, phenyzoline, CR4056, tracizoline, BU224 and S22687, 3.2–56 mg·kg–1, i.p.) dose-dependently and markedly decreased the rectal temperature (hypothermia) in rats, with varied duration of action. Pharmacological mechanism of the observed hypothermia was studied by combining the I2 receptor agonists (2-BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2 receptor/ α2 adrenoceptor antagonist idazoxan, selective I1 receptor antagonist efaroxan, α2 adrenoceptor antagonist/5-HT1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2-BFI, BU224, tracizoline and diphenyzoline, supporting the I2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the α2 adrenoceptor agonist clonidine. Among all the I2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONS Imidazoline I2 receptor agonists can produce hypothermic effects, which are primarily mediated by I2 receptors. These data suggest that I2 receptor agonist-induced hypothermia is a simple and sensitive in vivo assay for studying I2 receptor ligands. PMID:22324428

Pyrethroids Differentially Alter Voltage-Gated Sodium Channels from the Honeybee Central Olfactory Neurons

PubMed Central

Kadala, Aklesso; Charreton, Mercedes; Jakob, Ingrid; Cens, Thierry; Rousset, Matthieu; Chahine, Mohamed; Le Conte, Yves; Charnet, Pierre; Collet, Claude

2014-01-01

The sensitivity of neurons from the honey bee olfactory system to pyrethroid insecticides was studied using the patch-clamp technique on central ‘antennal lobe neurons’ (ALNs) in cell culture. In these neurons, the voltage-dependent sodium currents are characterized by negative potential for activation, fast kinetics of activation and inactivation, and the presence of cumulative inactivation during train of depolarizations. Perfusion of pyrethroids on these ALN neurons submitted to repetitive stimulations induced (1) an acceleration of cumulative inactivation, and (2) a marked slowing of the tail current recorded upon repolarization. Cypermethrin and permethrin accelerated cumulative inactivation of the sodium current peak in a similar manner and tetramethrin was even more effective. The slow-down of channel deactivation was markedly dependent on the type of pyrethroid. With cypermethrin, a progressive increase of the tail current amplitude along with successive stimulations reveals a traditionally described use-dependent recruitment of modified sodium channels. However, an unexpected decrease in this tail current was revealed with tetramethrin. If one considers the calculated percentage of modified channels as an index of pyrethroids effects, ALNs are significantly more susceptible to tetramethrin than to permethrin or cypermethrin for a single depolarization, but this difference attenuates with repetitive activity. Further comparison with peripheral neurons from antennae suggest that these modifications are neuron type specific. Modeling the sodium channel as a multi-state channel with fast and slow inactivation allows to underline the effects of pyrethroids on a set of rate constants connecting open and inactivated conformations, and give some insights to their specificity. Altogether, our results revealed a differential sensitivity of central olfactory neurons to pyrethroids that emphasize the ability for these compounds to impair detection and processing of information at several levels of the bees olfactory pathway. PMID:25390654

Temperature Regulation of Endogenous Gibberellin Activity and Development of Tulipa gesneriana L. 1

PubMed Central

Aung, L. H.; De Hertogh, A. A.; Staby, G.

1969-01-01

The changes in the contents of free and bound gibberellin-like activity (GA) of Tulipa gesneriana L. cv. Ralph during development under 2 temperature conditions were studied. The results show that the content of free GA of bulbs grown at 18° increased by 67% over the initial level during development. The bound GA showed a slight initial increase and was followed by a rapid decrease. In contrast, bulbs treated at 13° showed a marked decline in free GA and a 2-fold increase in the content of bound GA. However, after the transfer of these bulbs from 13° to 18° the free GA increased to the initial level while the bound GA decreased to a low level. The rate of floral shoot and root development and time of flowering were accelerated at 18° as compared to 13°. From the data obtained, it was suggested that a temperature-sensitive interconversion mechanism between free and bound GA exists in tulip bulbs and that there is apparent synthesis or transformation of these phytohormones during development of the bulbs. PMID:16657075

The important role of sleep in metabolism.

PubMed

Copinschi, Georges; Leproult, Rachel; Spiegel, Karine

2014-01-01

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity. © 2014 S. Karger AG, Basel.

Aging, inflammation, and HIV infection.

PubMed

Aberg, Judith A

2012-01-01

Prolonged survival in HIV infection is accompanied by an increased frequency of non-HIV-related comorbidities. A number of age-related comorbidities occur earlier in HIV-infected patients than in individuals without HIV infection. This "accelerated aging" appears to be largely related to chronic inflammation, chronic immune activation, and immunosenescence in HIV infection. Levels of markers of inflammation and coagulopathy are elevated in HIV-infected patients, and elevations in markers such as high-sensitivity C-reactive protein, D-dimer, and interleukin 6 (IL-6) have been associated with increased risk for cardiovascular disease, opportunistic conditions, or all-cause mortality. In both HIV infection and aging, immunosenescence is marked by an increased proportion of CD28-, CD57+ memory CD8+ T cells with reduced capacity to produce interleukin 2 (IL-2), increased production of IL-6, resistance to apoptosis, and shortened telomeres. A number of AIDS Clinical Trials Group studies are under way to examine treatment aimed at reducing chronic inflammation and immune activation in HIV infection. This article summarizes a presentation by Judith A. Aberg, MD, at the IAS-USA live continuing medical education course held in New York City in October 2011.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles.

PubMed

Naeem, Muhammad; Cao, Jiafu; Choi, Moonjeong; Kim, Woo Seong; Moon, Hyung Ryong; Lee, Bok Luel; Kim, Min-Soo; Jung, Yunjin; Yoo, Jin-Wook

2015-01-01

Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

PubMed Central

Naeem, Muhammad; Cao, Jiafu; Choi, Moonjeong; Kim, Woo Seong; Moon, Hyung Ryong; Lee, Bok Luel; Kim, Min-Soo; Jung, Yunjin; Yoo, Jin-Wook

2015-01-01

Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy. PMID:26213469

Superoxide Dismutase

PubMed Central

Lee, Edward H.; Bennett, Jesse H.

1982-01-01

An experimental chemical N-[2-(2-oxo-1-imidazolidinyl)ethyl]-N′-phenylurea (EDU), is an effective protectant against acute and chronic foliar injury due to ozone (03) when sprayed on intact leaves or supplied to the plants through soil application. An 03-sensitive snap bean cultivar (Phaseolus vulgaris L. `Bush Blue Lake 290') was systemically treated with EDU (0, 25, 50, and 100 milligrams per 15-centimeter diameter pot) to determine if EDU-induced or activated protective oxyradical and peroxyl scavenging enzymes. EDU-enhanced tolerance to O3 injury always correlated with increases in superoxide dismutase (SOD) and catalase activities in the leaves. Peroxidase levels correlated more closely with foliar injury. Greater SOD levels in young leves compared to older leaves were associated with lower ozone sensitivities in these tissues. Polyacrylamide slab gel electrophoresis separations and specific determinations of SOD activity showed that EDU-treated plants possessed markedly greater SOD activity than non-treated plants. Tolerant plant tissues may have enhanced enzyme scavenging capabilities for the protection against toxic oxyradicals. Experimental confirmation for the oxyradical theory for O3 phytotoxicity and SOD involvement in the detoxification process are presented. Images PMID:16662420

Identification of phosphoproteins associated with maintenance of transformed state in temperature-sensitive Rous sarcoma-virus infected cells by proteomic analysis

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

Yamaoka, Kazuko; Imajoh-Ohmi, Shinobu; Fukuda, Hiroyuki

2006-07-07

To identify phosphotyrosine-containing proteins essential for maintaining the transformed state, we studied the tyrosine phosphorylation profile of temperature-sensitive mutant of Rous sarcoma virus, tsNY68, infected cells (68N7). Shifting the temperature from 39 {sup o}C (nonpermissive) to 32 {sup o}C (permissive) markedly increased the expression of phosphotyrosine-containing cell membrane proteins of {approx}40 kDa, as assessed by SDS-PAGE. Membrane and nuclear proteins were separated by two-dimensional gel electrophoresis and immunoblotted with anti-phosphotyrosine antibody. Proteins showing temperature-dependent changes in phosphorylation profile were subjected to in-gel digestion with trypsin and analyzed by mass spectrometry. Five proteins were identified: heterogeneous nuclear ribonucleoprotein (hnRNP) A3, hnRNPmore » A2, annexin II, phosphoglycerate mutase 1, and triosephosphate isomerase 1. hnRNP A3 was phosphorylated at serine residues and had both serine and tyrosine phosphorylated sites. These results suggest an important complementary role for proteomics in identifying molecular abnormalities associated with tumor progression that may be attractive candidates for tumor diagnosis.« less

Effects of cadmium concentration on ozone-induced phytotoxicity in cress

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

Czuba, M.; Ormrod, D.P.

1974-01-01

Cadmium solutions at concentrations of 0, 10, 40, 100, 500 or 1000 ppm were applied to the soil around cress (Lepidium sativum L. cv. Fine Curled) every 4th day for several weeks. Four week old plants were fumigated once at ozone levels of 0, 5, 10, 20, 25 or 30-35 pphm for 6 hours. Plants that had received higher concentrations of cadmium showed markedly increased sensitivity to ozone in terms of visible leaf damage after ozone treatment. Plants receiving cadmium solution alone or those receiving ozone treatment alone either did not show leaf damage or as much leaf damage asmore » plants which had received both treatments. Mineral analyses of plant tissues showed the relationship between tissue content of both essential and toxic cations and the sensitivity of the plant to various ozone levels. Pigment analyses showed changes in chlorophyll amounts and ratios between treatments. Statistical analyses of data for morphological parameters showed that there is an interaction between Cd and ozone treatments over a range of concentrations.« less

Simple detection of residual enrofloxacin in meat products using microparticles and biochips.

PubMed

Ha, Mi-Sun; Chung, Myung-Sub; Bae, Dong-Ho

2016-05-01

A simple and sensitive method for detecting enrofloxacin, a major veterinary fluoroquinolone, was developed. Monoclonal antibody specific for enrofloxacin was immobilised on a chip and fluorescent dye-labelled microparticles were covalently bound to the enrofloxacin molecules. Enrofloxacin in solution competes with the microparticle-immobilised enrofloxacin (enroMPs) to bind to the antibody on the chip. The presence of enrofloxacin was verified by detecting the fluorescence of enrofloxacin-bound microparticles. Under optimum conditions, a high dynamic range was achieved at enrofloxacin concentrations ranging from 1 to 1000 μg kg(-1). The limits of detection and quantification for standard solutions were 5 and 20 μg kg(-1) respectively, which are markedly lower than the maximum residue limit. Using simple extraction methods, recoveries from fortified beef, pork and chicken samples were 43.4-62.3%. This novel method also enabled approximate quantification of enrofloxacin concentration: the enroMP signal intensity decreased with increasing enrofloxacin concentration. Because of its sensitivity, specificity, simplicity and rapidity, the method described herein will facilitate the detection and approximate quantification of enrofloxacin residues in foods in a high-throughput manner.

Using eye-tracking to study the on-line processing of case-marking information among intermediate L2 learners of German

PubMed Central

Jackson, Carrie N.; Dussias, Paola E.; Hristova, Adelina

2012-01-01

This study uses eye-tracking to examine the processing of case-marking information in ambiguous subject- and object-first wh-questions in German. The position of the lexical verb was also manipulated via verb tense to investigate whether verb location influences how intermediate L2 learners process L2 sentences. Results show that intermediate L2 German learners were sensitive to case-marking information, exhibiting longer processing times on subject-first than object-first sentences, regardless of verb location. German native speakers exhibited the opposite word order preference, with longer processing times on object-first than subject-first sentences, replicating previous findings. These results are discussed in light of current L2 processing research, highlighting how methodological constraints influence researchers’ abilities to measure the on-line processing of morphosyntactic information among intermediate L2 learners. PMID:23493761

Lineal energy calibration of mini tissue-equivalent gas-proportional counters (TEPC)

NASA Astrophysics Data System (ADS)

Conte, V.; Moro, D.; Grosswendt, B.; Colautti, P.

2013-07-01

Mini TEPCs are cylindrical gas proportional counters of 1 mm or less of sensitive volume diameter. The lineal energy calibration of these tiny counters can be performed with an external gamma-ray source. However, to do that, first a method to get a simple and precise spectral mark has to be found and then the keV/μm value of this mark. A precise method (less than 1% of uncertainty) to identify this markis described here, and the lineal energy value of this mark has been measured for different simulated site sizes by using a 137Cs gamma source and a cylindrical TEPC equipped with a precision internal 244Cm alpha-particle source, and filled with propane-based tissue-equivalent gas mixture. Mini TEPCs can be calibrated in terms of lineal energy, by exposing them to 137Cesium sources, with an overall uncertainty of about 5%.

Evaluation of retroreflective markings to increase rail car conspicuity

DOT National Transportation Integrated Search

1998-10-01

The purpose of this study was to develop guidelines and recommendations for the design of retroreflective marking systems to enhance the conspicuity of rail cars at night. Three methods were used to generate and evaluate the marking systems for a sta...

Short post-weaning social isolation induces long-term changes in the dopaminergic system and increases susceptibility to psychostimulants in female rats.

PubMed

Lampert, Carine; Arcego, Danusa Mar; de Sá Couto-Pereira, Natividade; Dos Santos Vieira, Aline; Toniazzo, Ana Paula; Krolow, Rachel; Garcia, Emily; Vendite, Deusa Aparecida; Calcagnotto, Maria Elisa; Dalmaz, Carla

2017-10-01

Childhood and adolescence are sensitive periods of development, marked by high brain maturation and plasticity. Exposure to early life stress, such as social isolation, is able to prompt changes in sensitive brain circuitries, essentially in the mesolimbic dopaminergic system and increase the risk for addictive behaviors later in life. Post-weaning social isolation can stimulate the consumption of rewarding substances, like drugs of abuse and palatable foods. However, most studies analyze long periods of social isolation and very little is known about the effects of a brief social isolation in a sensitive period of development and its association with palatable food on the reward system sensitization. Furthermore, females are more susceptible to the reinforcing effect of drugs than males. Therefore, the aim of this study was to analyze the effects of a short post-weaning social isolation combined with a free access to a chronic high sugar diet (HSD) on the dopaminergic system, oxidative status and behavioral response to an amphetamine-like drug in adulthood. We used female Wistar rats that were socially isolated from post-natal days (PD) 21 to 35 and received free access to a HSD until PD 60. On PD 65, animals were submitted to a challenge with diethylpropion (DEP), an amphetamine-like drug and different responses were analyzed: locomotor activity, immmunocontent of dopamine related proteins, and the oxidative status in the striatum, before and after the DEP challenge. We showed that a short post-weaning social isolation (SI) increased the locomotor response to DEP, when compared with previous saline administration. Social isolation also increased dopamine transporter, tyrosine hydroxylase, and decreased dopamine D2 receptor immunocontent. Additionally, SI increased the overall oxidative status parameters after the challenge with DEP. Interestingly, the exposure to a HSD prevented the SI effects on locomotor response, but did not interfere in the dopaminergic parameters evaluated, despite having modified some oxidative parameters. This study showed for the first time that a short post-weaning social isolation was able to induce long-term changes in the striatal dopaminergic system and increased the response to psychostimulants. These results emphasize the importance of stressful experiences during a short period of development on programming susceptibility to psychostimulants later in life. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

RDBE Development and Progress

NASA Astrophysics Data System (ADS)

Neill, A.; Bark, M.; Beaudoin, C.; Brisken, W.; Ben Frej, H.; Doeleman, S.; Durand, S.; Guerra, Ml; Hinton, A.; Luce, M.; McWhirter, R.; Morris, K.; Peck, G.; Revnell, M.; Rogers, A.; Romney, J.; Ruszczyk, C; Taveniku, M.; Walker, R.; Whitney, A.

2010-12-01

A digital backend based on the ROACH board has been developed jointly by the National Radio Astronomy Observatory and MIT Haystack Observatory. The RDBE will have both Polyphase Filterbank and Digital Downconverter personalities. The initial configuration outputs sixteen 32-MHz channels, comprised of half the channels from the PFB processing of the two IF inputs, for use in the VLBI2010 geodetic system and in the VLBA sensitivity upgrade project. The output rate is 2x10^9 bits/second (1x10^9 bits/sec = 1 Gbps) over a 10 GigE connection to the Mark 5C with the data written in Mark 5B format on disk.

RDBE Development and Progress

NASA Technical Reports Server (NTRS)

Niell, A.; Bark, M.; Beaudoin, C.; Brisken, W.; Frej, H. Ben; Doeleman, S.; Durand, S.; Guerra, M.; Hinton, A.; Luce, M.;

Gradient-based controllers for timed continuous Petri nets

NASA Astrophysics Data System (ADS)

Lefebvre, Dimitri; Leclercq, Edouard; Druaux, Fabrice; Thomas, Philippe

2015-07-01

This paper is about control design for timed continuous Petri nets that are described as piecewise affine systems. In this context, the marking vector is considered as the state space vector, weighted marking of place subsets are defined as the model outputs and the model inputs correspond to multiplicative control actions that slow down the firing rate of some controllable transitions. Structural and functional sensitivity of the outputs with respect to the inputs are discussed in terms of Petri nets. Then, gradient-based controllers (GBC) are developed in order to adapt the control actions of the controllable transitions according to desired trajectories of the outputs.

Efficient Multi-Source Data Fusion for Decentralized Sensor Networks

DTIC Science & Technology

2006-10-01

Operating Picture (COP). Robovolc, accessing a single DDF node associated with a CCTV camera (marked in orange in Figure 3a), defends a ‘ sensitive ...Gaussian environments. Figure 10: Particle Distribution Snapshots osition error between each target and the me ed particle set at the bearing-only

A net fishing enrichment strategy for colorimetric detection of E. coli O157:H7

USDA-ARS?s Scientific Manuscript database

The strict regulatory requirements for pathogen monitoring in food systems to ensure safety demands that the detection method can recognize small numbers of pathogens. Although significant efforts on the development of biosensors have been reported with marked improvement in sensitivity, appropriate...

Molecular Basis of Paralytic Neurotoxin Action on Voltage-Sensitive Sodium Channels

DTIC Science & Technology

1989-10-20

acting at neurotoxin receptor site 2, and markedly potentiated and prolonged by polypeptide a-scorpion toxins and sea anemone toxins acting at neurotoxin...to block the actions of scorpion toxins and sea anemone toxins on the sodium channel. Transmembrane organization of amino acid sequences between

Stable long-term blood formation by stem cells in murine steady-state hematopoiesis.

PubMed

Zavidij, Oksana; Ball, Claudia R; Herbst, Friederike; Oppel, Felix; Fessler, Sylvia; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno

2012-09-01

Hematopoietic stem cells (HSCs) generate all mature blood cells during the whole lifespan of an individual. However, the clonal contribution of individual HSC and progenitor cells in steady-state hematopoiesis is poorly understood. To investigate the activity of HSCs under steady-state conditions, murine HSC and progenitor cells were genetically marked in vivo by integrating lentiviral vectors (LVs) encoding green fluorescent protein (GFP). Hematopoietic contribution of individual marked clones was monitored by determination of lentiviral integration sites using highly sensitive linear amplification-mediated-polymerase chain reaction. A remarkably stable small proportion of hematopoietic cells expressed GFP in LV-injected animals for up to 24 months, indicating stable marking of murine steady-state hematopoiesis. Analysis of the lentiviral integration sites revealed that multiple hematopoietic clones with both myeloid and lymphoid differentiation potential contributed to long-term hematopoiesis. In contrast to intrafemoral vector injection, intravenous administration of LV preferentially targeted short-lived progenitor cells. Myelosuppressive treatment of mice prior to LV-injection did not affect the marking efficiency. Our study represents the first continuous analysis of clonal behavior of genetically marked hematopoietic cells in an unmanipulated system, providing evidence that multiple clones are simultaneously active in murine steady-state hematopoiesis. Copyright © 2012 AlphaMed Press.

A survey of some metallographic etching reagents for restoration of obliterated engraved marks on aluminium-silicon alloy surfaces.

PubMed

Uli, Norjaidi; Kuppuswamy, R; Amran, Mohd Firdaus Che

2011-05-20

A brief survey to assess the sensitivity and efficacy of some common etching reagents for revealing obliterated engraved marks on Al-Si alloy surfaces is presented. Experimental observations have recommended use of alternate swabbing of 10% NaOH and 10% HNO(3) on the obliterated surfaces for obtaining the desired results. The NaOH etchant responsible for bringing back the original marks resulted in the deposition of some dark coating that has masked the recovered marks. The coating had been well removed by dissolving it in HNO(3) containing 10-20% acid. However, the above etching procedure was not effective on aluminium (99% purity) and Al-Zn-Mg-Cu alloy surfaces. Also the two reagents (i) immersion in 10% aq. phosphoric acid and (ii) alternate swabbing of 60% HCl and 40% NaOH suggested earlier for high strength Al-Zn-Mg-Cu alloys [23] were quite ineffective on Al-Si alloys. Thus different aluminium alloys needed different etching treatments for successfully restoring the obliterated marks. Al-Si alloys used in casting find wide applications especially in the manufacture of engine blocks of motor vehicles. Hence, the results presented in this paper are of much relevance in serial number restoration problems involving this alloy. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

C-arm flat-panel CT arthrography of the shoulder: Radiation dose considerations and preliminary data on diagnostic performance.

PubMed

Guggenberger, Roman; Ulbrich, Erika J; Dietrich, Tobias J; Scholz, Rosemarie; Kaelin, Pascal; Köhler, Christoph; Elsässer, Thilo; Le Corroller, Thomas; Pfammatter, Thomas; Alkadhi, Hatem; Andreisek, Gustav

2017-02-01

To investigate radiation dose and diagnostic performance of C-arm flat-panel CT (FPCT) versus standard multi-detector CT (MDCT) shoulder arthrography using MRI-arthrography as reference standard. Radiation dose of two different FPCT acquisitions (5 and 20 s) and standard MDCT of the shoulder were assessed using phantoms and thermoluminescence dosimetry. FPCT arthrographies were performed in 34 patients (mean age 44 ± 15 years). Different joint structures were quantitatively and qualitatively assessed by two independent radiologists. Inter-reader agreement and diagnostic performance were calculated. Effective radiation dose was markedly lower in FPCT 5 s (0.6 mSv) compared to MDCT (1.7 mSv) and FPCT 20 s (3.4 mSv). Contrast-to-noise ratios (CNRs) were significantly (p < 0.05) higher in FPCT 20-s versus 5-s protocols. Inter-reader agreements of qualitative ratings ranged between к = 0.47-1.0. Sensitivities for cartilage and rotator cuff pathologies were low for FPCT 5-s (40 % and 20 %) and moderate for FPCT 20-s protocols (75 % and 73 %). FPCT showed high sensitivity (81-86 % and 89-99 %) for bone and acromioclavicular-joint pathologies. Using a 5-s protocol FPCT shoulder arthrography provides lower radiation dose compared to MDCT but poor sensitivity for cartilage and rotator cuff pathologies. FPCT 20-s protocol is moderately sensitive for cartilage and rotator cuff tendon pathology with markedly higher radiation dose compared to MDCT. • FPCT shoulder arthrography is feasible with fluoroscopy and CT in one workflow. • A 5-s FPCT protocol applies a lower radiation dose than MDCT. • A 20-s FPCT protocol is moderately sensitive for cartilage and tendon pathology.

Dietary alleviation of maternal obesity and diabetes: increased resistance to diet-induced obesity transcriptional and epigenetic signatures.

PubMed

Attig, Linda; Vigé, Alexandre; Gabory, Anne; Karimi, Moshen; Beauger, Aurore; Gross, Marie-Sylvie; Athias, Anne; Gallou-Kabani, Catherine; Gambert, Philippe; Ekstrom, Tomas J; Jais, Jean-Philippe; Junien, Claudine

2013-01-01

According to the developmental origins of health and diseases (DOHaD), and in line with the findings of many studies, obesity during pregnancy is clearly a threat to the health and well-being of the offspring, later in adulthood. We previously showed that 20% of male and female inbred mice can cope with the obesogenic effects of a high-fat diet (HFD) for 20 weeks after weaning, remaining lean. However the feeding of a control diet (CD) to DIO mice during the periconceptional/gestation/lactation period led to a pronounced sex-specific shift (17% to 43%) from susceptibility to resistance to HFD, in the female offspring only. Our aim in this study was to determine how, in the context of maternal obesity and T2D, a CD could increase resistance on female fetuses. Transcriptional analyses were carried out with a custom-built mouse liver microarray and by quantitative RT-PCR for muscle and adipose tissue. Both global DNA methylation and levels of pertinent histone marks were assessed by LUMA and western blotting, and the expression of 15 relevant genes encoding chromatin-modifying enzymes was analyzed in tissues presenting global epigenetic changes. Resistance was associated with an enhancement of hepatic pathways protecting against steatosis, the unexpected upregulation of neurotransmission-related genes and the modulation of a vast imprinted gene network. Adipose tissue displayed a pronounced dysregulation of gene expression, with an upregulation of genes involved in lipid storage and adipocyte hypertrophy or hyperplasia in obese mice born to lean and obese mothers, respectively. Global DNA methylation, several histone marks and key epigenetic regulators were also altered. Whether they were themselves lean (resistant) or obese (sensitive), the offspring of lean and obese mice clearly differed in terms of several metabolic features and epigenetic marks suggesting that the effects of a HFD depend on the leanness or obesity of the mother.

Mirror-Mark Tests Performed on Jackdaws Reveal Potential Methodological Problems in the Use of Stickers in Avian Mark-Test Studies

PubMed Central

Soler, Manuel; Pérez-Contreras, Tomás; Peralta-Sánchez, Juan Manuel

2014-01-01

Some animals are capable of recognizing themselves in a mirror, which is considered to be demonstrated by passing the mark test. Mirror self-recognition capacity has been found in just a few mammals having very large brains and only in one bird, the magpie (Pica pica). The results obtained in magpies have enormous biological and cognitive implications because the fact that magpies were able to pass the mark test meant that this species is at the same cognitive level with great apes, that mirror self-recognition has evolved independently in the magpie and great apes (which diverged 300 million years ago), and that the neocortex (which is not present in the bird's brains) is not a prerequisite for mirror self-recognition as previously believed. Here, we have replicated the experimental design used on magpies to determine whether jackdaws (Corvus monedula) are also capable of mirror self-recognition by passing the mark test. We found that our nine jackdaws showed a very high interest towards the mirror and exhibited self-contingent behavior as soon as mirrors were introduced. However, jackdaws were not able to pass the mark test: both sticker-directed actions and sticker removal were performed with a similar frequency in both the cardboard (control) and the mirror conditions. We conclude that our jackdaws' behaviour raises non-trivial questions about the methodology used in the avian mark test. Our study suggests that the use of self-adhesive stickers on sensitive throat feathers may open the way to artefactual results because birds might perceive the stickers tactilely. PMID:24475085

Mirror-mark tests performed on jackdaws reveal potential methodological problems in the use of stickers in avian mark-test studies.

PubMed

Soler, Manuel; Pérez-Contreras, Tomás; Peralta-Sánchez, Juan Manuel

2014-01-01

Some animals are capable of recognizing themselves in a mirror, which is considered to be demonstrated by passing the mark test. Mirror self-recognition capacity has been found in just a few mammals having very large brains and only in one bird, the magpie (Pica pica). The results obtained in magpies have enormous biological and cognitive implications because the fact that magpies were able to pass the mark test meant that this species is at the same cognitive level with great apes, that mirror self-recognition has evolved independently in the magpie and great apes (which diverged 300 million years ago), and that the neocortex (which is not present in the bird's brains) is not a prerequisite for mirror self-recognition as previously believed. Here, we have replicated the experimental design used on magpies to determine whether jackdaws (Corvus monedula) are also capable of mirror self-recognition by passing the mark test. We found that our nine jackdaws showed a very high interest towards the mirror and exhibited self-contingent behavior as soon as mirrors were introduced. However, jackdaws were not able to pass the mark test: both sticker-directed actions and sticker removal were performed with a similar frequency in both the cardboard (control) and the mirror conditions. We conclude that our jackdaws' behaviour raises non-trivial questions about the methodology used in the avian mark test. Our study suggests that the use of self-adhesive stickers on sensitive throat feathers may open the way to artefactual results because birds might perceive the stickers tactilely.

The Usefulness of Selected Physicochemical Indices, Cell Membrane Integrity and Sperm Chromatin Structure in Assessments of Boar Semen Sensitivity

PubMed Central

Wysokińska, A.; Kondracki, S.; Iwanina, M.

2015-01-01

The present work describes experiments undertaken to evaluate the usefulness of selected physicochemical indices of semen, cell membrane integrity and sperm chromatin structure for the assessment of boar semen sensitivity to processes connected with pre-insemination procedures. The experiments were carried out on 30 boars: including 15 regarded as providers of sensitive semen and 15 regarded as providers of semen that is little sensitive to laboratory processing. The selection of boars for both groups was based on sperm morphology analyses, assuming secondary morphological change incidence in spermatozoa as the criterion. Two ejaculates were manually collected from each boar at an interval of 3 to 4 months. The following analyses were carried out for each ejaculate: sperm motility assessment, sperm pH measurement, sperm morphology assessment, sperm chromatin structure evaluation and cell membrane integrity assessment. The analyses were performed three times. Semen storage did not cause an increase in the incidence of secondary morphological changes in the group of boars considered to provide sperm of low sensitivity. On the other hand, with continued storage there was a marked increase in the incidence of spermatozoa with secondary morphological changes in the group of boars regarded as producing more sensitive semen. Ejaculates of group I boars evaluated directly after collection had an approximately 6% smaller share of spermatozoa with undamaged cell membranes than the ejaculates of boars in group II (p≤0.05). In the process of time the percentage of spermatozoa with undamaged cell membranes decreased. The sperm of group I boars was characterised with a lower sperm motility than the semen of group II boars. After 1 hour of storing diluted semen, the sperm motility of boars producing highly sensitive semen was already 4% lower (p≤0.05), and after 24 hours of storage it was 6.33% lower than that of the boars that produced semen with a low sensitivity. Factors that confirm the accuracy of insemination male selection can include a low rate of sperm motility decrease during the storage of diluted semen, low and contained incidence of secondary morphological changes in spermatozoa during semen storage and a high frequency of spermatozoa with undamaged cell membranes. PMID:26580438

Iris registration in wavefront-guided LASIK to correct mixed astigmatism.

PubMed

Khalifa, Mounir; El-Kateb, Mohamed; Shaheen, Mohamed Shafik

2009-03-01

To investigate the predictability, safety, and efficiency of wavefront-guided laser in situ keratomileusis (LASIK) with iris-registration technology to correct mixed astigmatism. Vision correction center, Alexandria, Egypt. This retrospective double-blind study included randomly selected patients with mixed astigmatism who sought laser refractive surgery. Patients were divided equally into 3 groups and treated with conventional LASIK and manual marking, wavefront-guided LASIK and manual marking, or wavefront-guided LASIK with iris registration (LASIK+IR group). Eyes were analyzed preoperatively and up to 3 months postoperatively. The LASIK+IR group had better postoperative uncorrected visual acuity (100% 20/30 or better; 90% 20/20 or better; 20% 20/16 or better) than the other groups and did not lose preoperative best spectacle-corrected visual acuity, unlike the other groups. This group also had the highest percentage of eyes that gained lines of acuity (20% 1 line; 10% 2 lines). The LASIK+IR group had the highest predictability of spherical refraction (80% within +/-0.50 diopter [D]; 100% within +/-1.00 D [P<.05] and the highest predictability of cylinder refraction. The LASIK+IR eyes had a significantly smaller increase postoperatively in coma, trefoil, and secondary astigmatism. There was no significant difference between groups in spherical aberration or quadrafoil. The LASIK-IR group had the most improvement in scotopic contrast sensitivity (P<.05). Wavefront-guided LASIK with iris registration was more predictable, safe, and efficient than conventional or wavefront-guided LASIK with manual marking in correcting mixed astigmatism. Further studies are needed to confirm these results.

Genetic differences in the ethanol sensitivity of GABA sub A receptors expressed in Xenopus oocytes

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

Wafford, K.A.; Burnett, D.M.; Dunwiddie, T.V.

1990-07-20

Animal lines selected for differences in drug sensitivity can be used to help determine the molecular basis of drug action. Long-sleep (LS) and short-sleep (SS) mice differ markedly in their genetic sensitivity to ethanol. To investigate the molecular basis for this difference, mRNA from brains of LS and SS mice was expressed in Xenopus oocytes and the ethanol sensitivity of gamma-aminobutyric acid A (GABA{sub A})- and N-methyl D-aspartate (NMDA) - activated ion channels was tested. Ethanol facilitated GABA responses in oocytes injected with mRNA from LS mice but antagonized responses in oocytes injected with mRNA from SS animals. Ethanol inhibitedmore » NMDA responses equally in the two lines. Thus, genes coding for the GABA{sub A} receptor or associated proteins may be critical determinants of individual differences in ethanol sensitivity.« less

Respiratory Viral Infection in Neonatal Piglets Causes Marked Microglia Activation in the Hippocampus and Deficits in Spatial Learning

PubMed Central

Elmore, Monica R. P.; Burton, Michael D.; Conrad, Matthew S.; Rytych, Jennifer L.; Van Alstine, William G.

2014-01-01

Environmental insults during sensitive periods can affect hippocampal development and function, but little is known about peripheral infection, especially in humans and other animals whose brain is gyrencephalic and experiences major perinatal growth. Using a piglet model, the present study showed that inoculation on postnatal day 7 with the porcine reproductive and respiratory syndrome virus (PRRSV) caused microglial activation within the hippocampus with 82% and 43% of isolated microglia being MHC II+ 13 and 20 d after inoculation, respectively. In control piglets, <5% of microglia isolated from the hippocampus were MHC II+. PRRSV piglets were febrile (p < 0.0001), anorectic (p < 0.0001), and weighed less at the end of the study (p = 0.002) compared with control piglets. Increased inflammatory gene expression (e.g., IL-1β, IL-6, TNF-α, and IFN-γ) was seen across multiple brain regions, including the hippocampus, whereas reductions in CD200, NGF, and MBP were evident. In a test of spatial learning, PRRSV piglets took longer to acquire the task, had a longer latency to choice, and had a higher total distance moved. Overall, these data demonstrate that viral respiratory infection is associated with a marked increase in activated microglia in the hippocampus, neuroinflammation, and impaired performance in a spatial cognitive task. As respiratory infections are common in human neonates and infants, approaches to regulate microglial cell activity are likely to be important. PMID:24501353

Up-regulation of avian uncoupling protein in cold-acclimated and hyperthyroid ducklings prevents reactive oxygen species production by skeletal muscle mitochondria.

PubMed

Rey, Benjamin; Roussel, Damien; Romestaing, Caroline; Belouze, Maud; Rouanet, Jean-Louis; Desplanches, Dominique; Sibille, Brigitte; Servais, Stéphane; Duchamp, Claude

2010-04-28

Although identified in several bird species, the biological role of the avian homolog of mammalian uncoupling proteins (avUCP) remains extensively debated. In the present study, the functional properties of isolated mitochondria were examined in physiological or pharmacological situations that induce large changes in avUCP expression in duckling skeletal muscle. The abundance of avUCP mRNA, as detected by RT-PCR in gastrocnemius muscle but not in the liver, was markedly increased by cold acclimation (CA) or pharmacological hyperthyroidism but was down-regulated by hypothyroidism. Activators of UCPs, such as superoxide with low doses of fatty acids, stimulated a GDP-sensitive proton conductance across the inner membrane of muscle mitochondria from CA or hyperthyroid ducklings. The stimulation was much weaker in controls and not observed in hypothyroid ducklings or in any liver mitochondrial preparations. The production of endogenous mitochondrial reactive oxygen species (ROS) was much lower in muscle mitochondria from CA and hyperthyroid ducklings than in the control or hypothyroid groups. The addition of GDP markedly increased the mitochondrial ROS production of CA or hyperthyroid birds up to, or above, the level of control or hypothyroid ducklings. Differences in ROS production among groups could not be attributed to changes in antioxidant enzyme activities (superoxide dismutase or glutathione peroxidase). This work provides the first functional in vitro evidence that avian UCP regulates mitochondrial ROS production in situations of enhanced metabolic activity.

Up-regulation of avian uncoupling protein in cold-acclimated and hyperthyroid ducklings prevents reactive oxygen species production by skeletal muscle mitochondria

PubMed Central

2010-01-01

Background Although identified in several bird species, the biological role of the avian homolog of mammalian uncoupling proteins (avUCP) remains extensively debated. In the present study, the functional properties of isolated mitochondria were examined in physiological or pharmacological situations that induce large changes in avUCP expression in duckling skeletal muscle. Results The abundance of avUCP mRNA, as detected by RT-PCR in gastrocnemius muscle but not in the liver, was markedly increased by cold acclimation (CA) or pharmacological hyperthyroidism but was down-regulated by hypothyroidism. Activators of UCPs, such as superoxide with low doses of fatty acids, stimulated a GDP-sensitive proton conductance across the inner membrane of muscle mitochondria from CA or hyperthyroid ducklings. The stimulation was much weaker in controls and not observed in hypothyroid ducklings or in any liver mitochondrial preparations. The production of endogenous mitochondrial reactive oxygen species (ROS) was much lower in muscle mitochondria from CA and hyperthyroid ducklings than in the control or hypothyroid groups. The addition of GDP markedly increased the mitochondrial ROS production of CA or hyperthyroid birds up to, or above, the level of control or hypothyroid ducklings. Differences in ROS production among groups could not be attributed to changes in antioxidant enzyme activities (superoxide dismutase or glutathione peroxidase). Conclusion This work provides the first functional in vitro evidence that avian UCP regulates mitochondrial ROS production in situations of enhanced metabolic activity. PMID:20426850

Riboswitch-based sensor in low optical background

NASA Astrophysics Data System (ADS)

Harbaugh, Svetlana V.; Davidson, Molly E.; Chushak, Yaroslav G.; Kelley-Loughnane, Nancy; Stone, Morley O.

2008-08-01

Riboswitches are a type of natural genetic control element that use untranslated sequence in the RNA to recognize and bind to small molecules that regulate expression of that gene. Creation of synthetic riboswitches to novel ligands depends on the ability to screen for analyte binding sensitivity and specificity. In our work, we have coupled a synthetic riboswitch to an optical reporter assay based on fluorescence resonance energy transfer (FRET) between two genetically-coded fluorescent proteins. Specifically, a theophylline-sensitive riboswitch was placed upstream of the Tobacco Etch Virus (TEV) protease coding sequence, and a FRET-based construct, BFP-eGFP or eGFP-REACh, was linked by a peptide encoding the recognition sequence for TEV protease. Cells expressing the riboswitch showed a marked optical difference in fluorescence emission in the presence of theophylline. However, the BFP-eGFP FRET pair posses significant optical background that reduces the sensitivity of a FRET-based assay. To improve the optical assay, we designed a nonfluorescent yellow fluorescent protein (YFP) mutant called REACh (for Resonance Energy-Accepting Chromoprotein) as the FRET acceptor for eGFP. The advantage of using an eGFP-REACh pair is the elimination of acceptor fluorescence which leads to an improved detection of FRET via better signal-to-noise ratio. The EGFP-REACh fusion protein was constructed with the TEV protease cleavage site; thus upon TEV translation, cleavage occurs diminishing REACh quenching and increasing eGFP emission resulting in a 4.5-fold improvement in assay sensitivity.

Comparison of two stand-alone CADe systems at multiple operating points

NASA Astrophysics Data System (ADS)

Sahiner, Berkman; Chen, Weijie; Pezeshk, Aria; Petrick, Nicholas

2015-03-01

Computer-aided detection (CADe) systems are typically designed to work at a given operating point: The device displays a mark if and only if the level of suspiciousness of a region of interest is above a fixed threshold. To compare the standalone performances of two systems, one approach is to select the parameters of the systems to yield a target false-positive rate that defines the operating point, and to compare the sensitivities at that operating point. Increasingly, CADe developers offer multiple operating points, which necessitates the comparison of two CADe systems involving multiple comparisons. To control the Type I error, multiple-comparison correction is needed for keeping the family-wise error rate (FWER) less than a given alpha-level. The sensitivities of a single modality at different operating points are correlated. In addition, the sensitivities of the two modalities at the same or different operating points are also likely to be correlated. It has been shown in the literature that when test statistics are correlated, well-known methods for controlling the FWER are conservative. In this study, we compared the FWER and power of three methods, namely the Bonferroni, step-up, and adjusted step-up methods in comparing the sensitivities of two CADe systems at multiple operating points, where the adjusted step-up method uses the estimated correlations. Our results indicate that the adjusted step-up method has a substantial advantage over other the two methods both in terms of the FWER and power.

Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR

PubMed Central

Iwama, Eiji; Takayama, Koichi; Harada, Taishi; Okamoto, Isamu; Ookubo, Fumihiko; Kishimoto, Junji; Baba, Eishi; Oda, Yoshinao; Nakanishi, Yoichi

2015-01-01

The mutation of T790M in EGFR is a major mechanism of resistance to treatment with EGFR-TKIs. Only qualitative detection (presence or absence) of T790M has been described to date, however. Digital PCR (dPCR) analysis has recently been applied to the quantitative detection of target molecules in cancer with high sensitivity. In the present study, 25 tumor samples (13 obtained before and 12 after EGFR-TKI treatment) from 18 NSCLC patients with activating EGFR mutations were evaluated for T790M with dPCR. The ratio of the number of T790M alleles to that of activating mutation alleles (T/A) was determined. dPCR detected T790M in all 25 samples. Although T790M was present in all pre-TKI samples from 13 patients, 10 of these patients had a low T/A ratio and manifested substantial tumor shrinkage during treatment with EGFR-TKIs. In six of seven patients for whom both pre- and post-TKI samples were available, the T/A ratio increased markedly during EGFR-TKI treatment. Highly sensitive dPCR thus detected T790M in all NSCLC patients harboring activating EGFR mutations whether or not they had received EGFR-TKI treatment. Not only highly sensitive but also quantitative detection of T790M is important for evaluation of the contribution of T790M to EGFR-TKI resistance. PMID:26015401

Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam.

PubMed

Vágvölgyi, Máté; Martins, Ana; Kulmány, Ágnes; Zupkó, István; Gáti, Tamás; Simon, András; Tóth, Gábor; Hunyadi, Attila

2018-01-20

Multidrug resistance is a widespread problem among various diseases and cancer is no exception. We had previously described the chemo-sensitizing activity of ecdysteroid derivatives with low polarity on drug susceptible and multi-drug resistant (MDR) cancer cells. We have also shown that these molecules have a marked selectivity towards the MDR cells. Recent studies on the oximation of various steroid derivatives indicated remarkable increase in their antitumor activity, but there is no related bioactivity data on ecdysteroid oximes. In our present study, 13 novel ecdysteroid derivatives (oximes, oxime ethers and a lactam) and one known compound were synthesized from 20-hydroxyecdysone 2,3;20,22-diacetonide and fully characterized by comprehensive NMR techniques revealing their complete 1 H and 13 C signal assignments. The compounds exerted moderate to strong in vitro antiproliferative activity on HeLa, SiHa, MCF-7 and MDA-MB-231 cell lines. Oxime and particularly oxime ether formation strongly increased their inhibitory activity on the efflux of rhodamine 123 by P-glycoprotein (P-gp), while the new ecdysteroid lactam did not interfere with the efflux function. All compounds exerted potent chemo-sensitizing activity towards doxorubicin on a mouse lymphoma cell line and on its MDR counterpart, and, on the latter, the lactam was found the most active. Because of its MDR-selective chemo-sensitizing activity with no functional effect on P-gp, this lactam is of high potential interest as a new lead for further antitumor studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[The dry binders, Vivapur 102, Vivapur 12 and the effect of magnesium stearate on the strength of tablets containing these substances].

PubMed

Muzíková, J; Horácek, J

2003-07-01

Vivapur is microcrystalline cellulose manufactured by the German firm J. Rettenmeier & Söhne GmbH + Co. The types Vivapur 102 and 12 enjoy priority use as dry binders for direct tablet compression. The present paper evaluates tensile strength of tablets made from these substances and the effect of an addition of the lubricant magnesium stearate in connection with its concentration and the conditions of the process of mixing, particularly the period and intensity of mixing. The tested concentrations of stearate were 0.4 and 0.8%, the tested periods of mixing being 2.5, 5, 10, and 20 minutes, intensities of mixing 17 and 34 rot./min. Sensitivity of dry binders to added stearate was evaluated by means of the LSR (lubricant sensitivity ratio) values. The results demonstrated higher sensitivity to an addition of the lubricant in Vivapur 12 than in Vivapur 102. In the first part of the paper focused on the effect of stearate concentration on tensile strength of tablets, Vivapur 102 was also compared with Avicel PH-102. Tablets from Vivapur 102 alone were stronger than those from Avicel PH-102. A concentration of stearate of 0.8% decreased the binding capacity of Vivapur 102 more than that of Avicel PH-102. With a prolonged period of mixing and increased intensity of mixing with stearate, tensile strength of tablets from both Vivapur types was decresed, and a prolonged period of mixing exerted a more marked effect on Vivapur 12 and increased intensity of mixing, on Vivapur 102.

Relative importance of impervious area, drainage density, width function, and subsurface storm drainage on flood runoff from an urbanized catchment

NASA Astrophysics Data System (ADS)

Ogden, Fred L.; Raj Pradhan, Nawa; Downer, Charles W.; Zahner, Jon A.

2011-12-01

The literature contains contradictory conclusions regarding the relative effects of urbanization on peak flood flows due to increases in impervious area, drainage density and width function, and the addition of subsurface storm drains. We used data from an urbanized catchment, the 14.3 km2 Dead Run watershed near Baltimore, Maryland, USA, and the physics-based gridded surface/subsurface hydrologic analysis (GSSHA) model to examine the relative effect of each of these factors on flood peaks, runoff volumes, and runoff production efficiencies. GSSHA was used because the model explicitly includes the spatial variability of land-surface and hydrodynamic parameters, including subsurface storm drains. Results indicate that increases in drainage density, particularly increases in density from low values, produce significant increases in the flood peaks. For a fixed land-use and rainfall input, the flood magnitude approaches an upper limit regardless of the increase in the channel drainage density. Changes in imperviousness can have a significant effect on flood peaks for both moderately extreme and extreme storms. For an extreme rainfall event with a recurrence interval in excess of 100 years, imperviousness is relatively unimportant in terms of runoff efficiency and volume, but can affect the peak flow depending on rainfall rate. Changes to the width function affect flood peaks much more than runoff efficiency, primarily in the case of lower density drainage networks with less impermeable area. Storm drains increase flood peaks, but are overwhelmed during extreme rainfall events when they have a negligible effect. Runoff in urbanized watersheds with considerable impervious area shows a marked sensitivity to rainfall rate. This sensitivity explains some of the contradictory findings in the literature.

The poet syndrome: opiates, psychosis and creativity.

PubMed

Rauch, L

2000-01-01

For some people, heroin is a self-medicating tool used to control innate psychic sensitivity. The habitual use of heroin provides the sensitive addict with a definition of consciousness by containment, psychic buffering, and psychic marking. This article is an examination of the political and social history of opiates, opiates as antipsychotics, "drug of choice" as a determinant of self-medication, and the connection between creativity, spirituality, psychosis and addiction. Using clinical observation, the article explores the poet syndrome hypothesis and offers direction for an alternative drug treatment paradigm.

Numerical parametric studies of spray combustion instability

NASA Technical Reports Server (NTRS)

Pindera, M. Z.

1993-01-01

A coupled numerical algorithm has been developed for studies of combustion instabilities in spray-driven liquid rocket engines. The model couples gas and liquid phase physics using the method of fractional steps. Also introduced is a novel, efficient methodology for accounting for spray formation through direct solution of liquid phase equations. Preliminary parametric studies show marked sensitivity of spray penetration and geometry to droplet diameter, considerations of liquid core, and acoustic interactions. Less sensitivity was shown to the combustion model type although more rigorous (multi-step) formulations may be needed for the differences to become apparent.

Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes.

PubMed

de Wit, H M; Engwerda, E E C; Tack, C J; de Galan, B E

2015-11-01

To test whether jet injection of insulin resulted in faster correction of marked hyperglycaemia than when insulin is injected by a conventional pen in patients with diabetes. Adult, overweight or obese (BMI ≥25 and ≤40 kg/m(2)) patients with type 1 diabetes (n = 10) or insulin-treated type 2 diabetes (n = 10) were enrolled in a randomized, controlled, crossover study. On two separate occasions, patients were instructed to reduce insulin dose(s) to achieve marked hyperglycaemia (18-23 mmol/l). Subsequently, insulin aspart was administered either by jet injection or by conventional pen, in a dose based on estimated individual insulin sensitivity. Pharmacodynamic and pharmacokinetic profiles were derived from plasma glucose and insulin levels, measured for 6 h after injection. After conventional injection, plasma glucose concentration dropped by ≥10 mmol/l after 192.5 ± 13.6 min. The jet injector advanced this time to 147.9 ± 14.4 min [difference 44.6 (95% confidence interval 4.3, 84.8); P = 0.03], except in 3 patients who failed to reach this endpoint. The time advantage exceeded 1.5 h in patients with a BMI above the median. Jet injection also reduced the hyperglycaemic burden during the first 2 h (2042 ± 37.2 vs 2168 ± 26.1 mmol/min; P = 0.01) and the time to peak insulin levels (40.5 ± 3.2 vs 76.8 ± 7.7 min; P < 0.001), but did not increase the risk for hypoglycaemia. Administration of rapid-acting insulin by jet injection results in faster correction of marked hyperglycaemia in overweight or obese patients with insulin-requiring diabetes. © 2015 John Wiley & Sons Ltd.

The Effect of Meal Frequency on the Fatty Acid Composition of Serum Phospholipids in Patients with Type 2 Diabetes.

PubMed

Kahleova, Hana; Malinska, Hana; Kazdova, Ludmila; Belinova, Lenka; Tura, Andrea; Hill, Martin; Pelikanova, Terezie

2016-01-01

Fatty acids are important cellular constituents that can affect many metabolic processes relevant for the development of diabetes and its complications. We previously demonstrated a positive effect of eating just 2 meals a day, breakfast and lunch, compared to 6 small meals. The aim of this secondary analysis was to explore the effect of meal frequency on the fatty acid composition of serum phospholipids in subjects with type 2 diabetes (T2D). In a randomized, crossover study, we assigned 54 patients with T2D to follow one of 2 regimens of a hypocaloric diet (-500 kcal/day), each for 12 weeks: 6 meals (A6) or 2 meals a day, breakfast and lunch (B2). The diet in both regimens had the same macronutrient and energy content. The fatty acid composition of serum phospholipids was measured at weeks 0, 12, and 24, using gas liquid chromatography. Insulin sensitivity was derived as an oral glucose insulin sensitivity (OGIS) index. Saturated fatty acids (mainly myristic and palmitic acids) decreased (p < 0.001) and n6 polyunsaturated fatty acids increased (p < 0.001) in response to both regimens but more with B2 (p < 0.001 for both). Monounsaturated fatty acids decreased (p < 0.05) and n3 polyunsaturated fatty acids increased (p < 0.001) in response to both regimens, with no difference between the regimens. An increase in OGIS correlated positively with changes in the proportion of linoleic acid in B2. This correlation remained significant even after adjustment for changes in body mass index (BMI; r = +0.38; p = 0.012). We demonstrated that meal frequency affects the fatty acid composition of serum phospholipids. The B2 regimen had more marked positive effects, with saturated fatty acids and the ratio of saturated to unsaturated fatty acids decreasing more. The increase in linoleic acid could partly explain the insulin-sensitizing effect of B2 in T2D.

Sensor Spatial Distortion, Visual Latency, and Update Rate Effects on 3D Tracking in Virtual Environments

NASA Technical Reports Server (NTRS)

Ellis, S. R.; Adelstein, B. D.; Baumeler, S.; Jense, G. J.; Jacoby, R. H.; Trejo, Leonard (Technical Monitor)

1998-01-01

Several common defects that we have sought to minimize in immersing virtual environments are: static sensor spatial distortion, visual latency, and low update rates. Human performance within our environments during large amplitude 3D tracking was assessed by objective and subjective methods in the presence and absence of these defects. Results show that 1) removal of our relatively small spatial sensor distortion had minor effects on the tracking activity, 2) an Adapted Cooper-Harper controllability scale proved the most sensitive subjective indicator of the degradation of dynamic fidelity caused by increasing latency and decreasing frame rates, and 3) performance, as measured by normalized RMS tracking error or subjective impressions, was more markedly influenced by changing visual latency than by update rate.

Friedensdid Aktische Bausteine für Ausbildung, Unterricht und Sozialarbeit

NASA Astrophysics Data System (ADS)

Esser, Johannes

1983-09-01

In the context of the peace movement in the Federal Republic of Germany, certain central basic elements of peace activity at higher education institutions, school and/or in social welfare work are considered. Principles and objectives of effective teaching and practice in discerning peace work are focussed upon against a background of disturbing and menacing influences both within and between nations, increasingly threatening existence itself. Endeavours to achieve reform capable of changing society should be marked by the development and realisation of a repugnance of violence, civil disobedience and social sensitivity, and demonstrated in action and by specific measures by the general public. This supersedes by far the traditional set-up of peace education (so called) in educational institutions and areas of social work up to the present time.

Single-protein nanomechanical mass spectrometry in real time

PubMed Central

Hanay, M.S.; Kelber, S.; Naik, A.K.; Chi, D.; Hentz, S.; Bullard, E.C.; Colinet, E.; Duraffourg, L.; Roukes, M.L.

2012-01-01

Nanoelectromechanical systems (NEMS) resonators can detect mass with exceptional sensitivity. Previously, mass spectra from several hundred adsorption events were assembled in NEMS-based mass spectrometry using statistical analysis. Here, we report the first realization of single-molecule NEMS-based mass spectrometry in real time. As each molecule in the sample adsorbs upon the NEMS resonator, its mass and the position-of-adsorption are determined by continuously tracking two driven vibrational modes of the device. We demonstrate the potential of multimode NEMS-based mass spectrometry by analyzing IgM antibody complexes in real-time. NEMS-MS is a unique and promising new form of mass spectrometry: it can resolve neutral species, provides resolving power that increases markedly for very large masses, and allows acquisition of spectra, molecule-by-molecule, in real-time. PMID:22922541

Phenological sensitivity to climate across taxa and trophic levels.

PubMed

Thackeray, Stephen J; Henrys, Peter A; Hemming, Deborah; Bell, James R; Botham, Marc S; Burthe, Sarah; Helaouet, Pierre; Johns, David G; Jones, Ian D; Leech, David I; Mackay, Eleanor B; Massimino, Dario; Atkinson, Sian; Bacon, Philip J; Brereton, Tom M; Carvalho, Laurence; Clutton-Brock, Tim H; Duck, Callan; Edwards, Martin; Elliott, J Malcolm; Hall, Stephen J G; Harrington, Richard; Pearce-Higgins, James W; Høye, Toke T; Kruuk, Loeske E B; Pemberton, Josephine M; Sparks, Tim H; Thompson, Paul M; White, Ian; Winfield, Ian J; Wanless, Sarah

2016-07-14

Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5-2.9 days earlier on average), with substantial taxonomic variation (1.1-14.8 days earlier on average).

Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome.

PubMed

Yang, Sung-Sen; Lo, Yi-Fen; Yu, I-Shing; Lin, Shu-Wha; Chang, Tai-Hsiang; Hsu, Yu-Juei; Chao, Tai-Kuang; Sytwu, Huey-Kang; Uchida, Shinichi; Sasaki, Sei; Lin, Shih-Hua

2010-12-01

Gitelman syndrome (GS) is characterized by salt-losing hypotension, hypomagnesemia, hypokalemic metabolic alkalosis, and hypocalciuria. To better model human GS caused by a specific mutation in the thiazide-sensitive Na(+) -Cl(-) cotransporter (NCC) gene SLC12A3, we generated a nonsense Ncc Ser707X knockin mouse corresponding to human p.Ser710X (c.2135C>A), a recurrent mutation with severe phenotypes in Chinese GS patients. Compared with wild-type or heterozygous littermates, homozygous (Hom) knockin mice fully recapitulated the phenotype of human GS. The markedly reduced Ncc mRNA and virtually absent Ncc protein expression in kidneys of Hom mice was primarily due to nonsense-mediated mRNA decay (NMD) surveillance mechanisms. Expression of epithelial Na(+) channel (Enac), Ca(2+) channels (Trpv5 and Trpv6), and K(+) channels (Romk1 and maxi-K) were significantly increased. Late distal convoluted tubules (DCT) volume was increased and DCT cell ultrastructure appeared intact. High K(+) intake could not correct hypokalemia but caused a further increase in maxi-K but not Romk1 expression. Renal tissue from a patient with GS also showed the enhanced TRPV5 and ROMK1 expression in distal tubules. We suggest that the upregulation of TRPV5/6 and of ROMK1 and Maxi-K may contribute to hypocalciuria and hypokalemia in Ncc Ser707X knockin mice and human GS, respectively. © 2010 Wiley-Liss, Inc.

Amelioration of hypertensive heart failure by amlodipine may occur via antioxidative effects.

PubMed

Hasegawa, Hiroshi; Takano, Hiroyuki; Kohro, Takahide; Ueda, Kazutaka; Niitsuma, Yuriko; Aburatani, Hiroyuki; Komuro, Issei

2006-09-01

Although recent clinical studies have suggested that long-acting calcium channel blockers (CCBs) have beneficial effects on heart failure, the precise mechanism is unknown. In this study, Dahl salt-sensitive rats fed a high salt diet were treated with the long-acting CCB amlodipine, the low-molecular-weight membrane permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol), or saline from 11 weeks after birth. The cardiac geometry and function, and gene expression profiles were determined at 17 weeks. Dahl salt-sensitive rats fed a high salt diet followed by saline as a non-treatment control (HS group) showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricular (LV) dilation and congestive heart failure by 17 weeks. The treatment with amlodipine (AMLO group) or Tempol (TEMP group) significantly inhibited the development of LV hypertrophy and cardiac dysfunction. Analysis using an Affymetrix GeneChip U34 revealed that the expression levels of 195 genes were changed by the treatment with amlodipine. Among these 195 genes, 110 genes were increased in HS rats and decreased in AMLO rats. And of these 110 genes, 54 genes were also decreased in TEMP rats. In contrast, 85 genes were decreased in HS rats and increased in AMLO rats. Of these 85 genes, 38 genes were also increased in TEMP rats. Approximately 48% of the genes were changed in similar fashion in AMLO and TEMP rats, suggesting that amlodipine shows beneficial effects on heart failure mainly via antioxidative mechanisms.

Sensitivity of two green microalgae to copper stress: Growth, oxidative and antioxidants analyses.

PubMed

Hamed, Seham M; Selim, Samy; Klöck, Gerd; AbdElgawad, Hamada

2017-10-01

Depending on species, heavy metals, including copper (Cu), differentially affect algal growth and metabolism. Here, we aim to evaluate the differential responses of two green microalgae, Chlorella sorokiniana and Scenedesmus acuminatus, exposed to sub-lethal doses of Cu (25 and 50µM, respectively) for 7 days. The changes in growth, oxidative damage markers, and antioxidants were analysed. We found that S. acuminatus could acclimatise during long-term exposure to Cu stress. S. acuminatus accumulated lower Cu content and showed a slight decrease in H 2 O 2 levels when compared to C. sorokiniana. Cu stress induced membrane damage in the two microalgae species, however, this increase was slightly lower in S. acuminatus. To mitigate Cu stress impact, C. sorkiniana markedly increased proline, polyphenols, flavonoids, tocopherols, glutathione levels, as well as the activities of GST, APX, GR and SOD enzymes, which could explain less-stress sensitivity. On the other hand, S. acuminatus exhibited significant increases in proline, polyphenol, and tocopherol contents. Activity levels of POX, APX, GR and SOD enzymes, were also increased. These results suggest that the two microalgae differentially induced the antioxidant defence system to neutralise the oxidative damage induced by Cu stress. This study also provided new data for Cu tolerance and Cu removal abilities of two microalgal species, which commonly exist in surface water bodies, where low Cu uptake and efficient antioxidant defence system protected S. acuminatus against oxidative stress induced by Cu stress. This makes it feasible for treatment of Cu contaminated waters. Copyright © 2017 Elsevier Inc. All rights reserved.

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway

PubMed Central

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A.; Pfeffer, Lawrence M.

2017-01-01

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway. PMID:29348882

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway.

PubMed

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A; Pfeffer, Lawrence M

2017-12-22

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro , and inhibited GBM tumorigenesis in vivo . Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro , and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway.

Modelling high Arctic deep permafrost temperature sensitivity in Northeast Greenland based on experimental and field observations

NASA Astrophysics Data System (ADS)

Rasmussen, Laura Helene; Zhang, Wenxin; Hollesen, Jørgen; Cable, Stefanie; Hvidtfeldt Christiansen, Hanne; Jansson, Per-Erik; Elberling, Bo

2017-04-01

Permafrost affected areas in Greenland are expected to experience a marked temperature increase within decades. Most studies have considered near-surface permafrost sensitivity, whereas permafrost temperatures below the depths of zero annual amplitude is less studied despite being closely related to changes in near-surface conditions, such as changes in active layer thermal properties, soil moisture and snow depth. In this study, we measured the sensitivity of thermal conductivity (TC) to gravimetric water content (GWC) in frozen and thawed permafrost sediments from fine-sandy and gravelly deltaic and fine-sandy alluvial deposits in the Zackenberg valley, NE Greenland. We further calibrated a coupled heat and water transfer model, the "CoupModel", for one central delta sediment site with average snow depth and further forced it with meteorology from a nearby delta sediment site with a topographic snow accumulation. With the calibrated model, we simulated deep permafrost thermal dynamics in four 20-year scenarios with changes in surface temperature and active layer (AL) soil moisture: a) 3 °C warming and AL water table at 0.5 m depth; b) 3 °C warming and AL water table at 0.1 m depth; c) 6 °C warming and AL water table at 0.5 m depth and d) 6 °C warming and AL water table at 0.1 m depth. Our results indicate that frozen sediments have higher TC than thawed sediments. All sediments show a positive linear relation between TC and soil moisture when frozen, and a logarithmic one when thawed. Gravelly delta sediments were highly sensitive, but never reached above 12 % GWC, indicating a field effect of water retention capacity. Alluvial sediments are less sensitive to soil moisture than deltaic (fine and coarse) sediments, indicating the importance of unfrozen water in frozen sediment. The deltaic site with snow accumulation had 1 °C higher mean annual ground temperature than the average snow depth site. Permafrost temperature at the depth of 18 m increased with 1.5 °C and 3.5 °C in the scenarios with 3 °C and 6 °C warming, respectively. Increasing the soil moisture had no important additional effect to warming, although an increase in thermal offset was indicated. We conclude that below-ground sediment properties affect the sensitivity of TC to GWC, that surface temperature changes can influence the deep permafrost within a short time scale, and that differences in snow depth affect surface temperatures. Sediment type and the type of precipitation should thus be considered when estimating future High Arctic deep permafrost sensitivity.

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression

PubMed Central

Komura, Kazumasa; Jeong, Seong Ho; Hinohara, Kunihiko; Qu, Fangfang; Wang, Xiaodong; Hiraki, Masayuki; Azuma, Haruhito; Lee, Gwo-Shu Mary; Kantoff, Philip W.; Sweeney, Christopher J.

2016-01-01

The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity. PMID:27185910

On denture marking.

PubMed

Borrman, H I; DiZinno, J A; Wasén, J; René, N

1999-06-01

During the last decades in Sweden dentures have been permanently marked with a stainless steel metal band incorporated into the acrylic and containing the patient's birth date, a special number, and "S" for Sweden. The last recommendation issued by the National Board of Health and Welfare states that "the patients shall always be offered denture marking and be informed about the benefit thereof. Denture marking is not permitted if the patient refuses it". Requirements for denture markers have been that they should be biologically inert (when incorporated into the denture), not be expensive, be easy to inscribe, be possible to retrieve after an accident, and survive elevated temperatures for a reasonable time under normal circumstances. Although the frequency of edentulousness has decreased in recent years due to the improvement in oral health there remains a need to address the issue of marking of complete dentures, because there is a large variation in the oral status of populations in different countries. Given that only one marked denture can reveal the identity of a deceased person when all other methods fail to do so, makes it worthwhile. Furthermore, denture marking is important in long-term care facilities. We have investigated the issue of denture marking in Europe and in the United States. The results from the European survey show that denture marking is, to our knowledge regulated by law only in Sweden and Iceland. In the US denture marking is so far mandatory in 21 states while New York State requires dentures to be marked if the patient requests it and several other states impose the obligation to mark dentures on long-term care facilities. Since there is no international consensus regarding the issue of denture marking it is important to address it. A survey from the Nordic countries has shown that if denture marking was in general use, the contribution to the establishment of identity by forensic odontology in cases of fire would increase by about 10%. This means that about 25 more individuals could have been identified if their dentures were marked. Increased international collaboration is needed to solve the issue of denture marking for clinical and forensic purposes.

Virtue, Practical Wisdom and Character in Teaching

ERIC Educational Resources Information Center

Cooke, Sandra; Carr, David

2014-01-01

Recent reflection on the professional knowledge of teachers has been marked by a shift away from more reductive competence and skill-focused models of teaching towards a view of teacher expertise as involving complex context-sensitive deliberation and judgement. Much of this shift has been inspired by an Aristotelian conception of practical wisdom…

Rank Weighting in Multiattribute Utility Decision Making: Avoiding the Pitfalls of Equal Weights.

DTIC Science & Technology

1979-09-01

set change are discussed in relation to the conditions of Wainer’s (Wainer, 1976) ’ equal weights theorem’ and the resulting sensitivity to weighting of...as equal weights. Rank weighting of importance dimensions demonstrate marked improvement of approximation as reflected in both Pearson and rank order

L2 Gender Facilitation and Inhibition in Spoken Word Recognition

ERIC Educational Resources Information Center

Behney, Jennifer N.

2011-01-01

This dissertation investigates the role of grammatical gender facilitation and inhibition in second language (L2) learners' spoken word recognition. Native speakers of languages that have grammatical gender are sensitive to gender marking when hearing and recognizing a word. Gender facilitation refers to when a given noun that is preceded by an…

Post-fledging survival of Northern Goshawks: the importance of prey abundance, weather, and dispersal

Treesearch

J. David Wiens; Barry R. Noon; Richard T. Reynolds

2006-01-01

Effective wildlife conservation strategies require an understanding of how fluctuating environmental conditions affect sensitive life stages. As part of a long-term study, we examined post-fledging and post-independence survival of 89 radio-marked juvenile Northern Goshawks (Accipiter gentilis) produced from 48 nests in northern Arizona, USA, during...

Quantitative Susceptibility Mapping of the Midbrain in Parkinson’s Disease

PubMed Central

Du, Guangwei; Liu, Tian; Lewis, Mechelle M.; Kong, Lan; Wang, Yi; Connor, James; Mailman, Richard B.; Huang, Xuemei

2017-01-01

Background Parkinson’s disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. Methods Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson’s Disease Rating Scale (UPDRS) I, II, and III sub-scores, and levodopa-equivalent daily dosage. All studies were done while PD patients were “on drug.” Results Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm3) and left (164 mm3) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm3) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. Conclusion The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD. PMID:26362242

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation.

PubMed

Aguiar-Oliveira, Manuel H; Souza, Anita H O; Oliveira, Carla R P; Campos, Viviane C; Oliveira-Neto, Luíz A; Salvatori, Roberto

2017-08-01

Twenty years ago, we described kindred of 105 individuals with isolated GH deficiency (IGHD) in Itabaianinha County, in northeast Brazil, carrying a homozygous mutation in the GH-releasing hormone receptor gene. These subjects exhibit markedly reduced GH responsiveness to stimulatory tests, and anterior pituitary hypoplasia. Serum concentrations of IGF-I, IGF binding protein type 3 and the acid-labile subunit are markedly reduced, with a lesser reduction of IGF-II. The most striking physical findings of these IGHD individuals are the proportionate short stature, doll facies, high-pitched voice and visceral obesity with reduced fat-free mass. There is neither microphallus, nor neonatal hypoglycemia. Puberty is delayed, menopause anticipated, but fertility is preserved in both genders. The reduction in bone sizes is not even, with mean standard deviation scores for height of -7.2, total maxillary length of -6.5, total facial height of -4.3 and cephalic perimeter of -2.7. In addition, the non-osseous growth is not uniform, preserving some organs, like pancreas, liver, kidney, brain and eyes, and compromising others such as thyroid, heart, uterus and spleen. These subjects present higher prevalence of dizziness, mild high-tones sensorineural hearing loss, reduction of vascular retinal branching points, increase of optic disk, genu valgum and increased systolic blood pressure. Biochemically, they have high low density lipoprotein cholesterol and C-reactive protein levels, but maintain increased insulin sensitivity, and do not show premature atherosclerosis. Finally, they have normal immune function, and normal longevity. This review details the findings and summarizes 20 years of clinical research carried out in this unique population. © 2017 European Society of Endocrinology.

Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis

PubMed Central

Greathouse, K. Leigh; Bredfeldt, Tiffany; Everitt, Jeffrey I.; Lin, Kevin; Berry, Tia; Kannan, Kurunthachalam; Mittelstadt, Megan L.; Ho, Shuk-mei; Walker, Cheryl L.

2013-01-01

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol (DES) during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyper-responsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein (GEN), a soy phytoestrogen, and the plasticizer bisphenol A (BPA), differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. While both GEN and BPA induce genomic estrogen receptor (ER) signaling in the developing uterus, only GEN induced PI3K/AKT non-genomic ER signaling to the histone methyltransferase Enhancer of Zeste homolog 2 (EZH2). As a result, this “pre-genomic” signaling phosphorylates and represses EZH2, and reduces levels of H3K27 repressive mark in chromatin. Furthermore, only GEN caused estrogen-responsive genes in the adult myometrium to become hyper-responsive to hormone; estrogen-responsive genes were repressed in BPA exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by GEN promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, while BPA did not. These data demonstrate that environmental estrogens have distinct non-genomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis. PMID:22504913

Mutation of the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia.

PubMed

Kemter, Elisabeth; Rathkolb, Birgit; Bankir, Lise; Schrewe, Anja; Hans, Wolfgang; Landbrecht, Christina; Klaften, Matthias; Ivandic, Boris; Fuchs, Helmut; Gailus-Durner, Valérie; Hrabé de Angelis, Martin; Wolf, Eckhard; Wanke, Ruediger; Aigner, Bernhard

2010-06-01

The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene (SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1(I299F) exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid excretion is twofold lower. In contrast to hyperreninemia present in human disease, plasma renin concentration in homozygotes is not increased. The polyuria observed in homozygotes may be due to the combination of two additive factors, a decrease in activity of mutant NKCC2 and an increase in medullary blood flow, due to prostaglandin-induced vasodilation, that impairs countercurrent exchange of urea in the medulla. In conclusion, this novel viable mouse line with a missense Slc12a1 mutation exhibits most of the features of type I Bartter syndrome and may represent a new model for the study of this human disease.

Self-reported body silhouette trajectories across the lifespan and excessive daytime sleepiness in adulthood: a retrospective analysis. The Paris Prospective Study III

PubMed Central

Tafflet, Muriel; Charles, Marie-Aline; Thomas, Frédérique; Boutouyrie, Pierre; Guibout, Catherine; Haba-Rubio, José; Périer, Marie Cécile; Pannier, Bruno; Marques-Vidal, Pedro; Jouven, Xavier; Empana, Jean-Philippe

2018-01-01

Objectives Excessive daytime sleepiness (EDS) is a common sleep complaint in the population and is increasingly recognised as deleterious for health. Simple and sensitive tools allowing identifying individuals at greater risk of EDS would be of public health importance. Hence, we determined trajectories of body silhouette from early childhood to adulthood and evaluated their association with EDS in adulthood. Design A retrospective analysis in a prospective community-based study. Participants 6820 men and women self-reported their silhouette at ages 8, 15, 25, 35 and 45 using the body silhouettes proposed by Stunkard et al. EDS was defined by an Epworth Sleepiness Scale score ≥11. Main outcome measure Presence of EDS in adulthood. Results The study population comprised 6820 participants (mean age 59.8 years, 61.1% men). Five distinct body silhouettes trajectories over the lifespan were identified: 31.9% ‘lean stable’, 11.1% ‘lean increase’, 16.1% ‘lean-marked increase’, 32.5% ‘moderate stable’ and 8.4% ‘heavy stable’. Subjects with a ‘heavy-stable’ trajectory (OR 1.24, 95% CI 0.94 to 1.62) and those with a ‘lean-marked increase’ trajectory (OR 1.46, 95% CI 1.18 to 1.81) were more likely to have EDS when compared with the ‘lean-stable’ group after adjusting for confounding. Further adjustment for birth weight strengthened the magnitude of the ORs. Conclusion Increasing body silhouette and to a lesser extent constantly high body silhouette trajectory from childhood to adulthood are associated with increased likelihood of EDS, independently of major confounding variables. Trial registration number NCT00741728; Pre-results. PMID:29593025

Rats undernourished in utero have altered Ca2+ signaling and reduced fertility in adulthood

PubMed Central

Muzi-Filho, Humberto; Souza, Alessandro M; Bezerra, Camila G P; Boldrini, Leonardo C; Takiya, Christina M; Oliveira, Felipe L; Nesi, Renata T; Valença, Samuel S; Silva, Ananssa M S; Zapata-Sudo, Gisele; Sudo, Roberto T; Einicker-Lamas, Marcelo; Vieyra, Adalberto; Lara, Lucienne S; Cunha, Valeria M N

2015-01-01

Epidemiological and animal studies have shown that placental undernutrition impairs reproduction in adult offspring, but the underlying molecular mechanisms within the male genital tract remain unknown. Due to its special physiological characteristics in transport and the modulation of the environment to which its luminal content is exposed, we hypothesized that the vas deferens would be a highly sensitive target. The goals were to investigate whether intrauterine malnutrition affects molecular mechanisms related to Ca2+- and oxidative stress-modulated processes and causes structural alterations in the adult rat vas deferens that could attenuate fecundity and fertility. Male adult rats malnourished in utero had increased vas deferens weight associated with thickening of the muscular coat, a decrease in the total and haploid germ cells, a marked increase in the immature cells, and a decline in the numbers of pregnant females and total offspring per male rat. The ex vivo response of vas deferens from malnourished rats demonstrated an accentuated decrease in the contractile response to phenylephrine. The vas deferens had a marked decrease in Ca2+ transport due to the uncoupling of Ca2+-stimulated ATP hydrolysis and ATP-driven Ca2+ flux, and the downregulation of both sarco-endoplasmic reticulum Ca2+-ATPase 2 and the coupling factor 12-kDa FK506-binding protein. An increase in protein carbonylation (a marker of oxidative damage) and an imbalance between protein kinases C and A were observed as a legacy of undernutrition in early life. These results provide the structural and molecular basis to explain at least in part how maternal undernutrition affects fecundity and fertility in adult male rats. PMID:26508737

Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis

PubMed Central

Meyer-Bahlburg, Almut; Becker-Herman, Shirly; Humblet-Baron, Stephanie; Khim, Socheath; Weber, Michele; Bouma, Gerben; Thrasher, Adrian J.; Batista, Facundo D.

2008-01-01

To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro functional assays, we show that these deficits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that: (1) WASp expression levels increase with cell maturity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease. PMID:18687984

Dissociation between the effects of P1, P4-diadenosine tetraphosphate (Ap4A) on renal haemodynamics and tubular function in anaesthetized rats.

PubMed

Jankowski, M; Angielski, S; Szczepańska-Konkel, M

2008-03-01

Previous studies from our laboratory have reported a marked reduction in glomerular filtration rate (GFR) and sodium reabsorption in renal proximal tubule during intravenous infusion of P(1),P(4)-diadenosine tetraphosphate (Ap(4)A) at dose of 1.0 micromol/kg + 10 nmol/kg/min (i.v., injection followed by infusion) in anaesthetized Wistar rats. In the present study, the changes of GFR and urine sodium excretion were investigated in response to systemic infusion of Ap(4)A at different doses. Ap(4)A at dose of 0.1 micromol/kg + 1.0 nmol/kg/min did not change GFR and sodium urinary excretion whereas 2-fold higher dose produced significant (3.4-fold) increase in sodium excretion without changes in GFR. Significant but transient reduction in GFR by approximately 21% was observed during infusion of Ap(4)A at dose of 0.5 micromol/kg + 5.0 nmol/kg/min. Higher doses of Ap(4)A (1.0 micromol/kg + 10 nmol/kg/min and 2.0 micromol/kg + 20 nmol/kg/min) reduction in GFR and marked natriuresis. Our results suggest that tubular sodium transport systems are more sensitive to Ap(4)A than systems involved in GFR regulation.

Eupafolin enhances TRAIL-mediated apoptosis through cathepsin S-induced down-regulation of Mcl-1 expression and AMPK-mediated Bim up-regulation in renal carcinoma Caki cells.

PubMed

Han, Min Ae; Min, Kyoung-Jin; Woo, Seon Min; Seo, Bo Ram; Kwon, Taeg Kyu

2016-10-04

Eupafolin, a flavone found in Artemisia princeps, has been reported for its anti-tumor activity in several cancer cells. In this study, we examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that eupafolin alone and TRAIL alone had no effect on apoptosis. However, combined treatment with eupafolin and TRAIL markedly induced apoptosis in human renal carcinoma (Caki) cells, glioma cells (U251MG), and prostate cancer cells (DU145), but not normal cells [mesangial cells (MC) and normal mouse kidney cells (TCMK-1)]. Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in cathepsin S-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. In addition, eupafolin increased Bim expression at the post-translational levels via AMP-activated protein kinase (AMPK)-mediated inhibition of proteasome activity. Knock-down of Bim expression by siRNA inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells.

Eupafolin enhances TRAIL-mediated apoptosis through cathepsin S-induced down-regulation of Mcl-1 expression and AMPK-mediated Bim up-regulation in renal carcinoma Caki cells

PubMed Central

Woo, Seon Min; Seo, Bo Ram; Kwon, Taeg Kyu

2016-01-01

Eupafolin, a flavone found in Artemisia princeps, has been reported for its anti-tumor activity in several cancer cells. In this study, we examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that eupafolin alone and TRAIL alone had no effect on apoptosis. However, combined treatment with eupafolin and TRAIL markedly induced apoptosis in human renal carcinoma (Caki) cells, glioma cells (U251MG), and prostate cancer cells (DU145), but not normal cells [mesangial cells (MC) and normal mouse kidney cells (TCMK-1)]. Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in cathepsin S-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. In addition, eupafolin increased Bim expression at the post-translational levels via AMP-activated protein kinase (AMPK)-mediated inhibition of proteasome activity. Knock-down of Bim expression by siRNA inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells. PMID:27582546

Ischemic syndromes causing dizziness and vertigo.

PubMed

Choi, K-D; Lee, H; Kim, J-S

2016-01-01

Dizziness/vertigo and imbalance are the most common symptoms of vertebrobasilar ischemia. Even though dizziness/vertigo usually accompanies other neurologic symptoms and signs in cerebrovascular disorders, a diagnosis of isolated vascular vertigo is increasing markedly by virtue of recent developments in clinical neurotology and neuroimaging. It is important to differentiate isolated vertigo of a vascular cause from more benign disorders involving the inner ear, since therapeutic strategies and prognosis differ between these two conditions. Over the last decade, we have achieved a marked development in the understanding and diagnosis of vascular dizziness/vertigo. Introduction of diffusion-weighted magnetic resonance imaging (MRI) has greatly enhanced detection of infarctions in patients with vascular dizziness/vertigo, especially in the posterior-circulation territories. However, well-organized bedside neurotologic evaluation is even more sensitive than MRI in detecting acute infarction as a cause of spontaneous prolonged vertigo. Furthermore, detailed evaluation of strategic infarctions has elucidated the function of various vestibular structures of the brainstem and cerebellum. In contrast, diagnosis of isolated labyrinthine infarction still remains a challenge. This diagnostic difficulty also applies to isolated transient dizziness/vertigo of vascular origin. Regarding the common nonlacunar mechanisms in the acute vestibular syndrome from small infarctions, individual strategies may be indicated to prevent recurrences of stroke in patients with vascular vertigo. © 2016 Elsevier B.V. All rights reserved.

Interplay Between Cytosolic Free Zn2+ and Mitochondrion Morphological Changes in Rat Ventricular Cardiomyocytes.

PubMed

Billur, Deniz; Tuncay, Erkan; Okatan, Esma Nur; Olgar, Yusuf; Durak, Aysegul Toy; Degirmenci, Sinan; Can, Belgin; Turan, Belma

2016-11-01

The Zn 2+ in cardiomyocytes is buffered by structures near T-tubulus and/or sarcoplasmic/endoplasmic reticulum (S(E)R) while playing roles as either an antioxidant or a toxic agent, depending on the concentration. Therefore, we aimed first to examine a direct effect of ZnPO 4 (extracellular exposure) or Zn 2+ pyrithione (ZnPT) (intracellular exposure) application on the structure of the mitochondrion in ventricular cardiomyocytes by using histological investigations. The light microscopy data demonstrated that Zn 2+ exposure induced marked increases on cellular surface area, an indication of hypertrophy, in a concentration-dependent manner. Furthermore, a whole-cell patch-clamp measurement of cell capacitance also supported the hypertrophy in the cells. We observed marked increases in mitochondrial matrix/cristae area and matrix volume together with increased lysosome numbers in ZnPO 4 - or ZnPT-incubated cells by using transmission electron microscopy, again in a concentration-dependent manner. Furthermore, we observed notable clustering and vacuolated mitochondrion, markedly disrupted and damaged myofibrils, and electron-dense small granules in Zn 2+ -exposed cells together with some implications of fission-fusion defects in the mitochondria. Moreover, we observed marked depolarization in mitochondrial membrane potential during 1-μM ZnPT minute applications by using confocal microscopy. We also showed that 1-μM ZnPT incubation induced significant increases in the phosphorylation levels of GSK3β (Ser21 and Ser9), Akt (Ser473), and NFκB (Ser276 and Thr254) together with increased expression levels in ER stress proteins such as GRP78 and calregulin. Furthermore, a new key player at ER-mitochondria sites, promyelocytic leukemia protein (PML) level, was markedly increased in ZnPT-incubated cells. As a summary, our present data suggest that increased cytosolic free Zn 2+ can induce marked alterations in mitochondrion morphology as well as depolarization in mitochondrion membrane potential and changes in some cytosolic signaling proteins as well as a defect in ER-mitochondria cross talk.

The bed nucleus of the stria terminalis is critical for sexual solicitation, but not for opposite-sex odor preference, in female Syrian hamsters.

PubMed

Martinez, Luis A; Petrulis, Aras

2011-11-01

Successful reproduction in vertebrates depends critically upon a suite of precopulatory behaviors that occur prior to mating. In Syrian hamsters (Mesocricetus auratus), these behaviors include vaginal scent marking and preferential investigation of male odors. The neural regulation of vaginal marking and opposite-sex odor preference likely involves an interconnected set of steroid-sensitive nuclei that includes the medial amygdala (MA), the bed nucleus of the stria terminalis (BNST), and the medial preoptic area (MPOA). For example, lesions of MA eliminate opposite-sex odor preference and reduce overall levels of vaginal marking, whereas lesions of MPOA decrease vaginal marking in response to male odors. Although BNST is densely interconnected with both MA and MPOA, little is known about the role of BNST in female precopulatory behaviors. To address this question, females received either bilateral, excitotoxic lesions of BNST (BNST-X) or sham lesions (SHAM), and were tested for scent marking and for investigatory responses to male and female odors. Whereas SHAM females vaginal marked more to male odors than female odors on two days of the estrous cycle, BNST-X females marked at equivalent levels to both odors. This deficit is not due to alterations in social odor investigation, as both BNST-X and SHAM females investigated male odors more than female odors. Finally, BNST lesions did not generally disrupt the cyclic changes in reproductive behaviors that occur across the estrous cycle. Taken together, these results demonstrate that BNST is critical for the normal expression of solicitational behaviors by females in response to male odor stimuli. Copyright © 2011 Elsevier Inc. All rights reserved.

The bed nucleus of the stria terminalis is critical for sexual solicitation, but not for opposite-sex odor preference, in female Syrian hamsters

PubMed Central

Martinez, Luis A.; Petrulis, Aras

2011-01-01

Successful reproduction in vertebrates depends critically upon a suite of precopulatory behaviors that occur prior to mating. In Syrian hamsters (Mesocricetus auratus), these behaviors include vaginal scent marking and preferential investigation of male odors. The neural regulation of vaginal marking and opposite-sex odor preference likely involves an interconnected set of steroid-sensitive nuclei that includes the medial amygdala (MA), the bed nucleus of the stria terminalis (BNST), and the medial preoptic area (MPOA). For example, lesions of MA eliminate opposite-sex odor preference and reduce overall levels of vaginal marking, whereas lesions of MPOA decrease vaginal marking in response to male odors. Although BNST is densely interconnected with both MA and MPOA, little is known about the role of BNST in female precopulatory behaviors. To address this question, females received either bilateral, excitotoxic lesions of BNST (BNST-X) or sham lesions (SHAM), and were tested for scent marking and for investigatory responses to male and female odors. Whereas SHAM females vaginal marked more to male odors than female odors on two days of the estrous cycle, BNST-X females marked at equivalent levels to both odors. This deficit is not due to alterations in social odor investigation, as both BNST-X and SHAM females investigated male odors more than female odors. Finally, BNST lesions did not generally disrupt the cyclic changes in reproductive behaviors that occur across the estrous cycle. Taken together, these results demonstrate that BNST is critical for the normal expression of solicitational behaviors by females in response to male odor stimuli. PMID:21925504

Modulation of epithelial sodium channel trafficking and function by sodium 4-phenylbutyrate in human nasal epithelial cells.

PubMed

Prulière-Escabasse, Virginie; Planès, Carole; Escudier, Estelle; Fanen, Pascale; Coste, André; Clerici, Christine

2007-11-23

Sodium 4-phenylbutyrate (4-PBA) has been shown to correct the cellular trafficking of several mutant or nonmutant plasma membrane proteins such as cystic fibrosis transmembrane conductance regulator through the expression of 70-kDa heat shock proteins. The objective of the study was to determine whether 4-PBA may influence the functional expression of epithelial sodium channels (ENaC) in human nasal epithelial cells (HNEC). Using primary cultures of HNEC, we demonstrate that 4-PBA (5 mm for 6 h) markedly stimulated amiloride-sensitive sodium channel activity and that this was related to an increased abundance of alpha-, beta-, and gamma-ENaC subunits in the apical membrane. The increase in ENaC cell surface expression (i) was due to insertion of newly ENaC subunits as determined by brefeldin A experiments and (ii) was not associated with cell surface retention of ENaC subunits because endocytosis of ENaC subunits was unchanged. In addition, we find that ENaC co-immunoprecipitated with the heat shock protein constitutively expressed Hsc70, that has been reported to modulate ENaC trafficking, and that 4-PBA decreased Hsc70 protein level. Finally, we report that in cystic fibrosis HNEC obtained from two cystic fibrosis patients, 4-PBA increased functional expression of ENaC as demonstrated by the increase in amiloride-sensitive sodium transport and in alpha-, beta-, and gamma-ENaC subunit expression in the apical membrane. Our results suggest that in HNEC, 4-PBA increases the functional expression of ENaC through the insertion of new alpha-, beta-, and gamma-ENaC subunits into the apical membrane and also suggest that 4-PBA could modify ENaC trafficking by reducing Hsc70 protein expression.

Prospective and Retrospective Evaluation of the Performance of the FDA-Approved Cepheid Xpert Flu/RSV XC Assay.

PubMed

Arbefeville, Sophie; Thonen-Kerr, Elizabeth; Ferrieri, Patricia

2017-11-08

Rapid and accurate detection of respiratory viruses is important in patient care and in guiding therapy and infection prevention policy. Rapid viral antigen assays are simple to perform and provide results within 15 to 30 minutes but are limited by their modest-to-moderate sensitivity. Molecular assays are more sensitive and specific but require more technical time and expertise and are more expensive. We verified the performance of the Xpert Flu/RSV XC assay prospectively, using patient respiratory samples from the 2014-2015 respiratory season, and, retrospectively, with frozen patient samples from the previous respiratory season. A total of 60 specimens were assayed on the Xpert Flu/RSV XC assay and by the GenMark Diagnostics eSensor Respiratory Viral Panel. The sensitivity of the Xpert Flu/RSV XC for Flu A was 100% (23/23), for Flu B, 80% (8/10), and for respiratory syncytial virus (RSV), 94.1% (16/17), compared to the reference assay (GenMark). The specificity was 100%. Eight specimens were positive for viruses other than Flu A/B or RSV, and this did not interfere with detection of targets in the Xpert assay. We demonstrated that the performance of the Xpert Flu/RSV XC was comparable to the more comprehensive molecular respiratory assay. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A study of ecological red-line area partitioning in the Chishui River Basin in Guizhou

NASA Astrophysics Data System (ADS)

Yang, S. F.; An, Y. L.

2016-08-01

Maintaining ecosystem balance and realizing the strategic goal of sustainable development are key objectives in the field of environmental sciences. Accordingly, drawing ecological red lines in sensitive and vulnerable environmental areas and important ecological function areas, determining the distribution range of ecological red-line areas, providing scientific guidance for developmental activities, and effectively managing the ecological environment are significant work tasks supported by policy guidance from the State Council and from knowledge gained in educational circles. Taking the Chishui River Basin in Guizhou as the study object, this research selected water and soil loss sensitivity, as well as assessments of karst rocky desertification sensitivity as background assessments of the eco-environment. Furthermore, the functions of soil conservation, water conservation, and biodiversity protection were integrated with exploitation-prohibited areas, and an organic combination of ecological needs and social service functions was created. Spatial comprehensive overlay analysis and processing revealed that the combination marked nine major ecological red-line areas in a total area of 5,030.58 km2, which occupied 44.16% of the total basin area. By combining the current eco-environmental situation of the Chishui River Basin with the marked out red-line areas, this research proposed corresponding ecological red-line area management suggestions. These suggestions are expected to provide a scientific foundation for eco-environmental protection and subsequent scientific research in Chishui River Basin.

Concentrations of plasma metabolites, hormones, and mRNA abundance of adipose leptin and hormone-sensitive lipase in ketotic and nonketotic dairy cows.

PubMed

Xia, C; Wang, Z; Xu, C; Zhang, H Y

2012-01-01

Ketosis is an important metabolic disorder of dairy cows during the transition period. There have been many reports on the etiology of ketosis in periparturient cows, but little is known about its molecular etiology. The objective of this study was to clarify the status of fat mobilization and mRNA abundance of leptin and hormone-sensitive lipase in cows with spontaneous clinical ketosis. Ten ketotic Holstein cows and 10 nonketotic Holstein cows were used as the experimental animals. Six blood biochemical parameters were evaluated by means of individual analysis method for 2 groups of cows. The mRNA abundance of leptin and hormone-sensitive lipase in tail fat tissue from 2 groups of cows was measured by real-time (RT)-PCR, with a fluorescent Taqman probe and a standard curve. The plasma concentrations of glucose (P = 0.01), and leptin (P = 0.03), insulin (P = 0.05), and the ratio of insulin to glucagon (P = 0.04) were lower in ketotic compared with nonketotic cows, whereas there were marked increases in the plasma concentrations of nonesterified fatty acid and β-hydroxybutyric acid (P = 0.005). The mRNA abundance of leptin (P = 0.04) and hormone-sensitive lipase (P = 0.02) in the fat tissue of ketotic cows was lower relative to that of nonketotic cows. The ketotic cows showed characteristics of type I ketosis and some adaptive changes to negative energy balance in the plasma leptin concentration and mRNA abundance of fat leptin and hormone-sensitive lipase. Copyright © 2012 by the American College of Veterinary Internal Medicine.

Molecular basis and drug sensitivity of the delayed rectifier (IKr) in the fish heart.

PubMed

Hassinen, Minna; Haverinen, Jaakko; Vornanen, Matti

2015-01-01

Fishes are increasingly used as models for human cardiac diseases, creating a need for a better understanding of the molecular basis of fish cardiac ion currents. To this end we cloned KCNH6 channel of the crucian carp (Carassius carassius) that produces the rapid component of the delayed rectifier K(+) current (IKr), the main repolarising current of the fish heart. KCNH6 (ccErg2) was the main isoform of the Kv11 potassium channel family with relative transcript levels of 98.9% and 99.6% in crucian carp atrium and ventricle, respectively. KCNH2 (ccErg1), an orthologue to human cardiac Erg (Herg) channel, was only slightly expressed in the crucian carp heart. The native atrial IKr and the cloned ccErg2 were inhibited by similar concentrations of verapamil, terfenadine and KB-R7943 (P>0.05), while the atrial IKr was about an order of magnitude more sensitive to E-4031 than ccErg2 (P<0.05) suggesting that some accessory β-subunits may be involved. Sensitivity of the crucian carp atrial IKr to E-4031, terfenadine and KB-R7943 was similar to what has been reported for the Herg channel. In contrast, the sensitivity of the crucian carp IKr to verapamil was approximately 30 times higher than the previously reported values for the Herg current. In conclusion, the cardiac IKr is produced by non-orthologous gene products in fish (Erg2) and mammalian hearts (Erg1) and some marked differences exist in drug sensitivity between fish and mammalian Erg1/2 which need to be taken into account when using fish heart as a model for human heart. Copyright © 2015 Elsevier Inc. All rights reserved.

Aid to planning the marketing of mining area boundaries

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

Giles, R.H. Jr.

Reducing trespass, legal costs, and timber and wildlife poaching and increasing control, safety, and security are key reasons why mine land boundaries need to be marked. Accidents may be reduced, especially when associated with blast area boundaries, and in some cases increased income may be gained from hunting and recreational fees on well-marked areas. A BASIC computer program for an IBM-PC has been developed that requires minimum inputs to estimate boundary marking costs. This paper describes the rationale for the program and shows representative outputs. 3 references, 3 tables.

A global sensitivity analysis of crop virtual water content

NASA Astrophysics Data System (ADS)

Tamea, S.; Tuninetti, M.; D'Odorico, P.; Laio, F.; Ridolfi, L.

2015-12-01

The concepts of virtual water and water footprint are becoming widely used in the scientific literature and they are proving their usefulness in a number of multidisciplinary contexts. With such growing interest a measure of data reliability (and uncertainty) is becoming pressing but, as of today, assessments of data sensitivity to model parameters, performed at the global scale, are not known. This contribution aims at filling this gap. Starting point of this study is the evaluation of the green and blue virtual water content (VWC) of four staple crops (i.e. wheat, rice, maize, and soybean) at a global high resolution scale. In each grid cell, the crop VWC is given by the ratio between the total crop evapotranspiration over the growing season and the crop actual yield, where evapotranspiration is determined with a detailed daily soil water balance and actual yield is estimated using country-based data, adjusted to account for spatial variability. The model provides estimates of the VWC at a 5x5 arc minutes and it improves on previous works by using the newest available data and including multi-cropping practices in the evaluation. The model is then used as the basis for a sensitivity analysis, in order to evaluate the role of model parameters in affecting the VWC and to understand how uncertainties in input data propagate and impact the VWC accounting. In each cell, small changes are exerted to one parameter at a time, and a sensitivity index is determined as the ratio between the relative change of VWC and the relative change of the input parameter with respect to its reference value. At the global scale, VWC is found to be most sensitive to the planting date, with a positive (direct) or negative (inverse) sensitivity index depending on the typical season of crop planting date. VWC is also markedly dependent on the length of the growing period, with an increase in length always producing an increase of VWC, but with higher spatial variability for rice than for other crops. The sensitivity to the reference evapotranspiration is highly variable with the considered crop and ranges from positive values (for soybean), to negative values (for rice and maize) and near-zero values for wheat. This variability reflects the different yield response factors of crops, which expresses their tolerance to water stress.

Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines

PubMed Central

BAHARUDDIN, PUTERI; SATAR, NAZILAH; FAKIRUDDIN, KAMAL SHAIK; ZAKARIA, NORASHIKIN; LIM, MOON NIAN; YUSOFF, NARAZAH MOHD; ZAKARIA, ZUBAIDAH; YAHAYA, BADRUL HISHAM

2016-01-01

Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10–40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC. PMID:26531053

Detection of nitro-organic and peroxide explosives in latent fingermarks by DART- and SALDI-TOF-mass spectrometry.

PubMed

Rowell, Frederick; Seviour, John; Lim, Angelina Yimei; Elumbaring-Salazar, Cheryl Grace; Loke, Jason; Ma, Jan

2012-09-10

The ability of two mass spectrometric methods, surface-assisted laser desorption/ionization-time of flight-mass spectrometry (SALDI-TOF-MS) and direct analysis in real time (DART-MS), to detect the presence of seven common explosives (six nitro-organic- and one peroxide-type) in spiked latent fingermarks has been examined. It was found that each explosive could be detected with nanogram sensitivity for marks resulting from direct finger contact with a glass probe by DART-MS or onto stainless steel target plates using SALDI-TOF-MS for marks pre-dusted with one type of commercial black magnetic powder. These explosives also could be detected in latent marks lifted from six common surfaces (paper, plastic bag, metal drinks can, wood laminate, adhesive tape and white ceramic tile) whereas no explosive could be detected in equivalent pre-dusted marks on the surface of a commercial lifting tape by the DART-MS method due to high background interference from the tape material. The presence of TNT and Tetryl could be detected in pre-dusted latent fingermarks on a commercial lifting tape for up to 29 days sealed and stored under ambient conditions. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Diet, inflammation and prediabetes-impact of quality of diet.

PubMed

Uusitupa, Matti; Schwab, Ursula

2013-10-01

Low grade inflammation has been linked to risk of type 2 diabetes and atherosclerotic vascular diseases. Obesity and, in particular, abdominal obesity increase the risk of diabetes and atherosclerotic vascular diseases. One of the mechanisms could be low grade inflammation and vascular endothelial dysfunction. Permanent weight reduction is the first line of treatment both for obese individuals at increased risk of diabetes and for newly onset type 2 diabetes. Weight reduction lowers the level of several inflammatory factors in the body while increasing the level of adiponectin. Besides weight reduction the quality of diet and physical activity also modifies low grade inflammation. Based on the literature survey and our own studies in humans, it is possible to have dietary patterns that reduce inflammatory stress in the body and improves vascular endothelial dysfunction. There is strong evidence to suggest that IL-1 Ra is a very sensitive marker of low grade inflammation in obesity and related phenotypes; however, its level is markedly lowered by weight reduction and by choosing foods that have been shown to reduce inflammatory stress in the body. Copyright © 2013. Published by Elsevier Inc.

Butterfly Eyespots: Their Potential Influence on Aesthetic Preferences and Conservation Attitudes

PubMed Central

Manesi, Zoi; Van Lange, Paul A. M.; Pollet, Thomas V.

2015-01-01

Research has shown that the mere presence of stimuli that resemble eyes is sufficient to attract attention, elicit aesthetic responses, and can even enhance prosocial behavior. However, it is less clear whether eye-like stimuli could also be used as a tool for nature conservation. Several animal species, including butterflies, develop eye-like markings that are known as eyespots. In the present research, we explored whether the mere display of eyespots on butterfly wings can enhance: (a) liking for a butterfly species, and (b) attitudes and behaviors towards conservation of a butterfly species. Four online experimental studies, involving 613 participants, demonstrated that eyespots significantly increased liking for a butterfly species. Furthermore, eyespots significantly increased positive attitudes towards conservation of a butterfly species (Studies 1, 2 and 4), whereas liking mediated the eyespot effect on conservation attitudes (Study 2). However, we also found some mixed evidence for an association between eyespots and actual conservation behavior (Studies 3 and 4). Overall, these findings suggest that eyespots may increase liking for an animal and sensitize humans to conservation. We discuss possible implications for biodiversity conservation and future research directions. PMID:26544692

Butterfly Eyespots: Their Potential Influence on Aesthetic Preferences and Conservation Attitudes.

PubMed

Manesi, Zoi; Van Lange, Paul A M; Pollet, Thomas V

2015-01-01

Research has shown that the mere presence of stimuli that resemble eyes is sufficient to attract attention, elicit aesthetic responses, and can even enhance prosocial behavior. However, it is less clear whether eye-like stimuli could also be used as a tool for nature conservation. Several animal species, including butterflies, develop eye-like markings that are known as eyespots. In the present research, we explored whether the mere display of eyespots on butterfly wings can enhance: (a) liking for a butterfly species, and (b) attitudes and behaviors towards conservation of a butterfly species. Four online experimental studies, involving 613 participants, demonstrated that eyespots significantly increased liking for a butterfly species. Furthermore, eyespots significantly increased positive attitudes towards conservation of a butterfly species (Studies 1, 2 and 4), whereas liking mediated the eyespot effect on conservation attitudes (Study 2). However, we also found some mixed evidence for an association between eyespots and actual conservation behavior (Studies 3 and 4). Overall, these findings suggest that eyespots may increase liking for an animal and sensitize humans to conservation. We discuss possible implications for biodiversity conservation and future research directions.

Renal sodium reabsorption following induction of and recovery from volume expansion

NASA Technical Reports Server (NTRS)

Knight, T. F.; Weinman, E. J.

1977-01-01

In the rat, infusion of a volume of isotonic saline equal to 2% of body weight resulted in an 82% increase in the delivery of filtrate out of the proximal tubule but little or, in some animals, no change in the urinary excretion of sodium. By contrast, further degrees of volume expansion resulted in lesser increases in the distal delivery of filtrate, but were associated with a marked increase in the urinary excretion of sodium. Sixty minutes following completion of volume expansion, while the animals were still in positive sodium balance, the urinary excretion of sodium decreased 52% compared to a decrease of only 24% in the distal delivery of filtrate. During the course of progressive volume expansion and during the recovery phase, there was a dissociation between alterations in sodium reabsorption in the proximal convoluted tubule and in the whole kidney. These studies indicate that although the proximal tubule is more sensitive to changes in the extracellular fluid volume, distal nephron sites are ultimately responsible both for the natriuresis of volume expansion and the relative antinatriuresis of the recovery periods.

PRRT2 Is a Key Component of the Ca(2+)-Dependent Neurotransmitter Release Machinery.

PubMed

Valente, Pierluigi; Castroflorio, Enrico; Rossi, Pia; Fadda, Manuela; Sterlini, Bruno; Cervigni, Romina Ines; Prestigio, Cosimo; Giovedì, Silvia; Onofri, Franco; Mura, Elisa; Guarnieri, Fabrizia C; Marte, Antonella; Orlando, Marta; Zara, Federico; Fassio, Anna; Valtorta, Flavia; Baldelli, Pietro; Corradi, Anna; Benfenati, Fabio

2016-04-05

Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca(2+) sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca(2+)-sensing machinery and that it plays an important role in the final steps of neurotransmitter release. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Ageing increases reliance on sensorimotor prediction through structural and functional differences in frontostriatal circuits

PubMed Central

Wolpe, Noham; Ingram, James N.; Tsvetanov, Kamen A.; Geerligs, Linda; Kievit, Rogier A.; Henson, Richard N.; Wolpert, Daniel M.; Tyler, Lorraine K.; Brayne, Carol; Bullmore, Edward; Calder, Andrew; Cusack, Rhodri; Dalgleish, Tim; Duncan, John; Matthews, Fiona E.; Marslen-Wilson, William; Shafto, Meredith A.; Campbell, Karen; Cheung, Teresa; Davis, Simon; McCarrey, Anna; Mustafa, Abdur; Price, Darren; Samu, David; Taylor, Jason R.; Treder, Matthias; van Belle, Janna; Williams, Nitin; Bates, Lauren; Emery, Tina; Erzinçlioglu, Sharon; Gadie, Andrew; Gerbase, Sofia; Georgieva, Stanimira; Hanley, Claire; Parkin, Beth; Troy, David; Auer, Tibor; Correia, Marta; Gao, Lu; Green, Emma; Henriques, Rafael; Allen, Jodie; Amery, Gillian; Amunts, Liana; Barcroft, Anne; Castle, Amanda; Dias, Cheryl; Dowrick, Jonathan; Fair, Melissa; Fisher, Hayley; Goulding, Anna; Grewal, Adarsh; Hale, Geoff; Hilton, Andrew; Johnson, Frances; Johnston, Patricia; Kavanagh-Williamson, Thea; Kwasniewska, Magdalena; McMinn, Alison; Norman, Kim; Penrose, Jessica; Roby, Fiona; Rowland, Diane; Sargeant, John; Squire, Maggie; Stevens, Beth; Stoddart, Aldabra; Stone, Cheryl; Thompson, Tracy; Yazlik, Ozlem; Barnes, Dan; Dixon, Marie; Hillman, Jaya; Mitchell, Joanne; Villis, Laura; Rowe, James B.

2016-01-01

The control of voluntary movement changes markedly with age. A critical component of motor control is the integration of sensory information with predictions of the consequences of action, arising from internal models of movement. This leads to sensorimotor attenuation—a reduction in the perceived intensity of sensations from self-generated compared with external actions. Here we show that sensorimotor attenuation occurs in 98% of adults in a population-based cohort (n=325; 18–88 years; the Cambridge Centre for Ageing and Neuroscience). Importantly, attenuation increases with age, in proportion to reduced sensory sensitivity. This effect is associated with differences in the structure and functional connectivity of the pre-supplementary motor area (pre-SMA), assessed with magnetic resonance imaging. The results suggest that ageing alters the balance between the sensorium and predictive models, mediated by the pre-SMA and its connectivity in frontostriatal circuits. This shift may contribute to the motor and cognitive changes observed with age. PMID:27694879

Mincle suppresses Toll-like receptor 4 activation.

PubMed

Greco, Stephanie H; Mahmood, Syed Kashif; Vahle, Anne-Kristin; Ochi, Atsuo; Batel, Jennifer; Deutsch, Michael; Barilla, Rocky; Seifert, Lena; Pachter, H Leon; Daley, Donnele; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Miller, George

2016-07-01

Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation. © Society for Leukocyte Biology.

Microstructural, mechanical and tribological investigation of 30CrMnSiNi2A ultra-high strength steel under various tempering temperatures

NASA Astrophysics Data System (ADS)

Arslan Hafeez, Muhammad; Farooq, Ameeq

2018-01-01

The aim of the research was to investigate the variation in microstructural, mechanical and tribological characteristics of 30CrMnSiNi2A ultra-high strength steel as a function of tempering temperatures. Steel was quenched at 880 °C and tempered at five different tempering temperatures ranging from 250 °C to 650 °C. Optical microscopy and pin on disc tribometer was used to evaluate the microstructural and wear properties. Results show that characteristics of 30CrMnSiNi2A are highly sensitive to tempering temperatures. Lathe and plate shaped martensite obtained by quenching transform first into ε-carbide, second cementite, third coarsened and spheroidized cementite and finally into recovered ferrite and austenite. Hardness, tensile and yield strengths decreased while elongation increased with tempering temperatures. On the other hand, wear rate first markedly decreased and then increased. Optimum amalgamation of characteristics was achieved at 350 °C.

Emergence of context-dependent variability across a basal ganglia network.

PubMed

Woolley, Sarah C; Rajan, Raghav; Joshua, Mati; Doupe, Allison J

2014-04-02

Context dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from corticostriatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that corticostriatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions. Copyright © 2014 Elsevier Inc. All rights reserved.

Emergence of context-dependent variability across a basal ganglia network

PubMed Central

Woolley, Sarah C.; Rajan, Raghav; Joshua, Mati; Doupe, Allison J.

2014-01-01

Summary Context-dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds, the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from cortico-striatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that cortico-striatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context-sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions. PMID:24698276

Gadolinium-modulated 19F signals from Perfluorocarbon Nanoparticles as a New Strategy for Molecular Imaging

PubMed Central

Neubauer, Anne M.; Myerson, Jacob; Caruthers, Shelton D.; Hockett, Franklin D.; Winter, Patrick M.; Chen, Junjie; Gaffney, Patrick J.; Robertson, J. David; Lanza, Gregory M.; Wickline, Samuel A.

2008-01-01

Recent advances in the design of fluorinated nanoparticles for magnetic resonance molecular imaging have enabled specific detection of 19F nuclei, providing unique and quantifiable spectral signatures. However, a pressing need for signal enhancement exists because the total 19F in imaging voxels is often limited. By directly incorporating a relaxation agent (gadolinium) into the lipid monolayer that surrounds the perfluorocarbon, a marked augmentation of the 19F signal from 200nm nanoparticles was achieved. This design increases the magnetic relaxation rate of the 19F nuclei 4-fold at 1.5 T and effects a 125% increase in signal, an effect which is maintained when they are targeted to human plasma clots. By varying the surface concentration of gadolinium, the relaxation effect can be quantitatively modulated to tailor particle properties. This novel strategy dramatically improves the sensitivity and range of 19F MRI/MRS and forms the basis for designing contrast agents capable of sensing their surface chemistry. PMID:18956457

Gamma-oryzanol ameliorates insulin resistance and hyperlipidemia in rats with streptozotocin/nicotinamide-induced type 2 diabetes.

PubMed

Cheng, Hsing-Hsien; Ma, Chien-Ya; Chou, Tsui-Wei; Chen, Ya-Yen; Lai, Ming-Hoang

2010-01-01

Gamma-oryzanol is a component of rice bran oil (RBO) with purported health benefits. This study evaluated the effects of gamma-oryzanol on insulin resistance and lipid metabolism in Wistar rats with type 2 diabetes (T2DM). The rats were divided into three groups and consumed one of the following diets for 5 weeks: 15 % soybean oil (control group); 15 % palm oil (PO); and 15 % PO with the addition of 5.25 g gamma-oryzanol (POO). The results showed that PO markedly increased plasma low-density-lipoprotein cholesterol, plasma triglycerides, and hepatic triglyceride levels, but did not reduce the area under the curve for glucose and insulin significantly, compared with the control group. Adding gamma-oryzanol to PO improved the negative influence of PO on lipid metabolism in T2DM rats. In addition, gamma-oryzanol tended to increase insulin sensitivity in T2DM rats compared to control and PO groups. Longer-term studies are needed to evaluate these effects further.

Contagious equine metritis: artificial reproduction changes the epidemiologic paradigm.

PubMed

Schulman, Martin Lance; May, Catherine Edith; Keys, Bronwyn; Guthrie, Alan John

2013-11-29

Recent CEM outbreak reports reflect a novel epidemiologic manifestation with a markedly different risk association for transmission via artificial reproduction and subsequent to inadvertent importation of unapparent carrier stallions. Artificial breeding has an increased association with horizontal or fomite-associated transmission. Reported risk factors include inadequate biosecurity protocols at centralised breeding facilities associated with stallion management and methods of semen collection, processing and transport. Detection of carriers is based on traditional bacteriology from genital swabs and despite limitations inherent to Taylorella equigenitalis is currently the gold standard applied in all international trade and movement protocols. These limitations are reported to be overcome by PCR assays improving diagnostic sensitivity and specificity, practicality, turn-around times, through-put and cost efficacy. Molecular methods have increased understanding of the Taylorelleae, facilitate epidemiologic surveillance and outbreak control strategies. Validation and international regulatory acceptance of a robust PCR-based assay and the undefined risks in association with cryopreserved semen and embryos are future areas warranting further investigation. Copyright © 2013 Elsevier B.V. All rights reserved.

nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer

PubMed Central

Cook, Natalie; Bapiro, Tashinga E.; Lolkema, Martijn P.; Jodrell, Duncan I.; Tuveson, David A.

2016-01-01

nab-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the co-administration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels due to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase (Cda). Correspondingly, paclitaxel reduced Cda protein levels in cultured cells through reactive oxygen species-mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials. PMID:22585996

Ageing increases reliance on sensorimotor prediction through structural and functional differences in frontostriatal circuits.

PubMed

Wolpe, Noham; Ingram, James N; Tsvetanov, Kamen A; Geerligs, Linda; Kievit, Rogier A; Henson, Richard N; Wolpert, Daniel M; Rowe, James B

2016-10-03

The control of voluntary movement changes markedly with age. A critical component of motor control is the integration of sensory information with predictions of the consequences of action, arising from internal models of movement. This leads to sensorimotor attenuation-a reduction in the perceived intensity of sensations from self-generated compared with external actions. Here we show that sensorimotor attenuation occurs in 98% of adults in a population-based cohort (n=325; 18-88 years; the Cambridge Centre for Ageing and Neuroscience). Importantly, attenuation increases with age, in proportion to reduced sensory sensitivity. This effect is associated with differences in the structure and functional connectivity of the pre-supplementary motor area (pre-SMA), assessed with magnetic resonance imaging. The results suggest that ageing alters the balance between the sensorium and predictive models, mediated by the pre-SMA and its connectivity in frontostriatal circuits. This shift may contribute to the motor and cognitive changes observed with age.

Voltage-clamp study of the activation currents and fast block to polyspermy in the egg of Xenopus laevis.

PubMed

Glahn, David; Nuccitelli, Richard

2003-04-01

Voltage-clamped mature, jelly-intact Xenopus eggs were used to carefully examine the ionic currents crossing the plasma membrane before, during, and after fertilization. The bulk of the fertilization current was transient, of large amplitude, and reversed at the predicted Cl- reversal potential. However, the large amplitude fertilization current was preceded by a small, step-like increase in holding current. This small increase in holding current is referred to in this paper as Ion to acknowledge its qualitative similarity to the Ion current previously described in the sea urchin. It was observed in both fertilized and artificially activated eggs, and was found to be unaffected by 10 mm tetra-ethyl ammonium (TEA), a concentration found to block K+ currents in Rana pipiens. Current-voltage relationships are presented for the large fertilization potential, and show that the fertilization currents have a marked outward rectification and are voltage sensitive. These properties are in contrast to the total lack of rectification and slight voltage sensitivity seen before or after the fertilization currents. The time required for sperm to fertilize the egg was found to be voltage dependent with a relatively more depolarized voltage requiring a longer time for fertilization to occur. The percentage of eggs blocked with varying potential levels was determined and this information was fitted to a modified Boltzmann equation having a midpoint of -9 mV.

The antihypertensive effect of calorie restriction in obese adolescents: dissociation of effects on erythrocyte countertransport and cotransport.

PubMed

Weder, A B; Torretti, B A; Katch, V L; Rocchini, A P

1984-10-01

Measures of maximal rates of lithium-sodium countertransport and frusemide-sensitive sodium and potassium cotransport have been proposed as biochemical markers for human essential hypertension. The stability of these functions over time within the same individuals has led to the suggestion that maximal transport capacities are genetically determined. The present study confirms the reproducibility of functional assays of countertransport and cotransport in human erythrocytes after overnight storage and over a six-month period in normal volunteers and provides estimates of the magnitude of technical error for each assay. A long-term dietary intervention study in a group of obese adolescents demonstrated marked increases in erythrocyte sodium levels and maximal frusemide-sensitive sodium and potassium fluxes but no changes in cell potassium or water and no effect on lithium-sodium countertransport. A correlation between the decrease in percentage of body fat and the increase in cell sodium content suggests a link between the metabolic effects of dieting and control of erythrocyte cation handling. Although the mechanism linking dietary calorie restriction and changes in erythrocyte cation metabolism is unknown, evaluation of body weight, and especially recent weight loss, is important in studies of erythrocyte transport. Conclusions regarding genetic contributions to the activities of lithium-sodium countertransport and sodium-potassium cotransport systems will be strengthened by clarification of environmental regulators.

Quantitative analysis of the synthesis and secretion of type VII collagen in cultured human dermal fibroblasts with a sensitive sandwich enzyme-linked immunoassay.

PubMed

Amano, Satoshi; Ogura, Yuki; Akutsu, Nobuko; Nishiyama, Toshio

2007-02-01

Type VII collagen is the major component of anchoring fibrils in the epidermal basement membrane. Its expression has been analyzed by immunostaining or Northern blotting, but rarely at the protein level. In this study, we have quantitatively examined the effects of ascorbic acid and various cytokines/growth factors on the protein synthesis and secretion of type VII collagen by human dermal fibroblasts in culture, using a developed, highly sensitive sandwich enzyme-linked immunoassay with two kinds of specific monoclonal antibodies against the non-collagenous domain-1. Ascorbic acid and its derivative induced a twofold increase in type VII collagen synthesis, and markedly increased the secretion of type VII collagen into the medium when compared with the control culture. This effect was not influenced by the presence of transforming growth factor-beta1 (TGF-beta1). The synthesis of type VII collagen was elevated by TGF-beta1, platelet-derived growth factor, tumor necrosis factor-alpha, and interleukin-1beta, but not by TGF-alpha. Thus, our data indicate that the synthesis and secretion of type VII collagen in human dermal fibroblasts are regulated by ascorbate and the enhancement of type VII collagen gene expression by cytokines/growth factors is accompanied with elevated production of type VII collagen at the protein level.

The Role of Alveolar Epithelium in Radiation-Induced Lung Injury

PubMed Central

Almeida, Celine; Nagarajan, Devipriya; Tian, Jian; Leal, Sofia Walder; Wheeler, Kenneth; Munley, Michael; Blackstock, William; Zhao, Weiling

2013-01-01

Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11–13 Gy) and fractionated doses (24–36 Gy) of 137Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c), the number of pro-SP-c+ cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis. PMID:23326473

Pathogenetic mechanisms in immune polioencephalomyelitis: induction of disease in immunosuppressed mice

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

Duffey, P.S.; Martinez, D.; Abrams, G.D.

1976-02-01

Immune polioencephalomyelitis (IPE) was induced by the i. p. injection of x-irradiated (10,000 R) syngeneic line I/sub b/ malignant lymphocytes into C58 mice that were 7 or more months old and in young mice immunosuppressed by x-ray or drugs. The occurrence of IPE in young immunosuppressed C58 mice was systematically analyzed. When mice less than 2 weeks old were x-irradiated with 600 R, IPE could not be induced. The incidence in 1-month-old mice was approximately 50 percent and increased progressively with the age except for a drop in incidence at 3 months. An analysis of the dose effects of x-irradiationmore » on the occurrence of IPE in mice of different ages revealed a marked increase in the incidence in 3- and 5-month-old mice beginning at dose levels of 450 R and 300 R, respectively. Considered together, these data indicated that two sub- populations of immunocytes differing in x-ray sensitivity interacted to protect mice from IPE. It appears that under natural conditions an x-ray sensitive cell population, possibly having suppressor function, decreased with age and made mice susceptible to induction of IPE. Five-month-old mice were immunosuppressed with an LD$sub 10$ of cyclophosphamide, prednisolone, or methotrexate to determine whether mice immunosuppressed with drugs also were susceptible to the induction of IPE. (auth)« less

Submandibular Gland and Caries Susceptibility in the Obese Zucker Rat

PubMed Central

Mozaffari, Mahmood S.; Abdelsayed, Rafik; Zakhary, Ibrahim; El-Salanty, Mohammed; Liu, Jun Yao; Wimborne, Hereward; El-Marakby, Ahmed

2010-01-01

Background Obesity is a prevalent disorder characterized as marked insulin resistance and low grade inflammation. We tested the hypothesis that obesity upregulates inflammatory markers in the submandibular gland in association with derangements of its architecture and predisposition to caries in obese Zucker rats. We also examined the potential impact of chromium picolinate (Cr(Pic)3), a nutritional supplement suggested to improve glycemic control, on the aforementioned parameters. Design Male obese Zucker rats (OZR) were treated with diets lacking and containing 5 or 10 mg/kg chromium (as Cr(Pic)3) from 6 weeks to about 6 months of age; lean Zucker rats (LZR) served as controls. Thereafter, glycemic status, salivary tissue architecture and levels of several inflammatory markers were determined in association with caries susceptibility. Results OZR showed reduced insulin sensitivity, increased ratio of phospho-nuclear factor kappa B (NF-κB) to total NF-κB and increased intercellular adhesion molecule-1 level but similar histological features compared to LZR. Importantly, compared to LZR, OZR displayed rampant caries and a tendency for reduced dentin mineral density. Treatment of OZR with Cr(Pic)3 attenuated upregulation of these proinflammatory indicators in association with reduced severity of caries without improving insulin sensitivity. Conclusions Obesity promotes proinflammatory changes within the submandibular gland, without affecting glandular architecture, in association with rampant caries; Cr(Pic)3 treatment provided some protective effects. PMID:20973827

A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner.

PubMed

Sutton, Selina K; Carter, Daniel R; Kim, Patrick; Tan, Owen; Arndt, Greg M; Zhang, Xu Dong; Baell, Jonathan; Noll, Benjamin D; Wang, Shudong; Kumar, Naresh; McArthur, Grant A; Cheung, Belamy B; Marshall, Glenn M

2016-08-09

There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease.

Role of Prefrontal Cortex Glucocorticoid Receptors in Stress and Emotion

PubMed Central

McKlveen, Jessica M.; Myers, Brent; Flak, Jonathan N.; Bundzikova, Jana; Solomon, Matia B.; Seroogy, Kim B.; Herman, James P.

2013-01-01

Background Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyper-locomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation. PMID:23683655

A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner

PubMed Central

Sutton, Selina K.; Carter, Daniel R.; Kim, Patrick; Tan, Owen; Arndt, Greg M.; Zhang, Xu Dong; Baell, Jonathan; Noll, Benjamin D.; Wang, Shudong; Kumar, Naresh; McArthur, Grant A.; Cheung, Belamy B.; Marshall, Glenn M.

2016-01-01

There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease. PMID:27447557

Maternal protein restriction induces alterations in insulin signaling and ATP sensitive potassium channel protein in hypothalami of intrauterine growth restriction fetal rats.

PubMed

Liu, Xiaomei; Qi, Ying; Gao, Hong; Jiao, Yisheng; Gu, Hui; Miao, Jianing; Yuan, Zhengwei

2013-01-01

It is well recognized that intrauterine growth restriction leads to the development of insulin resistance and type 2 diabetes mellitus in adulthood. To investigate the mechanisms behind this "metabolic imprinting" phenomenon, we examined the impact of maternal undernutrition on insulin signaling pathway and the ATP sensitive potassium channel expression in the hypothalamus of intrauterine growth restriction fetus. Intrauterine growth restriction rat model was developed through maternal low protein diet. The expression and activated levels of insulin signaling molecules and K(ATP) protein in the hypothalami which were dissected at 20 days of gestation, were analyzed by western blot and real time PCR. The tyrosine phosphorylation levels of the insulin receptor substrate 2 and phosphatidylinositol 3'-kinase p85α in the hypothalami of intrauterine growth restriction fetus were markedly reduced. There was also a downregulation of the hypothalamic ATP sensitive potassium channel subunit, sulfonylurea receptor 1, which conveys the insulin signaling. Moreover, the abundances of gluconeogenesis enzymes were increased in the intrauterine growth restriction livers, though no correlation was observed between sulfonylurea receptor 1 and gluconeogenesis enzymes. Our data suggested that aberrant intrauterine milieu impaired insulin signaling in the hypothalamus, and these alterations early in life might contribute to the predisposition of the intrauterine growth restriction fetus toward the adult metabolic disorders.

Ionic solution and nanoparticle assisted MALDI-MS as bacterial biosensors for rapid analysis of yogurt.

PubMed

Lee, Chia-Hsun; Gopal, Judy; Wu, Hui-Fen

2012-01-15

Bacterial analysis from food samples is a highly challenging task because food samples contain intensive interferences from proteins and carbohydrates. Three different conditions of yogurt were analyzed: (1) the fresh yogurt immediately after purchasing, (2) the yogurt after expiry date stored in the refrigerator and (3) the yogurt left outside, without refrigeration. The shelf lives of both these yogurt was compared in terms of the decrease in bacterial signals. AB which initially contained 10(9) cells/mL drastically reduced to 10(7) cells/mL. However, Lin (Feng-Yin) yogurt which initially (fresh) had 10(8) cells/mL, even after two weeks beyond the expiry period showed no marked drop in bacterial count. Conventional MALDI-MS analysis showed limited sensitivity for analysis of yogurt bacteria amidst the complex milk proteins present in yogurt. A cost effective ionic solution, CrO(4)(2-) solution was used to enable the successful detection of bacterial signals (40-fold increased in sensitivity) selectively without the interference of the milk proteins. 0.035 mg of Ag nanoparticles (NPs) were also found to improve the detection of bacteria 2-6 times in yogurt samples. The current approach can be further applied as a rapid, sensitive and effective platform for bacterial analysis from food. Copyright © 2011 Elsevier B.V. All rights reserved.

Diagnosis of Polycystic Ovary Syndrome: AMH in combination with clinical symptoms.

PubMed

Sahmay, Sezai; Aydin, Yavuz; Oncul, Mahmut; Senturk, Levent M

2014-02-01

We assessed the utility of using anti-Müllerian hormone (AMH) and clinical features of polycystic ovary syndrome (PCOS), polycystic ovarian morphology (PCOM), oligo/amenorrhea (OA), and hyperandrogenism (HA) for diagnosing PCOS, and compared their diagnostic accuracy with those of classical diagnostic systems. A total of 606 females were admitted to a university hospital with menstrual irregularities or symptoms of hyperandrogenism were enrolled in this cross-sectional study. Fasting blood samples were collected. Pelvic and/or abdominal ultrasonography and clinical examination were performed. Patients were evaluated for the presence of PCOS according to conventional diagnostic criteria. The diagnostic performance of using serum AMH levels alone and in various combinations with the clinical features of PCOM, OA, and HA were investigated. For the diagnosis of PCOS, the combination of OA and/or HA with AMH showed 83% sensitivity and 100% specificity according to the Rotterdam criteria; 83% sensitivity and 89% specificity according to the National Institutes of Health (NIH) criteria; and 82% sensitivity and 93.5% specificity according to the Androgen Excess Society (AES) criteria. The serum AMH level is a useful diagnostic marker for PCOS and is correlated with conventional diagnostic criteria. The combination of AMH level with OA and/or HA markedly increased the clinical scope for PCOS diagnosis and can be introduced as a possible objective criterion for the diagnosis of this disease.

Effects of hypobaria and hypoxia on seed germination of six plant species

NASA Astrophysics Data System (ADS)

Tang, Yongkang; Gao, Feng; Guo, Shuangsheng; Li, Fang

2014-10-01

Hypobaria (low pressure) is typically associated with hypoxia (low oxygen partial pressure). There are several advantages of growing higher plants under hypobaria in the moon or mars habitat. The objectives of this research were to investigate the seed germination of six plant species under hypobaric and ambient total pressure conditions. Seeds were sown and germinated under three levels of total atmospheric pressure (101, 30 and 10 kPa) and three levels of oxygen partial pressures (21, 6 and 2 kPa) in an 8-day study. Hypoxia (6 or 2 kPa) significantly inhibited all seed germination under three levels of total atmospheric pressure by increasing the electrical conductivity and the optical density, decreasing the seed germination percentage and seed dehydrogenase activity and inhibiting the growth of the shoots and roots. Hypobaria (30 or 10 kPa) markedly improved seed germination and root growth by enhancing the oxygen diffusion rate under hypoxic conditions (6 or 2 kPa). The seeds of three dicot plants (lettuce, Chinese cabbage and cucumber) were more sensitive to hypoxia caused by hypobaria than were those of three monocot plants (maize, wheat and rice); lettuce and cucumber seeds had the highest sensitivity, whereas rice seeds had the lowest sensitivity. This research demonstrates that six experimental seeds can germinate normally under hypobaria (30 kPa), but the oxygen partial pressure should not be less than 6 kPa.

Adaptation and acclimatization to ocean acidification in marine ectotherms: an in situ transplant experiment with polychaetes at a shallow CO2 vent system

PubMed Central

Calosi, Piero; Rastrick, Samuel P. S.; Lombardi, Chiara; de Guzman, Heidi J.; Davidson, Laura; Jahnke, Marlene; Giangrande, Adriana; Hardege, Jörg D.; Schulze, Anja; Spicer, John I.; Gambi, Maria-Cristina

2013-01-01

Metabolic rate determines the physiological and life-history performances of ectotherms. Thus, the extent to which such rates are sensitive and plastic to environmental perturbation is central to an organism's ability to function in a changing environment. Little is known of long-term metabolic plasticity and potential for metabolic adaptation in marine ectotherms exposed to elevated pCO2. Consequently, we carried out a series of in situ transplant experiments using a number of tolerant and sensitive polychaete species living around a natural CO2 vent system. Here, we show that a marine metazoan (i.e. Platynereis dumerilii) was able to adapt to chronic and elevated levels of pCO2. The vent population of P. dumerilii was physiologically and genetically different from nearby populations that experience low pCO2, as well as smaller in body size. By contrast, different populations of Amphiglena mediterranea showed marked physiological plasticity indicating that adaptation or acclimatization are both viable strategies for the successful colonization of elevated pCO2 environments. In addition, sensitive species showed either a reduced or increased metabolism when exposed acutely to elevated pCO2. Our findings may help explain, from a metabolic perspective, the occurrence of past mass extinction, as well as shed light on alternative pathways of resilience in species facing ongoing ocean acidification. PMID:23980245

Adaptation and acclimatization to ocean acidification in marine ectotherms: an in situ transplant experiment with polychaetes at a shallow CO2 vent system.

PubMed

Calosi, Piero; Rastrick, Samuel P S; Lombardi, Chiara; de Guzman, Heidi J; Davidson, Laura; Jahnke, Marlene; Giangrande, Adriana; Hardege, Jörg D; Schulze, Anja; Spicer, John I; Gambi, Maria-Cristina

2013-01-01

Metabolic rate determines the physiological and life-history performances of ectotherms. Thus, the extent to which such rates are sensitive and plastic to environmental perturbation is central to an organism's ability to function in a changing environment. Little is known of long-term metabolic plasticity and potential for metabolic adaptation in marine ectotherms exposed to elevated pCO2. Consequently, we carried out a series of in situ transplant experiments using a number of tolerant and sensitive polychaete species living around a natural CO2 vent system. Here, we show that a marine metazoan (i.e. Platynereis dumerilii) was able to adapt to chronic and elevated levels of pCO2. The vent population of P. dumerilii was physiologically and genetically different from nearby populations that experience low pCO2, as well as smaller in body size. By contrast, different populations of Amphiglena mediterranea showed marked physiological plasticity indicating that adaptation or acclimatization are both viable strategies for the successful colonization of elevated pCO2 environments. In addition, sensitive species showed either a reduced or increased metabolism when exposed acutely to elevated pCO2. Our findings may help explain, from a metabolic perspective, the occurrence of past mass extinction, as well as shed light on alternative pathways of resilience in species facing ongoing ocean acidification.

GCF Mark IV development

NASA Technical Reports Server (NTRS)

Mortensen, L. O.

1982-01-01

The Mark IV ground communication facility (GCF) as it is implemented to support the network consolidation program is reviewed. Changes in the GCF are made in the area of increased capacity. Common carrier circuits are the medium for data transfer. The message multiplexing in the Mark IV era differs from the Mark III era, in that all multiplexing is done in a GCF computer under GCF software control, which is similar to the multiplexing currently done in the high speed data subsystem.

Dietary calcein marking of brook trout, Atlantic salmon, yellow perch, and coho salmon scales

USGS Publications Warehouse

Honeyfield, D.C.; Ostrowski, C.S.; Fletcher, J.W.; Mohler, J.W.

2006-01-01

Brook trout Salvelinus fontinalis, Atlantic salmon Salmo salar, coho salmon Oncorhynchus kisutch, and yellow perch Perca flavescens fed calcein for 5 d showed characteristic calcein scale marks 7-10 d postmarking. In fish fed 0.75 or 1.25 g of calcein per kilogram of feed, the percentage of fish that exhibited a calcein mark was 100% in brook trout, 93-98% in Atlantic salmon, 60% in yellow perch, and 0% in coho salmon. However, when coho salmon were fed 5.25 g calcein/kg feed, 100% marking was observed 7-10 d postmarking. Brook trout were successfully marked twice with distinct bands when fed calcein 5 months apart. Brook trout scale pixel luminosity increased as dietary calcein increased in experiment 2. For the second calcein mark, scale pixel luminosity from brook trout fed 1.25 g calcein/kg feed was numerically higher (P < 0.08) than scales from fish fed 0.75 g calcein/kg feed. Mean pixel luminosity of calcein-marked Atlantic salmon scales was 57.7 for fish fed 0.75 g calcein/kg feed and 55.2 for fish fed 1.25 g calcein/kg feed. Although feed acceptance presented a problem in yellow perch, these experiments provide evidence that dietary calcein is a viable tool for marking fish for stock identification. ?? Copyright by the American Fisheries Society 2006.

The research of laser marking control technology

NASA Astrophysics Data System (ADS)

Zhang, Qiue; Zhang, Rong

2009-08-01

In the area of Laser marking, the general control method is insert control card to computer's mother board, it can not support hot swap, it is difficult to assemble or it. Moreover, the one marking system must to equip one computer. In the system marking, the computer can not to do the other things except to transmit marking digital information. Otherwise it can affect marking precision. Based on traditional control methods existed some problems, introduced marking graphic editing and digital processing by the computer finish, high-speed digital signal processor (DSP) control marking the whole process. The laser marking controller is mainly contain DSP2812, digital memorizer, DAC (digital analog converting) transform unit circuit, USB interface control circuit, man-machine interface circuit, and other logic control circuit. Download the marking information which is processed by computer to U disk, DSP read the information by USB interface on time, then processing it, adopt the DSP inter timer control the marking time sequence, output the scanner control signal by D/A parts. Apply the technology can realize marking offline, thereby reduce the product cost, increase the product efficiency. The system have good effect in actual unit markings, the marking speed is more quickly than PCI control card to 20 percent. It has application value in practicality.

Physiological and Thermal Responses of MS Patients to Head and Vest Cooling: A Case Study

NASA Technical Reports Server (NTRS)

Luna, Bernadette; Webbon, Bruce W.; Ku, Yu-Tsuan E.; Lee, Hank C.; Montgomery, Leslie D.; Kliss, Mark (Technical Monitor)

1997-01-01

Personal cooling systems are used to alleviate symptoms of multiple sclerosis (MS) and to prevent increased core temperature during daily activities. The objective of this study was to determine the operating characteristics and the physiologic changes produced by short term application of the stationary thermal control system used by most clinical institutions. The Life Enhancement Tech (LET) Mark VII portable cooling system and a lightweight Head-vest active cooling garment were used to cool the head and chest regions of 4 male and 3 female MS patients (30 to 66 yrs. old) in this study. The subjects, seated in an upright position at normal room temperature (approx. 24 C), were tested for 60 min. with the liquid cooling garment (LCG) operated at 50 F. Oral, right and left ear temperatures and cooling system parameters were logged manually every 5 min. Arm, leg, chest and rectal temperatures, heart rate, respiration, and an activity index were recorded continuously on a U.F.I., Inc., Biolog ambulatory monitor. All temperature responses showed extreme variation among subjects. The cold-sensitive subject's rectal temperature increased initially in response to cooling; the heat sensitive subject's rectal temperature decreased. After 40 min. of cooling and during recovery, all subjects'rectal temperatures decreased. Oral temperatures began to decrease after 30 min. of cooling. After 60 min. of cooling, temperature drops ranged from approx. 0.3 - 0.8 C. Oral temperatures continued to decrease during recovery (approx. 0.2 C). The car temperature of the heat sensitive subject was increased after cooling, other subjects exhibited an ear temperature decrease (0.0 - 0.5 C). These data indicate that head and vest cooling may be used to reduce the oral temperatures of MS patients by the approximate amount needed for symptomatic relief as shown by other researchers. The combination of a small subject population and a large subject variance does not permit us to draw statistical conclusions about the temperature response of MS patients. An individual's heat or cold sensitivity may influence their thermal response to cooling. This factor should be considered in the prescribed use of liquid cooling garments in the therapeutic management of MS.

Three methionine residues located within the regulator of conductance for K+ (RCK) domains confer oxidative sensitivity to large-conductance Ca2+-activated K+ channels

PubMed Central

Santarelli, Lindsey Ciali; Wassef, Ramez; Heinemann, Stefan H; Hoshi, Toshinori

2006-01-01

Methionine-directed oxidation of the human Slo1 potassium channel (hSlo1) shifts the half-activation voltage by −30 mV and markedly slows channel deactivation at low concentrations of intracellular Ca2+ ([Ca2+]i). We demonstrate here that the contemporaneous mutation of M536, M712 and M739 to leucine renders the channel functionally insensitive to methionine oxidation caused by the oxidant chloramine-T (Ch-T) without altering other functional characteristics. Coexpression with the auxiliary β1 subunit fails to restore the full oxidative sensitivity to this triple mutant channel. The Ch-T effect is mediated specifically by M536, M712 and M739 because even small changes in this residue combination interfere with the ability to remove the oxidant sensitivity following mutation. Replacement of M712 or M739, but not M536, with the hydrophilic residue glutamate largely mimics oxidation of the channel and essentially removes the Ch-T sensitivity, suggesting that M712 and M739 may be part of a hydrophobic pocket disrupted by oxidation of non-polar methionine to the more hydrophilic methionine sulfoxide. The increase in wild-type hSlo1 open probability caused by methionine oxidation disappears at high [Ca2+]i and biophysical modelling of the Ch-T effect on steady-state activation implicates a decrease in the allosteric coupling between Ca2+ binding and the pore. The dramatic increase in open probability at low [Ca2+]i especially within the physiological voltage range suggests that oxidation of M536, M712 or M739 may enhance the Slo1 BK activity during conditions of oxidative stress, such as those associated with ischaemia-reperfusion and neurodegenerative disease, or in response to metabolic cues. PMID:16396928

Computer-aided detection of colorectal polyps: can it improve sensitivity of less-experienced readers? Preliminary findings.

PubMed

Baker, Mark E; Bogoni, Luca; Obuchowski, Nancy A; Dass, Chandra; Kendzierski, Renee M; Remer, Erick M; Einstein, David M; Cathier, Pascal; Jerebko, Anna; Lakare, Sarang; Blum, Andrew; Caroline, Dina F; Macari, Michael

2007-10-01

To determine whether computer-aided detection (CAD) applied to computed tomographic (CT) colonography can help improve sensitivity of polyp detection by less-experienced radiologist readers, with colonoscopy or consensus used as the reference standard. The release of the CT colonographic studies was approved by the individual institutional review boards of each institution. Institutions from the United States were HIPAA compliant. Written informed consent was waived at all institutions. The CT colonographic studies in 30 patients from six institutions were collected; 24 images depicted at least one confirmed polyp 6 mm or larger (39 total polyps) and six depicted no polyps. By using an investigational software package, seven less-experienced readers from two institutions evaluated the CT colonographic images and marked or scored polyps by using a five-point scale before and after CAD. The time needed to interpret the CT colonographic findings without CAD and then to re-evaluate them with CAD was recorded. For each reader, the McNemar test, adjusted for clustered data, was used to compare sensitivities for readers without and with CAD; a Wilcoxon signed-rank test was used to analyze the number of false-positive results per patient. The average sensitivity of the seven readers for polyp detection was significantly improved with CAD-from 0.810 to 0.908 (P=.0152). The number of false-positive results per patient without and with CAD increased from 0.70 to 0.96 (95% confidence interval for the increase: -0.39, 0.91). The mean total time for the readings was 17 minutes 54 seconds; for interpretation of CT colonographic findings alone, the mean time was 14 minutes 16 seconds; and for review of CAD findings, the mean time was 3 minutes 38 seconds. Results of this feasibility study suggest that CAD for CT colonography significantly improves per-polyp detection for less-experienced readers. Copyright (c) RSNA, 2007.

Changes in the sensitivity of GABAA current rundown to drug treatments in a model of temporal lobe epilepsy

PubMed Central

Cifelli, Pierangelo; Palma, Eleonora; Roseti, Cristina; Verlengia, Gianluca; Simonato, Michele

2013-01-01

The pharmacological treatment of mesial temporal lobe epilepsy (mTLE), the most common epileptic syndrome in adults, is still unsatisfactory, as one-third of the patients are or become refractory to antiepileptic agents. Refractoriness may depend upon drug-induced alterations, but the disease per se may also undergo a progressive evolution that affects the sensitivity to drugs. mTLE has been shown to be associated with a dysfunction of the inhibitory signaling mediated by GABAA receptors. In particular, the repetitive activation of GABAA receptors produces a use-dependent decrease (rundown) of the evoked currents (IGABA), which is markedly enhanced in the hippocampus and cortex of drug-resistant mTLE patients. This phenomenon has been also observed in the pilocarpine model, where the increased IGABA rundown is observed in the hippocampus at the time of the first spontaneous seizure, then extends to the cortex and remains constant in the chronic phase of the disease. Here, we examined the sensitivity of IGABA to pharmacological modulation. We focused on the antiepileptic agent levetiracetam (LEV) and on the neurotrophin brain-derived neurotrophic factor (BDNF), which were previously reported to attenuate mTLE-induced increased rundown in the chronic human tissue. In the pilocarpine model, BDNF displayed a paramount effect, decreasing rundown in the hippocampus at the time of the first seizure, as well as in the hippocampus and cortex in the chronic period. In contrast, LEV did not affect rundown in the hippocampus, but attenuated it in the cortex. Interestingly, this effect of LEV was also observed on the still unaltered rundown observed in the cortex at the time of the first spontaneous seizure. These data suggest that the sensitivity of GABAA receptors to pharmacological interventions undergoes changes during the natural history of mTLE, implicating that the site of seizure initiation and the timing of treatment may highly affect the therapeutic outcome. PMID:23874269

Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes.

PubMed

Sinha, Rajita; Fox, Helen C; Hong, Kwang-Ik Adam; Hansen, Julie; Tuit, Keri; Kreek, Mary Jeanne

2011-09-01

Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied. To investigate these responses in treatment-engaged, 1-month-abstinent, recovering alcohol-dependent patients relative to matched controls (study 1) and to assess whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome (study 2). Experimental exposure to stress, alcohol cues, and neutral, relaxing context to provoke alcohol craving, anxiety, and HPA axis responses (corticotropin and cortisol levels and cortisol to corticotropin ratio) and a prospective 90-day follow-up outcome design to assess alcohol relapse and aftercare treatment outcomes. Inpatient treatment in a community mental health center and hospital-based research unit. Treatment-engaged alcohol-dependent individuals and healthy controls. Time to alcohol relapse and to heavy drinking relapse. Significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, was seen in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress-induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed-state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse. These results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress- and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress- and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes.

Homosexuality via canalized sexual development: a testing protocol for a new epigenetic model.

PubMed

Rice, William R; Friberg, Urban; Gavrilets, Sergey

2013-09-01

We recently synthesized and reinterpreted published studies to advance an epigenetic model for the development of homosexuality (HS). The model is based on epigenetic marks laid down in response to the XX vs. XY karyotype in embryonic stem cells. These marks boost sensitivity to testosterone in XY fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our model predicts that a subset of these canalizing epigenetic marks stochastically carry over across generations and lead to mosaicism for sexual development in opposite-sex offspring--the homosexual phenotype being one such outcome. Here, we begin by outlining why HS has been under-appreciated as a commonplace phenomenon in nature, and how this trend is currently being reversed in the field of neurobiology. We next briefly describe our epigenetic model of HS, develop a set of predictions, and describe how epigenetic profiles of human stem cells can provide for a strong test of the model. © 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.