WorldWideScience

Sample records for strong association signals

  1. A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness.

    Science.gov (United States)

    Barcelos, Rosimeire Coura; Pelizzaro-Rocha, Karin Juliane; Pastre, Julio Cezar; Dias, Marina Pereira; Ferreira-Halder, Carmen Veríssima; Pilli, Ronaldo Aloise

    2014-11-24

    In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 μM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 μM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. A multivariate analysis of variation in genome size and endoreduplication in angiosperms reveals strong phylogenetic signal and association with phenotypic traits.

    Science.gov (United States)

    Bainard, Jillian D; Bainard, Luke D; Henry, Thomas A; Fazekas, Aron J; Newmaster, Steven G

    2012-12-01

    Genome size (C-value) and endopolyploidy (endoreduplication index, EI) are known to correlate with various morphological and ecological traits, in addition to phylogenetic placement. A phylogenetically controlled multivariate analysis was used to explore the relationships between DNA content and phenotype in angiosperms. Seeds from 41 angiosperm species (17 families) were grown in a common glasshouse experiment. Genome size (2C-value and 1Cx-value) and EI (in four tissues: leaf, stem, root, petal) were determined using flow cytometry. The phylogenetic signal was calculated for each measure of DNA content, and phylogenetic canonical correlation analysis (PCCA) explored how the variation in genome size and EI was correlated with 18 morphological and ecological traits. Phylogenetic signal (λ) was strongest for EI in all tissues, and λ was stronger for the 2C-value than the 1Cx-value. PCCA revealed that EI was correlated with pollen length, stem height, seed mass, dispersal mechanism, arbuscular mycorrhizal association, life history and flowering time, and EI and genome size were both correlated with stem height and life history. PCCA provided an effective way to explore multiple factors of DNA content variation and phenotypic traits in a phylogenetic context. Traits that were correlated significantly with DNA content were linked to plant competitive ability. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

  3. Strong electroweak symmetry breaking signals in WW scattering at TESLA

    CERN Document Server

    Chierici, R; Kobel, M

    2000-01-01

    A realistic study of the sensitivity to signals of strong electroweak symmetry breaking at TESLA energies using ee to WW nu nu and ee to ZZ nu nu processes is presented. Limits on alpha /sub 4/ and alpha /sub 5/, parameters of the electroweak chiral lagrangian, are given and discussed. (8 refs).

  4. Metagenome-based diversity analyses suggest a strong locality signal for bacterial communities associated with oyster aquaculture farms in Ofunato Bay

    KAUST Repository

    Kobiyama, Atsushi

    2018-04-30

    Ofunato Bay, in Japan, is the home of buoy-and-rope-type oyster aquaculture activities. Since the oysters filter suspended materials and excrete organic matter into the seawater, bacterial communities residing in its vicinity may show dynamic changes depending on the oyster culture activities. We employed a shotgun metagenomic technique to study bacterial communities near oyster aquaculture facilities at the center of the bay (KSt. 2) and compared the results with those of two other localities far from the station, one to the northeast (innermost bay, KSt. 1) and the other to the southwest (bay entrance, KSt. 3). Seawater samples were collected every month from January to December 2015 from the surface (1 m) and deeper (8 or 10 m) layers of the three locations, and the sequentially filtered fraction on 0.2-μm membranes was sequenced on an Illumina MiSeq system. The acquired reads were uploaded to MG-RAST for KEGG functional abundance analysis, while taxonomic analyses at the phylum and genus levels were performed using MEGAN after parsing the BLAST output. Discrimination analyses were then performed using the ROC-AUC value of the cross validation, targeting the depth (shallow or deep), locality [(KSt. 1 + KSt. 2) vs. KSt 3; (KSt. 1 + KSt. 3) vs. KSt. 2 or the (KSt. 2 + KSt. 3) vs. KSt. 1] and seasonality (12 months). The matrix discrimination analysis on the adjacent 2 continuous seasons by ROC-AUC, which was based on the datasets that originated from different depths, localities and months, showed the strongest discrimination signal on the taxonomy matrix at the phylum level for the datasets from July to August compared with those from September to June, while the KEGG matrix showed the strongest signal for the datasets from March to June compared with those from July to February. Then, the locality combination was subjected to the same ROC-AUC discrimination analysis, resulting in significant differences between KSt. 2 and KSt. 1 + KSt. 3

  5. High-Rate Strong-Signal Quantum Cryptography

    Science.gov (United States)

    Yuen, Horace P.

    1996-01-01

    Several quantum cryptosystems utilizing different kinds of nonclassical lights, which can accommodate high intensity fields and high data rate, are described. However, they are all sensitive to loss and both the high rate and the strong-signal character rapidly disappear. A squeezed light homodyne detection scheme is proposed which, with present-day technology, leads to more than two orders of magnitude data rate improvement over other current experimental systems for moderate loss.

  6. Maximum Likelihood Joint Tracking and Association in Strong Clutter

    Directory of Open Access Journals (Sweden)

    Leonid I. Perlovsky

    2013-01-01

    Full Text Available We have developed a maximum likelihood formulation for a joint detection, tracking and association problem. An efficient non-combinatorial algorithm for this problem is developed in case of strong clutter for radar data. By using an iterative procedure of the dynamic logic process “from vague-to-crisp” explained in the paper, the new tracker overcomes the combinatorial complexity of tracking in highly-cluttered scenarios and results in an orders-of-magnitude improvement in signal-to-clutter ratio.

  7. Body-image dissatisfaction is strongly associated with chronic dysphoria.

    Science.gov (United States)

    Rosenström, Tom; Jokela, Markus; Hintsanen, Mirka; Josefsson, Kim; Juonala, Markus; Kivimäki, Mika; Pulkki-Råback, Laura; Viikari, Jorma S A; Hutri-Kähönen, Nina; Heinonen, Erkki; Raitakari, Olli T; Keltikangas-Järvinen, Liisa

    2013-09-05

    Individual depressive symptoms may contribute to the risk of chronic depression. This study aimed to explore which symptoms predict chronic dysphoria, a hallmark of depression. 1057 participants from the population-based Young Finns study were examined for four times during a 16-year period. Those with a modified Beck's Depression Inventory score in the upper third at all four screenings were considered to have chronic dysphoria (n=135). Participants with only one high depression score formed the reference group of transient dysphoria (n=179). Individual items of the Inventory were analyzed in terms of their association with dysphoria status and chronicity, controlling for potential confounding factors, such as personality assessed using the Temperament and Character Inventory. Body-image dissatisfaction was strongly associated with chronically elevated dysphoria (Bonferroni-corrected p=0.006). The degree of body-image dissatisfaction was associated with the probability for chronic dysphoria in a dose-response manner, with the estimated probability ranging from 0.01 to 0.60 as a function of item response. The association remained after adjustments for a wide range of personality characteristics. The study relied on self-reports of mood and personality, and lacked information on external opinion on participants appearances. The requirement of full time-series data may have resulted in attrition-related bias. Body-image dissatisfaction was a strong predictor of chronic depression characterized by dysphoria. This finding suggests that dysfunctional attitude towards oneself might represent a potentially important target for cognitive therapies and preventive interventions. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Strong association between earlier abuse and revictimization in youth.

    Science.gov (United States)

    Blom, Helena; Högberg, Ulf; Olofsson, Niclas; Danielsson, Ingela

    2014-07-14

    Violence victimization among youth is recognized as a public health problem. The objective was to analyze the risk pattern of emotional, physical, and sexual abuse during the past 12 months by gender, sociodemographic factors, health risk behaviors, and exposure to abuse before the age of 15, among young men and women attending youth health centers in Sweden. A cross-sectional survey was conducted using a nationally representative sample of youth health centers. A total of 2,250 young women and 920 young men aged 15-23 completed a self-administered questionnaire. Odds ratios (OR) and adjusted odds ratios (AOR) with 95% CI were calculated. A consistent and strong association was noted between exposure to all types of violence during the past year and victimization before the age of 15 for all types of violence for both women and men. The only exceptions were childhood sexual victimization and sexual violence during the past year for men. Younger age was associated with all violence exposure for the women and with emotional violence for the men. For the women, drug use was associated with all types of violence, while the association with hazardous alcohol use and not living with parents was restricted to physical and sexual violence exposure, present smoking was restricted to emotional and physical violence exposure, and partnership and living in urban areas were restricted to sexual violence. For men, not being partnered, hazardous alcohol consumption, and drug use meant increased risk for physical violence, while smoking and living in urban areas were associated with sexual violence. After adjustment, immigration had no association with violence exposure. Violence victimization in young men and women is often not a single experience. Findings underline the importance of early interventions among previously abused youth.

  9. Hydrochlorothiazide use is strongly associated with risk of lip cancer.

    Science.gov (United States)

    Pottegård, A; Hallas, J; Olesen, M; Svendsen, M T; Habel, L A; Friedman, G D; Friis, S

    2017-10-01

    The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer. © 2017 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

  10. The No-Higgs Signal: Strong WW Scattering at the LHC

    Energy Technology Data Exchange (ETDEWEB)

    Michael S. Chanowitz

    2004-12-07

    Strong WW scattering at the LHC is discussed as a manifestation of electroweak symmetry breaking in the absence of a light Higgs bosom. The general framework of the Higgs mechanism--with or without a Higgs boson--is reviewed, and unitarity is shown to fix the scale of strong WW scattering. Strong WW scattering is also shown to be a possible outcome of five-dimensional models, which do not employ the usual Higgs mechanism at the TeV scale. Precision electroweak constraints are briefly discussed. Illustrative LHC signals are reviewed for models with QCD-like dynamics, stressing the complementarity of the W{sup {+-}}Z and like-charge W{sup +}W{sup +} + W{sup -}W{sup -} channels.

  11. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

    DEFF Research Database (Denmark)

    Willsey, A Jeremy; Fernandez, Thomas V; Yu, Dongmei

    2017-01-01

    damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1...... trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably...... (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT....

  12. Spectrum of absorption of a weak signal by an atom in a strong field

    International Nuclear Information System (INIS)

    Bakaev, D.S.; Vdovin, Y.A.; Ermachenko, V.M.; Yakovlenko, S.I.

    1985-01-01

    An analysis is made of the spectrum of absorption of a weak probe electromagnetic field by two-level atoms in a strong resonant laser field, undergoing collision with buffer gas atoms. The analysis is made using an approach that allows for the direct influence of a strong electromagnetic field on the dynamics of an elastic collision between an active atom and a buffer gas atom. Rate equations are analyzed for a combined ''atom--strong electromagnetic field'' system (an atom ''dressed'' by the field) allowing for spontaneous and optical collisional transitions, and also for the interaction with the probe field. In the steady-state case, an expression is derived for the electric susceptibility of the medium at the small-signal frequency. This expression contains the rates of the optical collisional transitions that depend nontrivially on the parameters of the strong electromagnetic field. The phenomenological characteristics of optical collisional transitions generally used are only valid at low intensities and for small frequency detunings of the strong electromagnetic field, i.e., in the impact limit

  13. Strongly lensed gravitational waves and electromagnetic signals as powerful cosmic rulers

    Science.gov (United States)

    Wei, Jun-Jie; Wu, Xue-Feng

    2017-12-01

    In this paper, we discuss the possibility of using strongly lensed gravitational waves (GWs) and their electromagnetic (EM) counterparts as powerful cosmic rulers. In the EM domain, it has been suggested that joint observations of the time delay (Δτ) between lensed quasar images and the velocity dispersion (σ) of the lensing galaxy (i.e. the combination Δτ/σ2) are able to constrain the cosmological parameters more strongly than Δτ or σ2 separately. Here, for the first time, we propose that this Δτ/σ2 method can be applied to the strongly lensed systems observed in both GW and EM windows. Combining the redshifts, images and σ observed in the EM domain with the very precise Δτ derived from lensed GW signals, we expect that accurate multimessenger cosmology can be achieved in the era of third-generation GW detectors. Comparing with the constraints from the Δτ method, we prove that using Δτ/σ2 can improve the discrimination between cosmological models. Furthermore, we demonstrate that with ∼50 strongly lensed GW-EM systems, we can reach a constraint on the dark energy equation of state w comparable to the 580 Union2.1 Type Ia supernovae data. Much more stringent constraints on w can be obtained when combining the Δτ and Δτ/σ2 methods.

  14. Illusory Paschen curves associated with strongly electronegative gases

    DEFF Research Database (Denmark)

    McAllister, Iain Wilson

    1991-01-01

    Using analytical linear regression analysis, it is shown that, for a strongly electronegative gas, the (direct) breakdown voltage curve obtained with a moderately nonuniform field is effectively linear. For a strongly electronegative gas, breakdown voltage measurements made on a moderately...... nonuniform field test gap give rise to an apparently liner curve. The curve can be designated a Paschen curve, but the erroneous nature of this designation becomes apparent from a linear regression analysis of the experimental breakdown data...

  15. Analysis of luminosity distributions of strong lensing galaxies: subtraction of diffuse lensed signal

    Science.gov (United States)

    Biernaux, J.; Magain, P.; Hauret, C.

    2017-08-01

    Context. Strong gravitational lensing gives access to the total mass distribution of galaxies. It can unveil a great deal of information about the lenses' dark matter content when combined with the study of the lenses' light profile. However, gravitational lensing galaxies, by definition, appear surrounded by lensed signal, both point-like and diffuse, that is irrelevant to the lens flux. Therefore, the observer is most often restricted to studying the innermost portions of the galaxy, where classical fitting methods show some instabilities. Aims: We aim at subtracting that lensed signal and at characterising some lenses' light profile by computing their shape parameters (half-light radius, ellipticity, and position angle). Our objective is to evaluate the total integrated flux in an aperture the size of the Einstein ring in order to obtain a robust estimate of the quantity of ordinary (luminous) matter in each system. Methods: We are expanding the work we started in a previous paper that consisted in subtracting point-like lensed images and in independently measuring each shape parameter. We improve it by designing a subtraction of the diffuse lensed signal, based only on one simple hypothesis of symmetry. We apply it to the cases where it proves to be necessary. This extra step improves our study of the shape parameters and we refine it even more by upgrading our half-light radius measurement method. We also calculate the impact of our specific image processing on the error bars. Results: The diffuse lensed signal subtraction makes it possible to study a larger portion of relevant galactic flux, as the radius of the fitting region increases by on average 17%. We retrieve new half-light radii values that are on average 11% smaller than in our previous work, although the uncertainties overlap in most cases. This shows that not taking the diffuse lensed signal into account may lead to a significant overestimate of the half-light radius. We are also able to measure

  16. Development of an Earthquake Early Warning System Using Real-Time Strong Motion Signals.

    Science.gov (United States)

    Wu, Yih-Min; Kanamori, Hiroo

    2008-01-09

    As urbanization progresses worldwide, earthquakes pose serious threat to livesand properties for urban areas near major active faults on land or subduction zonesoffshore. Earthquake Early Warning (EEW) can be a useful tool for reducing earthquakehazards, if the spatial relation between cities and earthquake sources is favorable for suchwarning and their citizens are properly trained to respond to earthquake warning messages.An EEW system forewarns an urban area of forthcoming strong shaking, normally with afew sec to a few tens of sec of warning time, i.e., before the arrival of the destructive Swavepart of the strong ground motion. Even a few second of advanced warning time willbe useful for pre-programmed emergency measures for various critical facilities, such asrapid-transit vehicles and high-speed trains to avoid potential derailment; it will be alsouseful for orderly shutoff of gas pipelines to minimize fire hazards, controlled shutdown ofhigh-technological manufacturing operations to reduce potential losses, and safe-guardingof computer facilities to avoid loss of vital databases. We explored a practical approach toEEW with the use of a ground-motion period parameter τc and a high-pass filtered verticaldisplacement amplitude parameter Pd from the initial 3 sec of the P waveforms. At a givensite, an earthquake magnitude could be determined from τ c and the peak ground-motionvelocity (PGV) could be estimated from Pd. In this method, incoming strong motion acceleration signals are recursively converted to ground velocity and displacement. A Pwavetrigger is constantly monitored. When a trigger occurs, τ c and Pd are computed. Theearthquake magnitude and the on-site ground-motion intensity could be estimated and thewarning could be issued. In an ideal situation, such warnings would be available within 10sec of the origin time of a large earthquake whose subsequent ground motion may last fortens of seconds.

  17. Development of an Earthquake Early Warning System Using Real-Time Strong Motion Signals

    Directory of Open Access Journals (Sweden)

    Hiroo Kanamori

    2008-01-01

    Full Text Available As urbanization progresses worldwide, earthquakes pose serious threat to livesand properties for urban areas near major active faults on land or subduction zonesoffshore. Earthquake Early Warning (EEW can be a useful tool for reducing earthquakehazards, if the spatial relation between cities and earthquake sources is favorable for suchwarning and their citizens are properly trained to respond to earthquake warning messages.An EEW system forewarns an urban area of forthcoming strong shaking, normally with afew sec to a few tens of sec of warning time, i.e., before the arrival of the destructive Swavepart of the strong ground motion. Even a few second of advanced warning time willbe useful for pre-programmed emergency measures for various critical facilities, such asrapid-transit vehicles and high-speed trains to avoid potential derailment; it will be alsouseful for orderly shutoff of gas pipelines to minimize fire hazards, controlled shutdown ofhigh-technological manufacturing operations to reduce potential losses, and safe-guardingof computer facilities to avoid loss of vital databases. We explored a practical approach toEEW with the use of a ground-motion period parameter τc and a high-pass filtered verticaldisplacement amplitude parameter Pd from the initial 3 sec of the P waveforms. At a givensite, an earthquake magnitude could be determined from τc and the peak ground-motionvelocity (PGV could be estimated from Pd. In this method, incoming strong motion acceleration signals are recursively converted to ground velocity and displacement. A Pwavetrigger is constantly monitored. When a trigger occurs, τc and Pd are computed. Theearthquake magnitude and the on-site ground-motion intensity could be estimated and thewarning could be issued. In an ideal situation, such warnings would be available within 10sec of the origin time of a large earthquake whose subsequent ground motion may last fortens of seconds.

  18. Strong association between myotonic dystrophy type 2 and autoimmune diseases.

    NARCIS (Netherlands)

    Tieleman, A.A.; Broeder, A. den; Logt, A. van de; Engelen, B.G.M. van

    2009-01-01

    BACKGROUND: Myotonic dystrophy type 2 (DM2) is a dominantly inherited multisystem disorder, characterised by progressive proximal weakness, myotonia, cataracts and cardiac conduction abnormalities. Our clinical impression of an association between DM2 and autoimmune diseases or autoantibody

  19. Diabetes mellitus is strongly associated with tuberculosis in Indonesia.

    NARCIS (Netherlands)

    Alisjahbana, B.; Crevel, R. van; Sahiratmadja, E.; Heijer, M. den; Maya, A.; Istriana, E.; Danusantoso, H.; Ottenhoff, T.H.; Nelwan, R.H.; Meer, J.W.M. van der

    2006-01-01

    SETTING: Diabetes mellitus is a known risk factor for tuberculosis (TB), but no studies have been reported from South-East Asia, which has a high burden of TB and a rapidly growing prevalence of diabetes. OBJECTIVE: To examine if and to what extent diabetes is associated with an increased risk of TB

  20. Atmospheric circulation patterns associated with strong wind events in Catalonia

    Directory of Open Access Journals (Sweden)

    J. C. Peña

    2011-01-01

    Full Text Available The benefit of having a daily synoptic weather type catalogue and even more, a detailed catalogue for high impact weather events is well recognised by both climatologist and meteorologist communities. In this way the Meteorological Service of Catalonia (SMC has produced some accurate classifications for extreme events, such as hailstorms or strong winds (SW. Within the framework of the MEDEX project, the SMC has been collaborating to increase the level of awareness about these events. Following this line of work, the aim of this study is to characterise the SW events in Catalonia.

    According to the guidelines of the MEDEX project we worked with its SW event database for the period June 1995 to May 2004. We also used the period 2005–2009 to test the methodology. The methodology is based on principal component, cluster and discriminant analyses and applied to four variables: SLP, temperature at 850 hPa and geopotential at 500 hPa on a synoptic-scale and local gust wind. We worked with ERA-Interim reanalysis and applied discriminant analysis to test the quality of the methodology and to classify the events of the validation period.

    We found seven patterns for the SW events. The strongest event corresponds to NW-Flow with the Azores Anticyclone and the passing of a low pressure through the Pyrenees. This methodology has distinguished the summer events in an independent cluster. The results obtained encourage us to follow this line of work.

  1. Hydrochlorothiazide use is strongly associated with risk of lip cancer

    DEFF Research Database (Denmark)

    Pottegård, A; Hallas, J; Olesen, M

    2017-01-01

    Background: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. Objectives: To study the association between use of hydrochlorothia......Background: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. Objectives: To study the association between use...... of hydrochlorothiazide and squamous cell carcinoma of the lip. Methods: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk......-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined...

  2. Speed of Gravitational Waves from Strongly Lensed Gravitational Waves and Electromagnetic Signals.

    Science.gov (United States)

    Fan, Xi-Long; Liao, Kai; Biesiada, Marek; Piórkowska-Kurpas, Aleksandra; Zhu, Zong-Hong

    2017-03-03

    We propose a new model-independent measurement strategy for the propagation speed of gravitational waves (GWs) based on strongly lensed GWs and their electromagnetic (EM) counterparts. This can be done in two ways: by comparing arrival times of GWs and their EM counterparts and by comparing the time delays between images seen in GWs and their EM counterparts. The lensed GW-EM event is perhaps the best way to identify an EM counterpart. Conceptually, this method does not rely on any specific theory of massive gravitons or modified gravity. Its differential setting (i.e., measuring the difference between time delays in GW and EM domains) makes it robust against lens modeling details (photons and GWs travel in the same lensing potential) and against internal time delays between GW and EM emission acts. It requires, however, that the theory of gravity is metric and predicts gravitational lensing similar to general relativity. We expect that such a test will become possible in the era of third-generation gravitational-wave detectors, when about 10 lensed GW events would be observed each year. The power of this method is mainly limited by the timing accuracy of the EM counterpart, which for kilonovae is around 10^{4}  s. This uncertainty can be suppressed by a factor of ∼10^{10}, if strongly lensed transients of much shorter duration associated with the GW event can be identified. Candidates for such short transients include short γ-ray bursts and fast radio bursts.

  3. On strongly J -clean rings associated with polynomial identity g ( x =0

    Directory of Open Access Journals (Sweden)

    Hamid Haj seyyed javadi

    2014-05-01

    Full Text Available In this paper‎, ‎we introduce the new notion of strongly $J $-clean rings associated with polynomial identity $g(x=0$‎, ‎as a generalization of strongly $ J $-clean rings‎. ‎We denote strongly $J $-clean rings associated with polynomial identity $g(x=0$ by strongly $ g(x $-$J $-clean rings‎. ‎Next‎, ‎we investigate some properties of strongly $ g(x $-$ J $-clean.

  4. Strong Static Magnetic Fields Increase the Gel Signal in Partially Hydrated DPPC/DMPC Membranes

    Directory of Open Access Journals (Sweden)

    Jennifer Tang

    2015-09-01

    Full Text Available NIt was recently reported that static magnetic fields increase lipid order in the hydrophobic membrane core of dehydrated native plant plasma membranes [Poinapen, Soft Matter 9:6804-6813, 2013]. As plasma membranes are multicomponent, highly complex structures, in order to elucidate the origin of this effect, we prepared model membranes consisting of a lipid species with low and high melting temperature. By controlling the temperature, bilayers coexisting of small gel and fluid domains were prepared as a basic model for the plasma membrane core. We studied molecular order in mixed lipid membranes made of dimyristoyl-sn-glycero-3-phosphocholine (DMPC and dipalmitoyl-sn-glycero-3-phosphocholine (DPPC using neutron diffraction in the presence of strong static magnetic fields up to 3.5 T. The contribution of the hydrophobic membrane core was highlighted through deuterium labeling the lipid acyl chains. There was no observable effect on lipid organization in fluid or gel domains at high hydration of the membranes. However, lipid order was found to be enhanced at a reduced relative humidity of 43%: a magnetic field of 3.5 T led to an increase of the gel signal in the diffraction patterns of 5%. While all biological materials have weak diamagnetic properties, the corresponding energy is too small to compete against thermal disorder or viscous effects in the case of lipid molecules. We tentatively propose that the interaction between the fatty acid chains’ electric moment and the external magnetic field is driving the lipid tails in the hydrophobic membrane core into a better ordered state.

  5. Strong Static Magnetic Fields Increase the Gel Signal in Partially Hydrated DPPC/DMPC Membranes.

    Science.gov (United States)

    Tang, Jennifer; Alsop, Richard J; Schmalzl, Karin; Epand, Richard M; Rheinstädter, Maikel C

    2015-09-29

    NIt was recently reported that static magnetic fields increase lipid order in the hydrophobic membrane core of dehydrated native plant plasma membranes [Poinapen, Soft Matter 9:6804-6813, 2013]. As plasma membranes are multicomponent, highly complex structures, in order to elucidate the origin of this effect, we prepared model membranes consisting of a lipid species with low and high melting temperature. By controlling the temperature, bilayers coexisting of small gel and fluid domains were prepared as a basic model for the plasma membrane core. We studied molecular order in mixed lipid membranes made of dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) using neutron diffraction in the presence of strong static magnetic fields up to 3.5 T. The contribution of the hydrophobic membrane core was highlighted through deuterium labeling the lipid acyl chains. There was no observable effect on lipid organization in fluid or gel domains at high hydration of the membranes. However, lipid order was found to be enhanced at a reduced relative humidity of 43%: a magnetic field of 3.5 T led to an increase of the gel signal in the diffraction patterns of 5%. While all biological materials have weak diamagnetic properties, the corresponding energy is too small to compete against thermal disorder or viscous effects in the case of lipid molecules. We tentatively propose that the interaction between the fatty acid chains' electric moment and the external magnetic field is driving the lipid tails in the hydrophobic membrane core into a better ordered state.

  6. A Novel Blind Source Separation Algorithm and Performance Analysis of Weak Signal against Strong Interference in Passive Radar Systems

    Directory of Open Access Journals (Sweden)

    Chengjie Li

    2016-01-01

    Full Text Available In Passive Radar System, obtaining the mixed weak object signal against the super power signal (jamming is still a challenging task. In this paper, a novel framework based on Passive Radar System is designed for weak object signal separation. Firstly, we propose an Interference Cancellation algorithm (IC-algorithm to extract the mixed weak object signals from the strong jamming. Then, an improved FastICA algorithm with K-means cluster is designed to separate each weak signal from the mixed weak object signals. At last, we discuss the performance of the proposed method and verify the novel method based on several simulations. The experimental results demonstrate the effectiveness of the proposed method.

  7. To analysis and identify various kinds of strong echo signal of ocular-perforating injury by B-scan ultrasound

    Directory of Open Access Journals (Sweden)

    Rui-Juan Wang

    2014-05-01

    Full Text Available AIM: To analysis the diagnostic value of B-scan on various kinds of strong echo signal of ocular-perforating injury.METHODS: Totally 176 patients(176 eyeswith ocular-perforating injury underwent B-scan ultrasound examination. We observed the B-scan imaging findings of the lens, vitreous cavity, eyeball wall and retrobulbar space.RESULTS: All 176 patients(176 eyesunderwent B-scan ultrasound examination had strong echo. Vitreous hemorrhage was found in 146 cases, dislocation of lens in 4 cases, intraocular foreign body in 105 cases, intravitreous bubble in 1 case, retinal detachment in 34 cases, choroidal detachment in 23 cases, posterior scleral rupture in 9 cases. Every patient had two or more signs above, and had strong echo signal. All kinds of strong echo signal of the cases were summarized as follows: thick vitreous hemorrhage; intraocular foreign body; dislocation of the lens; intravitreous bubble.CONCLUSION: Because of anterior chamber hemorrhage, cataract, vitreous hemorrhage, eyelid swelling and noncooperation of patients, we couldn't examine the posterior segment. So B-scan provides a great help to the ophthalmologist. It is very sensitive and has specific images on the detachment of retina, intraocular foreign body, posterior scleral laceration, hemorrhagic choroidal detachment. Complex perforating injury of eyeball often appears some confusing strong echo signals, but B-scan can identify those images. Thus, it is irreplaceable by other examinations.

  8. Wave failure at strong coupling in intracellular C a2 + signaling system with clustered channels

    Science.gov (United States)

    Li, Xiang; Wu, Yuning; Gao, Xuejuan; Cai, Meichun; Shuai, Jianwei

    2018-01-01

    As an important intracellular signal, C a2 + ions control diverse cellular functions. In this paper, we discuss the C a2 + signaling with a two-dimensional model in which the inositol 1,4,5-trisphosphate (I P3 ) receptor channels are distributed in clusters on the endoplasmic reticulum membrane. The wave failure at large C a2 + diffusion coupling is discussed in detail in the model. We show that with varying model parameters the wave failure is a robust behavior with either deterministic or stochastic channel dynamics. We suggest that the wave failure should be a general behavior in inhomogeneous diffusing systems with clustered excitable regions and may occur in biological C a2 + signaling systems.

  9. Gold Superparticles Functionalized with Azobenzene Derivatives: SERS Nanotags with Strong Signals.

    Science.gov (United States)

    Ma, Ying; Promthaveepong, Kittithat; Li, Nan

    2017-03-29

    The surface-enhanced Raman spectroscopy (SERS) nanotag was proposed as a substitute for fluorescent dye for imaging and biosensors several decades ago. However, its weak signal and poor reproducibility has hindered its application. Here, we report a new strategy to form Au superparticles (AuSPs) with high SERS enhancement via one-pot formation and self-assembly of Au nanoparticles (NPs). An azobenzene-carrying Raman reporter was synthesized to exhibit a large Raman cross-section and multiple bands. The self-assembly of the Raman reporter on AuSPs generated SERS nanotags with intense signals. A Raman reporter carrying boronic acid and azobenzene groups displayed six distinctive bands. Its corresponding SERS nanotag demonstrated a high sensing ability toward glycoprotein through aggregation-induced SERS enhancement or as a substitute for labeled antibodies in an immunoassay of the glycoprotein.

  10. Building a Strong Library Association: A Case of the Ghana Library ...

    African Journals Online (AJOL)

    The author explores ways of building a strong library association with specific reference to the Ghana Library Association. The paper states that library associations represent librarians and libraries that provide valuable services to them and their communities. The different types of library associations are discussed.

  11. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    LENUS (Irish Health Repository)

    Sattar, Naveed

    2009-06-23

    Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.

  12. Influence of inherent parameter of stabilized UHF oscillators on autodyne response formation at a strong reflected signal

    Directory of Open Access Journals (Sweden)

    Noskov V. Ya.

    2011-08-01

    Full Text Available Results of an autodyne response analysis in UHF oscillators stabilized by the external high-Q cavity in the case of the strong signal when the reflected wave amplitude commen-surable with the own oscillation amplitude. Coupling between the basic operation cavity and the stabilizing cavity is implemented as a pass-reflecting filter with a resistive bond. Key relations are obtained, which describe the autodyne response to the own re-reflected radiation from a target. The load and oscillating system influence on autodyne response formation is fulfilled.

  13. Looking for very low tectonic deformation in GNSS time series impacted by strong hydrological signal in the Okavango Delta, Botswana

    Science.gov (United States)

    Pastier, Anne-Morwenn; Dauteuil, Olivier; Murray-Hudson, Michael; Makati, Kaelo; Moreau, Frédérique; Crave, Alain; Longuevergne, Laurent; Walpersdorf, Andrea

    2017-04-01

    Located in northern Botswana, the Okavango Delta is a vast wetland, fed from the Angolan highlands and constrained by a half-graben in the Kalahari depression. Since the 70's, the Okavango graben is usually considered as the terminus of the East African Rift System. But a recent geodetic study showed there has been no extension on the tectonic structure over the past 5 years, and recent geophysical studies began to call this hypothesis into question. The deformation in the area could instead be related to far-field deformation accommodation due to the motion of the Kalahari craton relative to the rest of the Nubian plate and to the opening of the Rift Valley. Getting to the vertical deformation isn't trivial. The GNSS time series show a strong annual deformation of the ground surface (3 cm of amplitude). On the vertical component, this periodic signal is so strong that it hides the tectonic long-term deformation, while this information would give a crucial insight on the geodynamic process at play. This periodic signal is related to the seasonal loading of water due to the rainy season. This hypothesis is corroborated by the modeling of the surface deformation based on the GRACE satellites data, interpreted as the variation of groundwater amount. In the Okavango Delta, the peak of water level isn't paced with the local precipitations, but is driven by a flood pulse coming from the Angolan Highlands. The migration of this massive water body isn't visible at first order in GRACE data. Yet, local precipitations are supposed to undergo too much evapotranspiration to be significant in the hydrological balance. Thus this later water body isn't supposed to produce a mass anomaly in GRACE time series. This paradox could highlight a relationship not yet defined between groundwater and local rainfall. The wide spatial resolution of GRACE data (about 300 km) doesn't allow a modeling accurate enough to give access to the slow tectonic deformation, nor to determine the

  14. <strong/>Costs and benefits of cold acclimation in field released DrosophilaAssociating laboratory and field results<strong>. strong>

    DEFF Research Database (Denmark)

    Overgaard, Johannes; Sørensen, Jesper Givskov; A. Hoffmann, Ary

    2008-01-01

    Physiological and evolutionary responses to thermal variation are often investigated under controlled laboratory conditions. However, this approach may fail to account for the complexity of natural environments. Here we investigated the costs and benefits of developmental or adult cold acclimation...... that the ability to locate a field resource has a genetic basis with a high heritability since only round of selection on parental flies (F0) revealed clear differences in the ability of offspring (F1 and F2) to locate field resources at cold temperatures. Again we found a poor association between field...... and laboratory performance emphasising the importance of testing thermal resistance under relevant/natural conditions....

  15. Strong association of the SNP rs17822931 with wet earwax and ...

    Indian Academy of Sciences (India)

    and Peking Union Medical College, Beijing 100005, People's Republic of China. 3Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. [Shang D., Zhang X., Sun M., Wei Y. and Wen Y. 2013 Strong association of the SNP rs17822931 with wet earwax and bromhidrosis in a.

  16. Strong but variable associations between social dominance and clutch sex ratio in a colonial corvid

    NARCIS (Netherlands)

    Salomons, H. M.; Dijkstra, C.; Verhulst, S.

    2008-01-01

    We studied primary sex ratio of clutches in relation to social dominance for 6 years in a colony of free-living jackdaws, a small corvid. Social dominance was strongly associated with clutch sex ratio, with the difference in clutch sex ratio between the most and least dominant pairs being 30-40%. To

  17. Strong human association with plant invasion success for Trifolium introductions to New Zealand.

    Science.gov (United States)

    Gravuer, Kelly; Sullivan, Jon J; Williams, Peter A; Duncan, Richard P

    2008-04-29

    It has proven difficult, when focused only on biological determinants, to explain why some plant species become naturalized in or invade new locations, whereas others fail. We analyzed the invasion of Trifolium (true clover) species into New Zealand, assessing a range of human, biogeographic, and biological influences at three key invasion stages: introduction, naturalization, and spread. We used sparse principal component analysis (SPCA) to define suites of related attributes and aggregated boosted trees to model relationships with invasion outcomes. Human and biogeographic attributes were strongly associated with success at all stages. Whereas biogeographic attributes, notably large native range, were consistently associated with success, different human factors appeared to favor success at different stages, such as presence in early trade/immigration hotspots (introduction), intentional large-scale planting (naturalization), and frequent presence as a seed contaminant (relative spread rate). Biological traits were less strongly associated with success for introduction and spread and little if at all for naturalization; we found that tall perennials with long flowering periods were more frequently selected for introduction, whereas species with extended flowering in New Zealand spread more rapidly. In addition to causal relationships, the importance of human factors may reflect indirect associations, including ecological traits associated with both human use and invasion. Nevertheless, our results highlight key roles that humans can play in facilitating plant invasion via two pathways: (i) commercial introduction leading to widespread planting and concomitant naturalization and spread and (ii) unintentional introduction and spread of species associated with human activities, such as seed contaminants.

  18. Phenotypic plasticity in an ant with strong caste-genotype association.

    Science.gov (United States)

    Kuhn, Alexandre; Darras, Hugo; Aron, Serge

    2018-01-01

    Caste determination in social Hymenoptera (whether a female egg develops into a reproductive queen or a sterile worker) is a remarkable example of phenotypic plasticity where females with highly similar genomes exhibit striking differences in morphology and behaviour. This phenotypic dichotomy is typically influenced by environmental factors. However, recent studies have revealed a strong caste-genotype association in hybridogenetic ants: workers are all interlineage hybrids while queens are all purebred, suggesting that female caste fate is genetically determined. Using the hybridogenetic ant Cataglyphis mauritanica , we show that under laboratory conditions, purebred offspring develop into reproductive queens but occasionally give rise to workers. Moreover, while hybrids typically become workers, juvenile hormone treatment can switch their developmental pathway to the reproductive caste. These results indicate that phenotypic plasticity has been retained in an ant with a strong caste-genotype association, despite its lack of expression in natural conditions. © 2018 The Author(s).

  19. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    Directory of Open Access Journals (Sweden)

    Naveed Sattar

    2009-06-01

    Full Text Available BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD events, but robust prospective evidence is lacking. We tested whether interleukin (IL-6, C-reactive protein (CRP, and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER, baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672], fatal CVD (n = 190, death from other CV causes (n = 38, and non-CVD mortality (n = 300, over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12 than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31, in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction. The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001 improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20. CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

  20. Cross-Modal Associative Mnemonic Signals in Crow Endbrain Neurons.

    Science.gov (United States)

    Moll, Felix W; Nieder, Andreas

    2015-08-17

    The ability to associate stimuli across time and sensory modalities endows animals and humans with many of the complex, learned behaviors. For successful performance, associations need to be retrieved from long-term memory and maintained active in working memory. We investigated how this is accomplished in the avian brain. We trained carrion crows (Corvus corone) to perform a bimodal delayed paired associate task in which the crows had to match auditory stimuli to delayed visual items. Single-unit recordings from the association area nidopallium caudolaterale (NCL) revealed sustained memory signals that selectively correlated with the learned audio-visual associations across time and modality, and sustained activity prospectively encoded the crows' choices. NCL neurons carried an internal, stimulus-independent signal that was predictive of error and type of error. These results underscore the role of corvid NCL in synthesizing external multisensory information and internal mnemonic data needed for executive control of behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Visual evoked potentials show strong positive association with intracranial pressure in patients with cryptococcal meningitis

    Directory of Open Access Journals (Sweden)

    Marcelo Adriano da Cunha Silva Vieira

    2015-04-01

    Full Text Available Objective : To verify the relationship between intracranial pressure and flash visual evoked potentials (F-VEP in patients with cryptococcal meningitis. Method The sample included adults diagnosed with cryptococcal meningitis admitted at a reference hospital for infectious diseases. The patients were subjected to F-VEP tests shortly before lumbar puncture. The Pearson’s linear correlation coefficient was calculated and the linear regression analysis was performed. Results : Eighteen individuals were subjected to a total of 69 lumbar punctures preceded by F-VEP tests. At the first lumbar puncture performed in each patient, N2 latency exhibited a strong positive correlation with intracranial pressure (r = 0.83; CI = 0.60 - 0.94; p < 0.0001. The direction of this relationship was maintained in subsequent punctures. Conclusion : The intracranial pressure measured by spinal tap manometry showed strong positive association with the N2 latency F-VEP in patients with cryptococcal meningitis.

  2. Scabies is strongly associated with acute rheumatic fever in a cohort study of Auckland children.

    Science.gov (United States)

    Thornley, Simon; Marshall, Roger; Jarrett, Paul; Sundborn, Gerhard; Reynolds, Edwin; Schofield, Grant

    2018-02-14

    This study sought to determine whether scabies infection is associated with acute rheumatic fever (ARF) or chronic rheumatic heart disease (CRHD). A cohort study was undertaken using health records of children aged 3-12 years attending an oral health service for the first time. Subjects were then linked to hospital diagnoses of scabies and ARF or CRHD. A total of 213 957 children free of rheumatic heart disease at baseline were available for analysis. During a mean follow-up time of 5.1 years, 440 children were diagnosed with ARF or CRHD in hospital records. Children diagnosed with scabies during follow-up were 23 times more likely to develop ARF or CRHD, compared with children who had no scabies diagnosis. After adjustment for confounders in a Cox model, the association reduced but remained strong (adjusted hazard ratio: 8.98; 95% confidence interval: 6.33-20.2). In an analysis restricted to children hospitalised at least once during follow-up, the adjusted hazard ratio for the same comparison was 3.43 (95% confidence interval: 1.85-6.37). A recent diagnosis of scabies from hospital records is strongly associated with a subsequent diagnosis of ARF. Further investigation of the role that scabies infestation may play in the aetiology of ARF is warranted. © 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

  3. Strong ion gap is associated with mortality in pediatric burn injuries.

    Science.gov (United States)

    Sen, Soman; Wiktor, Arek; Berndtson, Allison; Greenhalgh, David; Palmieri, Tina

    2014-01-01

    Severe burn injury produces significant tissue damage, resulting in metabolic acidosis. Current methods of acid-base evaluation are based on dependent variables that may not be accurate after burn injury. The strong ion method of acid-base evaluation is based on independent variables and may accurately predict outcomes in severely burn-injured patients. The authors hypothesize that an increased strong ion gap present on admission will be associated with mortality in severely burn-injured pediatric patients. A retrospective chart review was performed of burn-injured pediatric patients with a TBSA 20% or greater. Data collected included age, TBSA burn injury, mechanism of injury, survival, ventilator days, hospital length of stay, intensive care unit length of stay, and admission laboratory values. Apparent and effective strong ion difference (SIDa, SIDe) were calculated. The strong ion gap (SIG) was determined as the difference between SIDa and SIDe. A total of 48 patients were included in the study. Mean age (years) and TBSA were 7.9 ± 0.8 years and 56.8 ± 2.6%. Eleven patients (23%) died. Mean TBSA for survivors (54.2 ± 2.9%) did not significantly differ from that of nonsurvivors (65.7 ± 5.34%). Ten patients suffered inhalation injury, which was associated with an odds ratio of 10.1* for mortality. Mean SIDa was 44.2 ± 3.2 for the entire study population. Survivors had a significantly lower SIDa (36.6 ± 0.5) than nonsurvivors (59.7 ± 13*). Mean SIDe for all patients was (25 ± 0.7) and did not differ significantly between survivors (24.7 ± 0.7) and nonsurvivors (25.8 ± 2). SIG for nonsurvivors (33.91 ± 14*) was significantly higher than for survivors (14.9 ± 0.3). Controlling for both TBSA and inhalation injury, death was associated with both an increased SIDa (B = 19.3*) and SIG (B = 17.3*). SIG is increased in severely burn-injured pediatric patients, indicating the presence of metabolic acidosis. Furthermore, an increased SIG is significantly

  4. Wind speed and direction shears with associated vertical motion during strong surface winds

    Science.gov (United States)

    Alexander, M. B.; Camp, D. W.

    1984-01-01

    Strong surface winds recorded at the NASA 150-Meter Ground Winds Tower facility at Kennedy Space Center, Florida, are analyzed to present occurrences representative of wind shear and vertical motion known to be hazardous to the ascent and descent of conventional aircraft and the Space Shuttle. Graphical (percentage frequency distributions) and mathematical (maximum, mean, standard deviation) descriptions of wind speed and direction shears and associated updrafts and downdrafts are included as functions of six vertical layers and one horizontal distance for twenty 5-second intervals of parameters sampled simultaneously at the rate of ten per second during a period of high surface winds.

  5. Association study of the oestrogen signalling pathway genes in ...

    Indian Academy of Sciences (India)

    Association study of the oestrogen signalling pathway genes in relation to age at natural menopause. Li-Na He ... The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China ...

  6. Partial Seizures Are Associated with Early Increases in Signal Complexity

    Science.gov (United States)

    Jouny, Christophe C; Bergey, Gregory K; Franaszczuk, Piotr J

    2009-01-01

    Objectives Partial seizures are often believed to be associated with EEG signals of low complexity because seizures are associated with increased neural network synchrony. The investigations reported here provide an assessment of the signal complexity of epileptic seizure onsets using newly developed quantitative measures. Methods Using the Gabor atom density (GAD) measure of signal complexity, 339 partial seizures in 45 patients with intracranial electrode arrays were analyzed. Segmentation procedures were applied to determine the timing and amplitude of GAD changes relative to the electrographic onset of the seizure. Results 330 out of 339 seizures have significant complexity level changes, with 319 (97%) having an increase in complexity. GAD increases occur within seconds of the onset of the partial seizure but are not observed in channels remote from the focus. The complexity increase is similar for seizures from mesial temporal origin, neocortical temporal and extra-temporal origin. Conclusions Partial onset seizures are associated with early increases in signal complexity as measured by GAD. This increase is independent of the location of the seizure focus. Significance Despite the often predominant rhythmic activity that characterizes onset and early evolution of epileptic seizures, partial seizure onset is associated with an early increase in complexity. These changes are common to partial seizures originating from different brain regions, indicating a similar seizure dynamic. PMID:19910249

  7. Association study of the oestrogen signalling pathway genes in ...

    Indian Academy of Sciences (India)

    [He Li-Na, Xiong D.-H., Liu Y.-J., Zhang F., Recker R. R. and Deng H.-W. 2007 Association study of the oestrogen signalling pathway genes in relation to age at natural menopause. J. Genet. 86, 269–276]. Introduction. Age at natural menopause (AANM) is closely related to women's psychological and physical well being. It.

  8. Oxidative and inflammatory signals in obesity-associated vascular abnormalities.

    Science.gov (United States)

    Reho, John J; Rahmouni, Kamal

    2017-07-15

    Obesity is associated with increased cardiovascular morbidity and mortality in part due to vascular abnormalities such as endothelial dysfunction and arterial stiffening. The hypertension and other health complications that arise from these vascular defects increase the risk of heart diseases and stroke. Prooxidant and proinflammatory signaling pathways as well as adipocyte-derived factors have emerged as critical mediators of obesity-associated vascular abnormalities. Designing treatments aimed specifically at improving the vascular dysfunction caused by obesity may provide an effective therapeutic approach to prevent the cardiovascular sequelae associated with excessive adiposity. In this review, we discuss the recent evidence supporting the role of oxidative stress and cytokines and inflammatory signals within the vasculature as well as the impact of the surrounding perivascular adipose tissue (PVAT) on the regulation of vascular function and arterial stiffening in obesity. In particular, we focus on the highly plastic nature of the vasculature in response to altered oxidant and inflammatory signaling and highlight how weight management can be an effective therapeutic approach to reduce the oxidative stress and inflammatory signaling and improve vascular function. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  9. Method for separation of a weak background signal from at the presence of a strong one in the Fourier spectroscopy

    International Nuclear Information System (INIS)

    Lib, Yu.N.; Zhukov, M.S.

    1985-01-01

    A method for solving a big signal problem in the nmr Fourier spectroscopy is described. Thus the digital filtration of a big signal is carried out, where from the droop of induced signal accumulated before the moment of memory content overflow, subtracted is a model interferogram, corresponding only to removed big signals (the model interferogram is the result of perocessing of an initial interferogram). Calculating formulae and dependences haracterizing the accumulation-subtraction process and minimal gain as compared with a common technique with scaling are given. Experimental results which confirm the method efficiency are stated

  10. Strong association between in-migration and HIV prevalence in urban sub-Saharan Africa.

    Science.gov (United States)

    Voeten, Hélène A C M; Vissers, Debby C J; Gregson, Simon; Zaba, Basia; White, Richard G; de Vlas, Sake J; Habbema, J Dik F

    2010-04-01

    Enormous variation exists in HIV prevalence between countries in sub-Saharan Africa. The contribution of migration to the spread of HIV has long been recognized, but its effect at the population level has never been assessed. In this ecological analysis, we explore how much variation in HIV prevalence in urban sub-Saharan Africa is explained by in-migration. We performed a linear regression to analyze the association between the proportion of recent in-migrants and HIV prevalence for men and women in urban areas, using 60 data points from 28 sub-Saharan African countries between 1987 and 2005. We found a strong association between recent in-migration and HIV prevalence for women (Pearson R = 57%, P Africa (R = 50%, P = 0.003). For both genders, the association was strongest between 1985 and 1994, slightly weaker between 1995 and 1999, and nonexistent as from 2000. The overall association for both men and women was not confounded by the developmental indicators GNI per capita, income inequalities, or adult literacy. Migration explains much of the variation in HIV spread in urban areas of sub-Saharan Africa, especially before the year 2000, after which HIV prevalences started to level off in many countries. Our findings suggest that migration is an important factor in the spread of HIV, especially in rapidly increasing epidemics. This may be of relevance to the current HIV epidemics in China and India.

  11. Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction.

    Directory of Open Access Journals (Sweden)

    Paul L Klarenbeek

    Full Text Available Every person carries a vast repertoire of CD4+ T-helper cells and CD8+ cytotoxic T cells for a healthy immune system. Somatic VDJ recombination at genomic loci that encode the T-cell receptor (TCR is a key step during T-cell development, but how a single T cell commits to become either CD4+ or CD8+ is poorly understood. To evaluate the influence of TCR sequence variation on CD4+/CD8+ lineage commitment, we sequenced rearranged TCRs for both α and β chains in naïve T cells isolated from healthy donors and investigated gene segment usage and recombination patterns in CD4+ and CD8+ T-cell subsets. Our data demonstrate that most V and J gene segments are strongly biased in the naïve CD4+ and CD8+ subsets with some segments increasing the odds of being CD4+ (or CD8+ up to five-fold. These V and J gene associations are highly reproducible across individuals and independent of classical HLA genotype, explaining ~11% of the observed variance in the CD4+ vs. CD8+ propensity. In addition, we identified a strong independent association of the electrostatic charge of the complementarity determining region 3 (CDR3 in both α and β chains, where a positively charged CDR3 is associated with CD4+ lineage and a negatively charged CDR3 with CD8+ lineage. Our findings suggest that somatic variation in different parts of the TCR influences T-cell lineage commitment in a predominantly additive fashion. This notion can help delineate how certain structural features of the TCR-peptide-HLA complex influence thymic selection.

  12. Traveltime dispersion in an isotropic elastic mantle: strong lower-mantle signal in differential-frequency residuals

    Science.gov (United States)

    Schuberth, Bernhard S. A.; Zaroli, Christophe; Nolet, Guust

    2015-12-01

    signals depending on the associated wavelengths and the length scales of structure at shallow depth. Differential-frequency residuals may thus prove useful to precondition tomographic inversions for the lower-mantle structure such as to reduce the influence of the upper mantle for certain length scales. Overall, standard deviations of the diffraction-induced traveltime dispersion between the longest (51 s) and the shortest (15 s) period considered here are 0.6 and 1.0 s for P- and S-waves, respectively. For comparison, the corresponding standard deviations of the 15 s residuals are 1.0 s and 2.8 s. In the lower-mantle model, standard deviations are 0.3 and 0.6 s, respectively, which gives an average lower-mantle contribution to the total dispersion of 50 per cent for P-waves and 60 per cent for S-waves.

  13. Erectile dysfunction among men with diabetes is strongly associated with premature ejaculation and reduced libido.

    Science.gov (United States)

    Malavige, Lasantha S; Jayaratne, Shanthilal D; Kathriarachchi, Samudra T; Sivayogan, Sivagurunathan; Fernando, Devaka J; Levy, Jonathan C

    2008-09-01

    = 3.3, CI = 1.2-8.8). ED was strongly associated with PE and reduced libido. Diabetic patients presenting with one of these three conditions should be screened for the other two.

  14. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates.

    Science.gov (United States)

    Vandeputte, Doris; Falony, Gwen; Vieira-Silva, Sara; Tito, Raul Y; Joossens, Marie; Raes, Jeroen

    2016-01-01

    The assessment of potentially confounding factors affecting colon microbiota composition is essential to the identification of robust microbiome based disease markers. Here, we investigate the link between gut microbiota variation and stool consistency using Bristol Stool Scale classification, which reflects faecal water content and activity, and is considered a proxy for intestinal colon transit time. Through 16S rDNA Illumina profiling of faecal samples of 53 healthy women, we evaluated associations between microbiome richness, Bacteroidetes:Firmicutes ratio, enterotypes, and genus abundance with self-reported, Bristol Stool Scale-based stool consistency. Each sample's microbiota growth potential was calculated to test whether transit time acts as a selective force on gut bacterial growth rates. Stool consistency strongly correlates with all known major microbiome markers. It is negatively correlated with species richness, positively associated to the Bacteroidetes:Firmicutes ratio, and linked to Akkermansia and Methanobrevibacter abundance. Enterotypes are distinctly distributed over the BSS-scores. Based on the correlations between microbiota growth potential and stool consistency scores within both enterotypes, we hypothesise that accelerated transit contributes to colon ecosystem differentiation. While shorter transit times can be linked to increased abundance of fast growing species in Ruminococcaceae-Bacteroides samples, hinting to a washout avoidance strategy of faster replication, this trend is absent in Prevotella-enterotyped individuals. Within this enterotype adherence to host tissue therefore appears to be a more likely bacterial strategy to cope with washout. The strength of the associations between stool consistency and species richness, enterotypes and community composition emphasises the crucial importance of stool consistency assessment in gut metagenome-wide association studies. Published by the BMJ Publishing Group Limited. For permission to

  15. Strong allelic association between Sjoegren-Larsson syndrome and D17S805

    Energy Technology Data Exchange (ETDEWEB)

    Pigg, M.; Jagell, S.; Sillen, A. [University Hospital, Uppsala (Sweden)] [and others

    1994-09-01

    Sjoegren-Larsson Syndrom (SLS) is characterized by congenital ichthyosis, spastic di- or tetraplegia and mental retardation. It is an autosomal recessive trait that has been described in many populations, but is particularly frequent in the northern part of Sweden. A defect in the enzyme fatty alcohol: NAD+ oxidoreductase (FAD) has been suggested, but the molecular mechanism has not been elucidated. Based on linkage analysis and allelic association, the disorder has now been mapped to chromosome 17. Meiotic recombinations suggests that the gene is flanked by D17S805 on the centromeric and D17S783 and D17S925 on the telomeric side. These three markers map to the same location in reference pedigrees. Strong allelic association (chi-square 60.28, p<0.0003) to D17S805 suggests that the mutation is located at a limited distance on the telomeric side of this marker. It is possible that the gene can be identified by functional complementation of SLS cells using YACs from this region. Alternatively, positional cloning should be possible in this presumable small area. The markers identified are close and informative enough to allow accurate genetic diagnosis.

  16. Membrane-associated signaling in human B-lymphoma lines

    Energy Technology Data Exchange (ETDEWEB)

    Tauzin, Sebastien; Ding, Heidrun; Burdevet, Dimitri [Department of Pathology and Immunology, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland); Borisch, Bettina [Department of Social and Preventive Medicine, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland); Hoessli, Daniel C., E-mail: danielhoessli@gmail.com [Department of Pathology and Immunology, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland)

    2011-01-15

    In B-non-Hodgkin lymphomas, Lyn and Cbp/PAG constitute the core of an oncogenic signalosome that captures the Phosphatidylinositol-3-kinase, the Spleen tyrosine kinase and the Signal transducer and activator of transcription-3 to generate pro-survival and proliferative signals. Lymphoma lines corresponding to follicular, mantle-cell and Burkitt-derived lymphomas display type-specific signalosome organizations that differentially activate PI3K, Syk and STAT3. In the follicular lymphoma line, PI3K, Syk and STAT3 were optimally activated upon association with the Lyn-Cbp/PAG signalosome, while in the Burkitt lymphoma-derived line, the association with Cbp/PAG and activation of PI3K were interfered with by the latent membrane proteins encoded by the Epstein-Barr virus. In the Jeko-1 mantle-cell line, a weak association of Syk with the Lyn-Cbp/PAG signalosome resulted in poor activation of Syk, but in those cells, as in the follicular and Burkitt-derived lines, efficient apoptosis induction by the Syk inhibitor R406 indicated that Syk is nonetheless an important prosurvival element and therefore a valuable therapeutic target. In all configurations described herein is the Lyn-Cbp/PAG signalosome independent of external signals and provides efficient means of activation for its associated lipid and protein kinases. In follicular and Burkitt-derived lines, Syk appears to be activated following binding to Cbp/PAG and no longer requires B-cell receptor-associated activation motifs for activation. Assessment of the different modalities of Lyn-Cbp/PAG signalosome organization could help in selecting the appropriate combination of kinase inhibitors to eliminate a particular type of lymphoma cells.

  17. Rapid growth and childhood obesity are strongly associated with lysoPC(14:0).

    Science.gov (United States)

    Rzehak, Peter; Hellmuth, Christian; Uhl, Olaf; Kirchberg, Franca F; Peissner, Wolfgang; Harder, Ulrike; Grote, Veit; Weber, Martina; Xhonneux, Annick; Langhendries, Jean-Paul; Ferre, Natalia; Closa-Monasterolo, Ricardo; Verduci, Elvira; Riva, Enrica; Socha, Piotr; Gruszfeld, Dariusz; Koletzko, Berthold

    2014-01-01

    Despite the growing interest in the early-origins-of-later-disease hypothesis, little is known about the metabolic underpinnings linking infant weight gain and childhood obesity. To discover biomarkers reflective of weight change in the first 6 months and overweight/obesity at age 6 years via a targeted metabolomics approach. This analysis comprised 726 infants from a European multicenter randomized trial (Childhood Obesity Programme, CHOP) for whom plasma blood samples at age 6 months and anthropometric data up to the age of 6 years were available. 'Rapid growth' was defined as a positive difference in weight within the first 6 months of life standardized to WHO growth standards. Weight change was regressed on each of 168 metabolites (acylcarnitines, lysophosphatidylcholines, sphingomyelins, and amino acids). Metabolites significant after Bonferroni's correction were tested as predictors of later overweight/obesity. Among the overall 19 significant metabolites, 4 were associated with rapid growth and 15 were associated with a less-than-ideal weight change. After adjusting for feeding group, only the lysophosphatidylcholine LPCaC14:0 remained significantly associated with rapid weight gain (β = 0.18). Only LPCaC14:0 at age 6 months was predictive of overweight/obesity at age 6 years (OR 1.33; 95% CI 1.04-1.69). LPCa14:0 is strongly related to rapid growth in infancy and childhood overweight/obesity. This suggests that LPCaC14:0 levels may represent a metabolically programmed effect of infant weight gain on the later obesity risk. However, these results require confirmation by independent cohorts. © 2014 S. Karger AG, Basel.

  18. Self-Reported Visual Perceptual Abnormalities Are Strongly Associated with Core Clinical Features in Psychotic Disorders.

    Science.gov (United States)

    Keane, Brian P; Cruz, Lisa N; Paterno, Danielle; Silverstein, Steven M

    2018-01-01

    Past studies using the Bonn Scale for the Assessment of Basic Symptoms (hereafter, Bonn Scale) have shown that self-reported perceptual/cognitive disturbances reveal which persons have or will soon develop schizophrenia. Here, we focused specifically on the clinical value of self-reported visual perceptual abnormalities (VPAs) since they are underexplored and have been associated with suicidal ideation, negative symptoms, and objective visual dysfunction. Using the 17 Bonn Scale vision items, we cross-sectionally investigated lifetime occurrence of VPAs in 21 first-episode psychosis and 22 chronic schizophrenia/schizoaffective disorder (SZ/SA) patients. Relationships were probed between VPAs and illness duration, symptom severity, current functioning, premorbid functioning, diagnosis, and age of onset. Increased VPAs were associated with: earlier age of onset; more delusions, hallucinations, bizarre behavior, and depressive symptoms; and worse premorbid social functioning, especially in the childhood and early adolescent phases. SZ/SA participants endorsed more VPAs as compared to those with schizophreniform or psychotic disorder-NOS, especially in the perception of color, bodies, faces, object movement, and double/reversed vision. The range of self-reported VPAs was strikingly similar between first-episode and chronic patients and did not depend on the type or amount of antipsychotic medication. As a comparative benchmark, lifetime occurrence of visual hallucinations did not depend on diagnosis and was linked only to poor premorbid social functioning. A brief 17-item interview derived from the Bonn Scale is strongly associated with core clinical features in schizophrenia. VPAs hold promise for clarifying diagnosis, predicting outcome, and guiding neurocognitive investigations.

  19. An intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs.

    Directory of Open Access Journals (Sweden)

    Richard Everson

    Full Text Available The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA. In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11 that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19. In a pooled analysis of both studies (73 cases and 186 controls, the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27. Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.

  20. Association of single nucleotide polymorphisms in Wnt signaling pathway genes with breast cancer in Saudi patients.

    Directory of Open Access Journals (Sweden)

    Mohammad Saud Alanazi

    Full Text Available Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.

  1. Streptomyces clavuligerus shows a strong association between TCA cycle intermediate accumulation and clavulanic acid biosynthesis.

    Science.gov (United States)

    Ramirez-Malule, Howard; Junne, Stefan; Nicolás Cruz-Bournazou, Mariano; Neubauer, Peter; Ríos-Estepa, Rigoberto

    2018-05-01

    Clavulanic acid (CA) is produced by Streptomyces clavuligerus (S. clavuligerus) as a secondary metabolite. Knowledge about the carbon flux distribution along the various routes that supply CA precursors would certainly provide insights about metabolic performance. In order to evaluate metabolic patterns and the possible accumulation of tricarboxylic acid (TCA) cycle intermediates during CA biosynthesis, batch and subsequent continuous cultures with steadily declining feed rates were performed with glycerol as the main substrate. The data were used to in silico explore the metabolic capabilities and the accumulation of metabolic intermediates in S. clavuligerus. While clavulanic acid accumulated at glycerol excess, it steadily decreased at declining dilution rates; CA synthesis stopped when glycerol became the limiting substrate. A strong association of succinate, oxaloacetate, malate, and acetate accumulation with CA production in S. clavuligerus was observed, and flux balance analysis (FBA) was used to describe the carbon flux distribution in the network. This combined experimental and numerical approach also identified bottlenecks during the synthesis of CA in a batch and subsequent continuous cultivation and demonstrated the importance of this type of methodologies for a more advanced understanding of metabolism; this potentially derives valuable insights for future successful metabolic engineering studies in S. clavuligerus.

  2. Strong and consistent natural selection associated with armour reduction in sticklebacks.

    Science.gov (United States)

    LE Rouzic, Arnaud; Østbye, Kjartan; Klepaker, Tom O; Hansen, Thomas F; Bernatchez, Louis; Schluter, Dolph; Vøllestad, L Asbjørn

    2011-06-01

    Measuring the strength of natural selection is tremendously important in evolutionary biology, but remains a challenging task. In this work, we analyse the characteristics of selection for a morphological change (lateral-plate reduction) in the threespine stickleback Gasterosteus aculeatus. Adaptation to freshwater, leading with the reduction or loss of the bony lateral armour, has occurred in parallel on numerous occasions in this species. Completely-plated and low-plated sticklebacks were introduced into a pond, and the phenotypic changes were tracked for 20 years. Fish from the last generation were genotyped for the Ectodysplasin-A (Eda) locus, the major gene involved in armour development. We found a strong fitness advantage for the freshwater-type fish (on average, 20% fitness advantage for the freshwater morph, and 92% for the freshwater genotype). The trend is best explained by assuming that this fitness advantage is maximum at the beginning of the invasion and decreases with time. Such fitness differences provide a quantifiable example of rapid selection-driven phenotypic evolution associated with environmental change in a natural population. © 2011 Blackwell Publishing Ltd.

  3. Anomalous ULF Emissions and Their Possible Association with the Strong Earthquakes in Sumatra, Indonesia, during 2007-2012

    Directory of Open Access Journals (Sweden)

    Suaidi Ahadi

    2015-03-01

    Full Text Available Eleven strong Sumatran earthquakes, with their epicenter less than 550 km away from the Kototabang (KTB geomagnetic station (2007-2012, were studied to examine the occurrence of anomalous ultra-low frequency emissions (ULF-EM. Anomalous ULF signals, possibly associated with the earthquake’s precursors, were determined by the Welch ratio SZ/SH at 0.06 Hz at the KTB station. These ULF anomalies were then compared with geomagnetic data observed from two reference stations in Darwin and Davao, to prevent misinterpretation of global geomagnetic disturbances as precursors. This study aims to analyze the relationship between earthquake magnitude and hypocenter radius, and seismic index against lead time during ULF-EM anomalies. We used the polarization ratio Welch method in terms of power spectrum density to evaluate the geomagnetic data by overlapping windows and applying fast Fourier transform (FFT. The results showed anomalous variations in onset and lead time, determined using the standard deviation controlling the SZ/SH power pattern. Our positive correlation between lead time of ULF emission and earthquake magnitude as well as between lead time and seismic index. It shows a negative correlation between hypocenter distances to KTB station against lead time.

  4. Strong association of epidermal growth factor receptor status with breast cancer FDG uptake

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joohee; Moon, Seung Hwan; Hyun, Seung Hyup; Cho, Young Seok; Choi, Joon Young; Kim, Byung-Tae; Lee, Kyung-Han [Sungkyunkwan University School of Medicine, Department of Nuclear Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Lee, Eun Jeong [Seoul Medical Center, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Seokhwi [Sungkyunkwan University School of Medicine, Department of Pathology, Samsung Medical Center, Seoul (Korea, Republic of)

    2017-08-15

    Imaging tumor FDG uptake could complement breast cancer biomarkers of risk and treatment response. Although breast cancer FDG uptake is reputedly influenced by major biomarker states, the role of epidermal growth factor receptor (EGFR) expression remains largely unexplored. This is a retrospective study that included 499 patients with primary breast cancer at initial presentation. Tumor FDG uptake was measured on pretreatment PET/CT as maximum standardized uptake value (SUVmax), and biomarkers were assessed by immunohistochemistry of tumor tissue. Regression analysis was performed for predictors of high tumor FDG uptake (SUVmax ≥ 8.6). SUVmax was higher in ER- (36.5%; 11.2 ± 6.0 vs. 8.3 ± 5.3), PR- (42.3%; 10.9 ± 6.0 vs. 8.2 ± 5.2), and triple-negative tumors (19.8%; 12.0 ± 6.9 vs. 8.7 ± 5.2; all p < 0.0001). EGFR expression (28.5%) was more frequent in ER-, PR-, triple-negative, cytokeratin 5/6 (CK5/6) + and mutant P53 (mP53) + tumors (all p < 0.0001). EGFR+ was associated with higher SUVmax among all tumors (11.9 ± 6.0 vs. 8.3 ± 5.3), ER- tumors (p < 0.0001), PR- and + tumors (p < 0.0001 and 0.027), hormone receptor- and + tumors (p < 0.0001 and 0.004), human epidermal growth factor receptor 2 (HER2)- and + tumors (p < 0.0001 and 0.006), non-triple negative tumors (p < 0.0001), CK5/6- and + tumors (p = 0.021 and <0.0001), and mP53- and + tumors (p < 0.0001 and 0.008). Tumors had high FDG uptake in 73.2% of EGFR+ and 40.6% of EGFR- tumors. On regression analysis, significant multivariate predictors of high tumor FDG uptake were large size, EGFR+ and CK5/6+ for the entire subjects, and EGFR+ and CK5/6+ for ER- and hormone receptor negative subgroups. High FDG uptake was able to sub-stratify EGFR+ tumors that were more likely to be ER- and CK5/6+, and EGFR- tumors more likely to be mP53 +. Primary breast tumor FDG uptake is strongly influenced by EGFR status beyond that by other major biomarkers including hormone receptor and HER2 status, and EGFR

  5. Wood properties in a long-lived conifer reveal strong climate signals where ring-width series do not.

    Science.gov (United States)

    Drew, David M; Allen, Kathryn; Downes, Geoffrey M; Evans, Robert; Battaglia, Michael; Baker, Patrick

    2013-01-01

    Although tree-ring-width chronologies have been widely used for temperature reconstructions, there are many sites around the world at which there is little evidence of a clear climate signal in the ring-width chronologies. This is the case with the long-lived conifer Huon pine (Lagarostrobos franklinii (Hook. F.) Quinn), endemic to Tasmania, Australia, when the species grows at low elevation. In this study, we developed chronologies of several wood properties (e.g., tracheid radial diameter, microfibril angle) from Huon pine growing at a low-elevation site. We found that despite the absence of a climate signal in the ring-width chronologies, there were significant correlations between wood density, tracheid radial diameter and microfibril angle and temperature, stream flow and a drought index, enabling the development of robust chronologies. This novel finding suggests that chronologies based on these wood properties may have important potential for climate reconstructions from sites and species that have not yet been realized. In particular, a relatively extensive resource of ancient, low-elevation Huon pine in western Tasmania, in which climate signals have not been found using ring widths, may now be useful as part of the broader effort to reconstruct Southern Hemisphere climate.

  6. Detection of a Low Power Communication Signal in the Presence of a Strong Co-Channel TV Broadcast Interference Using a Kalman Filter

    Science.gov (United States)

    2014-12-01

    Television Systems Committee AWGN additive white Gaussian noise BCH Bose-Chaudhuri-Hocquengham bps bits per second CIR channel impulse response... impulse responses (CIRs) are used both for equalization in the respective DVB-T2 receivers and in the KF to estimate the state of the DVB-T2 signal...if a communication system can operate reliably in the presence of a strong, co-channel interference, then there is no need to buy spectrum, an

  7. Mature habitats associated with genetic divergence despite strong dispersal ability in an arthropod

    Directory of Open Access Journals (Sweden)

    Taylor Derek J

    2007-04-01

    Full Text Available Abstract Background Populations may be bound by contemporary gene flow, selective sweeps, and extinction-recolonization processes. Indeed, existing molecular estimates indicate that species with low levels of gene flow are rare. However, strong priority effects and local selective regimes may hinder gene flow (despite dispersal sending populations on independent evolutionary trajectories. In this scenario (the monopolization hypothesis, population differentiation will increase with time and genealogical evidence should yield ample private haplotypes. Cyclical parthenogens (e.g. rotifers and cladocerans such as Daphnia have an increased capacity for rapid local adaptation and priority effects because sexual reproduction is followed by multiple generations of clonal selection and massive egg bank formation. We aimed to better understand the history of population differentiation and ongoing gene flow in Daphnia rosea s.l., by comparing population and regional divergences in mature unglaciated areas and younger previously glaciated areas. We also examined the timing and paths of colonization of previously-glaciated areas to assess the dispersal limitations of D. rosea s.l. We used DNA sequence variation (84 populations and >400 individuals at the mitochondrial ND2 and nuclear HSP90 loci from Holarctic populations for our genetic analyses. Results The genetic evidence indicated pronounced historical structure. Holarctic mtDNA phylogenies of D. rosea s.l. revealed three geographically restricted and divergent clades: European, Siberian and Japanese/American. The Japanese/American clade showed marked population genetic structure (FST > 0.8 that was weakly associated with geographic distance, and a high proportion of private haplotypes. Populations from older unglaciated habitats (i.e., Japan showed higher DNA sequence divergences than populations from presumed younger habitats (i.e. non-Beringian North America with nDNA and with mtDNA. Mismatch

  8. Strong selective sweeps associated with ampliconic regions in great ape X chromosomes

    DEFF Research Database (Denmark)

    Nam, Kiwoong; Munch, Kasper; Hobolth, Asger

    2014-01-01

    The unique inheritance pattern of X chromosomes makes them preferential targets of adaptive evolution. We here investigate natural selection on the X chromosome in all species of great apes. We find that diversity is more strongly reduced around genes on the X compared with autosomes, and that a ......The unique inheritance pattern of X chromosomes makes them preferential targets of adaptive evolution. We here investigate natural selection on the X chromosome in all species of great apes. We find that diversity is more strongly reduced around genes on the X compared with autosomes...

  9. Nuclear movement regulated by non-Smad Nodal signaling via JNK is associated with Smad signaling during zebrafish endoderm specification.

    Science.gov (United States)

    Hozumi, Shunya; Aoki, Shun; Kikuchi, Yutaka

    2017-11-01

    Asymmetric nuclear positioning is observed during animal development, but its regulation and significance in cell differentiation remain poorly understood. Using zebrafish blastulae, we provide evidence that nuclear movement towards the yolk syncytial layer, which comprises extraembryonic tissue, occurs in the first cells fated to differentiate into the endoderm. Nodal signaling is essential for nuclear movement, whereas nuclear envelope proteins are involved in movement through microtubule formation. Positioning of the microtubule-organizing center, which is proposed to be crucial for nuclear movement, is regulated by Nodal signaling and nuclear envelope proteins. The non-Smad JNK signaling pathway, which is downstream of Nodal signaling, regulates nuclear movement independently of the Smad pathway, and this nuclear movement is associated with Smad signal transduction toward the nucleus. Our study provides insight into the function of nuclear movement in Smad signaling toward the nucleus, and could be applied to the control of TGFβ signaling. © 2017. Published by The Company of Biologists Ltd.

  10. Working with MRI: An investigation of occupational exposure to strong static magnetic fields and associated symptoms

    NARCIS (Netherlands)

    Schaap, K.

    2015-01-01

    Magnetic resonance imaging (MRI) makes use of electromagnetic fields in the non-ionizing radiation frequency ranges. One of them is a continuously present strong static magnetic field (SMF), which extends up to several meters around the scanner. Each time an MRI worker performs tasks near the

  11. High procedure volume is strongly associated with improved survival after lung cancer surgery

    DEFF Research Database (Denmark)

    Lüchtenborg, Margreet; Riaz, Sharma P; Coupland, Victoria H

    2013-01-01

    Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect....

  12. RpoD promoters in Campylobacter jejuni exhibit a strong periodic signal instead of a-35 box

    DEFF Research Database (Denmark)

    Petersen, Lise; Larsen, Thomas Schou; Ussery, David

    2003-01-01

    We have used a hidden Markov model (HMM) to identify the consensus sequence of the RpoD promoters in the genome of Campylobacter jejuni. The identified promoter consensus sequence is unusual compared to other bacteria, in that the region upstream of the TATA-box does not contain a conserved -35...... region, but shows a very strong periodic variation in the AT-content and semi-conserved T-stretches, with a period of 10-11 nucleotides. The TATA-box is in some, but not all cases, preceded by a TGx, similar to an extended -10 promoter. We predicted a total of 764 presumed RpoD promoters in the C...... with a training set of 175 genes. This leads to the conclusion that the remaining genes (354) are more rarely preceded by a (RpoD) promoter, and consequently that operon structure may be more widespread in C.jejuni than has been assumed by others. Structural predictions of the regions upstream of the TATA...

  13. Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia.

    Directory of Open Access Journals (Sweden)

    Peilin Jia

    Full Text Available With the recent success of genome-wide association studies (GWAS, a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P(meta<1 × 10⁻⁴, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.

  14. Parametrized tests of the strong-field dynamics of general relativity using gravitational wave signals from coalescing binary black holes: Fast likelihood calculations and sensitivity of the method

    Science.gov (United States)

    Meidam, Jeroen; Tsang, Ka Wa; Goldstein, Janna; Agathos, Michalis; Ghosh, Archisman; Haster, Carl-Johan; Raymond, Vivien; Samajdar, Anuradha; Schmidt, Patricia; Smith, Rory; Blackburn, Kent; Del Pozzo, Walter; Field, Scott E.; Li, Tjonnie; Pürrer, Michael; Van Den Broeck, Chris; Veitch, John; Vitale, Salvatore

    2018-02-01

    Thanks to the recent discoveries of gravitational wave signals from binary black hole mergers by Advanced Laser Interferometer Gravitational Wave Observatory and Advanced Virgo, the genuinely strong-field dynamics of spacetime can now be probed, allowing for stringent tests of general relativity (GR). One set of tests consists of allowing for parametrized deformations away from GR in the template waveform models and then constraining the size of the deviations, as was done for the detected signals in previous work. In this paper, we construct reduced-order quadratures so as to speed up likelihood calculations for parameter estimation on future events. Next, we explicitly demonstrate the robustness of the parametrized tests by showing that they will correctly indicate consistency with GR if the theory is valid. We also check to what extent deviations from GR can be constrained as information from an increasing number of detections is combined. Finally, we evaluate the sensitivity of the method to possible violations of GR.

  15. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing ...

  16. Strong association of the SNP rs17822931 with wet earwax and ...

    Indian Academy of Sciences (India)

    Wet earwax is a dominant Mendelian trait associated with the. GA/GG genotype of SNP rs17822931 in the ABCC11 gene. It is also often associated with the axillary odour (bromhidro- sis). To investigate their possible relationship we genotyped rs17822931 in a Chinese family affected with axillary odour. Direct sequencing ...

  17. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing......*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P ... ratio = 0.02; P HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility....

  18. Neural signalling of food healthiness associated with emotion processing

    Directory of Open Access Journals (Sweden)

    Uwe eHerwig

    2016-02-01

    Full Text Available The ability to differentiate healthy from unhealthy foods is important in order to promote good health. Food, however, may have an emotional connotation, which could be inversely related to healthiness. The neurobiological background of differentiating healthy and unhealthy food and its relations to emotion processing are not yet well understood. We addressed the neural activations, particularly considering the single subject level, when one evaluates a food item to be of a higher, compared to a lower grade of healthiness with a particular view on emotion processing brain regionsThirty-seven healthy subjects underwent functional magnetic resonance imaging while evaluating the healthiness of food presented as photographs with a subsequent rating on a visual analogue scale. We compared individual evaluations of high and low healthiness of food items and also considered gender differences.We found increased activation when food was evaluated to be healthy in the left dorsolateral prefrontal cortex and precuneus in whole brain analyses. In ROI analyses, perceived and rated higher healthiness was associated with lower amygdala activity and higher ventral striatal and orbitofrontal cortex activity. Females exerted a higher activation in midbrain areas when rating food items as being healthy.Our results underline the close relationship between food and emotion processing, which makes sense considering evolutionary aspects. Actively evaluating and deciding whether food is healthy is accompanied by neural signalling associated with reward and self-relevance, which could promote salutary nutrition behaviour. The involved brain regions may be amenable to mechanisms of emotion regulation in the context of psychotherapeutic regulation of food intake.

  19. The gambler's fallacy is associated with weak affective decision making but strong cognitive ability.

    Directory of Open Access Journals (Sweden)

    Gui Xue

    Full Text Available Humans demonstrate an inherent bias towards making maladaptive decisions, as shown by a phenomenon known as the gambler's fallacy (GF. The GF has been traditionally considered as a heuristic bias supported by the fast and automatic intuition system, which can be overcome by the reasoning system. The present study examined an intriguing hypothesis, based on emerging evidence from neuroscience research, that the GF might be attributed to a weak affective but strong cognitive decision making mechanism. With data from a large sample of college students, we found that individuals' use of the GF strategy was positively correlated with their general intelligence and executive function, such as working memory and conflict resolution, but negatively correlated with their affective decision making capacities, as measured by the Iowa Gambling Task. Our result provides a novel insight into the mechanisms underlying the GF, which highlights the significant role of affective mechanisms in adaptive decision-making.

  20. The Gambler’s Fallacy Is Associated with Weak Affective Decision Making but Strong Cognitive Ability

    Science.gov (United States)

    Xue, Gui; He, Qinghua; Lei, Xuemei; Chen, Chunhui; Liu, Yuyun; Chen, Chuansheng; Lu, Zhong-Lin; Dong, Qi; Bechara, Antoine

    2012-01-01

    Humans demonstrate an inherent bias towards making maladaptive decisions, as shown by a phenomenon known as the gambler’s fallacy (GF). The GF has been traditionally considered as a heuristic bias supported by the fast and automatic intuition system, which can be overcome by the reasoning system. The present study examined an intriguing hypothesis, based on emerging evidence from neuroscience research, that the GF might be attributed to a weak affective but strong cognitive decision making mechanism. With data from a large sample of college students, we found that individuals’ use of the GF strategy was positively correlated with their general intelligence and executive function, such as working memory and conflict resolution, but negatively correlated with their affective decision making capacities, as measured by the Iowa Gambling Task. Our result provides a novel insight into the mechanisms underlying the GF, which highlights the significant role of affective mechanisms in adaptive decision-making. PMID:23071701

  1. Psychiatric disorders in Ehlers-Danlos syndrome are frequent, diverse and strongly associated with pain.

    Science.gov (United States)

    Hershenfeld, Samantha Aliza; Wasim, Syed; McNiven, Vanda; Parikh, Manasi; Majewski, Paula; Faghfoury, Hanna; So, Joyce

    2016-03-01

    Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS.

  2. Regular exercise is strongly associated with anticipated success for reducing health risks.

    Science.gov (United States)

    Wasson, John H

    2014-01-01

    Regular exercise is a healthy behavior associated with desirable benefits. Regular exercise also makes manifest 2 fundamental behaviors-a choice and the discipline to continuously act on that choice. This cross-sectional analysis of more than 10 000 adults examines the association of regular exercise with unhealthy behaviors. Compared with people who are more regularly exercising, nonexercisers are less likely to choose to change an unhealthy habit. Nonexercisers are also much less likely to be confident of their success when they do choose a habit to change. Regular exercise seems to be a gateway behavior for reducing other unhealthy habits.

  3. Familial Longevity Is Associated With Higher TSH Secretion and Strong TSH-fT3 Relationship

    DEFF Research Database (Denmark)

    Jansen, Steffy W; Roelfsema, Ferdinand; van der Spoel, Evie

    2015-01-01

    CONTEXT: Longevity is associated with changes in circulating levels of thyroid hormone (TH) and/or TSH in animals and humans, but underlying mechanisms remain elusive. OBJECTIVE: We explored in 38 offspring of nonagenarian participants from the Leiden Longevity Study, who are enriched for longevity...... properties of TSH. The temporal relationship between TSH and free T3 at zero delay was higher in offspring (0.48 ± 0.2) compared with partners (0.26 ± 0.4) (P = .05), but the feedback and forward interplay between TSH and TH did not differ. CONCLUSIONS: Familial longevity is associated with increased basal...

  4. Neighborhood deprivation is strongly associated with participation in a population-based health check.

    Directory of Open Access Journals (Sweden)

    Anne Mette Bender

    Full Text Available We sought to examine whether neighborhood deprivation is associated with participation in a large population-based health check. Such analyses will help answer the question whether health checks, which are designed to meet the needs of residents in deprived neighborhoods, may increase participation and prove to be more effective in preventing disease. In Europe, no study has previously looked at the association between neighborhood deprivation and participation in a population-based health check.The study population comprised 12,768 persons invited for a health check including screening for ischemic heart disease and lifestyle counseling. The study population was randomly drawn from a population of 179,097 persons living in 73 neighborhoods in Denmark. Data on neighborhood deprivation (percentage with basic education, with low income and not in work and individual socioeconomic position were retrieved from national administrative registers. Multilevel regression analyses with log links and binary distributions were conducted to obtain relative risks, intraclass correlation coefficients and proportional change in variance.Large differences between neighborhoods existed in both deprivation levels and neighborhood health check participation rate (mean 53%; range 35-84%. In multilevel analyses adjusted for age and sex, higher levels of all three indicators of neighborhood deprivation and a deprivation score were associated with lower participation in a dose-response fashion. Persons living in the most deprived neighborhoods had up to 37% decreased probability of participating compared to those living in the least deprived neighborhoods. Inclusion of individual socioeconomic position in the model attenuated the neighborhood deprivation coefficients, but all except for income deprivation remained statistically significant.Neighborhood deprivation was associated with participation in a population-based health check in a dose-response manner, in which

  5. Validating of Atmospheric Signals Associated with some of the Major Earthquakes in Asia (2003-2009)

    Science.gov (United States)

    Ouzounov, D. P.; Pulinets, S.; Liu, J. Y.; Hattori, K.; Oarritm N,; Taylor, P. T.

    2010-01-01

    The recent catastrophic earthquake in Haiti (January 2010) has provided and renewed interest in the important question of the existence of precursory signals related to strong earthquakes. Latest studies (VESTO workshop in Japan 2009) have shown that there were precursory atmospheric signals observed on the ground and in space associated with several recent earthquakes. The major question, still widely debated in the scientific community is whether such signals systematically precede major earthquakes. To address this problem we have started to validate the anomalous atmospheric signals during the occurrence of large earthquakes. Our approach is based on integration analysis of several physical and environmental parameters (thermal infrared radiation, electron concentration in the ionosphere, Radon/ion activities, air temperature and seismicity) that were found to be associated with earthquakes. We performed hind-cast detection over three different regions with high seismicity Taiwan, Japan and Kamchatka for the period of 2003-2009. We are using existing thermal satellite data (Aqua and POES); in situ atmospheric data (NOAA/NCEP); and ionospheric variability data (GPS/TEC and DEMETER). The first part of this validation included 42 major earthquakes (M greater than 5.9): 10 events in Taiwan, 15 events in Japan, 15 events in Kamchatka and four most recent events for M8.0 Wenchuan earthquake (May 2008) in China and M7.9 Samoa earthquakes (Sep 2009). Our initial results suggest a systematic appearance of atmospheric anomalies near the epicentral area, 1 to 5 days prior to the largest earthquakes, that could be explained by a coupling process between the observed physical parameters, and the earthquake preparation processes.

  6. Associations Between Participant Ratings of PREP for Strong Bonds and Marital Outcomes 1 Year Postintervention.

    Science.gov (United States)

    Allen, Elizabeth S; Post, Kristina M; Markman, Howard J; Rhoades, Galena K; Stanley, Scott M

    2017-07-01

    After completing a relationship education program, collecting participant evaluations of the program is common practice. These are generally used as an index of "consumer satisfaction" with the program, with implications for feasibility and quality. Rarely have these ratings been used as predictors of changes in marital quality, although such feedback may be the only data providers collect or have immediate access to when considering the success of their efforts. To better understand the utility of such ratings to predict outcomes, we evaluated links between participant ratings and changes in self-reported marital satisfaction and communication scores one year later for a sample of 191 Army couples who had participated in a relationship education program delivered by Army chaplains (PREP for Strong Bonds). Overall ratings of general satisfaction with the program and the leader did not predict changes in marital outcomes one year later, whereas higher ratings of how much was learned, program helpfulness, increased similarity in outlook regarding Army life, and helpfulness of communication skills training predicted greater change in communication skills one year later. Higher ratings of items reflecting intent to invest more time in the relationship, and increased confidence in constructive communication and working as a team with the spouse predicted greater increases in both marital satisfaction and communication skills one year later. The constructs of intention and confidence (akin to perceived behavioral control) suggest that the Theory of Planned Behavior may be particularly useful when considering which Army couples will show ongoing benefit after relationship education.

  7. Is the Number of Different MRI Findings More Strongly Associated with Low Back Pain Than Single MRI Findings?

    DEFF Research Database (Denmark)

    Hancock, Mark J; Kjaer, Per; Kent, Peter

    2017-01-01

    STUDY DESIGN: A cross-sectional and longitudinal analysis using 2 different data sets OBJECTIVE.: To investigate if the number of different MRI findings present is more strongly associated with low back pain (LBP) than single MRI findings. SUMMARY OF BACKGROUND DATA: Most previous studies have....... The outcome for the cross-sectional study was presence of LBP during the last year. The outcome for the longitudinal study was days to recurrence of activity limiting LBP. In both data sets we created an aggregate score of the number of different MRI findings present in each individual and assessed...... investigated the associations between single MRI findings and back pain rather than investigating combinations of MRI findings. If different individuals have different pathoanatomic sources contributing to their pain, then combinations of MRI findings may be more strongly associated with LBP. METHODS...

  8. Neighborhood deprivation is strongly associated with participation in a population-based health check

    DEFF Research Database (Denmark)

    Bender, Anne Mette; Kawachi, Ichiro; Jørgensen, Torben

    2015-01-01

    BACKGROUND: We sought to examine whether neighborhood deprivation is associated with participation in a large population-based health check. Such analyses will help answer the question whether health checks, which are designed to meet the needs of residents in deprived neighborhoods, may increase...... screening for ischemic heart disease and lifestyle counseling. The study population was randomly drawn from a population of 179,097 persons living in 73 neighborhoods in Denmark. Data on neighborhood deprivation (percentage with basic education, with low income and not in work) and individual socioeconomic...... in both deprivation levels and neighborhood health check participation rate (mean 53%; range 35-84%). In multilevel analyses adjusted for age and sex, higher levels of all three indicators of neighborhood deprivation and a deprivation score were associated with lower participation in a dose...

  9. Neonatal thalamic hemorrhage is strongly associated with electrical status epilepticus in slow wave sleep.

    Science.gov (United States)

    Kersbergen, Karina J; de Vries, Linda S; Leijten, Frans S S; Braun, Kees P J; Nievelstein, Rutger A J; Groenendaal, Floris; Benders, Manon J N L; Jansen, Floor E

    2013-04-01

    Thalamic hemorrhage has been associated with neonatal cerebral sinovenous thrombosis (CSVT), especially when the straight sinus is involved, and often presents with neonatal seizures. Early thalamic injury has previously been shown to predispose to epilepsy and electrical status epilepticus in slow wave sleep (ESES). The objective of this study was to assess the prevalence of sleep-induced epileptic electroencephalography (EEG) abnormalities and postneonatal epilepsy after neonatal thalamic hemorrhage associated with CSVT, in the absence of more widespread cerebral damage. Between 2003 and 2008 15 neonates were diagnosed with a thalamic hemorrhage due to suspected or proven CSVT. Neurodevelopment and the history of seizures were assessed at follow-up in the outpatient clinic in all 14 survivors (age 2-9 years). Whole-night or sleep-deprived EEG recordings were obtained to assess the prevalence of interictal epileptiform activity (EA) and calculate a sleep-induced spike and wave index (SWI). Three children were diagnosed with classic ESES (SWI >85%). Two children had ESES spectrum disorder (SWI between 50% and 85%), and in two children significant sleep-induced epileptiform activity (SIEA) was noted (SWI between 25% and 50%). Two other children were diagnosed with focal epilepsy, in the absence of sleep-induced epileptiform EEG abnormalities. Five children (age 2-7 years) had normal EEG recordings at follow-up. Deficits in neurodevelopment were seen significantly more often in children with ESES, ESES spectrum, or SIEA. Neonates with thalamic hemorrhage associated with straight sinus thrombosis, without evidence of more widespread cerebral damage, are at high risk of developing ESES (spectrum) disorder (35%), SIEA (14%), or focal epilepsy (14%). Electrographic abnormalities may already be present prior to recognition of cognitive deficits. Early diagnosis may guide parents and caregivers, and subsequent treatment may improve neurodevelopmental outcome. Routine

  10. Onset polarity in bipolar disorder: A strong association between first depressive episode and suicide attempts.

    Science.gov (United States)

    Cremaschi, Laura; Dell'Osso, Bernardo; Vismara, Matteo; Dobrea, Cristina; Buoli, Massimiliano; Ketter, Terence A; Altamura, A Carlo

    2017-02-01

    The role of onset polarity (OP) in patients with bipolar disorder (BD) has been increasingly investigated over the last few years, for its clinical, prognostic, and therapeutic implications. The present study sought to assess whether OP was associated with specific correlates, in particular with a differential suicidal risk in BD patients. A sample of 362 recovered BD patients was dichotomized by OP: depressed (DO) or elevated onset (EO: hypomanic/manic/mixed). Socio-demographic and clinical variables were compared between the subgroups. Additionally, binary logistic regression was performed to assess features associated with OP. DO compared with EO patients had older current age and were more often female, but less often single and unemployed. Clinically, DO versus EO had a more than doubled rate of suicide attempts, as well as significantly higher rates of BD II diagnosis, lifetime stressful events, current psychotropics and antidepressants use, longer duration of the most recent episode (more often depressive), but lower rates of psychosis and involuntary commitments. Retrospective design limiting the accurate assessment of total number of prior episodes of each polarity. Our results support the influence of OP on BD course and outcome. Moreover, in light of the relationship between DO and a higher rate of suicide attempts, further investigation may help clinicians in identifying patients at higher risk of suicide attempts. Copyright © 2016. Published by Elsevier B.V.

  11. Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures

    Science.gov (United States)

    McFarland, Karen N.; Liu, Jilin; Landrian, Ivette; Zeng, Desmond; Raskin, Salmo; Moscovich, Mariana; Gatto, Emilia M.; Ochoa, Adriana; Teive, Hélio A. G.; Rasmussen, Astrid; Ashizawa, Tetsuo

    2014-01-01

    Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed “ATCCT interruptions,” experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confers a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling. PMID:24318420

  12. Severity of rhinitis and wheezing is strongly associated in preschoolers: A population-based study.

    Science.gov (United States)

    Pereira, Ana Margarida; Morais-Almeida, Mário; Santos, Natacha; Nunes, Carlos; Bousquet, Jean; Fonseca, João Almeida

    2015-11-01

    In preschool children, no study assessed the relation between wheezing and rhinitis severity. Our aims were to estimate the prevalence of current wheezing (CW) in preschoolers and to study the association between CW and current rhinitis (CR), considering its severity/persistency. This is a cross-sectional, nationwide, population-based study including a representative sample of 5003 Portuguese children aged 3-5 years. Data were collected by a face-to-face interview with caregivers using an adapted ISAAC questionnaire. CW was defined as presence of ≥1 wheezing episode in the previous 12 months. Rhinitis severity/persistency was classified according to Allergic Rhinitis and its Impact on Asthma. Current wheezing prevalence was 24.5% [95% CI 23.3-25.7]; 9.4% of the participants had ≥4 wheezing episodes in the previous year. Children with CR had an odds ratio (OR) of 4.0 [95% CI 3.4-4.5] for CW; it was highest for children with moderate-severe persistent rhinitis (11.5 [95% CI 8.1-16.3]), even after adjusting for possible confounders. Wheezers with CR reported more wheezing treatment use (p = 0.024) than those without CR. There was a trend for a higher number of wheezing episodes with more persistent and severe nasal disease - 48.4% of children with moderate-severe persistent rhinitis had >4 wheezing episodes vs. 28.9% in moderate-severe intermittent, 20.0% in mild persistent, 10.8% in mild intermittent, and 3.6% in those without CR; p rhinitis, especially moderate-severe persistent disease. Preschoolers with both CW and rhinitis seem to have a more severe phenotype, emphasizing the need for concurrent evaluation of nasal and bronchial symptoms even in small children. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. The 8.1 ancestral MHC haplotype is strongly associated with colorectal cancer risk.

    Science.gov (United States)

    Tóth, Eva Katalin; Kocsis, Judit; Madaras, Balázs; Bíró, Adrienn; Pocsai, Zsuzsa; Fust, George; Blaskó, Bernadett; Karádi, István; Adány, Róza; Laki, Judit

    2007-10-15

    Many recent data indicate that some alleles encoded in the central major histocompatibility complex (MHC) region (Class III) of short arm of chromosome 6 may modify the risk of cancer development. Therefore we determined 4 single nucleotide polymorphisms (SNPs) of this region (TNF-alpha -308 G > A, RAGE -429 T > C, HSP70-2 -1267 A > G, LTA 252 A > G) in genomic DNA samples from 183 Hungarian patients with colorectal cancer and 141 age matched control subjects representing the Hungarian population of the same age and gender. No significant differences were found in either SNP tested. When, however, three- or four-locus haplotypes consisting of known constituents of the so-called 8.1 ancestral haplotype (8.1AH) were considered, marked differences were observed. Frequency of TNF-alpha -308A, RAGE -429C, HSP70-2 -1267G, LTA 252G (8.1AH) haplotype was significantly (p = 0.006) more frequent (19.1%) among patients than in the controls (7.7%). Age- and gender-adjusted ratio of the 8.1AH carriers vs. non-carriers to have colorectal cancer was 2.514 (1.130-5.594). This risk was higher in cancer-indicate that carriers of the 8.1AH, encoding for an altered immune response and known to be associated with alterations of several immune functions and autoimmune diseases have an increased risk for some cancer types. These findings may contribute to better understanding how the defense mechanisms against tumors could be enhanced/strengthened. (c) 2007 Wiley-Liss, Inc.

  14. Antiviral and Inflammatory Cellular Signaling Associated with Enterovirus 71 Infection

    Directory of Open Access Journals (Sweden)

    Yuefei Jin

    2018-03-01

    Full Text Available Enterovirus 71 (EV71 infection has become a major threat to global public health, especially in infants and young children. Epidemiological studies have indicated that EV71 infection is responsible for severe and even fatal cases of hand, foot, and mouth disease (HFMD. Accumulated evidence indicates that EV71 infection triggers a plethora of interactive signaling pathways, resulting in host immune evasion and inflammatory response. This review mainly covers the effects of EV71 infection on major antiviral and inflammatory cellular signal pathways. EV71 can activate cellular signaling networks including multiple cell surface and intracellular receptors, intracellular kinases, calcium flux, and transcription factors that regulate antiviral innate immunity and inflammatory response. Cellular signaling plays a critical role in the regulation of host innate immune and inflammatory pathogenesis. Elucidation of antiviral and inflammatory cellular signaling pathways initiated by EV71 will not only help uncover the potential mechanisms of EV71 infection-induced pathogenesis, but will also provide clues for the design of therapeutic strategies against EV71 infection.

  15. Type 2 diabetes associated variants of KCNQ1 strongly confer the risk of cardiovascular disease among the Saudi Arabian population

    Directory of Open Access Journals (Sweden)

    Maha S. Al-Shammari

    2017-08-01

    Full Text Available Abstract Genome-wide association studies have identified several loci associated with an increased risk for cardiovascular disease (CVD and type 2 diabetes (T2D. Polymorphisms within the KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1 gene are consistently associated with T2D in a number of populations. The current study was undertaken to evaluate the association of 3 polymorphisms of KCNQ1 (rs2237892, rs151290 and rs2237895 with T2D and/or CVD. Patients diagnosed with either T2D (320 patients, CVD (250 patients or both (60 patients and 516 healthy controls were genotyped by TaqMan assay run on a real time PCR thermocycler. A statistically significant association was found for SNPs rs151290 (OR = 1.76; 95%CI = 1.02-3.05; p = 0.0435 and rs2237895 (OR = 2.49; 95%CI = 1.72-3.61; p < 0.0001 with CVD. SNP rs151290 (OR = 7.43; 95%CI = 1.00-55.22; p = 0.0499 showed a strong association in patients with both T2D and CVD. None of the SNPs showed any significant association with T2D. Haploview analysis showed that the ACC (rs151290, rs2237892 and rs2237895 haplotype is the most significant risk allele combination for CVD, while CCA is the most significant risk haplotype for co-morbidity with T2D. KCNQ1 polymorphism at SNPs rs151290 and rs2237895 is strongly associated with CVD in this population, but presented no association with T2D.

  16. TRH receptor mobility in the plasma membrane is strongly affected by agonist binding and by interaction with some cognate signaling proteins.

    Science.gov (United States)

    Moravcova, Radka; Melkes, Barbora; Novotny, Jiri

    2018-02-01

    Extensive research has been dedicated to elucidating the mechanisms of signal transduction through different G protein-coupled receptors (GPCRs). However, relatively little is known about the regulation of receptor movement within the cell membrane upon ligand binding. In this study we focused our attention on the thyrotropin-releasing hormone (TRH) receptor that typically couples to G q/11 proteins. We monitored receptor diffusion in the plasma membrane of HEK293 cells stably expressing yellow fluorescent protein (YFP)-tagged TRH receptor (TRHR-YFP) by fluorescence recovery after photobleaching (FRAP). FRAP analysis indicated that the lateral movement of the TRH receptor was markedly reduced upon TRH binding as the value of its diffusion coefficient fell down by 55%. This effect was prevented by the addition of the TRH receptor antagonist midazolam. We also found that siRNA-mediated knockdown of G q/11 α, Gβ, β-arrestin2 and phospholipase Cβ1, but not of G i α1, β-arrestin1 or G protein-coupled receptor kinase 2, resulted in a significant decrease in the rate of TRHR-YFP diffusion, indicating the involvement of the former proteins in the regulation of TRH receptor behavior. The observed partial reduction of the TRHR-YFP mobile fraction caused by down-regulation of G i α1 and β-arrestin1 suggests that these proteins may also play distinct roles in THR receptor-mediated signaling. These results demonstrate for the first time that not only agonist binding but also abundance of some signaling proteins may strongly affect TRH receptor dynamics in the plasma membrane.

  17. The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease

    Science.gov (United States)

    Fu, Yi-Ping; Kohaar, Indu; Moore, Lee E.; Lenz, Petra; Figueroa, Jonine D.; Tang, Wei; Porter-Gill, Patricia; Chatterjee, Nilanjan; Scott-Johnson, Alexandra; Garcia-Closas, Montserrat; Muchmore, Brian; Baris, Dalsu; Paquin, Ashley; Ylaya, Kris; Schwenn, Molly; Apolo, Andrea B.; Karagas, Margaret R.; Tarway, McAnthony; Johnson, Alison; Mumy, Adam; Schned, Alan; Guedez, Liliana; Jones, Michael A.; Kida, Masatoshi; Monawar Hosain, GM; Malats, Nuria; Kogevinas, Manolis; Tardon, Adonina; Serra, Consol; Carrato, Alfredo; Garcia-Closas, Reina; Lloreta, Josep; Wu, Xifeng; Purdue, Mark; Andriole, Gerald L.; Grubb, Robert L.; Black, Amanda; Landi, Maria T.; Caporaso, Neil E.; Vineis, Paolo; Siddiq, Afshan; Bueno-de-Mesquita, H. Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Severi, Gianluca; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C.; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Govannucci, Edward; Hunter, David; Kraft, Peter; Lindstrom, Sara; Gapstur, Susan M.; Jacobs, Eric J.; Diver, W. Ryan; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Kooperberg, Charles; Hohensee, Chancellor; Rodabough, Rebecca J.; Cortessis, Victoria K.; Conti, David V.; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Haiman, Christopher A.; Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Porru, Stefano; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Grossman, H. Barton; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Fraumeni, Joseph; Chanock, Stephen J.; Hewitt, Stephen M.; Silverman, Debra T.; Rothman, Nathaniel; Prokunina-Olsson, Ludmila

    2014-01-01

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. PMID:25320178

  18. Household income is strongly associated with health-related quality of life among Japanese men but not women.

    Science.gov (United States)

    Yamazaki, S; Fukuhara, S; Suzukamo, Y

    2005-07-01

    As socio-economic status (SES) strongly reflects individual economic status, evaluating the association between SES and health could provide information that is important for planning integrated economic and public health policies. We examined the association between annual household income as a measure of SES and the eight scale scores of the Medical Outcomes Study Short Form-36 Health Survey (SF-36) as a quantifier of health-related quality of life (HRQOL) in Japan. Cross-sectional survey. Data were from the SF-36 national survey in Japan. A total of 4500 people aged 16 years or older were selected from the entire population of Japan using stratified-random sampling, and 3395 responded to the survey. Men with lower levels of annual household income had lower scores in all SF-36 domains. However, only 'general health perceptions' and 'social functioning' showed statistically significant trends among the women surveyed. In the subgroup of women working full-time, there were no domains that showed significant trends. A strong association exists between annual household income and SF-36 scores among men, but there is only a limited association among women. The employment and economic policies that affect annual household income potentially influence HRQOL.

  19. A strong pelvic floor is associated with higher rates of sexual activity in women with pelvic floor disorders

    Science.gov (United States)

    Kanter, Gregg; Rogers, Rebecca G; Pauls, Rachel N; Kammerer-Doak, Dorothy; Thakar, Ranee

    2015-01-01

    Introduction and Hypothesis We evaluated the associations between pelvic floor muscle strength and tone with sexual activity and sexual function in women with pelvic floor disorders. Methods This was a secondary analysis of a multicenter study of women with pelvic floor disorders from the US and UK performed to validate the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). Participants were surveyed about whether they were sexually active and completed the PISQ-IR and Female Sexual Function Index (FSFI) questionnaires to assess sexual function. Physical exams included assessment of pelvic floor strength by the Oxford Grading Scale, and assessment of pelvic floor tone per ICS guidelines. Results The cohort of 585 women was middle aged (mean age 54.9 +/−12.1) with 395 (67.5%) reporting sexual activity. Women with a strong pelvic floor (n=275) were more likely to report sexual activity than women with weak strength (n=280) (75.3 vs. 61.8%, ppelvic floor tone was not associated with sexual activity (68.8 vs. 60.2%, normal vs. hypoactive, p=0.08). After multivariable analysis, a strong pelvic floor remained predictive of sexual activity (OR 1.89, CI 1.18–3.03, ppelvic floor was associated with higher scores on the PISQ-IR domain of condition impact (Parameter Estimate 0.20+/−0.09, P=0.04), and FSFI orgasm domain (PE 0.51+/−0.17, P=0.004). Conclusion A strong pelvic floor is associated with higher rates of sexual activity as well as higher sexual function scores on the condition impact domain of the PISQ-IR and orgasm domain of the FSFI. PMID:25994625

  20. Atmospheric Signals Associated with Major Earthquakes. A Multi-Sensor Approach. Chapter 9

    Science.gov (United States)

    Ouzounov, Dimitar; Pulinets, Sergey; Hattori, Katsumi; Kafatos, Menas; Taylor, Patrick

    2011-01-01

    We are studying the possibility of a connection between atmospheric observation recorded by several ground and satellites as earthquakes precursors. Our main goal is to search for the existence and cause of physical phenomenon related to prior earthquake activity and to gain a better understanding of the physics of earthquake and earthquake cycles. The recent catastrophic earthquake in Japan in March 2011 has provided a renewed interest in the important question of the existence of precursory signals preceding strong earthquakes. We will demonstrate our approach based on integration and analysis of several atmospheric and environmental parameters that were found associated with earthquakes. These observations include: thermal infrared radiation, radon! ion activities; air temperature and humidity and a concentration of electrons in the ionosphere. We describe a possible physical link between atmospheric observations with earthquake precursors using the latest Lithosphere-Atmosphere-Ionosphere Coupling model, one of several paradigms used to explain our observations. Initial results for the period of2003-2009 are presented from our systematic hind-cast validation studies. We present our findings of multi-sensor atmospheric precursory signals for two major earthquakes in Japan, M6.7 Niigata-ken Chuetsu-oki of July16, 2007 and the latest M9.0 great Tohoku earthquakes of March 11,2011

  1. Tropospheric mid-latitude geopotential wave characteristics associated with strong wind events in the North Atlantic/European region

    Science.gov (United States)

    Wild, Simon; Simmonds, Ian; Leckebusch, Gregor C.

    2015-04-01

    The variability of strong synoptic scale wind events in the mid-latitudes have long been linked to baroclinic wave activity in the mid troposphere. Previous studies have also shown that greater amplitudes of planetary waves in the mid troposphere are likely to increase the occurrence of regional extremes in temperature and precipitation. In this study we examine whether characteristics of planetary and synoptic mid-latitude waves show systematic anomalies in the North Atlantic/ European region which can be related to the occurrence of a strong surface wind event. We will mainly focus on two questions: 1) Do amplitudes for waves with different wave lengths show a systematic anomaly when a strong wind event occurs? 2) Can phases of the individual wave components be detected that favour strong wind events? In order to decompose the mid-tropospheric flow into longitudinal waves we employ the fast Fourier transform to the meridional mean of the geopotential height in 500hPa between 35° and 60°N for i) the entire latitude belt and ii) for a North Atlantic/European sector (36°W to 36°E). Our definition of strong wind events is based on the Storm Severity Index (SSI) alongside a wind tracking algorithm identifying areas of exceedances of the local 98th percentile of the 10m wind speed. First results using ERA-Interim Reanalysis from 1979 - 2014 for the extended winter season (ONDJFM) for the 50 most intense strong wind systems with respect to the SSI reveal a greater amplitude for all investigated wave numbers. Especially waves with wave lengths below 2000km show an increase of about 25% of the daily standard deviation on average. The distribution of wave phases for the different wave numbers with respect to the location of a strong wind event shows a less homogenous picture. There is however a high proportion of events that can be associated with phases around 3π/4 and 5π/4 of waves with lengths of around 6000km, equivalent to wave number 5 on a planetary scale

  2. Psychobehavioural Factors Are More Strongly Associated with Successful Weight Management Than Predetermined Satiety Effect or Other Characteristics of Diet

    Directory of Open Access Journals (Sweden)

    Leila Karhunen

    2012-01-01

    Full Text Available This study aimed to investigate factors associated with weight management, especially whether satiety value of food as a part of a weight-maintenance diet would affect self-regulation of food intake and weight management. Altogether 82 obese subjects completed the study consisting of weight-loss and weight-maintenance (WM periods. During the WM, subjects were randomized into higher- and lower-satiety food groups. No differences were observed in the changes in body weight, energy intake, or eating behaviour between the groups, even despite the different macronutrient compositions of the diets. However, when regarding all study subjects, success in WM was most strongly associated with a greater increase in the flexible control of eating and experience of greater easiness of WM and control of food intake and a greater decrease in uncontrollable eating and psychological distress. Psychobehavioural factors seem to be more strongly associated with successful weight management than the predetermined satiety effect or other characteristics of the diet.

  3. Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1.

    Directory of Open Access Journals (Sweden)

    Sarah H Louie

    Full Text Available BACKGROUND: Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. METHODOLOGY: We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. CONCLUSIONS: These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene

  4. Psychobehavioural Factors Are More Strongly Associated with Successful Weight Management Than Predetermined Satiety Effect or Other Characteristics of Diet

    DEFF Research Database (Denmark)

    Karhunen, Leila; Lyly, Marika; Lapveteläinen, Anja

    2012-01-01

    This study aimed to investigate factors associated with weight management, especially whether satiety value of food as a part of a weight-maintenance diet would affect self-regulation of food intake and weight management. Altogether 82 obese subjects completed the study consisting of weight...... factors seem to be more strongly associated with successful weight management than the predetermined satiety effect or other characteristics of the diet.......-loss and weight-maintenance (WM) periods. During theWM, subjects were randomized into higher- and lower-satiety food groups. No differences were observed in the changes in body weight, energy intake, or eating behaviour between the groups, even despite the different macronutrient compositions of the diets...

  5. Integration of danger peptide signals with herbivore-associated molecular pattern signaling amplifies anti-herbivore defense responses in rice.

    Science.gov (United States)

    Shinya, Tomonori; Yasuda, Shigetaka; Hyodo, Kiwamu; Tani, Rena; Hojo, Yuko; Fujiwara, Yuka; Hiruma, Kei; Ishizaki, Takuma; Fujita, Yasunari; Saijo, Yusuke; Galis, Ivan

    2018-03-07

    Plant defense against herbivores is modulated by herbivore-associated molecular patterns (HAMPs) from oral secretions (OS) and/or saliva of insects. Furthermore, feeding wounds initiate plant self-damage responses modulated by danger-associated molecular patterns (DAMPs) such as immune defense-promoting plant elicitor peptides (Peps). While temporal and spatial co-existence of both patterns during herbivory implies a possibility of their close interaction, the molecular mechanisms remain undetermined. Here we report that exogenous application of rice (Oryza sativa) peptides (OsPeps) can elicit multiple defense responses in rice cell cultures. Specific activation of OsPROPEP3 gene transcripts in rice leaves by wounding and OS treatments further suggests a possible involvement of the OsPep3 peptide in rice-herbivore interactions. Correspondingly, we found that simultaneous application of OsPep3 and Mythimna loreyi OS significantly amplifies an array of defense responses in rice cells, including mitogen-activated protein kinase activation, and generation of defense-related hormones and metabolites. The induction of OsPROPEP3/4 by OsPep3 points to a positive auto-feedback loop in OsPep signaling which may contribute to additional enhancement of defense signal(s). Finally, the overexpression of the OsPep receptor OsPEPR1 increases the sensitivity of rice plants not only to the cognate OsPeps but also to OS signals. Our findings collectively suggest that HAMP-DAMP signal integration provides a critical step in the amplification of defense signaling in plants. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

  6. A missense mutation in growth differentiation factor 9 (GDF9 is strongly associated with litter size in sheep

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    Våge Dag I

    2013-01-01

    Full Text Available Abstract Background A genome wide association study for litter size in Norwegian White Sheep (NWS was conducted using the recently developed ovine 50K SNP chip from Illumina. After genotyping 378 progeny tested artificial insemination (AI rams, a GWAS analysis was performed on estimated breeding values (EBVs for litter size. Results A QTL-region was identified on sheep chromosome 5, close to the growth differentiation factor 9 (GDF9, which is known to be a strong candidate gene for increased ovulation rate/litter size. Sequencing of the GDF9 coding region in the most extreme sires (high and low BLUP values revealed a single nucleotide polymorphism (c.1111G>A, responsible for a Val→Met substitution at position 371 (V371M. This polymorphism has previously been identified in Belclare and Cambridge sheep, but was not found to be associated with fertility. In our NWS-population the c.1111G>A SNP showed stronger association with litter size than any other single SNP on the Illumina 50K ovine SNP chip. Based on the estimated breeding values, daughters of AI rams homozygous for c.1111A will produce minimum 0.46 - 0.57 additional lambs compared to daughters of wild-type rams. Conclusion We have identified a missense mutation in the bioactive part of the GDF9 protein that shows strong association with litter size in NWS. Based on the NWS breeding history and the marked increase in the c.1111A allele frequency in the AI ram population since 1983, we hypothesize that c.1111A allele originate from Finnish landrace imported to Norway around 1970. Because of the widespread use of Finnish landrace and the fact that the ewes homozygous for the c.1111A allele are reported to be fertile, we expect the commercial impact of this mutation to be high.

  7. BOLD signal and functional connectivity associated with loving kindness meditation.

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    Garrison, Kathleen A; Scheinost, Dustin; Constable, R Todd; Brewer, Judson A

    2014-05-01

    Loving kindness is a form of meditation involving directed well-wishing, typically supported by the silent repetition of phrases such as "may all beings be happy," to foster a feeling of selfless love. Here we used functional magnetic resonance imaging to assess the neural substrate of loving kindness meditation in experienced meditators and novices. We first assessed group differences in blood oxygen level-dependent (BOLD) signal during loving kindness meditation. We next used a relatively novel approach, the intrinsic connectivity distribution of functional connectivity, to identify regions that differ in intrinsic connectivity between groups, and then used a data-driven approach to seed-based connectivity analysis to identify which connections differ between groups. Our findings suggest group differences in brain regions involved in self-related processing and mind wandering, emotional processing, inner speech, and memory. Meditators showed overall reduced BOLD signal and intrinsic connectivity during loving kindness as compared to novices, more specifically in the posterior cingulate cortex/precuneus (PCC/PCu), a finding that is consistent with our prior work and other recent neuroimaging studies of meditation. Furthermore, meditators showed greater functional connectivity during loving kindness between the PCC/PCu and the left inferior frontal gyrus, whereas novices showed greater functional connectivity during loving kindness between the PCC/PCu and other cortical midline regions of the default mode network, the bilateral posterior insula lobe, and the bilateral parahippocampus/hippocampus. These novel findings suggest that loving kindness meditation involves a present-centered, selfless focus for meditators as compared to novices.

  8. Seismogenic ionospheric anomalies associated with the strong Indonesian earthquake occurred on 11 April 2012 (M = 8.5)

    Science.gov (United States)

    Pandey, Uma; Singh, Ashutosh K.; Kumar, Sanjay; Singh, A. K.

    2018-03-01

    Ionospheric perturbations in possible association with a major earthquake (EQ) (M = 8.5) which occurred in India-Oceania region are investigated by monitoring subionospheric propagation of VLF signals transmitted from the NWC transmitter (F = 19.8 kHz), Australia to a receiving station at Varanasi (geographic lat. 25.3°N, long 82.99°E), India. The EQ occurred on 11 April 2012 at 08:38:35 h UT (magnitude ≈ 8.5, depth = 10 km, and lat. = 2.3°N, long. = 93.0°E). A significant increase of few days before the EQ has been observed by using the VLF nighttime amplitude fluctuation method (fixed frequency transmitter signal). The analysis of total electron contents (TEC) derived from the global positioning system (GPS) at three different stations namely, Hyderabad (latitude 17.38°N, longitude 78.48°E), Singapore (latitude 1.37°N, longitude 103.84°E) and Port Blair (latitude 11.62°N, longitude 92.72°E) due to this EQ has also been presented. Significant perturbation in TEC data (enhancements and depletion) is noted before and after the main shock of the EQ. The possible mechanisms behind these perturbations due to EQ have also been discussed.

  9. Strong association of MRI meniscal derangement and bone marrow lesions in knee osteoarthritis: data from the osteoarthritis initiative.

    Science.gov (United States)

    Lo, G H; Hunter, D J; Nevitt, M; Lynch, J; McAlindon, T E

    2009-06-01

    Meniscal damage is common in knee Osteoarthritis (OA) and predictive of structural progression, suggesting that their disruption plays a role in the development of OA. The bone marrow lesion (BML) is associated with pain and is a strong risk factor for structural progression. These lesions are associated with abnormal loading in a knee joint. Therefore, our hypothesis was that in those with symptomatic knee OA, large BMLs would be associated with ipsi-compartmental meniscal derangement. This was a cross-sectional study of a subsample of the Osteoarthritis Initiative where one set of magnetic resonance (MR) images from each participant was scored for tibiofemoral BMLs and meniscal derangement. We performed chi-squared tests comparing the prevalence of large BMLs in those with ipsi-compartmental meniscal derangement and those without. 160 Participants had a mean age of 61 (+/-9.9), mean BMI of 30.3 (+/-4.7) and 50% were female. 79% of medial and 39% of lateral menisci showed MRI (Magnetic Resonance Imaging) derangement. In those with medial meniscal MRI derangement, 44% had large medial BMLs while in those without medial meniscal derangement, 0% had large BMLs. Similar results were seen in the lateral compartment. Medial and lateral MRI meniscal derangement are highly prevalent in symptomatic knee OA and BMLs are highly associated with ipsi-compartmental MRI meniscal derangement.

  10. Skin colonisation at the catheter exit site is strongly associated with catheter colonisation and catheter-related sepsis.

    Science.gov (United States)

    Ponnusamy, Vennila; Perperoglou, Aris; Venkatesh, Vidheya; Curley, Anna; Brown, Nicholas; Tremlett, Catherine; Clarke, Paul

    2014-12-01

    The commonest mode of catheter colonisation is via the extraluminal route with skin bacteria. Catheter-related sepsis causes significant mortality and morbidity in neonates. Our aim was to study the relationships between culture-positive catheter exit site skin swabs, percutaneous central venous catheter segments and blood to determine the magnitude of associations between exit site skin colonisation, catheter colonisation and catheter-related sepsis. In a prospective study, an exit site skin swab and three formerly in vivo catheter segments (proximal, middle and tip) were taken for culture at catheter removal. In those neonates who were clinically unwell at catheter removal, a peripheral blood culture was also collected. Univariate and multivariate analyses were used to study associations. Skin swabs were culture positive in 39 (21%) of 187 catheter removals. With a culture-positive skin swab, the risk of associated catheter colonisation was nearly eight times higher (OR: 7.84, 95% CI: 3.59-17.15) and the risk of definite catheter-related sepsis with the same organism was nearly 10 times higher (OR 9.86, 95% CI: 3.13-31.00). Culture-positive skin swabs from the catheter exit site were strongly associated with catheter colonisation and with definite catheter-related sepsis with the same organism. These data provide further evidence supporting catheter colonisation via the extraluminal route and highlight the importance of optimising skin disinfection before catheter insertion. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  11. Robust detection of heartbeats using association models from blood pressure and EEG signals.

    Science.gov (United States)

    Jeon, Taegyun; Yu, Jongmin; Pedrycz, Witold; Jeon, Moongu; Lee, Boreom; Lee, Byeongcheol

    2016-01-15

    The heartbeat is fundamental cardiac activity which is straightforwardly detected with a variety of measurement techniques for analyzing physiological signals. Unfortunately, unexpected noise or contaminated signals can distort or cut out electrocardiogram (ECG) signals in practice, misleading the heartbeat detectors to report a false heart rate or suspend itself for a considerable length of time in the worst case. To deal with the problem of unreliable heartbeat detection, PhysioNet/CinC suggests a challenge in 2014 for developing robust heart beat detectors using multimodal signals. This article proposes a multimodal data association method that supplements ECG as a primary input signal with blood pressure (BP) and electroencephalogram (EEG) as complementary input signals when input signals are unreliable. If the current signal quality index (SQI) qualifies ECG as a reliable input signal, our method applies QRS detection to ECG and reports heartbeats. Otherwise, the current SQI selects the best supplementary input signal between BP and EEG after evaluating the current SQI of BP. When BP is chosen as a supplementary input signal, our association model between ECG and BP enables us to compute their regular intervals, detect characteristics BP signals, and estimate the locations of the heartbeat. When both ECG and BP are not qualified, our fusion method resorts to the association model between ECG and EEG that allows us to apply an adaptive filter to ECG and EEG, extract the QRS candidates, and report heartbeats. The proposed method achieved an overall score of 86.26 % for the test data when the input signals are unreliable. Our method outperformed the traditional method, which achieved 79.28 % using QRS detector and BP detector from PhysioNet. Our multimodal signal processing method outperforms the conventional unimodal method of taking ECG signals alone for both training and test data sets. To detect the heartbeat robustly, we have proposed a novel multimodal data

  12. Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies

    Science.gov (United States)

    Ruhe, Alison L.; Erdman, Carolyn A.; Robertson, Kathryn R.; Webb, Aubrey A.; Williams, D. Colette; Chang, Melanie L.; Hytönen, Marjo K.; Lohi, Hannes; Hamilton, Steven P.; Neff, Mark W.

    2012-01-01

    Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders. PMID:23028339

  13. Variation in genes related to cochlear biology is strongly associated with adult-onset deafness in border collies.

    Directory of Open Access Journals (Sweden)

    Jennifer S Yokoyama

    2012-09-01

    Full Text Available Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years than typically expected for aging dogs (8-10 years. Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09 × 10(-13. To further localize disease-associated variants, targeted next-generation sequencing (NGS of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total and controls (n = 101 total and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.

  14. Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence.

    Science.gov (United States)

    Gmel, Gerhard; Holmes, John; Studer, Joseph

    2015-06-29

    There have been reviews on the association between density of alcohol outlets and harm including studies published up to December 2008. Since then the number of publications has increased dramatically. The study reviews the more recent studies with regard to their utility to inform policy. A systematic review found more than 160 relevant studies (published between January 2009 and October 2014). The review focused on: (i) outlet density and assaultive or intimate partner violence; (ii) studies including individual level data; or (iii) 'natural experiments'. Despite overall evidence for an association between density and harm, there is little evidence on causal direction (i.e. whether demand leads to more supply or increased availability increases alcohol use and harm). When outlet types (e.g. bars, supermarkets) are analysed separately, studies are too methodologically diverse and partly contradictory to permit firm conclusions besides those pertaining to high outlet densities in areas such as entertainment districts. Outlet density commonly had little effect on individual-level alcohol use, and the few 'natural experiments' on restricting densities showed little or no effects. Although outlet densities are likely to be positively related to alcohol use and harm, few policy recommendations can be given as effects vary across study areas, outlet types and outlet cluster size. Future studies should examine in detail outlet types, compare different outcomes associated with different strengths of association with alcohol, analyse non-linear effects and compare different methodologies. Purely aggregate-level studies examining total outlet density only should be abandoned. [Gmel G, Holmes J, Studer J. Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug Alcohol Rev 2015]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  15. A strong association between non-musculoskeletal symptoms and musculoskeletal pain symptoms: results from a population study

    Directory of Open Access Journals (Sweden)

    Tschudi-Madsen Hedda

    2011-12-01

    Full Text Available Abstract Background There is a lack of knowledge about the pattern of symptom reporting in the general population as most research focuses on specific diseases or symptoms. The number of musculoskeletal pain sites is a strong predictor for disability pensioning and, hence, is considered to be an important dimension in symptom reporting. The simple method of counting symptoms might also be applicable to non-musculoskeletal symptoms, rendering further dimensions in describing individual and public health. In a general population, we aimed to explore the association between self-reported non-musculoskeletal symptoms and the number of pain sites. Methods With a cross-sectional design, the Standardised Nordic Questionnaire and the Subjective Health Complaints Inventory were used to record pain at ten different body sites and 13 non-musculoskeletal symptoms, respectively, among seven age groups in Ullensaker, Norway (n = 3,227. Results Results showed a strong, almost linear relationship between the number of non-musculoskeletal symptoms and the number of pain sites (r = 0.55. The number and type of non-musculoskeletal symptoms had an almost equal explanatory power in the number of pain sites reported (27.1% vs. 28.2%. Conclusion The linear association between the number of non-musculoskeletal and musculoskeletal symptoms might indicate that the symptoms share common characteristics and even common underlying causal factors. The total burden of symptoms as determined by the number of symptoms reported might be an interesting generic indicator of health and well-being, as well as present and future functioning. Research on symptom reporting might also be an alternative pathway to describe and, possibly, understand the medically unexplained multisymptom conditions.

  16. Neurons in the barrel cortex turn into processing whisker and odor signals: a cellular mechanism for the storage and retrieval of associative signals.

    Science.gov (United States)

    Wang, Dangui; Zhao, Jun; Gao, Zilong; Chen, Na; Wen, Bo; Lu, Wei; Lei, Zhuofan; Chen, Changfeng; Liu, Yahui; Feng, Jing; Wang, Jin-Hui

    2015-01-01

    Associative learning and memory are essential to logical thinking and cognition. How the neurons are recruited as associative memory cells to encode multiple input signals for their associated storage and distinguishable retrieval remains unclear. We studied this issue in the barrel cortex by in vivo two-photon calcium imaging, electrophysiology, and neural tracing in our mouse model that the simultaneous whisker and olfaction stimulations led to odorant-induced whisker motion. After this cross-modal reflex arose, the barrel and piriform cortices connected. More than 40% of barrel cortical neurons became to encode odor signal alongside whisker signal. Some of these neurons expressed distinct activity patterns in response to acquired odor signal and innate whisker signal, and others encoded similar pattern in response to these signals. In the meantime, certain barrel cortical astrocytes encoded odorant and whisker signals. After associative learning, the neurons and astrocytes in the sensory cortices are able to store the newly learnt signal (cross-modal memory) besides the innate signal (native-modal memory). Such associative memory cells distinguish the differences of these signals by programming different codes and signify the historical associations of these signals by similar codes in information retrievals.

  17. Mining Research on Vibration Signal Association Rules of Quayside Container Crane Hoisting Motor Based on Apriori Algorithm

    Science.gov (United States)

    Yang, Chencheng; Tang, Gang; Hu, Xiong

    2017-07-01

    Shore-hoisting motor in the daily work will produce a large number of vibration signal data,in order to analyze the correlation among the data and discover the fault and potential safety hazard of the motor, the data are discretized first, and then Apriori algorithm are used to mine the strong association rules among the data. The results show that the relationship between day 1 and day 16 is the most closely related, which can guide the staff to analyze the work of these two days of motor to find and solve the problem of fault and safety.

  18. White matter hyperintensity signals associated with vascular risk factors in schizophrenia.

    Science.gov (United States)

    Brown, F W; Lewine, R R; Hudgins, P A

    1995-01-01

    1. A sample of 165 schizophrenic subjects was compared to a normal control group in order to evaluate associations between white matter hyperintensity signals and vascular risk factors. 2. A comprehensive medical chart review was completed on all subjects evaluating potential vascular risk factors. Brain MRI acquisition was performed with 0.5 and 1.5 Telsa Philips scanners. 3. Prevalence rates of WMH signals in schizophrenic subjects and normal controls were 4.8% and 4.9%, respectively. 4. A significant association was found for schizophrenics with WHM signals to schizophrenics without signals for hypertension and history of CVA's. 5. This finding is consistent with an etiology of WMH signals in schizophrenia being related to vascular disease.

  19. Consumption of preserved egg, a high-lead-containing food, is strongly associated with depressive symptoms in Chinese adults.

    Science.gov (United States)

    Yu, Bin; Shao, Junwei; Yu, Fei; Zhang, Qing; Liu, Li; Meng, Ge; Wu, Hongmei; Xia, Yang; Bao, Xue; Gu, Yeqing; Shi, Hongbin; Sun, Shaomei; Wang, Xing; Zhou, Ming; Jia, Qiyu; Liu, Huijun; Wu, Yuntang; Niu, Kaijun

    2017-11-01

    Previous studies have demonstrated adverse mental health effects of Pb exposure. The purpose of this study is to investigate the relationship between consumption of preserved egg (PE), a high-Pb-containing food and depressive symptoms among adults in China. A sample of 25 213 adults (mean age 41·4 (sd 11·8) years; males, 53·9 %) in Tianjin, China, was studied in a cross-sectional analysis. Dietary intake including PE was assessed using a valid self-administered FFQ. Depressive symptoms were assessed using the Self-Rating Depression Scale (SDS). The association was estimated by OR using logistic regression models adjusted for multiple confounders. The prevalence of elevated depressive symptoms was 6·6 % (SDS≥50). Compared with the least frequent PE consumption (strongly associated with depressive symptoms among adults in China. These findings underscore the need to consider dietary Pb exposure as a risk factor for psychological distress.

  20. Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration

    Science.gov (United States)

    Alves, Chrystian J.; Dariolli, Rafael; Jorge, Frederico M.; Monteiro, Matheus R.; Maximino, Jessica R.; Martins, Roberto S.; Strauss, Bryan E.; Krieger, José E.; Callegaro, Dagoberto; Chadi, Gerson

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinson's disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS

  1. A continental view of pine-associated ectomycorrhizal fungal spore banks: a quiescent functional guild with a strong biogeographic pattern.

    Science.gov (United States)

    Glassman, Sydney I; Peay, Kabir G; Talbot, Jennifer M; Smith, Dylan P; Chung, Judy A; Taylor, John W; Vilgalys, Rytas; Bruns, Thomas D

    2015-03-01

    Ecologists have long acknowledged the importance of seed banks; yet, despite the fact that many plants rely on mycorrhizal fungi for survival and growth, the structure of ectomycorrhizal (ECM) fungal spore banks remains poorly understood. The primary goal of this study was to assess the geographic structure in pine-associated ECM fungal spore banks across the North American continent. Soils were collected from 19 plots in forests across North America. Fresh soils were pyrosequenced for fungal internal transcribed spacer (ITS) amplicons. Adjacent soil cores were dried and bioassayed with pine seedlings, and colonized roots were pyrosequenced to detect resistant propagules of ECM fungi. The results showed that ECM spore banks correlated strongly with biogeographic location, but not with the identity of congeneric plant hosts. Minimal community overlap was found between resident ECM fungi vs those in spore banks, and spore bank assemblages were relatively simple and dominated by Rhizopogon, Wilcoxina, Cenococcum, Thelephora, Tuber, Laccaria and Suillus. Similar to plant seed banks, ECM fungal spore banks are, in general, depauperate, and represent a small and rare subset of the mature forest soil fungal community. Yet, they may be extremely important in fungal colonization after large-scale disturbances such as clear cuts and forest fires. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  2. Subcutaneous fat accumulation in early infancy is more strongly associated with motor development and delay than muscle growth.

    Science.gov (United States)

    Kanazawa, H; Kawai, M; Niwa, F; Hasegawa, T; Iwanaga, K; Ohata, K; Tamaki, A; Heike, T

    2014-06-01

    Physical growth in neurologically healthy preterm infants affects motor development. This study investigated the separate relationships between muscle and fat in infancy and later motor development and physical growth. Muscle thickness and subcutaneous fat thickness of the anterior thigh were measured using ultrasound images obtained from neurologically healthy preterm infants at birth, 3, 6, 12 and 18 months' corrected age. We also obtained the Pediatric Evaluation of Disability Inventory and Alberta Infant Motor Scale scores at 18 months' corrected age to assess motor ability and motor delay. Thirty preterm infants completed the study protocol. There was a significant positive correlation between motor ability and increments in subcutaneous fat thickness during the first 3 and 6 months' corrected age (r = 0.48 and 0.40, p motor ability and muscle thickness growth in any of the periods. A secondary, logistic regression analysis showed that increments in subcutaneous fat thickness during the first 3 months were a protective factor for motor delay. Subcutaneous fat accumulation in early infancy is more strongly associated with motor development and delay than muscle growth. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  3. Strong Association between Human and Animal Brucella Seropositivity in a Linked Study in Kenya, 2012–2013

    Science.gov (United States)

    Osoro, Eric Mogaka; Munyua, Peninah; Omulo, Sylvia; Ogola, Eric; Ade, Fredrick; Mbatha, Peter; Mbabu, Murithi; Ng'ang'a, Zipporah; Kairu, Salome; Maritim, Marybeth; Thumbi, Samuel M.; Bitek, Austine; Gaichugi, Stella; Rubin, Carol; Njenga, Kariuki; Guerra, Marta

    2015-01-01

    Brucellosis is a common bacterial zoonotic infection but data on the prevalence among humans and animals is limited in Kenya. A cross-sectional survey was conducted in three counties practicing different livestock production systems to simultaneously assess the seroprevalence of, and risk factors for brucellosis among humans and their livestock (cattle, sheep, camels, and goats). A two-stage cluster sampling method with random selection of sublocations and households was conducted. Blood samples were collected from humans and animals and tested for Brucella immunoglobulin G (IgG) antibodies. Human and animal individual seroprevalence was 16% and 8%, respectively. Household and herd seroprevalence ranged from 5% to 73% and 6% to 68%, respectively. There was a 6-fold odds of human seropositivity in households with a seropositive animal compared with those without. Risk factors for human seropositivity included regular ingestion of raw milk (adjusted odds ratio [aOR] = 3.5, 95% confidence interval [CI] = 2.8–4.4), exposure to goats (herding, milking, and feeding) (aOR = 3.1, 95% CI = 2.5–3.8), and handling of animal hides (aOR = 1.8, 95% CI = 1.5–2.2). Attaining at least high school education and above was a protective factor for human seropositivity (aOR = 0.3, 95% CI = 0.3–0.4). This linked study provides evidence of a strong association between human and animal seropositivity at the household level. PMID:26101275

  4. Initial epidemic area is strongly associated with the yearly extent of soybean rust spread in North America.

    Science.gov (United States)

    Mundt, Christopher C; Wallace, Larae D; Allen, Tom W; Hollier, Clayton A; Kemerait, Robert C; Sikora, Edward J

    2013-07-01

    Hosts of soybean rust ( Phakopsora pachyrhizi ) are sensitive to low temperatures, limiting this obligate parasite in the United States to overwintering sites in a restricted area along the Gulf Coast. This temperature sensitivity of soybean rust hosts allowed us to study spatial spread of epidemic invasions over similar territory for seven sequential years, 2005-2011. The epidemic front expanded slowly from early April through July, with the majority of expansion occurring from August through November. There was a 7.4-fold range of final epidemic extent (0.4 to 3.0 million km 2 ) from the year of smallest final disease extent (2011) to that of the largest (2007). The final epidemic area of each year was regressed against epidemic areas recorded at one-week intervals to determine the association of final epidemic extent with current epidemic extent. Coefficients of determination for these regressions varied between 0.44 to 0.62 during April and May. The correlation coefficients varied between 0.70 and 0.96 from early June through October, and then increased monotonically to 1.0 by year's end. Thus, the spatial extent of disease when the epidemics began rapid expansion may have been a crucial contributor to subsequent spread of soybean rust. Our analyses used presence/absence data at the county level to evaluate the spread of the epidemic front only; the subsequent local intensification of disease could be strongly influenced by other factors, including weather.

  5. Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xin-Hua [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Yao, Shen; Qiao, Rui-Fang; Levine, Alice C. [Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Kirschenbaum, Alexander [Department of Urology, Mount Sinai School of Medicine, New York, NY 10029 (United States); Pan, Jiangping; Wu, Yong [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Qin, Weiping [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Bauman, William A. [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Cardozo, Christopher P., E-mail: chris.cardozo@mssm.edu [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States)

    2011-10-14

    Highlights: {yields} Nerve transection increased Notch signaling in paralyzed muscle. {yields} Nandrolone prevented denervation-induced Notch signaling. {yields} Nandrolone induced the expression of an inhibitor of the Notch signaling, Numb. {yields} Reduction of denervation-induced Notch signaling by nandrolone is likely through upregulation of Numb. -- Abstract: Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy.

  6. Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression

    International Nuclear Information System (INIS)

    Liu, Xin-Hua; Yao, Shen; Qiao, Rui-Fang; Levine, Alice C.; Kirschenbaum, Alexander; Pan, Jiangping; Wu, Yong; Qin, Weiping; Bauman, William A.; Cardozo, Christopher P.

    2011-01-01

    Highlights: → Nerve transection increased Notch signaling in paralyzed muscle. → Nandrolone prevented denervation-induced Notch signaling. → Nandrolone induced the expression of an inhibitor of the Notch signaling, Numb. → Reduction of denervation-induced Notch signaling by nandrolone is likely through upregulation of Numb. -- Abstract: Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy.

  7. Extracellular ATP acts as a damage-associated molecular pattern (DAMP) signal in plants

    OpenAIRE

    Tanaka, Kiwamu; Choi, Jeongmin; Cao, Yangrong; Stacey, Gary

    2014-01-01

    As sessile organisms, plants have evolved effective mechanisms to protect themselves from environmental stresses. Damaged (i.e., wounded) plants recognize a variety of endogenous molecules as danger signals, referred to as damage-associated molecular patterns (DAMPs). ATP is among the molecules that are released by cell damage, and recent evidence suggests that ATP can serve as a DAMP. Although little studied in plants, extracellular ATP is well known for its signaling role in animals, includ...

  8. Improved Ventilatory Efficiency with Locomotor Muscle Afferent Inhibition is Strongly Associated with Leg Composition in Heart Failure.

    Science.gov (United States)

    Keller-Ross, Manda L; Johnson, Bruce D; Carter, Rickey E; Joyner, Michael J; Eisenach, John H; Curry, Timothy B; Olson, Thomas P

    2016-01-01

    Skeletal muscle atrophy contributes to increased afferent feedback (group III and IV) and may influence ventilatory control (high VE/VCO2 slope) in heart failure (HF). This study examined the influence of muscle mass on the change in VE/VCO2 with afferent neural block during exercise in HF. 17 participants [9 HF (60±6 yrs) and 8 controls (CTL) (63±7 yrs, mean±SD)] completed 3 sessions. Session 1: dual energy x-ray absorptiometry and graded cycle exercise to volitional fatigue. Sessions 2 and 3: 5 min of constant-work cycle exercise (65% of peak power) randomized to lumbar intrathecal injection of fentanyl (afferent blockade) or placebo. Ventilation (VE) and gas exchange (oxygen consumption, VO2; carbon dioxide production, VCO2) were measured. Peak work and VO2 were lower in HF (pLeg fat was greater in HF (34.4±3.0 and 26.3±1.8%) and leg muscle mass was lower in HF (63.0±2.8 and 70.4±1.8%, respectively, pleg muscle mass (r2=0.58, pleg fat mass (r2=0.73, pleg muscle mass had the greatest improvement in VE/VCO2 with afferent blockade with leg fat mass being the only predictor for the improvement in VE/VCO2 slope. Both leg muscle mass and fat mass are important contributors to ventilatory abnormalities and strongly associated to improvements in VE/VCO2 slope with locomotor afferent inhibition in HF. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions.

    Directory of Open Access Journals (Sweden)

    Joy Ogbechi

    2015-07-01

    Full Text Available A well-known histopathological feature of diseased skin in Buruli ulcer (BU is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM expression on the surface of human dermal microvascular endothelial cells (HDMVEC at doses as low as 2 ng/ml and as early as 8 hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this

  10. Height and sex is strongly associated with radial augmentation index in Korean patients with never-treated hypertension

    Directory of Open Access Journals (Sweden)

    Ahn KT

    2016-04-01

    Full Text Available Kye Taek Ahn, Kwang-In Park, Mi Joo Kim, Jin Kyung Oh, Ji Hye Han, Hee Jin Kwon, Seon-Ah Jin, Jun-Hyung Kim, Jae-Hyeong Park, Jae-Hwan Lee, Si Wan Choi, In-Whan Seong, Jin-Ok Jeong Department of Internal Medicine, Division of Cardiology, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Republic of Korea Objectives: Central hemodynamics may better represent the load imposed on the coronary and cerebral arteries and thereby bear a stronger relationship to cardiovascular outcomes. Methods: Patients who had confirmed hypertension as assessed by daytime 24-hour ambulatory blood pressure monitoring (≥135/85 mmHg were enrolled. Central blood pressure and radial augmentation index (AIx corrected for a heart rate of 75 bpm (radial AIx 75 were measured for all patients. We evaluated the association of age, height, and sex with central hemodynamics in patients with never-treated hypertension. Results: A total of 203 patients were enrolled, of whom men numbered 101 (49.7%. The median height of all patients was 162 cm, and mean age was 53.2 years. In the Pearson correlation analysis, regardless of sex difference (R=-0.627 for height, R=0.035 for age, P-value =0.005, a stronger relationship was observed between height and radial AIx 75 than between age and radial AIx 75. In the multiple regression analysis, the sex difference and height were strongly associated with elevated radial AIx 75 in all patients (adjusted R2=0.428, β=6.237, 95% confidence interval [CI] for women 1.480–10.995, P-value =0.011 and β=-0.632, 95% CI for height -0.929 to -0.335, P-value =0.009, respectively. Conclusion: In patients with never-treated hypertension, female sex and shorter height are the important risk factors of elevated radial AIx 75. Keywords: hypertension, augmentation index, height, sex

  11. In search of causal variants: refining disease association signals using cross-population contrasts

    Directory of Open Access Journals (Sweden)

    Rice John P

    2008-08-01

    Full Text Available Abstract Background Genome-wide association (GWA using large numbers of single nucleotide polymorphisms (SNPs is now a powerful, state-of-the-art approach to mapping human disease genes. When a GWA study detects association between a SNP and the disease, this signal usually represents association with a set of several highly correlated SNPs in strong linkage disequilibrium. The challenge we address is to distinguish among these correlated loci to highlight potential functional variants and prioritize them for follow-up. Results We implemented a systematic method for testing association across diverse population samples having differing histories and LD patterns, using a logistic regression framework. The hypothesis is that important underlying biological mechanisms are shared across human populations, and we can filter correlated variants by testing for heterogeneity of genetic effects in different population samples. This approach formalizes the descriptive comparison of p-values that has typified similar cross-population fine-mapping studies to date. We applied this method to correlated SNPs in the cholinergic nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4, in a case-control study of cocaine dependence composed of 504 European-American and 583 African-American samples. Of the 10 SNPs genotyped in the r2 ≥ 0.8 bin for rs16969968, three demonstrated significant cross-population heterogeneity and are filtered from priority follow-up; the remaining SNPs include rs16969968 (heterogeneity p = 0.75. Though the power to filter out rs16969968 is reduced due to the difference in allele frequency in the two groups, the results nevertheless focus attention on a smaller group of SNPs that includes the non-synonymous SNP rs16969968, which retains a similar effect size (odds ratio across both population samples. Conclusion Filtering out SNPs that demonstrate cross-population heterogeneity enriches for variants more likely to be important and

  12. Larger error signals in major depression are associated with better avoidance learning

    Directory of Open Access Journals (Sweden)

    James F eCavanagh

    2011-11-01

    Full Text Available The medial prefrontal cortex (mPFC is particularly reactive to signals of error, punishment, and conflict in the service of behavioral adaptation and it is consistently implicated in the etiology of Major Depressive Disorder (MDD. This association makes conceptual sense, given that MDD has been associated with hyper-reactivity in neural systems associated with punishment processing. Yet in practice, depression-related variance in measures of mPFC functioning often fails to relate to performance. For example, neuroelectric reflections of mediofrontal error signals are often found to be larger in MDD, but a deficit in post-error performance suggests that these error signals are not being used to rapidly adapt behavior. Thus, it remains unknown if depression-related variance in error signals reflects a meaningful alteration in the use of error or punishment information. However, larger mediofrontal error signals have also been related to another behavioral tendency: increased accuracy in avoidance learning. The integrity of this error-avoidance system remains untested in MDD. In this study, EEG was recorded as 21 symptomatic, drug-free participants with current or past MDD and 24 control participants performed a probabilistic reinforcement learning task. Depressed participants had larger mPFC EEG responses to error feedback than controls. The direct relationship between error signal amplitudes and avoidance learning accuracy was replicated. Crucially, this relationship was stronger in depressed participants for high conflict lose-lose situations, demonstrating a selective alteration of avoidance learning. This investigation provided evidence that larger error signal amplitudes in depression are associated with increased avoidance learning, identifying a candidate mechanistic model for hypersensitivity to negative outcomes in depression.

  13. Active elimination of radio frequency interference for improved signal-to-noise ratio for in-situ NMR experiments in strong magnetic field gradients

    Science.gov (United States)

    Ibrahim, M.; Pardi, C. I.; Brown, T. W. C.; McDonald, P. J.

    2018-02-01

    Improvement in the signal-to-noise ratio of Nuclear Magnetic Resonance (NMR) systems may be achieved either by increasing the signal amplitude or by decreasing the noise. The noise has multiple origins - not all of which are strictly "noise": incoherent thermal noise originating in the probe and pre-amplifiers, probe ring down or acoustic noise and coherent externally broadcast radio frequency transmissions. The last cannot always be shielded in open access experiments. In this paper, we show that pulsed, low radio-frequency data communications are a significant source of broadcast interference. We explore two signal processing methods of de-noising short T2∗ NMR experiments corrupted by these communications: Linear Predictive Coding (LPC) and the Discrete Wavelet Transform (DWT). Results are shown for numerical simulations and experiments conducted under controlled conditions with pseudo radio frequency interference. We show that both the LPC and DWT methods have merit.

  14. Broadband seismic signals associated with the 2000 volcanic unrest of Mount Bandai, northeastern Japan

    Science.gov (United States)

    Nishimura, Takeshi; Ueki, Sadato; Yamawaki, Teruo; Tanaka, Satoru; Hashino, Hironori; Sato, Minemori; Nakamichi, Haruhisa; Hamaguchi, Hiroyuki

    2003-01-01

    We have observed volcano-tectonic (VT) earthquakes, volcanic tremor and very long-period events (VLPEs) associated with the volcanic unrest of Mount Bandai since 2000 using a broadband seismic network closely deployed around the volcano. VT earthquakes are characterized by high-frequency (>10 Hz) signals with clear onsets of P and S phases, whereas volcanic tremor is characterized by a long coda comprising frequencies ranging from a few hertz to more than 10 Hz. In contrast, waveforms of VLPEs consist of very long-period (˜10 s) signals preceded by short-period (deflation at a depth of about 5 km beneath the volcano's north-northwestern flank and to thereby excite the subsequent very long period signals. Our analysis of these broadband seismic signals clarifies the recent activity of magmatic fluid beneath Mount Bandai, a volcano previously quiescent for more than 110 years.

  15. The evolution of sexual signal modes and associated sensor morphology in fireflies (Lampyridae, Coleoptera).

    Science.gov (United States)

    Stanger-Hall, Kathrin F; Sander Lower, Sarah E; Lindberg, Lauri; Hopkins, Andrew; Pallansch, Jenna; Hall, David W

    2018-01-31

    Animals employ different sexual signal modes (e.g. visual, acoustic, chemical) in different environments and behavioural contexts. If sensory structures are costly, then evolutionary shifts in primary signal mode should be associated with changes in sensor morphology. Further, sex differences are expected if male and female signalling behaviours differ. Fireflies are known for their light displays, but many species communicate exclusively with pheromones, including species that recently lost their light signals. We performed phylogenetically controlled analyses of male eye and antenna size in 46 North American taxa, and found that light signals are associated with larger eyes and shorter antennae. In addition, following a transition from nocturnal light displays to diurnal pheromones, eye size reductions occur more rapidly than antenna size increases. In agreement with the North American taxa, across 101 worldwide firefly taxa in 32 genera, we found light displays are associated with larger eye and smaller antenna sizes in both males and females. For those taxa with both male and female data, we found sex differences in eye size and, for diurnal species, in antenna size. © 2018 The Author(s).

  16. Signal Detection Analysis of Factors Associated with Diabetes among Semirural Mexican American Adults

    Science.gov (United States)

    Hanni, K. D.; Ahn, D. A.; Winkleby, M. A.

    2013-01-01

    Signal detection analysis was used to evaluate a combination of sociodemographic, acculturation, mental health, health care, and chronic disease risk factors potentially associated with diabetes in a sample of 4,505 semirural Mexican American adults. Overall, 8.9% of adults had been diagnosed with diabetes. The analysis resulted in 12 mutually…

  17. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Weigelt, Britta; Lo, Alvin T; Park, Catherine C; Gray, Joe W; Bissell, Mina J

    2009-07-27

    Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response. Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three-dimensional (3D) cultures as opposed to traditional two-dimensional (2D) monolayers. Here, we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix (ECM) on HER2 signaling and on the response of HER2-amplified breast cancer cell lines to the HER2-targeting agents Trastuzumab, Pertuzumab and Lapatinib. We show that the response of the HER2-amplified AU565, SKBR3 and HCC1569 cells to these anti-HER2 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin-rich ECM gels. Inhibition of {beta}1 integrin, a major cell-ECM receptor subunit, significantly increased the sensitivity of the HER2-amplified breast cancer cell lines to the humanized monoclonal antibodies Trastuzumab and Pertuzumab when grown in a 3D environment. Finally, in the absence of inhibitors, 3D cultures had substantial impact on HER2 downstream signaling and induced a switch between PI3K-AKT- and RAS-MAPKpathway activation in all cell lines studied, including cells lacking HER2 amplification and overexpression. Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival, events that may play a significant role in the acquisition of resistance to targeted therapies.

  18. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment.

    Science.gov (United States)

    Weigelt, Britta; Lo, Alvin T; Park, Catherine C; Gray, Joe W; Bissell, Mina J

    2010-07-01

    Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response. Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three-dimensional (3D) cultures as opposed to traditional two-dimensional (2D) monolayers. Here, we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix (ECM) on HER2 signaling and on the response of HER2-amplified breast cancer cell lines to the HER2-targeting agents Trastuzumab, Pertuzumab and Lapatinib. We show that the response of the HER2-amplified AU565, SKBR3 and HCC1569 cells to these anti-HER2 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin-rich ECM gels. Inhibition of beta1 integrin, a major cell-ECM receptor subunit, significantly increased the sensitivity of the HER2-amplified breast cancer cell lines to the humanized monoclonal antibodies Trastuzumab and Pertuzumab when grown in a 3D environment. Finally, in the absence of inhibitors, 3D cultures had substantial impact on HER2 downstream signaling and induced a switch between PI3K-AKT- and RAS-MAPK-pathway activation in all cell lines studied, including cells lacking HER2 amplification and overexpression. Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival, events that may play a significant role in the acquisition of resistance to targeted therapies.

  19. Platinum nanoparticles strongly associated with graphitic carbon nitride as efficient co-catalysts for photocatalytic hydrogen evolution under visible light.

    Science.gov (United States)

    Shiraishi, Yasuhiro; Kofuji, Yusuke; Kanazawa, Shunsuke; Sakamoto, Hirokatsu; Ichikawa, Satoshi; Tanaka, Shunsuke; Hirai, Takayuki

    2014-12-14

    Platinum (Pt) nanoparticles with C3N4) by reduction at 673 K behave as efficient co-catalysts for photocatalytic hydrogen evolution under visible light (λ >420 nm). This is achieved by strong Pt-support interaction due to the high temperature treatment, which facilitates efficient transfer of photoformed conduction band electrons on g-C3N4 to Pt particles.

  20. Cellular and Oxidative Mechanisms Associated with Interleukin-6 Signaling in the Vasculature

    Directory of Open Access Journals (Sweden)

    Sean P. Didion

    2017-11-01

    Full Text Available Reactive oxygen species, particularly superoxide, promote endothelial dysfunction and alterations in vascular structure. It is increasingly recognized that inflammatory cytokines, such as interleukin-6 (IL-6, contribute to endothelial dysfunction and vascular hypertrophy and fibrosis. IL-6 is increased in a number of cardiovascular diseases, including hypertension. IL-6 is also associated with a higher incidence of future cardiovascular events and all-cause mortality. Both immune and vascular cells produce IL-6 in response to a number of stimuli, such as angiotensin II. The vasculature is responsive to IL-6 produced from vascular and non-vascular sources via classical IL-6 signaling involving a membrane-bound IL-6 receptor (IL-6R and membrane-bound gp130 via Jak/STAT as well as SHP2-dependent signaling pathways. IL-6 signaling is unique because it can also occur via a soluble IL-6 receptor (sIL-6R which allows for IL-6 signaling in tissues that do not normally express IL-6R through a process referred to as IL-6 trans-signaling. IL-6 signaling mediates a vast array of effects in the vascular wall, including endothelial activation, vascular permeability, immune cell recruitment, endothelial dysfunction, as well as vascular hypertrophy and fibrosis. Many of the effects of IL-6 on vascular function and structure are representative of loss or reductions in nitric oxide (NO bioavailability. IL-6 has direct effects on endothelial nitric oxide synthase activity and expression as well as increasing vascular superoxide, which rapidly inactivates NO thereby limiting NO bioavailability. The goal of this review is to highlight both the cellular and oxidative mechanisms associated with IL-6-signaling in the vascular wall in general, in hypertension, and in response to angiotensin II.

  1. Bone signal abnormality, as seen on knee joint MRI : relationship between its location and associated injury

    International Nuclear Information System (INIS)

    Kim, Young Nam; Kim, Baek Hyun; Jung, Hoe Seok; Na, Eui Sung; Seol, Hye Young; Cha, In Ho; Lim, Hong Chul

    1998-01-01

    The purpose of the study was to evaluate the relationship between the location of bone signal abnormality and associated injury, as seen on MR, in patients with acute knee joint injury. Materials and Methods: Thirty-six patients with acute knee injury and bone signal abnormalities on MR were included in this study. The femur and tibia were each divided into six compartments, namely the anteromedial, medial, posteromedial,anterolateral, lateral, and posterolateral ; these were obtained in each knee joint. We evaluated the location of bone signal abnormality and the corresponding arthroscopic or operative findings of injury to ligaments and menisci. Cases with signal abnormalities involving more than three compartments were excluded. Results : Bone signal abnormalities were demonstrated in 51 compartments. Most(84%, 43/51) were noted in the lateral half of the knee joint, the most common location being the tibio- posterolateral compartment(13/51). The femoro-lateral(11/51) and tibio- anterolateral compartment(8/51) were the next most common locations. All cases(13/13)with bone signal abnormality in the tibio- posterolateral compartment had tears at the anterior cruciate ligament,while 9 of 11 cases(81%) with abnormality in the femoro- lateral compartment had tears at the anterior cruciate ligament. Six of eight cases(75%) with signal abnormality in the tibio- anterolateral compartment had tears at the posterior cruciate ligament ; 31 of 43 cases (72%) with abnormality in the lateral half of the knee joint had tears at the medial collateral ligament. Six of eight cases(75%) with signal abnormality in the medial half of the knee joint had tears at the medial meniscus, but no lateral meniscal tear was found. Among patients with signal abnormality in the lateral half of the knee joint, the tear was lateral meniscal in nine of 43 cases(21%) and medial meniscal in six of 43(14%). Conclusion : The location of bone signal abnormality, as seen on knee MR, inpatients with

  2. Genetic association of marbling score with intragenic nucleotide variants at selection signals of the bovine genome.

    Science.gov (United States)

    Ryu, J; Lee, C

    2016-04-01

    Selection signals of Korean cattle might be attributed largely to artificial selection for meat quality. Rapidly increased intragenic markers of newly annotated genes in the bovine genome would help overcome limited findings of genetic markers associated with meat quality at the selection signals in a previous study. The present study examined genetic associations of marbling score (MS) with intragenic nucleotide variants at selection signals of Korean cattle. A total of 39 092 nucleotide variants of 407 Korean cattle were utilized in the association analysis. A total of 129 variants were selected within newly annotated genes in the bovine genome. Their genetic associations were analyzed using the mixed model with random polygenic effects based on identical-by-state genetic relationships among animals in order to control for spurious associations produced by population structure. Genetic associations of MS were found (P<3.88×10-4) with six intragenic nucleotide variants on bovine autosomes 3 (cache domain containing 1, CACHD1), 5 (like-glycosyltransferase, LARGE), 16 (cell division cycle 42 binding protein kinase alpha, CDC42BPA) and 21 (snurportin 1, SNUPN; protein tyrosine phosphatase, non-receptor type 9, PTPN9; chondroitin sulfate proteoglycan 4, CSPG4). In particular, the genetic associations with CDC42BPA and LARGE were confirmed using an independent data set of Korean cattle. The results implied that allele frequencies of functional variants and their proximity variants have been augmented by directional selection for greater MS and remain selection signals in the bovine genome. Further studies of fine mapping would be useful to incorporate favorable alleles in marker-assisted selection for MS of Korean cattle.

  3. Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal.

    Science.gov (United States)

    Delgado, Dayana A; Zhang, Chenan; Chen, Lin S; Gao, Jianjun; Roy, Shantanu; Shinkle, Justin; Sabarinathan, Mekala; Argos, Maria; Tong, Lin; Ahmed, Alauddin; Islam, Tariqul; Rakibuz-Zaman, Muhammad; Sarwar, Golam; Shahriar, Hasan; Rahman, Mahfuzar; Yunus, Mohammad; Jasmine, Farzana; Kibriya, Muhammad G; Ahsan, Habibul; Pierce, Brandon L

    2018-01-01

    Leucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry. This study aims to enhance our understanding of genetic determinants of TL across populations. We performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes. Our results replicate previously reported associations in the TERC and TERT regions (P=2.2×10 -8 and P=6.4×10 -6 , respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82×10 -7 ) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (≥0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 ( ZNF208 ) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only. In this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  4. Serum aspirin esterase is strongly associated with glucose and lipids in healthy subjects: different association patterns in subjects with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Kotani Kazuhiko

    2010-07-01

    Full Text Available Abstract Background Aspirin esterase (AE activity can account for part of aspirin pharmacokinetics in the circulation, possibly being associated with the impairment of aspirin effectiveness as an inhibitor of platelet aggregation. Aims The study was aimed at investigating the correlations of serum AE activity with cholinesterase (ChE and metabolic variables in healthy subjects in comparison to subjects with type 2 diabetes mellitus (T2DM. Methods In cardiovascular disease-free T2DM subjects and healthy controls, the AE activity levels and/or the correlation patterns between AE and the other variables were analyzed. Results Neither AE nor ChE activities were higher in the subjects with T2DM. Serum AE activity strongly correlated with ChE as well as glucose/lipids variables such as total cholesterol and triglyceride in healthy subjects, while the correlations between AE and glucose/lipids variables were not present in T2DM subjects. Conclusions These data may reflect the pathophysiological changes between healthy and T2DM subjects. Our data may thus provide the basis for future studies to unravel the mechanisms.

  5. Role of alterations in Ca{sup 2+}-associated signaling pathways in the immunotoxicity of polycyclic aromatic hydrocarbons

    Energy Technology Data Exchange (ETDEWEB)

    Davila, D.R.; Davs, D.P.; Campbell, K. [Univ. of New Mexico College of Pharmacy, Albuquerque, NM (United States)] [and others

    1995-08-01

    Polycyclic aromatic hydrocarbons (PAHs) are an important class of environmental pollutants that are known to be carcinogenic and immunotoxic. The effects of PAHs on the immune system of various animals and models have been studied for at least 30 yr. Despite these efforts, the mechanism or mechanisms by which PAHs exert their effects on the immune system are still largely unknown. During recent years, the molecular events associated with lymphocyte activation and receptor-mediated signaling have become increasingly clear. Substantial progress has been made in understanding the molecular and cellular bases for toxicant-induced immune cell injury. Understanding mechanisms of drug or chemical effects on the immune system is an important area of research in the field of immunotoxicology, and indeed in all fields of toxicology. Mechanistic toxicology plays an important role in risk assessment and extrapolation of potential human health effects. In this review, we have summarized recent evidence that has examined the effects of PAHs on the immune system of animals and humans. In particular, we have focused on the effects of PAHs on cell signaling in lymphoid cells and have examined the hypothesis that PAHs alter lymphocyte activation via calcium-dependent mechanisms. Previously published reports are discussed, and new data obtained with murine B cells and cell lines are presented demonstrating the relationship between alterations in intracellular calcium and immune dysregulation. These data demonstrate a strong association between PAH-induced alterations in B- and T-lymphocyte activation and changes in calcium homeostasis. 111 refs., 6 figs., 1 tab.

  6. Investigations of the signal production in liquid-ionization-chambers by the passage of strongly ionizing particles and a now theoretical description of recombination

    International Nuclear Information System (INIS)

    Supper, R.

    1991-12-01

    Starting from the original Onsager-theory an extended theory is presented describing the recombination of charge carriers and of signal production in TMS (tetramethylsilane) liquid ionization chambers. The shielding by the impurities of the liquid is explicitly taken into account. By dedicated measurements various parameter dependencies of the theory are checked and the parameter values are experimentally determined. The studies comprise test procedures of the TMS chamber operation and are in context of a hadron calorimeter set up of the cosmic ray experiment KASCADE. (orig.) [de

  7. Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms.

    Science.gov (United States)

    Chen, Yan; Guo, Jeff J; Healy, Daniel P; Lin, Xiaodong; Patel, Nick C

    2008-12-01

    With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin. To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs). Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin. A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS. A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.

  8. Coherent response of a two-level atom to a signal field with account of suppression of phase relaxation by a strong field

    International Nuclear Information System (INIS)

    Grishanin, B.A.; Shatalova, G.G.

    1984-01-01

    Calculation is made of a coherent part of response to a weak test field of an atom located in a strong resonance field. The latter bads to a suppression of phase relaxation. This response is shown to appear both at a test field freq uency ω and at a combination frequency 2ωsub(l)-ω, where ωsub(l) is a resona nce field frequency. The spectrum of test field absorption by such a system has a symmetric form and consist of two parts, one of which corresponds to a test f ield absorption and another - to its amplification

  9. How we eat what we eat: identifying meal routines and practices most strongly associated with healthy and unhealthy dietary factors among young adults.

    Science.gov (United States)

    Laska, Melissa N; Hearst, Mary O; Lust, Katherine; Lytle, Leslie A; Story, Mary

    2015-08-01

    (i) To examine associations between young adults' meal routines and practices (e.g. food preparation, meal skipping, eating on the run) and key dietary indicators (fruit/vegetable, fast-food and sugar-sweetened beverage intakes) and (ii) to develop indices of protective and risky meal practices most strongly associated with diet. Cross-sectional survey. Minneapolis/St. Paul metropolitan area, Minnesota (USA). A diverse sample of community college and public university students (n 1013). Meal routines and practices most strongly associated with healthy dietary patterns were related to home food preparation (i.e. preparing meals at home, preparing meals with vegetables) and meal regularity (i.e. routine consumption of evening meals and breakfast). In contrast, factors most strongly associated with poor dietary patterns included eating on the run, using media while eating and purchasing foods/beverages on campus. A Protective Factors Index, summing selected protective meal routines and practices, was positively associated with fruit/vegetable consumption and negatively associated with fast-food and sugar-sweetened beverage consumption (PMeal routines and practices were significantly associated with young adults' dietary patterns, suggesting that ways in which individuals structure mealtimes and contextual characteristics of eating likely influence food choice. Thus, in addition to considering specific food choices, it also may be important to consider the context of mealtimes in developing dietary messaging and guidelines.

  10. Membrane-associated transcription factor peptidase, site-2 protease, antagonizes ABA signaling in Arabidopsis.

    Science.gov (United States)

    Zhou, Shun-Fan; Sun, Le; Valdés, Ana Elisa; Engström, Peter; Song, Ze-Ting; Lu, Sun-Jie; Liu, Jian-Xiang

    2015-10-01

    Abscisic acid plays important roles in maintaining seed dormancy while gibberellins (GA) and other phytohormones antagonize ABA to promote germination. However, how ABA signaling is desensitized during the transition from dormancy to germination is still poorly understood. We functionally characterized the role of membrane-associated transcription factor peptidase, site-2 protease (S2P), in ABA signaling during seed germination in Arabidopsis. Genetic analysis showed that loss-of-function of S2P conferred high ABA sensitivity during seed germination, and expression of the activated form of membrane-associated transcription factor bZIP17, in which the transmembrane domain and endoplasmic reticulum (ER) lumen-facing C-terminus were deleted, in the S2P mutant rescued its ABA-sensitive phenotype. MYC and green fluorescent protein (GFP)-tagged bZIP17 were processed and translocated from the ER to the nucleus in response to ABA treatment. Furthermore, genes encoding negative regulators of ABA signaling, such as the transcription factor ATHB7 and its target genes HAB1, HAB2, HAI1 and AHG3, were up-regulated in seeds of the wild-type upon ABA treatment; this up-regulation was impaired in seeds of S2P mutants. Our results suggest that S2P desensitizes ABA signaling during seed germination through regulating the activation of the membrane-associated transcription factor bZIP17 and therefore controlling the expression level of genes encoding negative regulators of ABA signaling. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  11. Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Yuan Tian

    2016-08-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC. The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.

  12. Development of high-brightness ultrafast electron microscope for studying nanoscale dynamics associated with strongly correlated materials

    Science.gov (United States)

    Tao, Zhensheng

    Strongly correlated-electron materials are a class of materials that exhibit numerous intriguing emergent phenomena, including metal-to-insulator transition, colossal magnetoresistance, high-temperature superconductivity, etc. These phenomena are beyond the reach of the conventional solid state physics, which is based on the band theory. Instead, strong electron-electron correlations are found to play important roles, which leads to complicated interplay between different degrees of freedoms (charge, lattice, spins...). In this thesis, ultrafast electron diffraction (UED) is used to investigate the photo-induced ultrafast structural dynamics of strongly correlated materials, among which VO2 is taken as an exemplar system, one that reveals the fundamental physics behind photo-induced phase transitions, electron-electron correlation on nanometer scales, and the electron-phonon coupling in this exotic class of materials. The phenomena presented here are expected to have more general significance as they may reflect the physics to which other strongly correlated materials also conform. In polycrystalline VO2 thin films, the structural changes resulting from photoexcitation with femtosecond laser pulses with different wavelengths are observed to lead to non-thermal phase transitions, which require less energy compared to the phase transitions induced by thermal excitation. The details of the structural change are extracted from the UED results revealing stepwise atomic movements after photoexcitation, which suggests the phase transition starts with a dilation of the correlated d electrons. On the other hand, the structural phase transition is found to be decoupled from the metal-to-insulator transition when the sample dimension is reduced to the sub-micrometer scale, which is attributed to the interface charge doping effects from different substrates. A new phase (M3, monoclinic metallic phase) is distinguished, which has not been discussed by the existing theoretical

  13. Genome-wide association study provides strong evidence of genes affecting the reproductive performance of Nellore beef cows.

    Science.gov (United States)

    Melo, Thaise Pinto de; de Camargo, Gregório Miguel Ferreira; de Albuquerque, Lucia Galvão; Carvalheiro, Roberto

    2017-01-01

    Reproductive traits are economically important for beef cattle production; however, these traits are still a bottleneck in indicine cattle since these animals typically reach puberty at older ages when compared to taurine breeds. In addition, reproductive traits are complex phenotypes, i.e., they are controlled by both the environment and many small-effect genes involved in different pathways. In this study, we conducted genome-wide association study (GWAS) and functional analyses to identify important genes and pathways associated with heifer rebreeding (HR) and with the number of calvings at 53 months of age (NC53) in Nellore cows. A total of 142,878 and 244,311 phenotypes for HR and NC53, respectively, and 2,925 animals genotyped with the Illumina Bovine HD panel (Illumina®, San Diego, CA, USA) were used in GWAS applying the weighted single-step GBLUP (WssGBLUP) method. Several genes associated with reproductive events were detected in the 20 most important 1Mb windows for both traits. Significant pathways for HR and NC53 were associated with lipid metabolism and immune processes, respectively. MHC class II genes, detected on chromosome 23 (window 25-26Mb) for NC53, were significantly associated with pregnancy success of Nellore cows. These genes have been proved previously to be associated with reproductive traits such as mate choice in other breeds and species. Our results suggest that genes associated with the reproductive traits HR and NC53 may be involved in embryo development in mammalian species. Furthermore, some genes associated with mate choice may affect pregnancy success in Nellore cattle.

  14. Absence of Granzyme B Positive Tumour-Infiltrating Lymphocytes in Primary Melanoma Excisional Biopsies is Strongly Associated with the Presence of Sentinel Lymph Node Metastasis

    Directory of Open Access Journals (Sweden)

    I. S. van Houdt

    2009-01-01

    Full Text Available Background: Sentinel Lymph Node (SLN status is strongly related to clinical outcome in melanoma patients. In this study we investigated the possible association between the presence of activated and/or suppressive Tumour Infiltrating Lymphocytes (TILs and SLN status in clinically stage I/II melanoma patients.

  15. Self-organization of associative memory and pattern classification: recurrent signal processing on topological feature maps.

    Science.gov (United States)

    Tavan, P; Grubmüller, H; Kühnel, H

    1990-01-01

    We extend the neural concepts of topological feature maps towards self-organization of auto-associative memory and hierarchical pattern classification. As is well-known, topological maps for statistical data sets store information on the associated probability densities. To extract that information we introduce a recurrent dynamics of signal processing. We show that the dynamics converts a topological map into an auto-associative memory for real-valued feature vectors which is capable to perform a cluster analysis. The neural network scheme thus developed represents a generalization of non-linear matrix-type associative memories. The results naturally lead to the concept of a feature atlas and an associated scheme of self-organized, hierarchical pattern classification.

  16. Property Values Associated with the Failure of Individual Links in a System with Multiple Weak and Strong Links.

    Energy Technology Data Exchange (ETDEWEB)

    Helton, Jon C. [Arizona State Univ., Tempe, AZ (United States); Brooks, Dusty Marie [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Sallaberry, Cedric Jean-Marie. [Engineering Mechanics Corp. of Columbus, OH (United States)

    2018-02-01

    Representations are developed and illustrated for the distribution of link property values at the time of link failure in the presence of aleatory uncertainty in link properties. The following topics are considered: (i) defining properties for weak links and strong links, (ii) cumulative distribution functions (CDFs) for link failure time, (iii) integral-based derivation of CDFs for link property at time of link failure, (iv) sampling-based approximation of CDFs for link property at time of link failure, (v) verification of integral-based and sampling-based determinations of CDFs for link property at time of link failure, (vi) distributions of link properties conditional on time of link failure, and (vii) equivalence of two different integral-based derivations of CDFs for link property at time of link failure.

  17. Lean Mass Appears to Be More Strongly Associated with Bone Health than Fat Mass in Urban Black South African Women.

    Science.gov (United States)

    Sotunde, O F; Kruger, H S; Wright, H H; Havemann-Nel, L; Kruger, I M; Wentzel-Viljoen, E; Kruger, A; Tieland, M

    2015-06-01

    To examine the association between body composition (fat mass, lean mass and body mass index, BMI) and bone health (bone mineral density, BMD and fracture risk) in urban black South African women. A cross sectional study examining associations between body composition, dietary intake (food frequency questionnaire), habitual physical activity (Activity energy expenditure (AEE) measured using an accelerometer with combined heart rate monitor and physical activity questionnaire) and bone health (BMD using dual-energy X ray absorptiometry, DXA and fracture risk). Urban community dwellers from Ikageng in the North-West Province of South Africa. One hundred and eighty nine (189) healthy postmenopausal women aged ≥43 years. Fat mass and lean mass were significantly associated with BMD and fracture risk when adjusted for potential confounders. However, lean mass and not fat mass remained significantly associated with femoral neck BMD (β = 0.49, p South African women. Our finding suggests that increasing lean mass rather than fat mass is beneficial to bone health. Our study emphasises the importance of positive lifestyle changes, intake of calcium from dairy and adequate weight to maintain and improve bone health of postmenopausal women.

  18. Mechanism of ROS scavenging and antioxidant signalling by redox metallic and fullerene nanomaterials: Potential implications in ROS associated degenerative disorders.

    Science.gov (United States)

    Akhtar, Mohd Javed; Ahamed, Maqusood; Alhadlaq, Hisham A; Alshamsan, Aws

    2017-04-01

    The balance between oxidation and anti-oxidation is believed to be critical in maintaining healthy biological systems. However, our endogenous antioxidant defense systems are incomplete without exogenous antioxidants and, therefore, there is a continuous demand for exogenous antioxidants to prevent stress and ageing associated disorders. Nanotechnology has yielded enormous variety of nanomaterials (NMs) of which metallic and carbonic (mainly fullerenes) NMs, with redox property, have been found to be strong scavengers of ROS and antioxidants in preclinical in vitro and in vivo models. Redox activity of metal based NMs and membrane translocation time of fullerene NMs seem to be the major determinants in ROS scavenging potential exhibited by these NMs. A comprehensive knowledge about the effects of ROS scavenging NMs in cellular antioxidant signalling is largely lacking. This review compiles the mechanisms of ROS scavenging as well as antioxidant signalling of the aforementioned metallic and fullerene NMs. Direct interaction between NMs and proteins does greatly affect the corona/adsorption formation dynamics but such interaction does not provide the explanation behind diverse biological outcomes induced by NMs. Indirect interaction, however, that could occur via NMs uptake and dissolution, NMs ROS induction and ROS scavenging property, and NMs membrane translocation time seem to work as a central mode of interaction. The usage of potential antioxidant NMs in biological systems would greatly impact the field of nanomedicine. ROS scavenging NMs hold great promise in the future treatment of ROS related degenerative disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Comparison of simultaneous variations of the ionospheric total electron content and geomagnetic field associated with strong earthquakes

    Directory of Open Access Journals (Sweden)

    Sh. Naaman

    2001-01-01

    Full Text Available In this paper, perturbations of the ionospheric Total Electron Content (TEC are compared with geomagnetic oscillations. Comparison is made for a few selected periods, some during earthquakes in California and Japan and others at quiet periods in Israel and California. Anomalies in TEC were extracted using Global Positioning System (GPS observations collected by GIL (GPS in Israel and the California permanent GPS networks. Geomagnetic data were collected in some regions where geomagnetic observatories and the GPS network overlaps. Sensitivity of the GPS method and basic wave characteristics of the ionospheric TEC perturbations are discussed. We study temporal variations of ionospheric TEC structures with highest reasonable spatial resolution around 50 km. Our results show no detectable TEC disturbances caused by right-lateral strike-slip earthquakes with minor vertical displacement. However, geomagnetic observations obtained at two observatories located in the epicenter zone of a strong dip-slip earthquake (Kyuchu, M = 6.2, 26 March 1997 revealed geomagnetic disturbances occurred 6–7 h before the earthquake.

  20. Didecyldimethylammonium chloride induces pulmonary fibrosis in association with TGF-β signaling in mice.

    Science.gov (United States)

    Ohnuma-Koyama, Aya; Yoshida, Toshinori; Tajima-Horiuchi, Haruka; Takahashi, Naofumi; Yamaguchi, Satoru; Ohtsuka, Ryoichi; Takeuchi-Kashimoto, Yukiko; Kuwahara, Maki; Takeda, Makio; Nakashima, Nobuaki; Harada, Takanori

    2013-11-01

    Didecyldimethylammonium chloride (DDAC) is a representative dialkyl-quaternary ammonium compound that is used as a disinfectant against several pathogens and is also used in commercial, industrial, and residential settings. We previously investigated toxicity on air way system following single instillation of DDAC to the lungs in mice, and found that DDAC causes pulmonary injury, which is associated with altered antioxidant antimicrobial responses; the inflammatory phase is accompanied or followed by fibrotic response. The present study was conducted to monitor transforming growth factor-β (TGF-β) signaling in pulmonary fibrosis induced by DDAC. Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment to measure TGF-β signaling. In order to further evaluate TGF-β signaling, we treated isolated mouse lung fibroblasts with DDAC. Fibrotic foci were observed in the lungs on day 3, and were widely extended on day 7, with evidence of increased α-smooth muscle actin-positive mesenchymal cells and upregulation of Type I procollagen mRNA. Developing fibrotic foci were likely associated with increased expression of Tgf-β1 mRNA, in addition to decreased expression of Bone morphogenetic protein-7 mRNA. In fibrotic lung samples, the expression of phosphorylated SMAD2/3 was considerably higher than that of phosphorylated SMAD1/5. In isolated lung fibroblasts, the mRNA levels of Tgf-β1 were specifically increased by DDAC treatment, which prolonged phosphorylation of SMAD2/3. These effects were abolished by treatment with SD208 - a TGF-βRI kinase inhibitor. The results suggest that DDAC induces pulmonary fibrosis in association with TGF-β signaling. Copyright © 2013 Elsevier GmbH. All rights reserved.

  1. Extracellular ATP acts as a damage-associated molecular pattern (DAMP) signal in plants.

    Science.gov (United States)

    Tanaka, Kiwamu; Choi, Jeongmin; Cao, Yangrong; Stacey, Gary

    2014-01-01

    As sessile organisms, plants have evolved effective mechanisms to protect themselves from environmental stresses. Damaged (i.e., wounded) plants recognize a variety of endogenous molecules as danger signals, referred to as damage-associated molecular patterns (DAMPs). ATP is among the molecules that are released by cell damage, and recent evidence suggests that ATP can serve as a DAMP. Although little studied in plants, extracellular ATP is well known for its signaling roles in animals, including acting as a DAMP during the inflammatory response and wound healing. If ATP acts outside the cell, then it is reasonable to expect that it is recognized by a plasma membrane-localized receptor. Recently, DORN1, a lectin receptor kinase, was shown to recognize extracellular ATP in Arabidopsis. DORN1 is the founding member of a new purinoceptor subfamily, P2K (P2 receptor kinase), which is plant-specific. P2K1 (DORN1) is required for ATP-induced cellular responses (e.g., cytosolic Ca(2+) elevation, MAPK phosphorylation, and gene expression). Genetic analysis of loss-of-function mutants and overexpression lines showed that P2K1 participates in the plant wound response, consistent with the role of ATP as a DAMP. In this review, we summarize past research on the roles and mechanisms of extracellular ATP signaling in plants, and discuss the direction of future research on extracellular ATP as a DAMP signal.

  2. Orexin-1 receptor signaling increases motivation for cocaine-associated cues

    Science.gov (United States)

    Bentzley, Brandon S.; Aston-Jones, Gary

    2015-01-01

    The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1R), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light+tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then asked if cocaine demand is linked to cued-reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high demand animals, i.e., animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not for cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses. PMID:25754681

  3. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

    Science.gov (United States)

    Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel; Naitza, Silvia; Dehghan, Abbas; Johnson, Andrew D; Teumer, Alexander; Reiner, Alex P; Folkersen, Lasse; Basu, Saonli; Rudnicka, Alicja R; Trompet, Stella; Mälarstig, Anders; Baumert, Jens; Bis, Joshua C; Guo, Xiuqing; Hottenga, Jouke J; Shin, So-Youn; Lopez, Lorna M; Lahti, Jari; Tanaka, Toshiko; Yanek, Lisa R; Oudot-Mellakh, Tiphaine; Wilson, James F; Navarro, Pau; Huffman, Jennifer E; Zemunik, Tatijana; Redline, Susan; Mehra, Reena; Pulanic, Drazen; Rudan, Igor; Wright, Alan F; Kolcic, Ivana; Polasek, Ozren; Wild, Sarah H; Campbell, Harry; Curb, J David; Wallace, Robert; Liu, Simin; Eaton, Charles B; Becker, Diane M; Becker, Lewis C; Bandinelli, Stefania; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Fornage, Myriam; Green, David; Gross, Myron; Davies, Gail; Harris, Sarah E; Liewald, David C; Starr, John M; Williams, Frances M K; Grant, Peter J; Spector, Timothy D; Strawbridge, Rona J; Silveira, Angela; Sennblad, Bengt; Rivadeneira, Fernando; Uitterlinden, Andre G; Franco, Oscar H; Hofman, Albert; van Dongen, Jenny; Willemsen, Gonneke; Boomsma, Dorret I; Yao, Jie; Swords Jenny, Nancy; Haritunians, Talin; McKnight, Barbara; Lumley, Thomas; Taylor, Kent D; Rotter, Jerome I; Psaty, Bruce M; Peters, Annette; Gieger, Christian; Illig, Thomas; Grotevendt, Anne; Homuth, Georg; Völzke, Henry; Kocher, Thomas; Goel, Anuj; Franzosi, Maria Grazia; Seedorf, Udo; Clarke, Robert; Steri, Maristella; Tarasov, Kirill V; Sanna, Serena; Schlessinger, David; Stott, David J; Sattar, Naveed; Buckley, Brendan M; Rumley, Ann; Lowe, Gordon D; McArdle, Wendy L; Chen, Ming-Huei; Tofler, Geoffrey H; Song, Jaejoon; Boerwinkle, Eric; Folsom, Aaron R; Rose, Lynda M; Franco-Cereceda, Anders; Teichert, Martina; Ikram, M Arfan; Mosley, Thomas H; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M; Sudlow, Cathie L M; Hopewell, Jemma C; Chambers, John C; Saleheen, Danish; Kooner, Jaspal S; Danesh, John; Nelson, Christopher P; Erdmann, Jeanette; Reilly, Muredach P; Kathiresan, Sekar; Schunkert, Heribert; Morange, Pierre-Emmanuel; Ferrucci, Luigi; Eriksson, Johan G; Jacobs, David; Deary, Ian J; Soranzo, Nicole; Witteman, Jacqueline C M; de Geus, Eco J C; Tracy, Russell P; Hayward, Caroline; Koenig, Wolfgang; Cucca, Francesco; Jukema, J Wouter; Eriksson, Per; Seshadri, Sudha; Markus, Hugh S; Watkins, Hugh; Samani, Nilesh J; Wallaschofski, Henri; Smith, Nicholas L; Tregouet, David; Ridker, Paul M; Tang, Weihong; Strachan, David P; Hamsten, Anders; O'Donnell, Christopher J

    2013-09-17

    Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

  4. Latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus promotes angiogenesis through targeting notch signaling effector Hey1.

    Science.gov (United States)

    Wang, Xing; He, Zhiheng; Xia, Tian; Li, Xiaofan; Liang, Deguang; Lin, Xianzhi; Wen, Hao; Lan, Ke

    2014-04-01

    Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma-associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and γ-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma. ©2014 AACR.

  5. Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies

    OpenAIRE

    Yokoyama, Jennifer S.; Lam, Ernest T.; Ruhe, Alison L.; Erdman, Carolyn A.; Robertson, Kathryn R.; Webb, Aubrey A.; Williams, D. Colette; Chang, Melanie L.; Hytönen, Marjo K.; Lohi, Hannes; Hamilton, Steven P.; Neff, Mark W.

    2012-01-01

    Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in huma...

  6. Production of the effector cytokine interleukin-17, rather than interferon-γ, is more strongly associated with autoimmune hemolytic anemia

    Science.gov (United States)

    Hall, Andrew M.; Zamzami, Omar M.; Whibley, Natasha; Hampsey, Daniel P.; Haggart, Anne M.; Vickers, Mark A.; Barker, Robert N.

    2012-01-01

    Background Interleukin-17A is the signature cytokine of the Th17 subset and drives inflammatory pathology, but its relevance to autoantibody-mediated diseases is unclear. Th1 cells secreting interferon-γ have been implicated in autoimmune hemolytic anemia, so the aim was to determine which cytokine is more closely associated with disease severity. Design and Methods Interferon-γ and interleukin-17A were measured in the sera of patients with autoimmune hemolytic anemia and healthy donors, and in peripheral blood mononuclear cell cultures stimulated with autologous red blood cells, or a panel of peptides spanning red blood cell autoantigen. Results Serum interleukin-17A, but not interferon-γ, was significantly raised in patients with autoimmune hemolytic anemia (P anemia. Interleukin-17A was also more prominent in the responses of peripheral blood mononuclear cells from patients with autoimmune hemolytic anemia to red blood cells, and, again unlike interferon-γ, significantly associated with more severe anemia (P hemolytic anemia, challenging the model that the disease is driven primarily by Th1 cells. This raises the possibility that Th17, rather than Th1, cells should be the target for therapy. PMID:22419580

  7. Strong Association between Plasma Dipeptidyl Peptidase-4 Activity and Impaired Cognitive Function in Elderly Population with Normal Glucose Tolerance.

    Science.gov (United States)

    Chen, Bo; Zheng, Tianpeng; Qin, Linyuan; Hu, Xueping; Zhang, Xiaoxi; Liu, Yihong; Liu, Hongbo; Qin, Shenghua; Li, Gang; Li, Qinghua

    2017-01-01

    Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1) are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT). Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older) in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer's Association workgroups criteria. Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP), interleukin-6 (IL-6), 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA) scores compared with those in the lowest quartile ( P population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic target for the prevention and treatment of impaired cognitive function.

  8. Strong associations between national prevalence of various STIs suggests sexual network connectivity is a common underpinning risk factor.

    Science.gov (United States)

    Kenyon, Chris

    2017-10-12

    If national peak Human Immunodeficiency Virus (HIV) prevalence is positively associated with the prevalence of other sexually transmitted infections (STIs) from before or early on in the HIV epidemics this would suggest common underlying drivers. Pearson's correlations were calculated between the prevalence of seven STIs at a country-level: chlamydia, gonorrhoea, trichomoniasis, syphilis, bacterial vaginosis, herpes simplex virus-2 (HSV-2) and HIV. The prevalence of all the STIs was highest in the sub-Saharan African region excluding chlamydia. The prevalence of all seven STIs were positively correlated excluding chlamydia. The correlations were strongest for HIV-HSV-2 (r = 0.85, P < 0.0001) and HSV-2-trichomoniasis (r = 0.82, P < 0.0001). Our results of a generally positive association between the prevalences of a range of STIs suggests that higher prevalences were driven by common underlying determinants. We review different types of evidence which suggest that differential sexual connectivity is a plausible common determinant.

  9. Obesity is more strongly associated with inappropriate eating behaviors than with mental health in older adults receiving congregate meals.

    Science.gov (United States)

    Porter, Kathryn N; Johnson, Mary Ann

    2011-01-01

    This study explored the relationships of inappropriate eating behaviors and mental health with obesity in congregate meal participants in Georgia (N = 120, mean age = 75 years, 75% female, 43% African American). Inappropriate eating behaviors were evaluated with the Three-Factor Eating Questionnaire (18 questions); mental health was assessed with the Depression Anxiety Stress Scale (21 questions); history of depression was assessed with the Behavioral Risk Factor Surveillance Survey; and height and weight were measured to calculate body mass index (BMI) and obesity (52% ≥ 30 kg/m(2)). In bivariate analyses, obesity was associated with cognitive restraint (rho = 0.49, p eating (rho = 0.22; p emotional eating (rho = 0.32, p eating behavior and mental health indices, only cognitive restraint and emotional eating were consistently associated with obesity (p eating behaviors, particularly cognitive restraint and emotional eating, may be important targets for future research and intervention. Additional research is needed to better understand how cognitive restraint and emotional eating contribute to obesity in this population so that interdisciplinary research and health care teams can appropriately prevent and manage obesity in congregate meal participants.

  10. Role of Cbl-associated protein/ponsin in receptor tyrosine kinase signaling and cell adhesion

    Directory of Open Access Journals (Sweden)

    Ritva Tikkanen

    2012-10-01

    Full Text Available The Cbl-associated protein/ponsin (CAP is an adaptor protein that contains a so-called Sorbin homology (SoHo domain and three Src homology 3 (SH3 domains which are engaged in diverse protein-protein interactions. CAP has been shown to function in the regulation of the actin cytoskeleton and cell adhesion and to be involved in the differentiation of muscle cells and adipocytes. In addition, it participates in signaling pathways through several receptor tyrosine kinases such as insulin and neurotrophin receptors. In the last couple of years, several studies have shed light on the details of these processes and identified novel interaction partners of CAP. In this review, we summarize these recent findings and provide an overview on the function of CAP especially in cell adhesion and membrane receptor signaling.

  11. Strongly Agree or Strongly Disagree?

    DEFF Research Database (Denmark)

    Carrizosa, Emilio; Nogales-Gómez, Amaya; Morales, Dolores Romero

    2016-01-01

    In linear classifiers, such as the Support Vector Machine (SVM), a score is associated with each feature and objects are assigned to classes based on the linear combination of the scores and the values of the features. Inspired by discrete psychometric scales, which measure the extent to which...... a factor is in agreement with a statement, we propose the Discrete Level Support Vector Machine (DILSVM) where the feature scores can only take on a discrete number of values, defined by the so-called feature rating levels. The DILSVM classifier benefits from interpretability and it has visual appeal...

  12. Strong Association between Plasma Dipeptidyl Peptidase-4 Activity and Impaired Cognitive Function in Elderly Population with Normal Glucose Tolerance

    Directory of Open Access Journals (Sweden)

    Bo Chen

    2017-07-01

    Full Text Available Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1 are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4 was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT.Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer’s Association workgroups criteria.Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP, interleukin-6 (IL-6, 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA scores compared with those in the lowest quartile (P < 0.001. The odds ratios (ORs for increased CRP, IL-6, 8-iso-PGF2a, nitrotyrosine, and decreased active GLP-1 were higher with increasing DPP4 quartiles after adjustment for confounders (all P < 0.001. In the highest DPP4 quartile, impaired cognitive function risk was higher (OR, 2.26; 95% confidence interval, 1.36–3.76 than in the lowest quartile after adjustment for potential confounders. The risk for impaired cognitive function increased more with higher levels of DPP4 activity, nitrotyrosine and 8-iso-PGF2a (P < 0.05, but not with higher IL-6, CRP or lower GLP-1.Conclusion: Plasma DPP4 activity is significantly and independently associated with impaired cognitive function, mainly executive, in elderly Chinese population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic

  13. Notch Signaling Is Associated With ALDH Activity And An Aggressive Metastatic Phenotype In Murine Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Xiaodong eMu

    2013-06-01

    Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone, and pulmonary metastatic disease accounts for nearly all mortality. However, little is known about the biochemical signaling alterations that drive the progression of metastatic disease. Two murine OS cell populations, K7M2 and K12, are clonally related but differ significantly in their metastatic phenotypes and therefore represent excellent tools for studying metastatic OS molecular biology. K7M2 cells are highly metastatic, whereas K12 cells display limited metastatic potential. Here we report that the expression of Notch genes (Notch1, 2, 4 are up-regulated, including downstream targets Hes1 and Stat3, in the highly metastatic K7M2 cells compared to the less metastatic K12 cells, indicating that the Notch signaling pathway is more active in K7M2 cells. We have previously described that K7M2 cells exhibit higher levels of aldehyde dehydrogenase (ALDH activity. Here we report that K7M2 cell ALDH activity is reduced with Notch inhibition, suggesting that ALDH activity may be regulated in part by the Notch pathway. Notch signaling is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression in vitro. However, Notch inhibition did not significantly alter K7M2 cell proliferation. In conclusion, we provide evidence that Notch signaling is associated with ALDH activity and increased metastatic behavior in OS cells. Both Notch and ALDH are putative molecular targets for the treatment and prevention of OS metastasis.

  14. Antimicrobial drug use in food-producing animals and associated human health risks: what, and how strong, is the evidence?

    Science.gov (United States)

    Hoelzer, Karin; Wong, Nora; Thomas, Joe; Talkington, Kathy; Jungman, Elizabeth; Coukell, Allan

    2017-07-04

    Antimicrobial resistance is a public health threat. Because antimicrobial consumption in food-producing animals contributes to the problem, policies restricting the inappropriate or unnecessary agricultural use of antimicrobial drugs are important. However, this link between agricultural antibiotic use and antibiotic resistance has remained contested by some, with potentially disruptive effects on efforts to move towards the judicious or prudent use of these drugs. The goal of this review is to systematically evaluate the types of evidence available for each step in the causal pathway from antimicrobial use on farms to human public health risk, and to evaluate the strength of evidence within a 'Grades of Recommendations Assessment, Development and Evaluation'(GRADE) framework. The review clearly demonstrates that there is compelling scientific evidence available to support each step in the causal pathway, from antimicrobial use on farms to a public health burden caused by infections with resistant pathogens. Importantly, the pathogen, antimicrobial drug and treatment regimen, and general setting (e.g., feed type) can have significant impacts on how quickly resistance emerges or spreads, for how long resistance may persist after antimicrobial exposures cease, and what public health impacts may be associated with antimicrobial use on farms. Therefore an exact quantification of the public health burden attributable to antimicrobial drug use in animal agriculture compared to other sources remains challenging. Even though more research is needed to close existing data gaps, obtain a better understanding of how antimicrobial drugs are actually used on farms or feedlots, and quantify the risk associated with antimicrobial use in animal agriculture, these findings reinforce the need to act now and restrict antibiotic use in animal agriculture to those instances necessary to ensure the health and well-being of the animals.

  15. Strong positive associations between seafood, vegetables, and alcohol with blood mercury and urinary arsenic levels in the Korean adult population.

    Science.gov (United States)

    Park, Sunmin; Lee, Byung-Kook

    2013-01-01

    Blood mercury and urinary arsenic levels are more than fivefold greater in the Korean population compared with those of the United States. This may be related to the foods people consumed. Therefore, we examined the associations between food categories and mercury and arsenic exposure in the Korean adult population. Data regarding nutritional, biochemical, and health-related parameters were obtained from a cross-sectional study, the 2008-2009 Korean National Health and Nutrition Examination Survey (3,404 men and women age ≥ 20 years). The log-transformed blood mercury and urinary arsenic levels were regressed against the frequency tertiles of each food group after covariate adjustment for sex, age, residence area, education level, smoking status, and drinking status using food-frequency data. Blood mercury levels in the high consumption groups compared to the low consumption groups were elevated by about 20 percents with salted fish, shellfish, whitefish, bluefish, and alcohol, and by about 9-14 percents with seaweeds, green vegetables, fruits and tea, whereas rice did not affect blood mercury levels. Urinary arsenic levels were markedly increased with consumption of rice, bluefish, salted fish, shellfish, whitefish, and seaweed, whereas they were moderately increased with consumption of grains, green and white vegetables, fruits, coffee, and alcohol. The remaining food categories tended to lower these levels only minimally. In conclusion, the typical Asian diet, which is high in rice, salted fish, shellfish, vegetables, alcoholic beverages, and tea, may be associated with greater blood mercury and urinary arsenic levels. This study suggests that mercury and arsenic contents should be monitored and controlled in soil and water used for agriculture to decrease health risks from heavy-metal contamination.

  16. A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease

    Science.gov (United States)

    Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel; Naitza, Silvia; Dehghan, Abbas; Johnson, Andrew D; Teumer, Alexander; Reiner, Alex P; Folkersen, Lasse; Basu, Saonli; Rudnicka, Alicja R; Trompet, Stella; Mälarstig, Anders; Baumert, Jens; Bis, Joshua C.; Guo, Xiuqing; Hottenga, Jouke J; Shin, So-Youn; Lopez, Lorna M; Lahti, Jari; Tanaka, Toshiko; Yanek, Lisa R; Oudot-Mellakh, Tiphaine; Wilson, James F; Navarro, Pau; Huffman, Jennifer E; Zemunik, Tatijana; Redline, Susan; Mehra, Reena; Pulanic, Drazen; Rudan, Igor; Wright, Alan F; Kolcic, Ivana; Polasek, Ozren; Wild, Sarah H; Campbell, Harry; Curb, J David; Wallace, Robert; Liu, Simin; Eaton, Charles B.; Becker, Diane M.; Becker, Lewis C.; Bandinelli, Stefania; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Fornage, Myriam; Green, David; Gross, Myron; Davies, Gail; Harris, Sarah E; Liewald, David C; Starr, John M; Williams, Frances M.K.; Grant, P.J.; Spector, Timothy D.; Strawbridge, Rona J; Silveira, Angela; Sennblad, Bengt; Rivadeneira, Fernando; Uitterlinden, Andre G; Franco, Oscar H; Hofman, Albert; van Dongen, Jenny; Willemsen, G; Boomsma, Dorret I; Yao, Jie; Jenny, Nancy Swords; Haritunians, Talin; McKnight, Barbara; Lumley, Thomas; Taylor, Kent D; Rotter, Jerome I; Psaty, Bruce M; Peters, Annette; Gieger, Christian; Illig, Thomas; Grotevendt, Anne; Homuth, Georg; Völzke, Henry; Kocher, Thomas; Goel, Anuj; Franzosi, Maria Grazia; Seedorf, Udo; Clarke, Robert; Steri, Maristella; Tarasov, Kirill V; Sanna, Serena; Schlessinger, David; Stott, David J; Sattar, Naveed; Buckley, Brendan M; Rumley, Ann; Lowe, Gordon D; McArdle, Wendy L; Chen, Ming-Huei; Tofler, Geoffrey H; Song, Jaejoon; Boerwinkle, Eric; Folsom, Aaron R.; Rose, Lynda M.; Franco-Cereceda, Anders; Teichert, Martina; Ikram, M Arfan; Mosley, Thomas H; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M.; Sudlow, Cathie L M; Hopewell, Jemma C.; Chambers, John C.; Saleheen, Danish; Kooner, Jaspal S.; Danesh, John; Nelson, Christopher P; Erdmann, Jeanette; Reilly, Muredach P.; Kathiresan, Sekar; Schunkert, Heribert; Morange, Pierre-Emmanuel; Ferrucci, Luigi; Eriksson, Johan G; Jacobs, David; Deary, Ian J; Soranzo, Nicole; Witteman, Jacqueline CM; de Geus, Eco JC; Tracy, Russell P.; Hayward, Caroline; Koenig, Wolfgang; Cucca, Francesco; Jukema, J Wouter; Eriksson, Per; Seshadri, Sudha; Markus, Hugh S.; Watkins, Hugh; Samani, Nilesh J; Wallaschofski, Henri; Smith, Nicholas L.; Tregouet, David; Ridker, Paul M.; Tang, Weihong; Strachan, David P.; Hamsten, Anders; O’Donnell, Christopher J.

    2013-01-01

    Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. Methods and Results We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. Conclusion We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE. PMID:23969696

  17. Application of kernel principal component analysis and computational machine learning to exploration of metabolites strongly associated with diet.

    Science.gov (United States)

    Shiokawa, Yuka; Date, Yasuhiro; Kikuchi, Jun

    2018-02-21

    Computer-based technological innovation provides advancements in sophisticated and diverse analytical instruments, enabling massive amounts of data collection with relative ease. This is accompanied by a fast-growing demand for technological progress in data mining methods for analysis of big data derived from chemical and biological systems. From this perspective, use of a general "linear" multivariate analysis alone limits interpretations due to "non-linear" variations in metabolic data from living organisms. Here we describe a kernel principal component analysis (KPCA)-incorporated analytical approach for extracting useful information from metabolic profiling data. To overcome the limitation of important variable (metabolite) determinations, we incorporated a random forest conditional variable importance measure into our KPCA-based analytical approach to demonstrate the relative importance of metabolites. Using a market basket analysis, hippurate, the most important variable detected in the importance measure, was associated with high levels of some vitamins and minerals present in foods eaten the previous day, suggesting a relationship between increased hippurate and intake of a wide variety of vegetables and fruits. Therefore, the KPCA-incorporated analytical approach described herein enabled us to capture input-output responses, and should be useful not only for metabolic profiling but also for profiling in other areas of biological and environmental systems.

  18. hs-CRP is strongly associated with coronary heart disease (CHD): A data mining approach using decision tree algorithm.

    Science.gov (United States)

    Tayefi, Maryam; Tajfard, Mohammad; Saffar, Sara; Hanachi, Parichehr; Amirabadizadeh, Ali Reza; Esmaeily, Habibollah; Taghipour, Ali; Ferns, Gordon A; Moohebati, Mohsen; Ghayour-Mobarhan, Majid

    2017-04-01

    Coronary heart disease (CHD) is an important public health problem globally. Algorithms incorporating the assessment of clinical biomarkers together with several established traditional risk factors can help clinicians to predict CHD and support clinical decision making with respect to interventions. Decision tree (DT) is a data mining model for extracting hidden knowledge from large databases. We aimed to establish a predictive model for coronary heart disease using a decision tree algorithm. Here we used a dataset of 2346 individuals including 1159 healthy participants and 1187 participant who had undergone coronary angiography (405 participants with negative angiography and 782 participants with positive angiography). We entered 10 variables of a total 12 variables into the DT algorithm (including age, sex, FBG, TG, hs-CRP, TC, HDL, LDL, SBP and DBP). Our model could identify the associated risk factors of CHD with sensitivity, specificity, accuracy of 96%, 87%, 94% and respectively. Serum hs-CRP levels was at top of the tree in our model, following by FBG, gender and age. Our model appears to be an accurate, specific and sensitive model for identifying the presence of CHD, but will require validation in prospective studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Strong positive association of traditional Asian-style diets with blood cadmium and lead levels in the Korean adult population.

    Science.gov (United States)

    Park, Sunmin; Lee, Byung-Kook

    2013-12-01

    Blood lead and cadmium levels are more than twofold to fivefold higher in the Korean population compared to that of the USA. This may be related to the foods consumed. We examined which food categories are related to blood lead and cadmium levels in the Korean adult population using the 2008-2010 Korean National Health and Nutrition Examination Survey (n = 5504). High and moderate consumption of bread and crackers, potatoes, meat and meat products, milk and dairy products, and pizza and hamburger resulted in significantly lower odds ratios for blood lead levels than their low consumption. However, consumption of salted fish, white fish, green vegetables, white and yellow vegetables, coffee, and alcohol resulted in significantly higher odds ratios of blood lead and cadmium. In conclusion, the typical Asian diet based on rice, fish, vegetables, regular coffee, and alcoholic drinks may be associated with higher blood cadmium and lead levels. This study suggests that lead and cadmium contents should be monitored and controlled in agricultural products to reduce health risks from heavy metals.

  20. Regulation of mitochondrial antiviral signaling (MAVS) expression and signaling by the mitochondria-associated endoplasmic reticulum membrane (MAM) protein Gp78.

    Science.gov (United States)

    Jacobs, Jana L; Zhu, Jianzhong; Sarkar, Saumendra N; Coyne, Carolyn B

    2014-01-17

    In a previous study, we identified the E3 ubiquitin ligase Gp78 by RNAi high-throughput screening as a gene whose depletion restricted enterovirus infection. In the current study, we show that Gp78, which localizes to the ER-mitochondria interface, is a regulator of RIG-I-like receptor (RLR) antiviral signaling. We show that depletion of Gp78 results in a robust decrease of vesicular stomatitis virus (VSV) infection and a corresponding enhancement of type I interferon (IFN) signaling. Mechanistically, we show that Gp78 modulates type I IFN induction by altering both the expression and signaling of the mitochondria-localized RLR adaptor mitochondrial antiviral signaling (MAVS). Expression of mutants of Gp78 that abolish its E3 ubiquitin ligase and its participation in ER-associated degradation (ERAD) lost their ability to degrade MAVS, but surprisingly maintained their ability to repress RLR signaling. In contrast, Gp78 lacking its entire C terminus lost both its ability to degrade MAVS and repress RLR signaling. We show that Gp78 interacts with both the N- and C-terminal domains of MAVS via its C-terminal RING domain, and that this interaction is required to abrogate Gp78-mediated attenuation of MAVS signaling. Our data thus implicate two parallel pathways by which Gp78 regulates MAVS signaling; one pathway requires its E3 ubiquitin ligase and ERAD activity to directly degrade MAVS, whereas the other pathway occurs independently of these activities, but requires the Gp78 RING domain and occurs via a direct association between this region and MAVS.

  1. CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba.

    Science.gov (United States)

    Kouri, Vivian; Khouri, Ricardo; Alemán, Yoan; Abrahantes, Yeissel; Vercauteren, Jurgen; Pineda-Peña, Andrea-Clemencia; Theys, Kristof; Megens, Sarah; Moutschen, Michel; Pfeifer, Nico; Van Weyenbergh, Johan; Pérez, Ana B; Pérez, Jorge; Pérez, Lissette; Van Laethem, Kristel; Vandamme, Anne-Mieke

    2015-03-01

    Clinicians reported an increasing trend of rapid progression (RP) (AIDS within 3 years of infection) in Cuba. Recently infected patients were prospectively sampled, 52 RP at AIDS diagnosis (AIDS-RP) and 21 without AIDS in the same time frame (non-AIDS). 22 patients were sampled at AIDS diagnosis (chronic-AIDS) retrospectively assessed as > 3 years infected. Clinical, demographic, virological, epidemiological and immunological data were collected. Pol and env sequences were used for subtyping, transmission cluster analysis, and prediction of resistance, co-receptor use and evolutionary fitness. Host, immunological and viral predictors of RP were explored through data mining. Subtyping revealed 26 subtype B strains, 6 C, 6 CRF18_cpx, 9 CRF19_cpx, 29 BG-recombinants and other subtypes/URFs. All patients infected with CRF19 belonged to the AIDS-RP group. Data mining identified CRF19, oral candidiasis and RANTES levels as the strongest predictors of AIDS-RP. CRF19 was more frequently predicted to use the CXCR4 co-receptor, had higher fitness scores in the protease region, and patients had higher viral load at diagnosis. CRF19 is a recombinant of subtype D (C-part of Gag, PR, RT and nef), subtype A (N-part of Gag, Integrase, Env) and subtype G (Vif, Vpr, Vpu and C-part of Env). Since subtypes D and A have been associated with respectively faster and slower disease progression, our findings might indicate a fit PR driving high viral load, which in combination with co-infections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba.

  2. Dysfunctions of mitochondria in close association with strong perturbation of long noncoding RNAs expression in down syndrome.

    Science.gov (United States)

    Qiu, Jia-Jun; Liu, Yan-Na; Ren, Zhao-Rui; Yan, Jing-Bin

    2017-11-01

    Trisomy 21 is the most common chromosomal disorder and underlies Down syndrome. Epigenetics, such as DNA methylation and post-translational histone modifications, plays a vital role in Down syndrome. However, the functions of epigenetics-related long noncoding RNAs (lncRNAs), found to have an impact on neural diseases such as Alzheimer's disease, remain unknown in Down syndrome. In this study, we analyzed the RNA sequencing data from Down syndrome-induced pluripotent stem cells (iPSCs) and normal iPSCs. A large number of lncRNAs were identified differentially expressed in Down syndrome-iPSCs. Notably, stronger perturbation was shown in the expression of lncRNAs compared to protein coding genes (Kolmogorov-Smirnov test, PDown syndrome. Through gene set enrichment analysis and bi-clustering, we also found that most of the differential expressed lncRNAs were closely associated with mitochondrial functions (e.g. mitochondrion organization, P=3.21×10 -17 ; mitochondrial ATP synthesis coupled electron transport, P=1.73×10 -19 and mitochondrial membrane organization, P=4.04×10 -8 ). PCR-array and qRT-PCR results revealed that almost all genes related to mitochondria were down-regulated in Down syndrome-iPSCs, implying that mitochondria were dysfunctional in Down syndrome (e.g. ATP5B, Fold Change=-8.2317; COX6A1, Fold Change=-12.7788 and SLC25A17, Fold Change=-22.1296). All in all, our study indicated that a stronger perturbation of lncRNAs expression may lead to the dysfunction of mitochondria in Down syndrome. Copyright © 2017. Published by Elsevier Ltd.

  3. Seismic switch for strong motion measurement

    Science.gov (United States)

    Harben, P.E.; Rodgers, P.W.; Ewert, D.W.

    1995-05-30

    A seismic switching device is described that has an input signal from an existing microseismic station seismometer and a signal from a strong motion measuring instrument. The seismic switch monitors the signal level of the strong motion instrument and passes the seismometer signal to the station data telemetry and recording systems. When the strong motion instrument signal level exceeds a user set threshold level, the seismometer signal is switched out and the strong motion signal is passed to the telemetry system. The amount of time the strong motion signal is passed before switching back to the seismometer signal is user controlled between 1 and 15 seconds. If the threshold level is exceeded during a switch time period, the length of time is extended from that instant by one user set time period. 11 figs.

  4. Anomalous variation in the wireless signals propagation associated with earthquake preparation processes

    Science.gov (United States)

    Ouzounov, Dimitar; Velichkova-Yotsova, Sylvia; Pulinets, Sergey

    2016-04-01

    propagation correlated with earthquake preparation processes. Our observations revealed a phenomena associated with the artificially enhancement of the intensity 3.5GHz signals by using WiMax technology (no change in the transmitting level) as a result of electric and electrochemical processes in atmosphere over the regions of ongoing earthquake preparation. To illustrate the nature of such variations in the range of 3.5GHz in relation to earthquake processes we present two case studies: 1/ for M5.8 of May 22, 2012 in Bulgaria and 2/ for M6.9 of May 24, 2014 in Aegean Sea. Concerning the M5.8 of May 22, 2012 the abnormal intensity modulation started on 05.17.2012 (five days in advance) and reached 200% increase. Epicenter of the M5.8 of May 25 was on 15 km from the wireless receiver. Concerning and M6.9 of May 24, 2014 in Aegean Sea abnormal signal was observed on May 22 (two days in advance) with 30% intensity increase. Epicenter of M6.9 of May 24 was at 260 km from the wireless receiver. Most likely the observed increase in the intensity is a direct result of the change in the atmospheric properties in the Atmospheric boundary level (ABL) triggered by intensification of radon and other gases release, which lead to change in lowers atmosphere conductivity, already suggested by Lithosphere-Atmosphere-Ionosphere Coupling concept (Pulinets and Ouzounov, 2011). Another possible reason is the forward scattering of WiMax signal (similar to meteor wakes scattering) on aerosol layers formed over the earthquake preparation zone. We are registering an effect of systematic increase (with different rate) at 3.5 GHz associated with the regional seismicity and no significant intensify modulation with an absence of major seismicity in the region.

  5. The Obesity-Linked Gene Nudt3 Drosophila Homolog Aps Is Associated With Insulin Signaling.

    Science.gov (United States)

    Williams, Michael J; Eriksson, Anders; Shaik, Muksheed; Voisin, Sarah; Yamskova, Olga; Paulsson, Johan; Thombare, Ketan; Fredriksson, Robert; Schiöth, Helgi B

    2015-09-01

    Several genome-wide association studies have linked the Nudix hydrolase family member nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to obesity. However, the manner of NUDT3 involvement in obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3 mRNA and protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3 mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the insulin-producing cells (IPCs), induces hyperinsulinemia-like phenotypes, including a decrease in circulating trehalose levels as well as significantly decreasing all carbohydrate levels under starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these lipids during starvation. Also, loss of neuronal Aps expression caused a starvation susceptibility phenotype while inducing hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, Ilp6, and Ilp3, genes known to be inhibited by insulin signaling. These results point toward a role for this gene in the regulation of insulin signaling, which could explain the robust association with obesity in humans.

  6. The suppression of ghrelin signaling mitigates age‐associated thermogenic impairment.

    Science.gov (United States)

    Lin, Ligen; Lee, Jong Han; Bongmba, Odelia Y N; Ma, Xiaojun; Zhu, Xiongwei; Sheikh-Hamad, David; Sun, Yuxiang

    2014-12-01

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS‐R), attenuates age‐associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS‐R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS‐R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS‐R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS‐R regulates thermogenesis via both central and peripheral mechanisms.Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS‐R may serve as unique anti‐obesity agents, combating obesity by activating thermogenesis.

  7. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    Science.gov (United States)

    Bongmba, Odelia Y. N.; Ma, Xiaojun; Zhu, Xiongwei; Sheikh-Hamad, David; Sun, Yuxiang

    2014-01-01

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms. Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis. PMID:25543537

  8. Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages

    Directory of Open Access Journals (Sweden)

    Martin J. Cannon

    2015-05-01

    Full Text Available The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

  9. Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.

    Directory of Open Access Journals (Sweden)

    Daniel P S Osborn

    Full Text Available Common intronic variants in the Human fat mass and obesity-associated gene (FTO are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo (zebrafish and in vitro (Fto(-/- MEFs and HEK293T. Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca(2+ pathway is activated via its key signal mediators CaMKII and PKCδ. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.

  10. Growth anomalies on the coral genera Acropora and Porites are strongly associated with host density and human population size across the Indo-Pacific.

    Directory of Open Access Journals (Sweden)

    Greta S Aeby

    Full Text Available Growth anomalies (GAs are common, tumor-like diseases that can cause significant morbidity and decreased fecundity in the major Indo-Pacific reef-building coral genera, Acropora and Porites. GAs are unusually tractable for testing hypotheses about drivers of coral disease because of their pan-Pacific distributions, relatively high occurrence, and unambiguous ease of identification. We modeled multiple disease-environment associations that may underlie the prevalence of Acropora growth anomalies (AGA (n = 304 surveys and Porites growth anomalies (PGA (n = 602 surveys from across the Indo-Pacific. Nine predictor variables were modeled, including coral host abundance, human population size, and sea surface temperature and ultra-violet radiation anomalies. Prevalence of both AGAs and PGAs were strongly host density-dependent. PGAs additionally showed strong positive associations with human population size. Although this association has been widely posited, this is one of the first broad-scale studies unambiguously linking a coral disease with human population size. These results emphasize that individual coral diseases can show relatively distinct patterns of association with environmental predictors, even in similar diseases (growth anomalies found on different host genera (Acropora vs. Porites. As human densities and environmental degradation increase globally, the prevalence of coral diseases like PGAs could increase accordingly, halted only perhaps by declines in host density below thresholds required for disease establishment.

  11. Growth anomalies on the coral genera Acropora and Porites are strongly associated with host density and human population size across the Indo-Pacific.

    Science.gov (United States)

    Aeby, Greta S; Williams, Gareth J; Franklin, Erik C; Haapkyla, Jessica; Harvell, C Drew; Neale, Stephen; Page, Cathie A; Raymundo, Laurie; Vargas-Ángel, Bernardo; Willis, Bette L; Work, Thierry M; Davy, Simon K

    2011-02-18

    Growth anomalies (GAs) are common, tumor-like diseases that can cause significant morbidity and decreased fecundity in the major Indo-Pacific reef-building coral genera, Acropora and Porites. GAs are unusually tractable for testing hypotheses about drivers of coral disease because of their pan-Pacific distributions, relatively high occurrence, and unambiguous ease of identification. We modeled multiple disease-environment associations that may underlie the prevalence of Acropora growth anomalies (AGA) (n = 304 surveys) and Porites growth anomalies (PGA) (n = 602 surveys) from across the Indo-Pacific. Nine predictor variables were modeled, including coral host abundance, human population size, and sea surface temperature and ultra-violet radiation anomalies. Prevalence of both AGAs and PGAs were strongly host density-dependent. PGAs additionally showed strong positive associations with human population size. Although this association has been widely posited, this is one of the first broad-scale studies unambiguously linking a coral disease with human population size. These results emphasize that individual coral diseases can show relatively distinct patterns of association with environmental predictors, even in similar diseases (growth anomalies) found on different host genera (Acropora vs. Porites). As human densities and environmental degradation increase globally, the prevalence of coral diseases like PGAs could increase accordingly, halted only perhaps by declines in host density below thresholds required for disease establishment.

  12. High resolution MRI of the breast at 3 T: which BI-RADS {sup registered} descriptors are most strongly associated with the diagnosis of breast cancer?

    Energy Technology Data Exchange (ETDEWEB)

    Pinker-Domenig, K.; Helbich, T.H. [Medical University Vienna, Dept. of Radiology, Division of Molecular and Gender Imaging, Vienna (Austria); Bogner, W.; Gruber, S. [Medical University Vienna, Dept. of Radiology, MR Centre of Excellence, Vienna (Austria); Medical University Vienna, Dept. of Radiology, Vienna (Austria); Bickel, H. [Medical University Vienna, Dept. of Radiology, Division of Molecular and Gender Imaging, Vienna (Austria); Medical University Vienna, Dept. of Radiology, Vienna (Austria); Duffy, S. [Queen Mary University of London, Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London (United Kingdom); Schernthaner, M. [Medical University Vienna, Dept. of Radiology, Vienna (Austria); Dubsky, P. [Medical University Vienna, Dept. of Surgery, Vienna (Austria); Pluschnig, U. [Medical University Vienna, Dept. of Internal Medicine, Division of Oncology, Vienna (Austria); Rudas, M. [Medical University Vienna, Clinical Institute of Pathology, Vienna (Austria); Trattnig, S. [Medical University Vienna, Dept. of Radiology, MR Centre of Excellence, Vienna (Austria)

    2012-02-15

    To identify which breast lesion descriptors in the ACR BI-RADS registered MRI lexicon are most strongly associated with the diagnosis of breast cancer when performing breast MR imaging at 3 T. 150 patients underwent breast MR imaging at 3 T. Lesion size, morphology and enhancement kinetics were assessed according to the BI-RADS {sup registered} classification. Sensitivity, specificity and diagnostic accuracy were assessed. The effects of the BI-RADS {sup registered} descriptors on sensitivity and specificity were evaluated. Data were analysed using logistic regression. Histopathological diagnoses were used as the standard of reference. The sensitivity, specificity and diagnostic accuracy of breast MRI at 3 T was 99%, 81% and 93%, respectively. In univariate analysis, the final diagnosis of malignancy was positively associated with irregular shape (p < 0.001), irregular margin (p < 0.001), heterogeneous enhancement (p < 0.001), Type 3 enhancement kinetics (p = 0.02), increasing patient age (p = 0.02) and larger lesion size (p < 0.001). In multivariate analysis, significant associations with malignancy remained for mass shape (p = 0.06), mass margin (p < 0.001), internal enhancement pattern (p = 0.03) and Type 3 enhancement kinetics (p = 0.06). The ACR BI-RADS {sup registered} breast lesion descriptors that are mostly strongly associated with breast cancer in breast MR imaging at 3 T are lesion shape, lesion margin, internal enhancement pattern and Type 3 enhancement kinetics. (orig.)

  13. The origins of rimmed vacuoles and granulovacuolar degeneration bodies are associated with the Wnt signaling pathway.

    Science.gov (United States)

    Murata-Shinozaki, Yukari; Takahashi, Tetsuya; Matsubara, Tomoyasu; Maruyama, Hirofumi; Izumi, Yuishin; Matsumoto, Masayasu

    2017-01-18

    Inclusion-body myositis (IBM) and Alzheimer's disease (AD) are biochemically characterized by the presence of aggregated β-amyloid protein and tau protein. In addition, both diseases are pathologically characterized by vacuolar changes, including rimmed vacuoles (RVs) in IBM and granulovacuolar degeneration (GVD) in AD. Previously, we demonstrated that RVs and GVD bodies are associated with a set of common molecules, leading us to speculate that both RVs and GVD bodies originate from similar structures on the plasma membrane of muscle cells and neuronal cells, namely, the neuromuscular junction (NMJ) and the postsynaptic spine especially in terms of Wnt signaling pathway. In this study, we investigated the presence of components of NMJ in RVs and/or postsynaptic spine in GVD bodies respectively by immunohistochemistry and immunofluorescence. The antigens probed included the following: (1) dishevelled (Dvl) family proteins (Dvl1, Dvl2 and Dvl3), (2) NMJ-associated proteins (low density lipoprotein-related protein 4 [Lrp4], heat shock protein 70 [Hsp70], β-catenin, phospho-β-catenin, rapsyn, P21-activated kinase 1 [PAK1], adenomatous polyposis coli [APC] and ADP-ribosylation factor 6 [Arf6]), (3) a lipid raft-associated molecule (phosphatidylinositol 4, 5-bisphosphate [PIP2]), and (4) other proteins [prion, glycogen-synthase kinase 3β (GSK-3β)]. In all cases of sporadic IBM examined, RVs were immunopositive for Dvl3, Hsp70, β-catenin, PIP2, APC, prion and GSK-3β. In all cases of AD examined, GVD bodies were immunopositive for Dvl3, phospho-β-catenin, rapsyn, APC and PIP2. These findings show that RVs and GVD bodies share common molecules associated with the Wnt signaling pathway, indicating that these structures share a common structural and functional origin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. LIGO: The strong belief

    CERN Multimedia

    Antonella Del Rosso

    2016-01-01

    Twenty years of designing, building and testing a number of innovative technologies, with the strong belief that the endeavour would lead to a historic breakthrough. The Bulletin publishes an abstract of the Courier’s interview with Barry Barish, one of the founding fathers of LIGO.   The plots show the signals of gravitational waves detected by the twin LIGO observatories at Livingston, Louisiana, and Hanford, Washington. (Image: Caltech/MIT/LIGO Lab) On 11 February, the Laser Interferometer Gravitational-Wave Observatory (LIGO) and Virgo collaborations published a historic paper in which they showed a gravitational signal emitted by the merger of two black holes. These results come after 20 years of hard work by a large collaboration of scientists operating the two LIGO observatories in the US. Barry Barish, Linde Professor of Physics, Emeritus at the California Institute of Technology and former Director of the Global Design Effort for the Internat...

  15. Meta-analysis of associations between human brain volume and intelligence differences: How strong are they and what do they mean?

    Science.gov (United States)

    Pietschnig, Jakob; Penke, Lars; Wicherts, Jelte M; Zeiler, Michael; Voracek, Martin

    2015-10-01

    Positive associations between human intelligence and brain size have been suspected for more than 150 years. Nowadays, modern non-invasive measures of in vivo brain volume (Magnetic Resonance Imaging) make it possible to reliably assess associations with IQ. By means of a systematic review of published studies and unpublished results obtained by personal communications with researchers, we identified 88 studies examining effect sizes of 148 healthy and clinical mixed-sex samples (>8000 individuals). Our results showed significant positive associations of brain volume and IQ (r=.24, R(2)=.06) that generalize over age (children vs. adults), IQ domain (full-scale, performance, and verbal IQ), and sex. Application of a number of methods for detection of publication bias indicates that strong and positive correlation coefficients have been reported frequently in the literature whilst small and non-significant associations appear to have been often omitted from reports. We show that the strength of the positive association of brain volume and IQ has been overestimated in the literature, but remains robust even when accounting for different types of dissemination bias, although reported effects have been declining over time. While it is tempting to interpret this association in the context of human cognitive evolution and species differences in brain size and cognitive ability, we show that it is not warranted to interpret brain size as an isomorphic proxy of human intelligence differences. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists.

    Directory of Open Access Journals (Sweden)

    Gunnar Kleinau

    Full Text Available Trace amine-associated receptors (TAAR are rhodopsin-like G-protein-coupled receptors (GPCR. TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR, phenylethylamine (PEA, octopamine (OA, but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1 and 2 (ADRB2 have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR octopamine (OAR, ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes.

  17. Logistic regression analysis for the identification of the metastasis-associated signaling pathways of osteosarcoma.

    Science.gov (United States)

    Liu, Yang; Sun, Wei; Ma, Xiaojun; Hao, Yuedong; Liu, Gang; Hu, Xiaohui; Shang, Houlai; Wu, Pengfei; Zhao, Zexue; Liu, Weidong

    2018-03-01

    Osteosarcoma (OS) is the most common histological type of primary bone cancer. The present study was designed to identify the key genes and signaling pathways involved in the metastasis of OS. Microarray data of GSE39055 were downloaded from the Gene Expression Omnibus database, which included 19 OS biopsy specimens before metastasis (control group) and 18 OS biopsy specimens after metastasis (case group). After the differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Analysis package, hierarchical clustering analysis and unsupervised clustering analysis were performed separately, using orange software and the self-organization map method. Based upon the Database for Annotation, Visualization and Integrated Discovery tool and Cytoscape software, enrichment analysis and protein-protein interaction (PPI) network analysis were conducted, respectively. After function deviation scores were calculated for the significantly enriched terms, hierarchical clustering analysis was performed using Cluster 3.0 software. Furthermore, logistic regression analysis was used to identify the terms that were significantly different. Those terms that were significantly different were validated using other independent datasets. There were 840 DEGs in the case group. There were various interactions in the PPI network [including intercellular adhesion molecule-1 (ICAM1), transforming growth factor β1 (TGFB1), TGFB1-platelet-derived growth factor subunit B (PDGFB) and PDGFB-platelet‑derived growth factor receptor-β (PDGFRB)]. Regulation of cell migration, nucleotide excision repair, the Wnt signaling pathway and cell migration were identified as the terms that were significantly different. ICAM1, PDGFB, PDGFRB and TGFB1 were identified to be enriched in cell migration and regulation of cell migration. Nucleotide excision repair and the Wnt signaling pathway were the metastasis-associated pathways of OS. In addition, ICAM1, PDGFB, PDGFRB

  18. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy

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    Buchanan David J

    2009-08-01

    Full Text Available Abstract Painful distal sensory polyneuropathy (DSP is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2 and stromal derived factor-1 (SDF1/CXCL12 and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC, we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14–48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior

  19. IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population

    OpenAIRE

    Ferguson, Lynnette R.; Han, Dug Yeo; Fraser, Alan G.; Huebner, Claudia; Lam, Wen Jiun; Morgan, Angharad R.

    2010-01-01

    DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly re...

  20. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

    International Nuclear Information System (INIS)

    Noda, Saori; Takahashi, Atsushi; Hayashi, Takeru; Tanuma, Sei-ichi; Hatakeyama, Masanori

    2016-01-01

    SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

  1. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Noda, Saori [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Takahashi, Atsushi; Hayashi, Takeru [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Tanuma, Sei-ichi [Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Hatakeyama, Masanori, E-mail: mhata@m.u-tokyo.ac.jp [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

    2016-01-22

    SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

  2. Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy.

    Science.gov (United States)

    Goruppi, Sandro; Bonventre, Joseph V; Kyriakis, John M

    2002-10-15

    In chronic diseases such as diabetes mellitus, continuous stress stimuli trigger a persistent, self-reinforcing reprogramming of cellular function and gene expression that culminates in the pathological state. Late-onset, stable changes in gene expression hold the key to understanding the molecular basis of chronic diseases. Renal failure is a common, but poorly understood complication of diabetes. Diabetic nephropathy begins with mesangial cell hypertrophy and hyperplasia, combined with excess matrix deposition. The vasoactive peptide endothelin promotes the mesangial cell hypertophy characteristic of diabetic nephropathy. In this study, we examined the signaling pathways and changes in gene expression required for endothelin-induced mesangial cell hypertrophy. Transcriptional profiling identified seven genes induced with slow kinetics by endothelin. Of these, p8, which encodes a small basic helix-loop-helix protein, was most strongly and stably induced. p8 is also induced in diabetic kidney. Mesangial cell hypertrophy and p8 induction both require activation of the ERK, JNK/SAPK and PI-3-K pathways. Small interfering RNA (siRNA)-mediated RNA interference indicates that p8 is required for endothelin-induced hypertrophy. Thus, p8 is a novel marker for diabetic renal hypertrophy.

  3. Metabolite transport and associated sugar signalling systems underpinning source/sink interactions.

    Science.gov (United States)

    Griffiths, Cara A; Paul, Matthew J; Foyer, Christine H

    2016-10-01

    Metabolite transport between organelles, cells and source and sink tissues not only enables pathway co-ordination but it also facilitates whole plant communication, particularly in the transmission of information concerning resource availability. Carbon assimilation is co-ordinated with nitrogen assimilation to ensure that the building blocks of biomass production, amino acids and carbon skeletons, are available at the required amounts and stoichiometry, with associated transport processes making certain that these essential resources are transported from their sites of synthesis to those of utilisation. Of the many possible posttranslational mechanisms that might participate in efficient co-ordination of metabolism and transport only reversible thiol-disulphide exchange mechanisms have been described in detail. Sucrose and trehalose metabolism are intertwined in the signalling hub that ensures appropriate resource allocation to drive growth and development under optimal and stress conditions, with trehalose-6-phosphate acting as an important signal for sucrose availability. The formidable suite of plant metabolite transporters provides enormous flexibility and adaptability in inter-pathway coordination and source-sink interactions. Focussing on the carbon metabolism network, we highlight the functions of different transporter families, and the important of thioredoxins in the metabolic dialogue between source and sink tissues. In addition, we address how these systems can be tailored for crop improvement. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Local perinuclear calcium signals associated with mitosis-entry in early sea urchin embryos.

    Science.gov (United States)

    Wilding, M; Wright, E M; Patel, R; Ellis-Davies, G; Whitaker, M

    1996-10-01

    Using calcium-sensitive dyes together with their dextran conjugates and confocal microscopy, we have looked for evidence of localized calcium signaling in the region of the nucleus before entry into mitosis, using the sea urchin egg first mitotic cell cycle as a model. Global calcium transients that appear to originate from the nuclear area are often observed just before nuclear envelope breakdown (NEB). In the absence of global increases in calcium, confocal microscopy using Calcium Green-1 dextran indicator dye revealed localized calcium transients in the perinuclear region. We have also used a photoinactivatable calcium chelator, nitrophenyl EGTA (NP-EGTA), to test whether the chelator-induced block of mitosis entry can be reversed after inactivation of the chelator. Cells arrested before NEB by injection of NP-EGTA resume the cell cycle after flash photolysis of the chelator. Photolysis of chelator triggers calcium release. TreatmenT with caFfeine to enhance calcium-induced calcium release increases the amplitude of NEB-associated calcium transients. These results indicate that calcium increases local to the nucleus are required to trigger entry into mitosis. Local calcium transients arise in the perinuclear region and can spread from this region into the cytoplasm. Thus, cell cycle calcium signals are generated by the perinuclear mitotic machinery in early sea urchin embryos.

  5. Nicotinic modulation of hippocampal cell signaling and associated effects on learning and memory.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2016-03-01

    The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Coenzyme Q(10) supplementation ameliorates inflammatory signaling and oxidative stress associated with strenuous exercise.

    Science.gov (United States)

    Díaz-Castro, Javier; Guisado, Rafael; Kajarabille, Naroa; García, Carmen; Guisado, Isabel M; de Teresa, Carlos; Ochoa, Julio J

    2012-10-01

    Exhausting exercise induces muscle damage associated with high production of free radicals and pro-inflammatory mediators. The objective of this study was to determine for the first time and simultaneously whether oral coenzyme Q(10) (CoQ(10)) supplementation can prevent over-expression of inflammatory mediators and oxidative stress associated with strenuous exercise. The participants were classified in two groups: CoQ(10) group (CG) and placebo group (PG). The physical test consisted in a constant run (50 km) that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing. Exercise was associated with an increase in TNF-α, IL-6, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and isoprostane levels, revealing the degree of inflammation and oxidative stress induced. Oral supplementation of CoQ(10) during exercise was efficient reducing oxidative stress (decreased membrane hydroperoxides, 8-OHdG and isoprostanes generation, increased catalase, and total antioxidant status), which would lead to the maintenance of the cell integrity. Data obtained also indicate that CoQ(10) prevents over-expression of TNF-α after exercise, together with an increase in sTNF-RII that limits the pro-inflammatory actions of TNF. Moreover, CoQ(10) supplementation reduced creatinine production. CoQ(10) supplementation before strenuous exercise decreases the oxidative stress and modulates the inflammatory signaling, reducing the subsequent muscle damage.

  7. BMP-2 signaling in ovarian cancer and its association with poor prognosis

    Directory of Open Access Journals (Sweden)

    Le Page Cécile

    2009-04-01

    Full Text Available Abstract Background We previously observed the over-expression of BMP-2 in primary cultures of epithelial ovarian cancer (EOC cells as compared to normal epithelial cells based on Affymetrix microarray profiling 1. Here we investigate the effect of BMP-2 on several parameters of ovarian cancer tumorigenesis using the TOV-2223, TOV-1946 and TOV-112D EOC cell lines. Methods We treated each EOC cell line with recombinant BMP-2 and assayed various parameters associated with tumorigenesis. More specifically, cell signaling events induced by BMP-2 treatment were investigated by western-blot using anti-phosphospecific antibodies. Induction of Id1, Snail and Smad6 mRNA expression was investigated by real time RT-PCR. The ability of cells to migrate was tested using the scratch assay. Cell-cell adhesion was analyzed by the ability of cells to form spheroids. We also investigated BMP-2 expression in tissue samples from a series of EOC patients. Results Treatment of these cell lines with recombinant BMP-2 induced a rapid phosphorylation of Smad1/5/8 and Erk MAPKs. Increased expression of Id1, Smad6 and Snail mRNAs was also observed. Only in the TOV-2223 cell line were these signaling events accompanied by an alteration in cell proliferation. We also observed that BMP-2 efficiently increased the motility of all three cell lines. In contrast, BMP-2 treatment decreased the ability of TOV-1946 and TOV-112D cell lines to form spheroids indicating an inhibition of cell-cell adhesion. The expression of BMP-2 in tumor tissues from patients was inversely correlated with survival. Conclusion These results suggest that EOC cell secretion of BMP-2 in the tumor environment contributes to a modification of tumor cell behavior through a change in motility and adherence. We also show that BMP-2 expression in tumor tissues is associated with a poorer prognosis for ovarian cancer patients.

  8. PIP kinases define PI4,5P₂signaling specificity by association with effectors.

    Science.gov (United States)

    Choi, Suyong; Thapa, Narendra; Tan, Xiaojun; Hedman, Andrew C; Anderson, Richard A

    2015-06-01

    Phosphatidylinositol 4,5-bisphosphate (PI4,5P₂) is an essential lipid messenger with roles in all eukaryotes and most aspects of human physiology. By controlling the targeting and activity of its effectors, PI4,5P₂modulates processes, such as cell migration, vesicular trafficking, cellular morphogenesis, signaling and gene expression. In cells, PI4,5P₂has a much higher concentration than other phosphoinositide species and its total content is largely unchanged in response to extracellular stimuli. The discovery of a vast array of PI4,5P₂ binding proteins is consistent with data showing that the majority of cellular PI4,5P₂is sequestered. This supports a mechanism where PI4,5P₂functions as a localized and highly specific messenger. Further support of this mechanism comes from the de novo synthesis of PI4,5P₂which is often linked with PIP kinase interaction with PI4,5P₂effectors and is a mechanism to define specificity of PI4,5P₂signaling. The association of PI4,5P₂-generating enzymes with PI4,5P₂effectors regulate effector function both temporally and spatially in cells. In this review, the PI4,5P₂effectors whose functions are tightly regulated by associations with PI4,5P₂-generating enzymes will be discussed. This article is part of a Special Issue entitled Phosphoinositides. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists.

    Science.gov (United States)

    Panagiotou, Orestis A; Ioannidis, John P A

    2012-07-01

    To assess the interpretation of a highly heterogeneous meta-analysis by authors of primary studies and by methodologists. We surveyed the authors of studies on the association between insulin-like growth factor 1 (IGF-1) and prostate cancer, and 20 meta-analysis methodologists. Authors and methodologists presented with the respective meta-analysis results were queried about the effect size and potential causality of the association. We evaluated whether author responses correlated with the number of IGF-related articles they had published and their study results included in the meta-analysis. We also compared authors' and methodologists' responses. Authors who had published more IGF-related papers offered more generous effect size estimates for the association (ρ(s)=0.61, P=0.01) and higher likelihood that the odds ratio (OR) was greater than 1.20 (ρ(s)=0.63, P=0.01). Authors who had published themselves studies with statistically significant effects for a positive association were more likely to believe that the true OR is greater than 1.20 compared with methodologists (median likelihood 50% versus 2.5%, P=0.01). Researchers are influenced by their own investment in the field, when interpreting a meta-analysis that includes their own study. Authors who published significant results are more likely to believe that a strong association exists compared with methodologists. Copyright © 2012. Published by Elsevier Inc.

  10. Strong association between serological status and probability of progression to clinical visceral leishmaniasis in prospective cohort studies in India and Nepal.

    Directory of Open Access Journals (Sweden)

    Epco Hasker

    Full Text Available Asymptomatic persons infected with the parasites causing visceral leishmaniasis (VL usually outnumber clinically apparent cases by a ratio of 4-10 to 1. We assessed the risk of progression from infection to disease as a function of DAT and rK39 serological titers.We used available data on four cohorts from villages in India and Nepal that are highly endemic for Leishmania donovani. In each cohort two serosurveys had been conducted. Based on results of initial surveys, subjects were classified as seronegative, moderately seropositive or strongly seropositive using both DAT and rK39. Based on the combination of first and second survey results we identified seroconvertors for both markers. Seroconvertors were subdivided in high and low titer convertors. Subjects were followed up for at least one year following the second survey. Incident VL cases were recorded and verified.We assessed a total of 32,529 enrolled subjects, for a total follow-up time of 72,169 person years. Altogether 235 incident VL cases were documented. The probability of progression to disease was strongly associated with initial serostatus and with seroconversion; this was particularly the case for those with high titers and most prominently among seroconvertors. For high titer DAT convertors the hazard ratio reached as high as 97.4 when compared to non-convertors. The strengths of the associations varied between cohorts and between markers but similar trends were observed between the four cohorts and the two markers.There is a strongly increased risk of progressing to disease among DAT and/or rK39 seropositives with high titers. The options for prophylactic treatment for this group merit further investigation, as it could be of clinical benefit if it prevents progression to disease. Prophylactic treatment might also have a public health benefit if it can be corroborated that these asymptomatically infected individuals are infectious for sand flies.

  11. High-density lipoprotein levels are strongly associated with the recovery rate of insulin sensitivity during the acute phase of myocardial infarction: a study by euglycemic hyperinsulinemic clamp.

    Science.gov (United States)

    Carvalho, Luiz Sergio F; Martins, Naiara V; Moura, Filipe A; Cintra, Riobaldo M R; Almeida, Osorio L R; Quinaglia e Silva, Jose C; Sposito, Andrei C

    2013-01-01

    The decrease of insulin sensitivity (IS) during myocardial infarction (MI) is strongly associated with increased morbidity and mortality. Recent data suggest that in individuals under stable conditions, high-density lipoprotein (HDL) may improve IS. To date, the role of HDL in the modulation of IS in acute metabolic stress conditions such as MI remains unknown. To explore the association between plasma HDL-C and the change in IS during the acute phase of MI. Consecutive nondiabetic patients with ST-segment elevation MI (n = 22) underwent direct measurement of IS through the euglycemic hyperinsulinemic clamp on the first morning and on the fifth day after onset of MI. Patients were grouped according to HDL-C levels at admission above and below the median value (35 mg/dL). At admission, there was no significant difference in baseline IS index, clinical, anthropometric, or treatment characteristics between low and high HDL groups. Between admission and fifth day, there was a decrease of 8% in IS index in the low HDL group and an 11% increase in the high HDL group (P = .001 for intragroup and P = .012 for intergroup difference). This difference remained significant after we controlled for the sex, age, waist circumference, triglycerides, baseline IS index, and statin dose during hospitalization. This is the first study to provide evidence that plasma levels of HDL-C are strongly associated with the recovery rate of IS during the acute phase of MI. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  12. A-FABP Concentration Is More Strongly Associated with Cardiometabolic Risk Factors and the Occurrence of Metabolic Syndrome in Premenopausal Than in Postmenopausal Middle-Aged Women

    Directory of Open Access Journals (Sweden)

    Anna Stefanska

    2014-01-01

    Full Text Available We aimed at the evaluation of the relationship between adipocyte fatty acid binding protein (A-FABP and cardiometabolic risk factors in premenopausal and postmenopausal women. Additionally, we compared A-FABP with adipokines related to metabolic syndrome (MetS such as leptin and adiponectin. 94 premenopausal and 90 early postmenopausal middle-aged Caucasian women were subject to examinations. Postmenopausal women had higher A-FABP than premenopausal; this difference became insignificant after controlling for age. We found significantly higher correlation coefficients between A-FABP and TC/HDL-C ratio and number of MetS components in premenopausal women, compared to postmenopausal. Each 1 ng/dL increase in A-FABP concentration significantly increased the probability of occurrence of atherogenic lipid profile in premenopausal women, even after multivariate adjustment. All odds ratios became insignificant after controlling for BMI in postmenopausal women. A-FABP was more strongly associated with MetS than leptin and adiponectin in premenopausal women. Adiponectin concentration was a better biomarker for MetS after menopause. Our results suggest that the A-FABP is more strongly associated with some cardiometabolic risk factors in premenopausal than in postmenopausal women. Higher values of A-FABP after menopause are mainly explained by the fact that postmenopausal women are older. Because of the limitation of study, these results should be interpreted with caution.

  13. Is prehypertension more strongly associated with long-term ambient air pollution exposure than hypertension? Findings from the 33 Communities Chinese Health Study.

    Science.gov (United States)

    Yang, Bo-Yi; Qian, Zhengmin Min; Vaughn, Michael G; Nelson, Erik J; Dharmage, Shyamali C; Heinrich, Joachim; Lin, Shao; Lawrence, Wayne R; Ma, Huimin; Chen, Duo-Hong; Hu, Li-Wen; Zeng, Xiao-Wen; Xu, Shu-Li; Zhang, Chuan; Dong, Guang-Hui

    2017-10-01

    Numerous studies have evaluated the effects of long-term exposure to ambient air pollution on hypertension. However, little information exists regarding its effects on prehypertension, a very common, but understudied cardiovascular indicator. We evaluated data from 24,845 adults (ages 18-74 years) living in three Northeastern Chinese cities in 2009. Blood pressure (BP) was measured by trained observers using a standardized mercuric-column sphygmomanometer. Three-year (from 2006 to 2008) average concentrations of particles with an aerodynamic diameter ≤10 μm (PM 10 ), sulfur dioxide (SO 2 ), nitrogen dioxides (NO 2 ), and ozone (O 3 ) were calculated using data from monitoring stations. Effects were analyzed using generalized additive models and two-level regression analyses, controlling for covariates. We found positive associations of all pollutants with prehypertension (e.g. odds ratio (OR) was 1.17 (95% confidence interval (CI), 1.09-1.25) per interquartile range (IQR) of PM 10 ) in a fully adjusted model, as compared to normotensive participants. These associations were stronger than associations with hypertension (e.g. OR was 1.03 (95% CI, 1.00, 1.07) per IQR of PM 10 ). We have also found positive associations of all studied pollutants with systolic and diastolic BP: e.g., associations with PM 10 per IQR were 1.24 mmHg (95% CI, 1.03-1.45) for systolic BP and 0.47 mmHg (95% CI, 0.33-0.61) for diastolic BP. Further, we observed that associations with BP were stronger in women and in older participants (systolic BP only). In conclusion, long-term exposure to ambient air pollution was more strongly associated with prehypertension than with hypertension, especially among females and the elderly. Thus, interventions to reduce air pollution are of great significance for preventing future cardiovascular events, particularly among individuals with prehypertension. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Cancer association study of aminoacyl-tRNA synthetase signaling network in glioblastoma.

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    Yong-Wan Kim

    Full Text Available Aminoacyl-tRNA synthetases (ARSs and ARS-interacting multifunctional proteins (AIMPs exhibit remarkable functional versatility beyond their catalytic activities in protein synthesis. Their non-canonical functions have been pathologically linked to cancers. Here we described our integrative genome-wide analysis of ARSs to show cancer-associated activities in glioblastoma multiforme (GBM, the most aggressive malignant primary brain tumor. We first selected 23 ARS/AIMPs (together referred to as ARSN, 124 cancer-associated druggable target genes (DTGs and 404 protein-protein interactors (PPIs of ARSs using NCI's cancer gene index. 254 GBM affymetrix microarray data in The Cancer Genome Atlas (TCGA were used to identify the probe sets whose expression were most strongly correlated with survival (Kaplan-Meier plots versus survival times, log-rank t-test <0.05. The analysis identified 122 probe sets as survival signatures, including 5 of ARSN (VARS, QARS, CARS, NARS, FARS, and 115 of DTGs and PPIs (PARD3, RXRB, ATP5C1, HSP90AA1, CD44, THRA, TRAF2, KRT10, MED12, etc. Of note, 61 survival-related probes were differentially expressed in three different prognosis subgroups in GBM patients and showed correlation with established prognosis markers such as age and phenotypic molecular signatures. CARS and FARS also showed significantly higher association with different molecular networks in GBM patients. Taken together, our findings demonstrate evidence for an ARSN biology-dominant contribution in the biology of GBM.

  15. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.

    Directory of Open Access Journals (Sweden)

    In Ah Park

    Full Text Available Tumor-infiltrating lymphocytes (TILs have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC. Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042; larger amounts of TILs (p < 0.001; frequent formations of tertiary lymphoid structures (p < 0.001; higher expression of myxovirus resistance gene A, one of the main mediators of the interferon signaling pathway (p < 0.001; and higher expression of double-stranded RNA-activated protein kinase, which can be induced by interferons (p = 0.008. Moreover, tumors that showed high MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p < 0.001. Positive MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009. In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy.

  16. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organisms as diverse as humans and fruit flies. It plays a pivotal role in cell fate determination. Dysregulated Notch signalling is oncogenic, inhibits apoptosis and promotes cell survival. Abnormal Notch ...

  17. Redox-Dependent Calcium-Mediated Signaling Networks that Control the Senescence-Associated Secretory Phenotype

    Science.gov (United States)

    Chandrasekaran, Akshaya

    Cellular senescence has evolved as a protective mechanism to arrest growth of cells with oncogenic potential. While senescent cells have lost the ability to divide, they remain metabolically active and adapt a deleterious senescence associated secretory phenotype (SASP) central to the progression of several age-associated disease pathologies. The SASP is mechanistically regulated by the pro-inflammatory cytokine interleukin-1 alpha (IL-1alpha) whose expression and activity is responsive to the senescence associated (SA) oxidant production and the accompanying disruption of calcium (Ca2+) homeostasis. Using primary IMR-90 human fetal lung fibroblasts as a model of replicative senescence, we explored the molecular underpinnings driving Ca2+ dysregulation in senescent cells. We establish that the redox-responsive Transient Receptor Potential TRPC6 channel is compromised due to desensitization owing to SA increases in steady state hydrogen peroxide (H2O2) production. SA dysregulation of Ca2+ is also accompanied by loss of response to H2O2-induced Ca2+ influx that can be rescued with catalase pre-treatments. Senescent cells are also insensitive to Ca2+ entry induced by hyperforin, a specific activator of TRPC6, that can be restored by catalase pre-treatments, further suggesting redox regulation of TRPC6 in senescence. Inhibition of TRPC6 channel activity restores the ability of senescent cells to respond to peroxide-induced Ca2+ in addition to suppressing SASP gene expression. Furthermore, mammalian target of rapamycin (mTOR) signaling regulates SASP by means of modulating TRPC6 channel expression. Together, our findings provide compelling evidence that redox and mTOR-mediated regulation of TRPC6 channel modulate SASP gene expression. Further, the gain-of-function mutation of TRPC6 has pathological implications in several chronic pathologies and renders it a viable target in age-associated diseases.

  18. A model for the biosynthesis and transport of plasma membrane-associated signaling receptors to the cell surface

    Directory of Open Access Journals (Sweden)

    Sorina Claudia Popescu

    2012-04-01

    Full Text Available Intracellular protein transport is emerging as critical in determining the outcome of receptor-activated signal transduction pathways. In plants, relatively little is known about the nature of the molecular components and mechanisms involved in coordinating receptor synthesis and transport to the cell surface. Recent advances in this field indicate that signaling pathways and intracellular transport machinery converge and coordinate to render receptors competent for signaling at their plasma membrane activity sites. The biogenesis and transport to the cell surface of signaling receptors appears to require both general trafficking and receptor-specific factors. Several molecular determinants, residing or associated with compartments of the secretory pathway and known to influence aspects in receptor biogenesis, are discussed and integrated into a predictive cooperative model for the functional expression of signaling receptors at the plasma membrane.

  19. Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes.

    Science.gov (United States)

    Liu, Lin; Feng, Jitao; Zhang, Gong; Yuan, Xiaodan; Li, Fan; Yang, Tingting; Hao, Shujie; Huang, Dejian; Hsue, Cunyi; Lou, Qinging

    2018-01-01

    To investigate the value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in a cohort of a community's residents who were diagnosed as pre-diabetes, and to evaluate the association of VAT and SAT with insulin resistance. This study was based on cross-sectional analysis of data from 107 adults. VAT and SAT were assessed by computed tomography. Insulin resistance was defined by homeostasis model assessment of insulin resistance >2.69. The relationship of VAT and SAT with insulin resistance were examined by linear regression. Logistic regression was used to analyze the association of VAT and SAT with insulin resistance. A total of 87 subjects had VAT ≥100 cm 2 . Thirty-six out of 107 (33.6%) subjects were detected to have insulin resistance, 71 were normal (66.4%), and all had insulin resistance with VAT ≥100 cm 2 . VAT (r = 0.378, p VAT and SAT were simultaneously included after adjustment for age, gender, BMI, and WC, the association between VAT and insulin resistance was still maintained (p = .003), but that of SAT was lost. Pre-diabetic subjects with insulin resistance had elevated levels of VAT. VAT was more strongly associated with insulin resistance than SAT in Chinese subjects with pre-diabetes.

  20. Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation.

    Science.gov (United States)

    Feld, Gordon B; Wilhem, Ines; Benedict, Christian; Rüdel, Benjamin; Klameth, Corinna; Born, Jan; Hallschmid, Manfred

    2016-05-01

    The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18-30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information.

  1. Cell Death-Associated Molecular-Pattern Molecules: Inflammatory Signaling and Control

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    Beatriz Sangiuliano

    2014-01-01

    Full Text Available Apoptosis, necroptosis, and pyroptosis are different cellular death programs characterized in organs and tissues as consequence of microbes infection, cell stress, injury, and chemotherapeutics exposure. Dying and death cells release a variety of self-proteins and bioactive chemicals originated from cytosol, nucleus, endoplasmic reticulum, and mitochondria. These endogenous factors are named cell death-associated molecular-pattern (CDAMP, damage-associated molecular-pattern (DAMP molecules, and alarmins. Some of them cooperate or act as important initial or delayed inflammatory mediators upon binding to diverse membrane and cytosolic receptors coupled to signaling pathways for the activation of the inflammasome platforms and NF-κB multiprotein complexes. Current studies show that the nonprotein thiols and thiol-regulating enzymes as well as highly diffusible prooxidant reactive oxygen and nitrogen species released together in extracellular inflammatory milieu play essential role in controlling pro- and anti-inflammatory activities of CDAMP/DAMP and alarmins. Here, we provide an overview of these emerging concepts and mechanisms of triggering and maintenance of tissue inflammation under massive death of cells.

  2. Serum uric acid is more strongly associated with impaired fasting glucose in women than in men from a community-dwelling population.

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    Ryuichi Kawamoto

    Full Text Available Serum uric acid (SUA levels are associated with metabolic syndrome (MetS and its components such as glucose intolerance and type 2 diabetes. It is unknown whether there are gender-specific differences regarding the relationship between SUA levels, impaired fasting glucose (IFG and newly detected diabetes. We recruited 1,209 men aged 60±15 (range, 19-89 years and 1,636 women aged 63±12 (range, 19-89 years during their annual health examination from a single community. We investigated the association between SUA levels and six categories according to fasting plasma glucose (FPG level {normal fasting glucose (NFG, <100 mg/dL; high NFG-WHO, 100 to 109 mg/dL; IFG-WHO, 110 to 125 mg/dL; IFG-ADA, 100 to 125 mg/dL; newly detected diabetes, ≥126 mg/dL; known diabetes} SUA levels were more strongly associated with the different FPG categories in women compared with men. In women, the associations remained significant for IFG-WHO (OR, 1.23, 95% CI, 1.00-1.50 and newly detected diabetes (OR, 1.33, 95% CI, 1.03-1.72 following multivariate adjustment. However, in men all the associations were not significant. Thus, there was a significant interaction between gender and SUA level for newly detected diabetes (P = 0.005. SUA levels are associated with different categories of impaired fasting glucose in participants from community-dwelling persons, particularly in women.

  3. Association of BAFF with PI3K/Akt/mTOR signaling in lupus nephritis.

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    Ge, Fengmei; Wang, Fangfang; Yan, Xiuqing; Li, Zhao; Wang, Xuebin

    2017-11-01

    Systemic lupus erythematosus is a connective tissue disease characterized by autoimmune inflammation, which leads to specific and nonspecific immune disorders with the formation of various autoantibodies by activated B cells. B‑cell‑activating factor (BAFF) is secreted by macrophages and activated T cells, and is responsible for the proliferation, maturation and differentiation of B cells. However, the mechanism of BAFF involvement in lupus nephritis (LN) remains unclear. The aim of the present study was to investigate the association between BAFF and phosphoinositide 3‑kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling in order to elucidate the pathogenesis of LN. In the present study, 18 patients with LN and 20 controls were included. The clinical data were analyzed and plasma levels of BAFF were measured using an ELISA. The mRNA and protein levels of BAFF, phosphorylated (p)‑PI3K, p‑Akt and p‑mTOR in kidney tissues were measured using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting. Plasma BAFF levels were significantly increased in patients with LN compared with the controls (PBAFF, p‑PI3K, p‑Akt and p‑mTOR in kidney tissue were significantly increased in patients with LN compared with the controls (all PBAFF in the kidney tissues of patients with LN were positively correlated with the levels of p‑PI3K, p‑Akt and p‑mTOR. The results of the present study revealed a correlation between BAFF and the PI3K/Akt/mTOR signaling pathway, and it is hypothesized that they are involved in the pathogenesis of LN.

  4. Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche.

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    Chen-Yuan Tseng

    2014-12-01

    Full Text Available Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs, and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.

  5. Musicianship and Tone Language Experience Are Associated with Differential Changes in Brain Signal Variability.

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    Hutka, Stefanie; Carpentier, Sarah M; Bidelman, Gavin M; Moreno, Sylvain; McIntosh, Anthony R

    2016-12-01

    Musicianship has been associated with auditory processing benefits. It is unclear, however, whether pitch processing experience in nonmusical contexts, namely, speaking a tone language, has comparable associations with auditory processing. Studies comparing the auditory processing of musicians and tone language speakers have shown varying degrees of between-group similarity with regard to perceptual processing benefits and, particularly, nonlinguistic pitch processing. To test whether the auditory abilities honed by musicianship or speaking a tone language differentially impact the neural networks supporting nonlinguistic pitch processing (relative to timbral processing), we employed a novel application of brain signal variability (BSV) analysis. BSV is a metric of information processing capacity and holds great potential for understanding the neural underpinnings of experience-dependent plasticity. Here, we measured BSV in electroencephalograms of musicians, tone language-speaking nonmusicians, and English-speaking nonmusicians (controls) during passive listening of music and speech sound contrasts. Although musicians showed greater BSV across the board, each group showed a unique spatiotemporal distribution in neural network engagement: Controls had greater BSV for speech than music; tone language-speaking nonmusicians showed the opposite effect; musicians showed similar BSV for both domains. Collectively, results suggest that musical and tone language pitch experience differentially affect auditory processing capacity within the cerebral cortex. However, information processing capacity is graded: More experience with pitch is associated with greater BSV when processing this cue. Higher BSV in musicians may suggest increased information integration within the brain networks subserving speech and music, which may be related to their well-documented advantages on a wide variety of speech-related tasks.

  6. IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population

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    Lynnette R. Ferguson

    2010-01-01

    Full Text Available DNA samples from 339 Crohn's disease (CD and 407 randomly selected controls from the Auckland (New Zealand IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677 and two in IL-12B (rs1363670 and rs6887695. While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17–40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.

  7. Quantitative analysis of species specificity of two anti-parvalbumin antibodies for detecting southern hemisphere fish species demonstrating strong phylogenetic association.

    Science.gov (United States)

    Liang, Ji; Tan, Chui Choo; Taylor, Steve L; Baumert, Joseph L; Lopata, Andreas L; Lee, N Alice

    2017-12-15

    This study aimed to develop a novel approach to determine the correlation between the parvalbumin (PAV) contents and their corresponding immunoreactivity (detectability) in southern hemisphere fish species. The immuno-detected PAV contents of the test fish species were estimated by a quantitative SDS-PAGE. A quantitative Enzyme-Linked ImmunoSorbent Assay (ELISA) was formatted to assess relative immunoreactivity of PAV. Sixteen species (forty-three percent) displayed a positive correlation with the anti-cod PAV polyclonal antibody, but no correlation with the anti-carp PAV monoclonal antibody. There was a strong phylogenetic association of the PAV immunoreactivity. Species from the order of Perciformes showed strong binding with both antibodies; whereas species from Salmoniformes, Ophidiiformes, Scombriformes, Scorpaeniformes, and Tetraodontiformes showed weak or no binding. This approach showed for the first time a statistical correlation between the PAV content and the immunoreactivity and allowed to rank the relative species/order specificity of the two antibodies for the southern hemisphere fish PAV. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Peripheral Zone Inflammation is Not Strongly Associated with Lower Urinary Tract Symptom Incidence and Progression in the Placebo Arm of the Prostate Cancer Prevention Trial*

    Science.gov (United States)

    Kulac, Ibrahim; Gumuskaya, Berrak; Drake, Charles G.; Gonzalez, Beverly; Arnold, Kathryn B.; Goodman, Phyllis J.; Kristal, Alan R.; Lucia, M. Scott; Thompson, Ian M.; Isaacs, William B.; De Marzo, Angelo M.; Platz, Elizabeth A.

    2017-01-01

    Background Intraprostatic inflammation has been associated with lower urinary tract symptom (LUTS) progression. However, prior studies used tissue removed for clinical indications, potentially skewing inflammation extent or biasing the association. We, therefore, evaluated inflammation and LUTS incidence and progression in men who underwent biopsy of the prostate peripheral zone irrespective of indication. Material and Methods We developed nested case-control sets in men in the placebo arm of the Prostate Cancer Prevention Trial who were free of clinical BPH and had a protocol-directed year 7 biopsy. Cases had baseline IPSS 75th percentile (N = 46) and controls had a slope 75th percentile (N = 46) and controls had a slope inflammation and mean extent (%) of tissue area with inflammation. Results Inflammation prevalence in low cases (64%) was similar to controls (66%), but higher in moderate (69%) and high (73%) cases (P-trend = 0.4). Extent did not differ across LUTS categories (P-trend = 0.5). For progression from IPSS inflammation (10.1% versus 4.6%, P = 0.06). Conclusion Peripheral zone intraprostatic inflammation is not strongly associated with LUTS incidence or progression. PMID:27325488

  9. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

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    Cox, David G.; Curtit, Elsa; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Hervé; Bachelot, Thomas; Soulié, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine; Darut-Jouve, Ariane; Ferrero, Jean-Marc; Tarpin, Carole; Lévy, Christelle; Delecroix, Valérie; Trillet-Lenoir, Véronique; Cojocarasu, Oana; Meunier, Jérôme; Pierga, Jean-Yves; Faure-Mercier, Céline; Blanché, Hélène; Sahbatou, Mourad; Boland, Anne; Bacq, Delphine; Besse, Céline; Deleuze, Jean-François; Pauporté, Iris; Thomas, Gilles; Pivot, Xavier

    2016-01-01

    Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10−12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10−11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors. PMID:27764800

  10. Extracellular cAMP activates molecular signalling pathways associated with sperm capacitation in bovines.

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    Alonso, Carlos Agustín I; Osycka-Salut, Claudia E; Castellano, Luciana; Cesari, Andreína; Di Siervi, Nicolás; Mutto, Adrián; Johannisson, Anders; Morrell, Jane M; Davio, Carlos; Perez-Martinez, Silvina

    2017-08-01

    Is extracellular cAMP involved in the regulation of signalling pathways in bovine sperm capacitation? Extracellular cAMP induces sperm capacitation through the activation of different signalling pathways that involve phospholipase C (PLC), PKC/ERK1-2 signalling and an increase in sperm Ca2+ levels, as well as soluble AC and cAMP/protein kinase A (PKA) signalling. In order to fertilize the oocyte, ejaculated spermatozoa must undergo a series of changes in the female reproductive tract, known as capacitation. This correlates with a number of membrane and metabolic modifications that include an increased influx of bicarbonate and Ca2+, activation of a soluble adenylyl cyclase (sAC) to produce cAMP, PKA activation, protein tyrosine phosphorylation and the development of hyperactivated motility. We previously reported that cAMP efflux by Multidrug Resistance Protein 4 (MRP4) occurs during sperm capacitation and the pharmacological blockade of this inhibits the process. Moreover, the supplementation of incubation media with cAMP abolishes the inhibition and leads to sperm capacitation, suggesting that extracellular cAMP regulates crucial signalling cascades involved in this process. Bovine sperm were selected by the wool glass column method, and washed by centrifugation in BSA-Free Tyrode's Albumin Lactate Pyruvate (sp-TALP). Pellets were resuspended then diluted for each treatment. For in vitro capacitation, 10 to 15 × 106 SPZ/ml were incubated in 0.3% BSA sp-TALP at 38.5°C for 45 min under different experimental conditions. To evaluate the role of extracellular cAMP on different events associated with sperm capacitation, 10 nM cAMP was added to the incubation medium as well as different inhibitors of enzymes associated with signalling transduction pathways: U73122 (PLC inhibitor, 10 μM), Gö6983 (PKC inhibitor, 10 μM), PD98059 (ERK-1/2 inhibitor, 30 μM), H89 and KT (PKA inhibitors, 50 μM and 100 nM, respectively), KH7 (sAC inhibitor, 10 μM), BAPTA

  11. Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis.

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    Nishi Gupta

    Full Text Available Methylenetetrahydrofolate reductase (MTHFR is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies.We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522 and confirmed fertile (N = 315 individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2. The frequency of mutant (T allele (p = 0.0025 and genotypes (CT+TT (p = 0.0187 was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR for allele and genotype meta-analysis were 1.304 (p = 0.000, 1.310 (p = 0.000, respectively, establishing significant association of 677C>T polymorphism with male infertility.677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.

  12. DMPD: The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling networks controlling inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available ases (IRAKs) incellular signaling networks controlling inflammation. PubmedID 182...49132 Title The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling network...18249132 The involvement of the interleukin-1 receptor-associated kinases (IRAKs) i...ncellular signaling networks controlling inflammation. Ringwood L, Li L. Cytokine. 2008 Apr;42(1):1-7. Epub

  13. The Mediterranean Diet Score Is More Strongly Associated with Favorable Cardiometabolic Risk Factors over 2 Years Than Other Diet Quality Indexes in Puerto Rican Adults.

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    Mattei, Josiemer; Sotos-Prieto, Mercedes; Bigornia, Sherman J; Noel, Sabrina E; Tucker, Katherine L

    2017-04-01

    Background: Multiple diet quality scores have been used to evaluate adherence to specific dietary recommendations or to consumption of healthful foods and nutrients. It remains unknown which score can more strongly predict longitudinal changes in cardiometabolic risk factors. Objective: We aimed to determine associations of 5 diet quality scores [AHA diet score (AHA-DS), Dietary Approaches to Stop Hypertension (DASH), Healthy Eating Index (HEI)-2005, Mediterranean diet score (MeDS), and Alternative Healthy Eating Index (AHEI)] with 2-y changes in cardiometabolic risk factors in adults 45-75 y old. Methods: Data from the Boston Puerto Rican Health Study were analyzed ( n = 1194). Diet quality scores were calculated from a baseline-validated food-frequency questionnaire. Multivariable-adjusted, repeated-subjects, mixed-effects models, adjusted for baseline measures, estimated associations between each z score and 14 individual cardiometabolic factors measured at 2 y. Results: MeDS was significantly associated with lower 2-y waist circumference (β coefficient ± SE: -0.52 ± 0.26, P = 0.048); body mass index (BMI; -0.23 ± 0.08, P = 0.005); log-insulin (-0.06 ± 0.02, P = 0.005); log-homeostasis model assessment of insulin resistance (HOMA-IR; -0.05 ± 0.02, P = 0.030), and log-C-reactive protein (-0.13 ± 0.03, P = 0.0002). Similar but weaker associations were observed for the AHEI with BMI, insulin, and HOMA-IR. The AHA-DS was inversely associated with BMI (-0.17 ± 0.08, P = 0.033). Neither the HEI-2005 nor DASH was significantly associated with any variable. Traditional Puerto Rican foods consumed by individuals with high MeDSs included vegetables and meats in homemade soups, orange juice, oatmeal, beans and legumes, fish, whole milk, corn oil, and beer. Conclusions: The MeDS comprises food components and scores associated with a favorable cardiometabolic profile over 2 y in Puerto Rican adults. An overall healthy diet may be particularly beneficial for

  14. Is arson the crime most strongly associated with psychosis?--A national case-control study of arson risk in schizophrenia and other psychoses.

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    Anwar, Sophia; Långström, Niklas; Grann, Martin; Fazel, Seena

    2011-05-01

    The association of psychosis with certain serious crimes, such as homicide, has been clearly demonstrated, but it is uncertain to what extent psychotic disorders are associated with arson. We used a case-control design to investigate the association of being diagnosed with schizophrenia and other psychoses and committing arson. Data were obtained from Swedish national registers for criminal convictions, hospital discharge diagnoses (International Classification of Diseases, Ninth Revision [ICD-9], and International Classification of Diseases, Tenth Revision [ICD-10]), and sociodemographic factors for 1988-2000. We included all convicted arson offenders of both sexes in Sweden (N=1689) and compared them with a random sample of general population control subjects (N=40,560). After adjustment for sociodemographic confounders, arson offenders were more likely to be diagnosed with schizophrenia (in men, adjusted odds ratio [OR]=22.6, 95% confidence interval [CI]=14.8-34.4; in women, adjusted OR=38.7, 95% CI=20.4-73.5) or other psychoses (in men, adjusted OR=17.4, 95% CI=11.1-27.5; in women, adjusted OR=30.8, 95% CI=18.8-50.6). Individuals with schizophrenia and other psychoses have significantly increased risks of an arson conviction. These risk estimates are higher than those reported for other violent crimes and place arson in the same category as homicide as crimes that are most strongly associated with psychotic disorders. © The Author 2009. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

  15. Association of interleukin-6 signalling with the muscle stem cell response following muscle-lengthening contractions in humans.

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    Bryon R McKay

    IL-6 within SCs demonstrate that IL-6/STAT3 signaling occurred in SCs, correlating with an increase in SC proliferation, evidenced by increased Pax7(+/PCNA(+ cell number in the early stages of the time-course. Collectively, these data illustrate that IL-6 is an important signaling molecule associated with the SC response to acute muscle-lengthening contractions in humans.

  16. Heavy Metal Stress, Signaling, and Tolerance Due to Plant-Associated Microbes: An Overview

    Science.gov (United States)

    Tiwari, Shalini; Lata, Charu

    2018-01-01

    Several anthropogenic activities including mining, modern agricultural practices, and industrialization have long-term detrimental effect on our environment. All these factors lead to increase in heavy metal concentration in soil, water, and air. Soil contamination with heavy metals cause several environmental problems and imparts toxic effect on plant as well as animals. In response to these adverse conditions, plants evolve complex molecular and physiological mechanisms for better adaptability, tolerance, and survival. Nowadays conventional breeding and transgenic technology are being used for development of metal stress resistant varieties which, however, are time consuming and labor intensive. Interestingly the use of microbes as an alternate technology for improving metal tolerance of plants is gaining momentum recently. The use of these beneficial microorganisms is considered as one of the most promising methods for safe crop-management practices. Interaction of plants with soil microorganisms can play a vital role in acclimatizing plants to metalliferous environments, and can thus be explored to improve microbe-assisted metal tolerance. Plant-associated microbes decrease metal accumulation in plant tissues and also help to reduce metal bioavailability in soil through various mechanisms. Nowadays, a novel phytobacterial strategy, i.e., genetically transformed bacteria has been used to increase remediation of heavy metals and stress tolerance in plants. This review takes into account our current state of knowledge of the harmful effects of heavy metal stress, the signaling responses to metal stress, and the role of plant-associated microbes in metal stress tolerance. The review also highlights the challenges and opportunities in this continued area of research on plant–microbe–metal interaction. PMID:29681916

  17. Heavy Metal Stress, Signaling, and Tolerance Due to Plant-Associated Microbes: An Overview

    Directory of Open Access Journals (Sweden)

    Shalini Tiwari

    2018-04-01

    Full Text Available Several anthropogenic activities including mining, modern agricultural practices, and industrialization have long-term detrimental effect on our environment. All these factors lead to increase in heavy metal concentration in soil, water, and air. Soil contamination with heavy metals cause several environmental problems and imparts toxic effect on plant as well as animals. In response to these adverse conditions, plants evolve complex molecular and physiological mechanisms for better adaptability, tolerance, and survival. Nowadays conventional breeding and transgenic technology are being used for development of metal stress resistant varieties which, however, are time consuming and labor intensive. Interestingly the use of microbes as an alternate technology for improving metal tolerance of plants is gaining momentum recently. The use of these beneficial microorganisms is considered as one of the most promising methods for safe crop-management practices. Interaction of plants with soil microorganisms can play a vital role in acclimatizing plants to metalliferous environments, and can thus be explored to improve microbe-assisted metal tolerance. Plant-associated microbes decrease metal accumulation in plant tissues and also help to reduce metal bioavailability in soil through various mechanisms. Nowadays, a novel phytobacterial strategy, i.e., genetically transformed bacteria has been used to increase remediation of heavy metals and stress tolerance in plants. This review takes into account our current state of knowledge of the harmful effects of heavy metal stress, the signaling responses to metal stress, and the role of plant-associated microbes in metal stress tolerance. The review also highlights the challenges and opportunities in this continued area of research on plant–microbe–metal interaction.

  18. Gastric Metaplasia Induced by Helicobacter pylori Is Associated with Enhanced SOX9 Expression via Interleukin-1 Signaling.

    Science.gov (United States)

    Serizawa, Takako; Hirata, Yoshihiro; Hayakawa, Yoku; Suzuki, Nobumi; Sakitani, Kosuke; Hikiba, Yohko; Ihara, Sozaburo; Kinoshita, Hiroto; Nakagawa, Hayato; Tateishi, Keisuke; Koike, Kazuhiko

    2016-02-01

    Histopathological changes of the gastric mucosa after Helicobacter pylori infection, such as atrophy, metaplasia, and dysplasia, are considered to be precursors of gastric cancer, yet the mechanisms of histological progression are unknown. The aim of this study was to analyze the histopathological features of the gastric mucosa in mice infected with H. pylori strain PMSS1 in relation to gastric stem cell marker expression. C57BL/6J mice infected with PMSS1 were examined for histopathological changes, levels of proinflammatory cytokines, and expression of stem cell markers. Histopathological gastritis scores, such as atrophy and metaplasia, and levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), were increased after PMSS1 infection. Expression levels of the cell proliferation and stem cell markers CD44 and SOX9 were also significantly increased in PMSS1-infected mice. Importantly, almost all metaplastic cells induced by PMSS1 infection expressed SOX9. When IL-1 receptor (IL-1R) knockout mice were infected with PMSS1, metaplastic changes and expression levels of stem cell markers were significantly decreased compared with those in wild-type (WT) mice. In conclusion, H. pylori infection induced the expression of cytokines and stem cell markers and histopathological metaplasia in the mouse gastric mucosa. SOX9 expression, in particular, was strongly associated with metaplastic changes, and these changes were dependent on IL-1 signaling. The results suggested the importance of SOX9 in gastric carcinogenesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  19. Signal transduction of MCP-1 expression induced by pancreatitis-associated ascitic fluid in pancreatic acinar cells

    Science.gov (United States)

    Ramudo, Laura; Yubero, Sara; Manso, Manuel A; Vicente, Secundino; De Dios, Isabel

    2009-01-01

    Pancreatitis-associated ascitic fluid (PAAF) is known to contribute to the progression of acute pancreatitis (AP). We have investigated the capability of PAAF to activate the expression of MCP-1 in pancreatic acinar cells and the involvement of MAPK, NF-κB and STAT3 as downstream signalling transduction pathways. The actions of dexamethasone (Dx) and N-acetylcysteine (NAC) on the PAAF’s acinar effects have also been evaluated. Acinar cells were incubated for 1 hr with PAAF collected from rats with severe AP induced by sodium taurocholate in the absence or presence of Dx (10−7 M) or NAC (30 mM). MCP-1 mRNA expression, phospho-p38-MAPK, IκBα, nuclear p65 levels and nuclear translocation of STAT3 were analysed. In response to PAAF, overexpression of MCP-1, phosphorylation of p38-MAPK, degradation of IκBα and increases in p65 nuclear levels and STAT3 activity were found in acinar cells. PAAF-mediated MCP-1 up-regulation was completely suppressed by Dx and NAC. MAPK activation was only inhibited by NAC, NF-κB activation was repressed by Dx and NAC, and STAT3 pathway was strongly blocked by Dx and significantly reduced by NAC. In conclusion, acinar cells were activated by PAAF to produce MCP-1, mainly via NF-κB and STAT3 pathways. Both downstream pathways were targeted by Dx and NAC to repress the PAAF-mediated acinar MCP-1 up-regulation. PMID:19604316

  20. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage.

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    Pavel Krejci

    Full Text Available Activating mutations in FGFR3 tyrosine kinase cause several forms of human skeletal dysplasia. Although the mechanisms of FGFR3 action in cartilage are not completely understood, it is believed that the STAT1 transcription factor plays a central role in pathogenic FGFR3 signaling. Here, we analyzed STAT1 activation by the N540K, G380R, R248C, Y373C, K650M and K650E-FGFR3 mutants associated with skeletal dysplasias. In a cell-free kinase assay, only K650M and K650E-FGFR3 caused activatory STAT1(Y701 phosphorylation. Similarly, in RCS chondrocytes, HeLa, and 293T cellular environments, only K650M and K650E-FGFR3 caused strong STAT1 activation. Other FGFR3 mutants caused weak (HeLa or no activation (293T and RCS. This contrasted with ERK MAP kinase activation, which was strongly induced by all six mutants and correlated with the inhibition of proliferation in RCS chondrocytes. Thus the ability to activate STAT1 appears restricted to the K650M and K650E-FGFR3 mutants, which however account for only a small minority of the FGFR3-related skeletal dysplasia cases. Other pathways such as ERK should therefore be considered as central to pathological FGFR3 signaling in cartilage.

  1. Problems Associated with Statistical Pattern Recognition of Acoustic Emission Signals in a Compact Tension Fatigue Specimen

    Science.gov (United States)

    Hinton, Yolanda L.

    1999-01-01

    Acoustic emission (AE) data were acquired during fatigue testing of an aluminum 2024-T4 compact tension specimen using a commercially available AE system. AE signals from crack extension were identified and separated from noise spikes, signals that reflected from the specimen edges, and signals that saturated the instrumentation. A commercially available software package was used to train a statistical pattern recognition system to classify the signals. The software trained a network to recognize signals with a 91-percent accuracy when compared with the researcher's interpretation of the data. Reasons for the discrepancies are examined and it is postulated that additional preprocessing of the AE data to focus on the extensional wave mode and eliminate other effects before training the pattern recognition system will result in increased accuracy.

  2. Association of cannabis use during adolescence, prefrontal CB1 receptor signaling and schizophrenia

    Directory of Open Access Journals (Sweden)

    Adriana eCaballero

    2012-05-01

    Full Text Available The cannabinoid receptor 1 (CB1R is the G-protein coupled receptor responsible for the majority of the endocannabinoid signaling in the human brain. It is widely distributed in the limbic system, basal ganglia, and cerebellum, which are areas responsible for cognition, memory, and motor control. Because of this widespread distribution, it is not surprising that drugs that co-opt CB1R have expected behavioral outcomes consistent with dysregulated signaling from these areas (e.g. memory loss, cognitive deficits, etc. In the context of this review, we present evidence for the role of CB1R signaling in the prefrontal cortex (PFC, an area involved in executive functions, with emphasis on the developmental regulation of CB1R signaling in the acquisition of mature PFC function. We further hypothesize how alterations of CB1R signaling specifically during adolescent maturation might confer liability to psychiatric disorders.

  3. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.

    Science.gov (United States)

    Park, In Ah; Hwang, Seong-Hye; Song, In Hye; Heo, Sun-Hee; Kim, Young-Ae; Bang, Won Seon; Park, Hye Seon; Lee, Miseon; Gong, Gyungyub; Lee, Hee Jin

    2017-01-01

    Tumor-infiltrating lymphocytes (TILs) have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC). Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II) is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042); larger amounts of TILs (p MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009). In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy.

  4. A meta-analysis of drug resistant tuberculosis in Sub-Saharan Africa: how strongly associated with previous treatment and HIV co-infection?

    Science.gov (United States)

    Berhan, Asres; Berhan, Yifru; Yizengaw, Desalegn

    2013-11-01

    In Sub-Saharan Africa, the fight against tuberculosis (TB) has encountered a great challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV infection. The aim of this meta-analysis was to determine the association of drug-resistant TB with anti-TB drug treatment history and HIV co-infection. After electronic based literature search in the databases of Medline, HINARI, EMBASE and the Cochrane library, article selection and data extraction were carried out. HIV co-infection and previous history of TB treatment were used as predictors for the occurrence of any anti-TB drug resistant or multiple drug resistant TB (MDR-TB). The risk ratios for each included study and for the pooled sample were computed using the random-effects model. Heterogeneity test, sensitivity analyses and funnel plots were also done. The pooled analysis showed that the risk of developing drug-resistant TB to at least one anti-TB drug was about 3 times higher in individuals who had a previous history of anti-TB treatment than new TB cases. The risk of having MDR-TB in previously anti-TB treated TB cases was more than 5-fold higher than that of new TB cases. Resistance to Ethambutol and Rifampicin was more than fivefold higher among the previously treated with anti-TB drugs. However, HIV infection was not associated with drug-resistant TB. There was a strong association of previous anti-TB treatment with MDR-TB. Primary treatment warrants special emphasis, and screening for anti-TB drugs sensitivity has to be strengthened.

  5. Epithelial-stromal interaction via Notch signaling is essential for the full maturation of gut-associated lymphoid tissues.

    Science.gov (United States)

    Obata, Yuuki; Kimura, Shunsuke; Nakato, Gaku; Iizuka, Keito; Miyagawa, Yurika; Nakamura, Yutaka; Furusawa, Yukihiro; Sugiyama, Machiko; Suzuki, Keiichiro; Ebisawa, Masashi; Fujimura, Yumiko; Yoshida, Hisahiro; Iwanaga, Toshihiko; Hase, Koji; Ohno, Hiroshi

    2014-12-01

    Intrinsic Notch signaling in intestinal epithelial cells restricts secretory cell differentiation. In gut-associated lymphoid tissue (GALT), stromal cells located beneath the follicle-associated epithelium (FAE) abundantly express the Notch ligand delta-like 1 (Dll1). Here, we show that mice lacking Rbpj-a gene encoding a transcription factor implicated in Notch signaling-in intestinal epithelial cells have defective GALT maturation. This defect can be attributed to the expansion of goblet cells, which leads to the down-regulation of CCL20 in FAE. These data demonstrate that epithelial Notch signaling maintained by stromal cells contributes to the full maturation of GALT by restricting secretory cell differentiation in FAE. © 2014 The Authors.

  6. Epithelial–stromal interaction via Notch signaling is essential for the full maturation of gut-associated lymphoid tissues

    Science.gov (United States)

    Obata, Yuuki; Kimura, Shunsuke; Nakato, Gaku; Iizuka, Keito; Miyagawa, Yurika; Nakamura, Yutaka; Furusawa, Yukihiro; Sugiyama, Machiko; Suzuki, Keiichiro; Ebisawa, Masashi; Fujimura, Yumiko; Yoshida, Hisahiro; Iwanaga, Toshihiko; Hase, Koji; Ohno, Hiroshi

    2014-01-01

    Intrinsic Notch signaling in intestinal epithelial cells restricts secretory cell differentiation. In gut-associated lymphoid tissue (GALT), stromal cells located beneath the follicle-associated epithelium (FAE) abundantly express the Notch ligand delta-like 1 (Dll1). Here, we show that mice lacking Rbpj—a gene encoding a transcription factor implicated in Notch signaling—in intestinal epithelial cells have defective GALT maturation. This defect can be attributed to the expansion of goblet cells, which leads to the down-regulation of CCL20 in FAE. These data demonstrate that epithelial Notch signaling maintained by stromal cells contributes to the full maturation of GALT by restricting secretory cell differentiation in FAE. Subject Categories Development & Differentiation; Immunology; Signal Transduction PMID:25378482

  7. Childhood ADHD is strongly associated with a broad range of psychiatric disorders during adolescence: a population-based birth cohort study.

    Science.gov (United States)

    Yoshimasu, Kouichi; Barbaresi, William J; Colligan, Robert C; Voigt, Robert G; Killian, Jill M; Weaver, Amy L; Katusic, Slavica K

    2012-10-01

    To evaluate associations between attention-deficit/hyperactivity disorder (ADHD) and comorbid psychiatric disorders using research-identified incident cases of ADHD and population-based controls. Subjects included a birth cohort of all children born 1976-1982 remaining in Rochester, MN after age five (n = 5,718). Among them we identified 379 ADHD incident cases and 758 age-gender matched non-ADHD controls, passively followed to age 19 years. All psychiatric diagnoses were identified and abstracted, but only those confirmed by qualified medical professionals were included in the analysis. For each psychiatric disorder, cumulative incidence rates for subjects with and without ADHD were estimated using the Kaplan-Meier method. Corresponding hazard ratios (HR) were estimated using Cox models adjusted for gender and mother's age and education at the subject's birth. The association between ADHD and the likelihood of having an internalizing or externalizing disorder was summarized by estimating odds ratios (OR). Attention-deficit/hyperactivity disorder was associated with a significantly increased risk of adjustment disorders (HR = 3.88), conduct/oppositional defiant disorder (HR = 9.54), mood disorders (HR = 3.67), anxiety disorders (HR = 2.94), tic disorders (HR = 6.53), eating disorders (HR = 5.68), personality disorders (HR = 5.80), and substance-related disorders (HR = 4.03). When psychiatric comorbidities were classified on the internalization-externalization dimension, ADHD was strongly associated with coexisting internalizing/externalizing (OR = 10.6), or externalizing-only (OR = 10.0) disorders. This population-based study confirms that children with ADHD are at significantly increased risk for a wide range of psychiatric disorders. Besides treating the ADHD, clinicians should identify and provide appropriate treatment for psychiatric comorbidities. © 2012 The Authors. Journal of Child Psychology and Psychiatry

  8. Validation of Atmosphere/Ionosphere Signals Associated with Major Earthquakes by Multi-Instrument Space-Borne and Ground Observations

    Science.gov (United States)

    Ouzounov, Dimitar; Pulinets, Sergey; Hattori, Katsumi; Parrot, Michel; Liu, J. Y.; Yang, T. F.; Arellano-Baeza, Alonso; Kafatos, M.; Taylor, Patrick

    2012-01-01

    The latest catastrophic earthquake in Japan (March 2011) has renewed interest in the important question of the existence of pre-earthquake anomalous signals related to strong earthquakes. Recent studies have shown that there were precursory atmospheric/ionospheric signals observed in space associated with major earthquakes. The critical question, still widely debated in the scientific community, is whether such ionospheric/atmospheric signals systematically precede large earthquakes. To address this problem we have started to investigate anomalous ionospheric / atmospheric signals occurring prior to large earthquakes. We are studying the Earth's atmospheric electromagnetic environment by developing a multisensor model for monitoring the signals related to active tectonic faulting and earthquake processes. The integrated satellite and terrestrial framework (ISTF) is our method for validation and is based on a joint analysis of several physical and environmental parameters (thermal infrared radiation, electron concentration in the ionosphere, lineament analysis, radon/ion activities, air temperature and seismicity) that were found to be associated with earthquakes. A physical link between these parameters and earthquake processes has been provided by the recent version of Lithosphere-Atmosphere-Ionosphere Coupling (LAIC) model. Our experimental measurements have supported the new theoretical estimates of LAIC hypothesis for an increase in the surface latent heat flux, integrated variability of outgoing long wave radiation (OLR) and anomalous variations of the total electron content (TEC) registered over the epicenters. Some of the major earthquakes are accompanied by an intensification of gas migration to the surface, thermodynamic and hydrodynamic processes of transformation of latent heat into thermal energy and with vertical transport of charged aerosols in the lower atmosphere. These processes lead to the generation of external electric currents in specific

  9. Potential association between TLR4 and chitinase 3-like 1 (CHI3L1/YKL-40) signaling on colonic epithelial cells in inflammatory bowel disease and colitis-associated cancer

    Science.gov (United States)

    Kamba, Alan; Lee, In-Ah; Mizoguchi, Emiko

    2013-01-01

    Inflammatory bowel disease (IBD) is a group of inflammatory disorders in the small and large intestines. Several studies have proved that persistent and disregulated host/microbial interactions are required for the development of IBD. It is well known that chronic IBD is strongly associated with an increased risk of developing colorectal cancer by 0.5–1% annually, 8–10 years after the initial diagnosis. To detect the tiny dysplasia or early stage of cancer in chronic IBD patients, a tremendous amount of effort is currently directed for improving colonoscopic technology and noninvasive serological marker development. However, there is only a limited amount of data available to understand the exact mechanism of how long term chronic colitis is connected to the development of colorectal tumors. Recently, our group has identified that significantly increased expression of chitinase 3-like 1 (CHI3L1) molecule in non-dysplastic mucosa from patients with IBD and remote dysplasia/cancer, compared to patients with IBD without dysplasia or healthy controls. CHI3L1 seems to contribute to the proliferation, migration, and neoplastic progression of colonic epithelial cells (CECs) under inflammatory conditions. Furthermore, the CHI3L1-mediated intracellular signaling cascade is likely to interact with TLR4 signaling in CECs. In this review article, we have concisely summarized the cellular and molecular mechanisms underlining the development of IBD and colitis-associated cancer, with particular focus on the CHI3L1-and TLR4-signaling pathways in CECs. PMID:23170831

  10. BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway.

    Science.gov (United States)

    Chen, Mei-Rong; Dai, Ping; Wang, Shu-Fen; Song, Shu-Hua; Wang, Hang-Ping; Zhao, Ya; Wang, Ting-Hua; Liu, Jia

    2016-10-01

    Spinal cord injury (SCI), a severe health problem in worldwide, was commonly associated with functional disability and reduced quality of life. As the expression of brain-derived neurotrophic factor (BDNF) was substantial event in injured spinal cord, we hypothesized whether BDNF-overexpression could be in favor of the recovery of both sensory function and hindlimb function after SCI. By using BDNF-overexpression transgene mice [CMV-BDNF 26 (CB26) mice] we assessed the role of BDNF on the recovery of neurological behavior in spinal cord transection (SCT) model. BMS score and tail-flick test was performed to evaluate locomotor function and sensory function, respectively. Immunohistochemistry was employed to detect the location and the expression of BDNF, NeuN, 5-HT, GAP-43, GFAP as well as CGRP, and the level of p-AKT and AKT were examined through western blot analysis. BDNF overexpressing resulted in significant locomotor functional recovery from 21 to 28 days after SCT, compared with wild type (WT)+SCT group. Meanwhile, the NeuN, 5-HT and GAP-43 positive cells were markedly increased in ventral horn in BDNF overexpression animals, compared with WT mice with SCT. Moreover, the crucial molecular signal, p-AKT/AKT has been largely up-regulated, which is consistent with the improvement of locomotor function. However, in this study, thermal hyperpathia encountered in sham (CB26) group and WT+SCT mice and further aggravated in CB26 mice after SCT. Also, following SCT, the significant augment of positive-GFAP astrocytes and CGRP fibers were found in WT+SCT mice, and further increase was seen in BDNF over-expression transgene mice. BDNF-overexpression may not only facilitate the recovery of locomotor function via AKT pathway, but also contributed simultaneously to thermal hyperalgesia after SCT.

  11. Validation of EM Signals Associated with Major Earthquakes by Joint Analysis of Space and Terrestrial Data

    Science.gov (United States)

    Ouzounov, D.; Pulinets, S.; Parrot, M.; Liu, J. Y.; Hattori, K.; Habib, S.; Taylor, P.; Kafatos, M.

    2009-04-01

    Ground and space observations have shown that there were precursory electromagnetic signals associated with several recent earthquakes. The goals of this work are: (1) to identify the common methodology for statistical validation of the major EQ precursory phenomena; and (2) to cross-examine these results of precursory detection for several major earthquakes by using different methodologies. Our approach is based on data fusion of satellite thermal infrared observations from Aqua, GOES, POES and space plasma parameters variations from DEMETER, simultaneously with ground based multi parameter continuous measurements of GPS/TEC, ion concentration, atmospheric electrical field and magnetic array. We used existing satellite sensors and ground observations and linked them together with the Lithosphere-Atmosphere-Ionosphere Coupling (LAIC) model. This model describes a physical coupling between the boundary layer of atmosphere and the ionosphere with the observed ground and space data prior to some major earthquakes. The significance of joint satellite and ground based EM precursors search was defined by cross validating with different techniques the precursory phenomena around the time of four more recent major earthquakes: (1) M 9.3 Sumatra (Indonesia) 2004.12.26; (2) M7.0 Ping Tong (Taiwan) 2006.12.24; (3) M6.8 Chuetsu Oki (Japan) 2007.7.16; and (4) M7.9 Wenchuan (China) 2008.5.12. Our first results show that simultaneous satellite and ground measurements, using the integrated web, can help to understand better the pre-earthquake processes and provides opportunity for global scale monitoring framework by combining multiple sensor sources.

  12. PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma

    LENUS (Irish Health Repository)

    Keld, R

    2011-06-28

    Background: Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells.\\r\

  13. Association between polymorphisms in Wnt signaling pathway genes and bone mineral density in postmenopausal Korean women.

    Science.gov (United States)

    Lee, Dong-Yun; Kim, Hoon; Ku, Seung Yup; Kim, Seok Hyun; Choi, Young Min; Kim, Jung Gu

    2010-01-01

    The purpose of this study was to investigate the association between single nucleotide polymorphisms in Wnt signal pathway genes and circulating osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-κB ligand (sRANKL) levels, bone turnover markers, and bone mineral density (BMD) in postmenopausal Korean women. Wnt9a c256G>A; low-density lipoprotein receptor-related protein (LRP) 5 c266A>G, c2245C>G, c3893C>T, and c4099G>A; secreted frizzled-related protein (sFRP) 4 c1019G>A; axin II c148C>T and c1615G>A; glycogen synthase kinase binding protein (GBP) c455C>A; β-catenin c94G>T and c101G>T; T-cell factor 1 c663G>T, c734C>T, and c766G>A; and adenomatous polyposis coli c5465T>A polymorphisms were analyzed in 392 postmenopausal Korean women. Serum levels of OPG, sRANKL, and bone turnover markers were measured, and BMDs at the lumbar spine and femoral neck were examined. Wnt9a c256G>A, LRP5 c2245C>G and c4099G>A, axin II c1615G>A, GBP c455C>A, β-catenin c94G>T and c101G>T, and T-cell factor 1 c663G>T and c734C>T single nucleotide polymorphisms were not observed. Among the genes showing polymorphisms, only the sFRP4 c1019G>A polymorphism was associated with BMD. The AA genotype in the sFRP4 c1019G>A polymorphism showed significantly lower lumbar spine BMD and a higher serum bone alkaline phosphatase level than did the GG genotype and showed a 6.39 times higher risk for osteoporosis at the lumbar spine compared with the GG genotype. No significant differences in bone turnover markers, OPG, and sRANKL were detected among the other single genotypes or the LRP haplotype genotype. Our results suggest that the sFRP4 c1019G>A polymorphism may be one of the genetic factors affecting lumbar spine BMD in postmenopausal Korean women.

  14. Back pain's association with vertebral end-plate signal changes in sciatica.

    Science.gov (United States)

    el Barzouhi, Abdelilah; Vleggeert-Lankamp, Carmen L A M; van der Kallen, Bas F; Lycklama à Nijeholt, Geert J; van den Hout, Wilbert B; Koes, Bart W; Peul, Wilco C

    2014-02-01

    Patients with sciatica frequently experience disabling back pain. One of the proposed causes for back pain is vertebral end-plate signal changes (VESC) as visualized by magnetic resonance imaging (MRI). To report on VESC findings, changes of VESC findings over time, and the correlation between VESC and disabling back pain in patients with sciatica. A randomized clinical trial with 1 year of follow-up. Patients with 6 to 12 weeks of sciatica who participated in a multicenter, randomized clinical trial comparing an early surgery strategy with prolonged conservative care with surgery if needed. Patients were assessed by means of the 100-mm visual analog scale (VAS) for back pain (with 0 representing no pain and 100 the worst pain ever experienced) at baseline and 1 year. Disabling back pain was defined as a VAS score of at least 40 mm. Patients underwent MRI both at baseline and after 1 year follow-up. Presence and change of VESC was correlated with disabling back pain using chi-square tests and logistic regression analysis. At baseline, 39% of patients had disabling back pain. Of the patients with VESC at baseline, 40% had disabling back pain compared with 38% of the patients with no VESC (p=.67). The prevalence of type 1 VESC increased from 1% at baseline to 35% 1 year later in the surgical group compared with an increase from 3% to 11% in the conservative group. The prevalence of type 2 VESC decreased from 40% to 29% in the surgical group while remaining almost stable in the conservative group at 41%. The prevalence of disabling back pain at 1 year was 12% in patients with no VESC at 1 year, 16% in patients with type 1 VESC, 11% in patients with type 2 VESC, and 3% in patients with both types 1 and 2 VESC (p=.36). Undergoing surgery was associated with increase in the extent of VESC (odds ratio [OR], 8.6; 95% confidence interval [CI], 4.7-15.7; psciatica was highly associated with the development of VESC after 1 year. However, in contrast with the intuitive feeling

  15. Conflict and disfluency as aversive signals: context-specific processing adjustments are modulated by affective location associations.

    Science.gov (United States)

    Dreisbach, Gesine; Reindl, Anna-Lena; Fischer, Rico

    2018-03-01

    Context-specific processing adjustments are one signature feature of flexible human action control. However, up to now the precise mechanisms underlying these adjustments are not fully understood. Here it is argued that aversive signals produced by conflict- or disfluency-experience originally motivate such context-specific processing adjustments. We tested whether the efficiency of the aversive conflict signal for control adaptation depends on the affective nature of the context it is presented in. In two experiments, high vs. low proportions of aversive signals (Experiment 1: conflict trials; Experiment 2: disfluent trials) were presented either above or below the screen center. This location manipulation was motivated by existing evidence that verticality is generally associated with affective valence with up being positive and down being negative. From there it was hypothesized that the aversive signals would lose their trigger function for processing adjustments when presented at the lower (i.e., more negative) location. This should then result in a reduced context-specific proportion effect when the high proportion of aversive signals was presented at the lower location. Results fully confirmed the predictions. In both experiments, the location-specific proportion effects were only present when the high proportion of aversive signals occurred at the more positive location above but were reduced (Experiment 1) or even eliminated (Experiment 2) when the high proportion occurred at the more negative location below. This interaction of processing adjustments with affective background contexts can thus be taken as further hint for an affective origin of control adaptations.

  16. Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival

    Directory of Open Access Journals (Sweden)

    Hsieh Fu-Chuan

    2008-10-01

    Full Text Available Abstract Background Constitutive activation of signal transducer and activator of transcription 3 (Stat3 signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer. Results We found that elevated Stat3 phosphorylation in 19 of 100 (19% bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC. The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin and a cell cycle regulating gene (cyclin D1 was associated with the cell growth inhibition and apoptosis. Conclusion These results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.

  17. A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice.

    Science.gov (United States)

    Maupin, Kevin A; Droscha, Casey J; Williams, Bart O

    2013-03-01

    The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone.

  18. Elongation Factor Tu and Heat Shock Protein 70 Are Membrane-Associated Proteins from Mycoplasma ovipneumoniae Capable of Inducing Strong Immune Response in Mice.

    Science.gov (United States)

    Jiang, Fei; He, Jinyan; Navarro-Alvarez, Nalu; Xu, Jian; Li, Xia; Li, Peng; Wu, Wenxue

    2016-01-01

    Chronic non-progressive pneumonia, a disease that has become a worldwide epidemic has caused considerable loss to sheep industry. Mycoplasma ovipneumoniae (M. ovipneumoniae) is the causative agent of interstitial pneumonia in sheep, goat and bighorn. We here have identified by immunogold and immunoblotting that elongation factor Tu (EF-Tu) and heat shock protein 70 (HSP 70) are membrane-associated proteins on M. ovipneumonaiea. We have evaluated the humoral and cellular immune responses in vivo by immunizing BALB/c mice with both purified recombinant proteins rEF-Tu and rHSP70. The sera of both rEF-Tu and rHSP70 treated BALB/c mice demonstrated increased levels of IgG, IFN-γ, TNF-α, IL-12(p70), IL-4, IL-5 and IL-6. In addition, ELISPOT assay showed significant increase in IFN-γ+ secreting lymphocytes in the rHSP70 group when compared to other groups. Collectively our study reveals that rHSP70 induces a significantly better cellular immune response in mice, and may act as a Th1 cytokine-like adjuvant in immune response induction. Finally, growth inhibition test (GIT) of M. ovipneumoniae strain Y98 showed that sera from rHSP70 or rEF-Tu-immunized mice inhibited in vitro growth of M. ovipneumoniae. Our data strongly suggest that EF-Tu and HSP70 of M. ovipneumoniae are membrane-associated proteins capable of inducing antibody production, and cytokine secretion. Therefore, these two proteins may be potential candidates for vaccine development against M. ovipneumoniae infection in sheep.

  19. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance.

    Science.gov (United States)

    Mannerås-Holm, Louise; Leonhardt, Henrik; Kullberg, Joel; Jennische, Eva; Odén, Anders; Holm, Göran; Hellström, Mikael; Lönn, Lars; Olivecrona, Gunilla; Stener-Victorin, Elisabet; Lönn, Malin

    2011-02-01

    Comprehensive characterization of the adipose tissue in women with polycystic ovary syndrome (PCOS), over a wide range of body mass indices (BMIs), is lacking. Mechanisms behind insulin resistance in PCOS are unclear. To characterize the adipose tissue of women with PCOS and controls matched pair-wise for age and BMI, and to identify factors, among adipose tissue characteristics and serum sex steroids, that are associated with insulin sensitivity in PCOS. Seventy-four PCOS women and 31 controls were included. BMI was 18-47 (PCOS) and 19-41 kg/m(2) (controls). Anthropometric variables, volumes of subcutaneous/visceral adipose tissue (magnetic resonance imaging; MRI), and insulin sensitivity (clamp) were investigated. Adipose tissue biopsies were obtained to determine adipocyte size, lipoprotein lipase (LPL) activity, and macrophage density. Circulating testosterone, free testosterone, free 17β-estradiol, SHBG, glycerol, adiponectin, and serum amyloid A were measured/calculated. Comparison of 31 pairs revealed lower insulin sensitivity, hyperandrogenemia, and higher free 17β-estradiol in PCOS. Abdominal adipose tissue volumes/distribution did not differ in the groups, but PCOS women had higher waist-to-hip ratio, enlarged adipocytes, reduced adiponectin, and lower LPL activity. In regression analysis, adipocyte size, adiponectin, and waist circumference were the factors most strongly associated with insulin sensitivity in PCOS (R(2)=0.681, P fat accumulation, but this is not supported by MRI. Enlarged adipocytes and reduced serum adiponectin, together with a large waistline, rather than androgen excess, may be central factors in the pathogenesis/maintenance of insulin resistance in PCOS.

  20. Elongation Factor Tu and Heat Shock Protein 70 Are Membrane-Associated Proteins from Mycoplasma ovipneumoniae Capable of Inducing Strong Immune Response in Mice.

    Directory of Open Access Journals (Sweden)

    Fei Jiang

    Full Text Available Chronic non-progressive pneumonia, a disease that has become a worldwide epidemic has caused considerable loss to sheep industry. Mycoplasma ovipneumoniae (M. ovipneumoniae is the causative agent of interstitial pneumonia in sheep, goat and bighorn. We here have identified by immunogold and immunoblotting that elongation factor Tu (EF-Tu and heat shock protein 70 (HSP 70 are membrane-associated proteins on M. ovipneumonaiea. We have evaluated the humoral and cellular immune responses in vivo by immunizing BALB/c mice with both purified recombinant proteins rEF-Tu and rHSP70. The sera of both rEF-Tu and rHSP70 treated BALB/c mice demonstrated increased levels of IgG, IFN-γ, TNF-α, IL-12(p70, IL-4, IL-5 and IL-6. In addition, ELISPOT assay showed significant increase in IFN-γ+ secreting lymphocytes in the rHSP70 group when compared to other groups. Collectively our study reveals that rHSP70 induces a significantly better cellular immune response in mice, and may act as a Th1 cytokine-like adjuvant in immune response induction. Finally, growth inhibition test (GIT of M. ovipneumoniae strain Y98 showed that sera from rHSP70 or rEF-Tu-immunized mice inhibited in vitro growth of M. ovipneumoniae. Our data strongly suggest that EF-Tu and HSP70 of M. ovipneumoniae are membrane-associated proteins capable of inducing antibody production, and cytokine secretion. Therefore, these two proteins may be potential candidates for vaccine development against M. ovipneumoniae infection in sheep.

  1. HIV prevalence is strongly associated with geographical variations in male circumcision and foreskin cutting in Papua New Guinea: an ecological study.

    Science.gov (United States)

    MacLaren, David J; McBride, W John H; Kelly, Gerard C; Muller, Reinhold; Tommbe, Rachael; Kaldor, John M; Vallely, Andrew J

    2015-11-01

    To examine the correlation between HIV prevalence and male circumcision and other foreskin cutting practices across the four regions of Papua New Guinea (PNG). An ecological substudy using unique data from an interdisciplinary research programme to evaluate the acceptability, sociocultural context and public health impact of male circumcision for HIV prevention in PNG. Published data describing (a) self-reported circumcision status by region from the 'Acceptability and Feasibility of Male Circumcision for HIV prevention in PNG' study and (b) HIV prevalence by region from PNG National Department of Health were used to correlate male circumcision and other foreskin cutting practices and HIV prevalence. Maps were constructed to visually represent variations across the four regions of PNG. Regions of PNG with the highest HIV prevalence had the lowest prevalence of male circumcision and other forms of foreskin cutting and vice versa. Male circumcision and dorsal longitudinal cuts were strongly associated with HIV prevalence and able to explain 99% of the observed geographical variability in HIV prevalence in PNG (pPNG appears to be closely correlated with the regional distribution of male circumcision and dorsal longitudinal foreskin cuts. Further research is warranted to investigate causality of this correlation as well as the potential of dorsal longitudinal cuts to confer protection against HIV acquisition in heterosexual men. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  2. Precursory strong-signal characteristics of the convective clouds of the Central Tibetan Plateau detected by radar echoes with respect to the evolutionary processes of an eastward-moving heavy rainstorm belt in the Yangtze River Basin

    Science.gov (United States)

    Zhao, Yang; Xu, Xiangde; Ruan, Zheng; Chen, Bin; Wang, Fang

    2018-03-01

    The integrated analysis of the data from a C-band frequency-modulated continuous-wave (C-FMCW) radar site in Naqu obtained during a rainstorm over the middle and lower reaches of the Yangtze River and the data concerning the three-dimensional structure of the circulation of the precipitation system that occurred over the lower reaches of the Yangtze River Basin during the Third Tibetan Plateau (TP) Atmospheric Experiment from August 15th to 19th, 2014, was carried out. The changes in the echo intensity at the C-FMCW radar site in Naqu were of regional indicative significance for the characteristics of the whole-layer apparent heat source Q1 in local areas and the region of the adjacent river source area, including the Yangtze River, Yellow River, and Lancang River (hereinafter referred to as the "source area of three rivers"), as well as to the vertical speeds due to the development of convection. This study indicates that the C-FMCW radar echo intensity of the plateau convection zone and the related power structures of the coupled dipole circulations in the middle layer of the atmosphere, as well as in the upper atmospheric level divergence and lower atmospheric level convergence, are important stimuli for convective clouds in this region. Furthermore, these radar data provided a physical image of the development and maintenance mechanisms of an eastward-moving heavy rainstorm belt. This study also shows that changes in the echo intensities at the C-FMCW radar site of Naqu can provide strong signals related to heavy rainstorm processes in the upper reaches of the Yangtze River.

  3. Gene Expression of Pneumocystis murina after Treatment with Anidulafungin Results in Strong Signals for Sexual Reproduction, Cell Wall Integrity, and Cell Cycle Arrest, Indicating a Requirement for Asci Formation for Proliferation.

    Science.gov (United States)

    Cushion, Melanie T; Ashbaugh, Alan; Hendrix, Keeley; Linke, Michael J; Tisdale, Nikeya; Sayson, Steven G; Porollo, Aleksey

    2018-02-20

    The echinocandins are a class of anti-fungal agents that target β-1,3-D-glucan (BG) biosynthesis. In the ascigerous Pneumocystis species, treatment with these drugs deplete the asci life cycle stage which contain BG, but large numbers of forms which do not express BG remain in the infected lungs. In the present study, the gene expression profiles of Pneumocystis murina were compared between infected untreated mice and those treated with anidulafungin for 2 weeks to understand the metabolism of the persisting forms. Almost 80 genes were significantly up- or down-regulated. Like other fungi exposed to echinocandins, genes associated with sexual replication, cell wall integrity, cell cycle arrest and stress comprised the strongest up-regulated signals in P. murina from the treated mice. The up-regulation of the P. murina β-1,3-D-glucan endohydrolase and endo-1,3-glucanase was notable and may explain the disappearance of the existing asci in the lungs of treated mice since both enzymes can degrade BG. The biochemical measurement of BG in the lungs of treated mice and fluorescent microscopy with an anti-BG antibody supported the loss of BG. Down-regulated signals included genes involved in cell replication, genome stability, ribosomal biogenesis and function, and the Pneumocystis -specific genes encoding the major surface glycoproteins (Msg). These studies suggest that P. murina attempted to undergo sexual replication in response to a stressed environment and were halted in any type of proliferative cycle, likely due to a lack of BG. Asci appear to be a required part of the life cycle stage of Pneumocystis and BG may be needed to facilitate progression through the life cycle via sexual replication. Copyright © 2018 Cushion et al.

  4. Variations in the geomagnetic and gravitational background associated with two strong earthquakes of the May 2012 sequence in the Po Valley Plain (Italy).

    Science.gov (United States)

    Straser, Valentino

    2013-04-01

    Reawakening of seismic activity in the Emilian Po Valley Plain (Italy) resulted in 2,492 earthquakes over five and a half months: 2,270 with M= 7. The mainshock was recorded during the night of 20 May 2012, at 04:03:52 Italian time (02:03:52 UTC) with epicentre in Finale Emilia, at a depth of 6.3km, by the Italian National Institute of Geophysics and Vulcanology (INGV). A long sequence of telluric shocks occurred in the same seismic district in the areas between the provinces of Modena, Ferrara, Mantua, Reggio Emilia, Bologna and Rovigo. In addition to the general devastation plus damage to civil and industrial buildings and the historical heritage, the earthquakes resulted in a total of 27 victims. Concomitant with the two strongest quakes, recorded on 20 and 29 May 2012, respectively, as in the case of others, variations were noted in the geomagnetic background by the LTPA monitoring station in Rome (Italy). The geomagnetic background variations were associated with the appearance of radio-anomalies in a frequency range from 0.1 to 3.0Hz, as well as gravimetric variations found around 60km from the epicentre. The peak accelerations, detected in correspondence with the strongest shocks on 20 and 29 May 2012, were respectively 0.31g and 0.29g. The appearance of the radio-anomalies coincided, from a temporal point of view, with average gravimetric variations of approximately 30µGal around the epicentre areas, concurrent with the mainshock. In this study, both the appearance of radio-anomalies and the gravitational variations recorded before strong earthquakes were related to the dynamics of the fault and a progressive reduction in granulometry in the core of the fracture, until the point of dislocation was reached. The intense friction in the fault and the damping factors produced before the shock are hypothesized as being proportional to the number of radio-anomalies measured. The radio anomaly is an unknown radio emission that has no characteristics (duration

  5. High diversity in functional properties of melanocortin 1 receptor (MC1R) in divergent primate species is more strongly associated with phylogeny than coat color.

    Science.gov (United States)

    Haitina, Tatjana; Ringholm, Aneta; Kelly, Joanne; Mundy, Nicholas I; Schiöth, Helgi B

    2007-09-01

    We have characterized the biochemical function of the melanocortin 1 receptor (MC1R), a critical regulator of melanin synthesis, from 9 phylogenetically diverse primate species with varying coat colors. There is substantial diversity in melanocyte-stimulating hormone (MSH) binding affinity and basal levels of activity in the cloned MC1Rs. MSH binding was lost independently in lemur and New World monkey lineages, whereas high basal levels of MC1R activity occur in lemurs and some New World monkeys and Old World monkeys. Highest levels of basal activity were found in the MC1R of ruffed lemurs, which have the E94K mutation that leads to constitutive activation in other species. In 3 species (2 lemurs and the howler monkey), we report the novel finding that binding and inhibition of MC1R by agouti signaling protein (ASIP) can occur when MSH binding has been lost, thus enabling continuing regulation of the melanin type via ASIP expression. Together, these findings can explain the previous paradox of a predominantly pheomelanic coat in the red ruffed lemur (Varecia rubra). The presence of a functional, MSH-responsive MC1R in orangutan demonstrates that the mechanism of red hair generation in this ape is different from the prevalent mechanism in European human populations. Overall, we have found unexpected diversity in MC1R function among primates and show that the evolution of the regulatory control of MC1R activity occurs by independent variation of 3 distinct mechanisms: basal MC1R activity, MSH binding and activation, and ASIP binding and inhibition. This diversity of function is broadly associated with primate phylogeny and does not have a simple relation to coat color phenotype within primate clades.

  6. HLA-E: strong association with beta2-microglobulin and surface expression in the absence of HLA class I signal sequence-derived peptides

    Czech Academy of Sciences Publication Activity Database

    Lo Monaco, E.; Sibilio, L.; Melucci, E.; Tremante, E.; Suchánek, M.; Hořejší, Václav; Martayan, A.; Giacomini, P.

    2008-01-01

    Roč. 181, č. 8 (2008), s. 5442-5450 ISSN 0022-1767 Institutional research plan: CEZ:AV0Z50520514 Keywords : HLA-E * MHC * monoclonal antibodies Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.000, year: 2008

  7. Antigen Targeting to CD11b+ Dendritic Cells in Association with TLR4/TRIF Signaling Promotes Strong CD8+ T Cell Responses

    Czech Academy of Sciences Publication Activity Database

    Dadaglio, G.; Fayolle, C.; Zhang, X.; Ryffel, B.; Oberkampf, M.; Felix, T.; Hervas-Stubbs, S.; Osička, Radim; Šebo, Peter; Ladant, D.; Leclerc, C.

    2014-01-01

    Roč. 193, č. 2 (2014), s. 1787-1798 ISSN 0022-1767 R&D Projects: GA ČR(CZ) GAP302/11/0580; GA ČR GAP302/12/0460 Grant - others:EU´s Seventh Framework Programme 280873 Institutional support: RVO:61388971 Keywords : antigen * dendritic cells * receptors Subject RIV: EE - Microbiology, Virology Impact factor: 4.922, year: 2014

  8. Trypanosoma cruzi infection is a potent risk factor for non-alcoholic steatohepatitis enhancing local and systemic inflammation associated with strong oxidative stress and metabolic disorders.

    Directory of Open Access Journals (Sweden)

    Luisina I Onofrio

    2015-02-01

    Full Text Available The immune mechanisms underlying experimental non-alcoholic steatohepatitis (NASH, and more interestingly, the effect of T. cruzi chronic infection on the pathogenesis of this metabolic disorder are not completely understood.We evaluated immunological parameters in male C57BL/6 wild type and TLR4 deficient mice fed with a standard, low fat diet, LFD (3% fat as control group, or a medium fat diet, MFD (14% fat in order to induce NASH, or mice infected intraperitoneally with 100 blood-derived trypomastigotes of Tulahuen strain and also fed with LFD (I+LFD or MFD (I+MFD for 24 weeks. We demonstrated that MFD by itself was able to induce NASH in WT mice and that parasitic infection induced marked metabolic changes with reduction of body weight and steatosis revealed by histological studies. The I+MFD group also improved insulin resistance, demonstrated by homeostasis model assessment of insulin resistance (HOMA-IR analysis; although parasitic infection increased the triglycerides and cholesterol plasma levels. In addition, hepatic M1 inflammatory macrophages and cytotoxic T cells showed intracellular inflammatory cytokines which were associated with high levels of IL6, IFNγ and IL17 plasmatic cytokines and CCL2 chemokine. These findings correlated with an increase in hepatic parasite load in I+MFD group demonstrated by qPCR assays. The recruitment of hepatic B lymphocytes, NK and dendritic cells was enhanced by MFD, and it was intensified by parasitic infection. These results were TLR4 signaling dependent. Flow cytometry and confocal microscopy analysis demonstrated that the reactive oxygen species and peroxinitrites produced by liver inflammatory leukocytes of MFD group were also exacerbated by parasitic infection in our NASH model.We highlight that a medium fat diet by itself is able to induce steatohepatitis. Our results also suggest a synergic effect between damage associated with molecular patterns generated during NASH and parasitic infection

  9. CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk.

    Science.gov (United States)

    Peters, Nils; Opherk, Christian; Zacherle, Simone; Capell, Anja; Gempel, Petra; Dichgans, Martin

    2004-10-01

    Mutations in the NOTCH3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy leading to strokes and dementia. Pathogenic mutations remove or insert cysteine residues within epidermal growth factor (EGF) repeats in the extracellular domain of the Notch3 receptor (N3ECD). Vascular smooth muscle cells (VSMC) are the predominant site of Notch3 expression in adults. In CADASIL patients, VSMC degenerate and N3ECD is deposited within the vasculature. However, the mechanisms underlying VSMC degeneration and N3ECD accumulation are still unknown. In this study, we investigated the consequences of three pathogenic Notch3 mutations on the biological activity of the receptor by analyzing ligand (Delta-/Jagged-)-induced signaling via RBP-Jk. Two mutations (R133C and C183R) that are located outside the putative ligand binding domain (LBD) of the receptor were found to result in normal Jagged1-induced signaling in A7r5 VSMC, whereas the third mutation (C455R located within the putative LBD) showed strongly reduced signaling activity. Ligand binding assays with soluble Delta1 and Jagged1 revealed that C455R interferes with ligand binding through disruption of the LBD which, as we show here, is located in EGF repeats 10/11 of Notch3. All mutant receptors including Notch3C455R were targeted to the cell surface but showed an elevated ratio between the unprocessed full-length 280-kDa receptor and S1-cleaved receptor fragments. Taken together, these data indicate that CADASIL-associated Notch3 mutations differ with respect to their consequences both on ligand binding and ligand-induced signaling through RBP-Jk, whereas they have similar effects on receptor maturation. Moreover, the data suggest that ligand-induced receptor shedding may not be required for N3ECD deposition in CADASIL. Copyright 2004 Elsevier Inc.

  10. Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines.

    Science.gov (United States)

    Clay, Timothy M; Osada, Takuya; Hartman, Zachary C; Hobeika, Amy; Devi, Gayathri; Morse, Michael A; Lyerly, H Kim

    2011-04-01

    Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.

  11. Distortions in frequency spectra of signals associated with sampling-pulse shapes

    International Nuclear Information System (INIS)

    Njau, E.C.

    1983-04-01

    A method developed earlier by the author [IC/82/44; IC/82/45] is used to investigate distortions introduced into frequency spectra of signals by the shapes of the sampling pulses involved. Conditions are established under which the use of trapezoid or exponentially-edged pulses to digitize signals can make the frequency spectra of the resultant data samples devoid of the main features of the signals. This observation does not, however, apply in any way to cosinusoidally-edged pulses or to pulses with cosine-squared edges. Since parts of the Earth's surface and atmosphere receive direct solar energy in discrete samples (i.e. only from sunrise to sunset) we have extended the technique and attempted to develop a theory that explains the observed solar terrestrial relationships. A very good agreement is obtained between the theory and previous long-term and short-term observations. (author)

  12. Regulation of monocyte differentiation by specific signaling modules and associated transcription factor networks.

    Science.gov (United States)

    Huber, René; Pietsch, Daniel; Günther, Johannes; Welz, Bastian; Vogt, Nico; Brand, Korbinian

    2014-01-01

    Monocyte/macrophages are important players in orchestrating the immune response as well as connecting innate and adaptive immunity. Myelopoiesis and monopoiesis are characterized by the interplay between expansion of stem/progenitor cells and progression towards further developed (myelo)monocytic phenotypes. In response to a variety of differentiation-inducing stimuli, various prominent signaling pathways are activated. Subsequently, specific transcription factors are induced, regulating cell proliferation and maturation. This review article focuses on the integration of signaling modules and transcriptional networks involved in the determination of monocytic differentiation.

  13. Genome-wide gene expression profiling reveals aberrant MAPK and Wnt signaling pathways associated with early parthenogenesis.

    Science.gov (United States)

    Liu, Na; Enkemann, Steven A; Liang, Ping; Hersmus, Remko; Zanazzi, Claudia; Huang, Junjiu; Wu, Chao; Chen, Zhisheng; Looijenga, Leendert H J; Keefe, David L; Liu, Lin

    2010-12-01

    Mammalian parthenogenesis could not survive but aborted during mid-gestation, presumably because of lack of paternal gene expression. To understand the molecular mechanisms underlying the failure of parthenogenesis at early stages of development, we performed global gene expression profiling and functional analysis of parthenogenetic blastocysts in comparison with those of blastocysts from normally fertilized embryos. Parthenogenetic blastocysts exhibited changes in the expression of 749 genes, of which 214 had lower expression and 535 showed higher expressions than fertilized embryos using a minimal 1.8-fold change as a cutoff. Genes important for placenta development were decreased in their expression in parthenote blastocysts. Some maternally expressed genes were up-regulated and paternal-related genes were down-regulated. Moreover, aberrantly increased Wnt signaling and reduced mitogen-activated protein kinase (MAPK) signaling were associated with early parthenogenesis. The protein level of extracellular signal-regulated kinase 2 (ERK2) was low in parthenogenetic blastocysts compared with that of fertilized blastocysts 120 h after fertilization. 6-Bromoindirubin-3'-oxime, a specific glycogen synthase kinase-3 (GSK-3) inhibitor, significantly decreased embryo hatching. The expression of several imprinted genes was altered in parthenote blastocysts. Gene expression also linked reduced expression of Xist to activation of X chromosome. Our findings suggest that failed X inactivation, aberrant imprinting, decreased ERK/MAPK signaling and possibly elevated Wnt signaling, and reduced expression of genes for placental development collectively may contribute to abnormal placenta formation and failed fetal development in parthenogenetic embryos.

  14. Long-term clinical protection from falciparum malaria is strongly associated with IgG3 antibodies to merozoite surface protein 3.

    Directory of Open Access Journals (Sweden)

    Christian Roussilhon

    2007-11-01

    Full Text Available BACKGROUND: Surrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite to molecules that are considered as valuable vaccine candidates. METHODS AND FINDINGS: We analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults. The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3, was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week. Finally, the target epitopes of these antibodies were found to be fully conserved. CONCLUSIONS: Since anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be

  15. Chronically Increased G[subscript s][alpha] Signaling Disrupts Associative and Spatial Learning

    Science.gov (United States)

    Bourtchouladze, Rusiko; Patterson, Susan L.; Kelly, Michele P.; Kreibich, Arati; Kandel, Eric R.; Abel, Ted

    2006-01-01

    The cAMP/PKA pathway plays a critical role in learning and memory systems in animals ranging from mice to "Drosophila" to "Aplysia." Studies of olfactory learning in "Drosophila" suggest that altered expression of either positive or negative regulators of the cAMP/PKA signaling pathway beyond a certain optimum range may be deleterious. Here we…

  16. Associative, Bidirectional Changes in Neural Signaling Utilizing NMDA Receptor- and Endocannabinoid-Dependent Mechanisms

    Science.gov (United States)

    Li, Qin; Burrell, Brian D.

    2011-01-01

    Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre- and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We…

  17. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    screening, detection, diagnosis, staging and risk stratification of various cancers. DNA methylation can be therapeutically reversed and demethylating drugs have proven to be promising in cancer treatment. This review focusses on the methylation status of genes in Notch signalling pathway from various cancers and how ...

  18. Selfish strategies and honest signalling: reproductive conflicts in ant queen associations

    DEFF Research Database (Denmark)

    Holman, Luke; Dreier, Stephanie; d'Ettorre, Patrizia

    2010-01-01

    . Here, we use a brood transfer experiment to test whether cofounding queens of the ant Lasius niger 'selfishly' adjust their productivity when sharing the nest with future competitors. We simultaneously analysed queen cuticular hydrocarbon (CHC) profiles to investigate whether queens honestly signal...

  19. Mitigation of TGF-β/Smad signaling pathway-associated liver fibrosis ...

    African Journals Online (AJOL)

    The hydroxyproline content of proteins was measured as an indirect way of assessing collagen deposition. TGF-β1 levels and TGF-β/Smad signaling pathway-related genes and proteins were analyzed by quantitative polymerase chain reaction (qPCR) assay and Western blot assay. Results: After PF administration, serum ...

  20. Syndecans, signaling, and cell adhesion

    DEFF Research Database (Denmark)

    Couchman, J R; Woods, A

    1996-01-01

    with the microfilament cytoskeleton, thereby mediating signaling events. The molecular details are unknown, but the conservation of regions of syndecan cytoplasmic domains, and a strong tendency for homotypic association, support the idea that the ligand-induced clustering may be a discrete source of specific...

  1. Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition

    Directory of Open Access Journals (Sweden)

    Ramkumar Menon

    2017-08-01

    Full Text Available Human parturition is an inflammatory process that involves both fetal and maternal compartments. The precise immune cell interactions have not been well delineated in human uterine tissues during parturition, but insights into human labor initiation have been informed by studies in animal models. Unfortunately, the timing of parturition relative to fetal maturation varies among viviparous species—indicative of different phylogenetic clocks and alarms—but what is clear is that important common pathways must converge to control the birth process. Herein, we hypothesize a novel signaling mechanism initiated by human fetal membrane aging and senescence-associated inflammation. Programmed events of fetal membrane aging coincide with fetal growth and organ maturation. Mechanistically, senescence involves in telomere shortening and activation of p38 mitogen-activated signaling kinase resulting in aging-associated phenotypic transition. Senescent tissues release inflammatory signals that are propagated via exosomes to cause functional changes in maternal uterine tissues. In vitro, oxidative stress causes increased release of inflammatory mediators (senescence-associated secretory phenotype and damage-associated molecular pattern markers that can be packaged inside the exosomes. These exosomes traverse through tissues layers, reach maternal tissues to increase overall inflammatory load transitioning them from a quiescent to active state. Animal model studies have shown that fetal exosomes can travel from fetal to the maternal side. Thus, aging fetal membranes and membrane-derived exosomes cargo fetal signals to the uterus and cervix and may trigger parturition. This review highlights a novel hypothesis in human parturition research based on data from ongoing research using human fetal membrane model system.

  2. Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling

    NARCIS (Netherlands)

    Dwarkasing, J.T.; Boekschoten, M.V.; Witkamp, R.F.; Norren, van K.

    2015-01-01

    Background. Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy

  3. The Characteristics of Magnetic Signals Observed at Lulin ELF Station and Their Association with Earthquakes in Taiwan

    Directory of Open Access Journals (Sweden)

    Shao-Ming Ho

    2013-01-01

    Full Text Available Electromagnetic wave data from years 2009 - 2010 which were recorded by the extremely-low-frequency (ELF station at Lulin Observatory in Taiwan (120.87°E, 23.46°N; 2862 m are analyzed to explore the wave properties and their association with seismic and geomagnetic activities. Specifically, the power spectra, the ellipticity and the orientation of the below-10-Hz wave signals are studied. The correlation coefficients of these ELF signals and geomagnetic activity indices Dst and Kp are within -0.2 to 0.2, indicating geomagnetic activities are not likely sources for these emissions. In the frequency versus time (f-t spectrograms, a few events exhibit a frequency shift between 4 and 6 Hz and the possible association with seismic activities of magnitudes (M larger than 4 in the vicinity of Taiwan are examined. The subset of earthquakes in Taiwan with M/r2 (r is the epicenter distance in kilometer from the Lulin station of greater than 6 × 10-4, a total number of 50, show a higher association with ELF wave events showing a frequency down-shift within 7 days prior to the earthquakes and a frequency bounce-back within 7 days after the earthquakes. The epicenters of these earthquakes are all within a distance of 100 km from the Lulin station and with a depth of 50 km, suggesting that the detected ELF frequency-shift wave events maybe are pre-earthquake electromagnetic signals.

  4. Acquisition and extinction of human avoidance behavior: Attenuating effect of safety signals and associations with anxiety vulnerabilities

    Directory of Open Access Journals (Sweden)

    Jony eSheynin

    2014-09-01

    Full Text Available While avoidance behavior is often an adaptive strategy, exaggerated avoidance can be detrimental and result in the development of psychopathologies, such as anxiety disorders. A large animal literature shows that the acquisition and extinction of avoidance behavior in rodents depends on individual differences (e.g., sex, strain and might be modulated by the presence of environmental cues. However, there is a dearth of such reports in human literature, mainly due to the lack of adequate experimental paradigms. In the current study, we employed a computer-based task, where participants control a spaceship and attempt to gain points by shooting an enemy spaceship that appears on the screen. Warning signals predict on-screen aversive events; the participants can learn a protective response to escape or avoid these events. This task has been recently used to reveal facilitated acquisition of avoidance behavior in individuals with anxiety vulnerability, due to female sex or inhibited personality. Here, we extended the task to include an extinction phase, and tested the effect of signals that appeared during safe periods. Healthy young adults (n=122 were randomly assigned to a testing condition with or without such signals. Results showed that the addition of safety signals during the acquisition phase impaired acquisition (in females and facilitated extinction of the avoidance behavior. We also replicated our recent finding of an association between female sex and longer avoidance duration and further showed that females continued to demonstrate more avoidance behavior even on extinction trials when the aversive events no longer occurred. This study is the first to show sex differences on the acquisition and extinction of human avoidance behavior and to demonstrate the role of safety signals in such behavior, highlighting the potential relevance of safety signals for cognitive therapies that focus on extinction learning to treat anxiety symptoms.

  5. The Association of Endothelin-1 Signaling with Bone Alkaline Phosphatase Expression and Protumorigenic Activities in Canine Osteosarcoma.

    Science.gov (United States)

    Neumann, Z L; Pondenis, H C; Masyr, A; Byrum, M L; Wycislo, K L; Fan, T M

    2015-01-01

    Canine osteosarcoma (OS) is an aggressive sarcoma characterized by pathologic skeletal resorption and pulmonary metastases. A number of negative prognostic factors, including bone alkaline phosphatase, have been identified in dogs with OS, but the underlying biologic factors responsible for such observations have not been thoroughly investigated. Endothelin-1-mediated signaling is active during bone repair, and is responsible for osteoblast migration, survival, proliferation, and bone alkaline phosphatase expression. The endothelin-1 signaling axis is active in canine OS cells, and this pathway is utilized by malignant osteoblasts for promoting cellular migration, survival, proliferation, and bone alkaline phosphatase activities. 45 dogs with appendicular OS. The expressions of endothelin-1 and endothelin A receptor were studied in OS cell lines and in samples from spontaneously occurring tumors. Activities mediated by endothelin-1 signaling were investigated by characterizing responses in 3 OS cell lines. In 45 dogs with OS, bone alkaline phosphatase concentrations were correlated with primary tumor osteoproductivity. Canine OS cells express endothelin-1 and endothelin A receptor, and this signaling axis mediates OS migration, survival, proliferation, and bone alkaline phosphatase activities. In OS-bearing dogs, circulating bone alkaline phosphatase activities were positively correlated with primary tumor relative bone mineral densities. Canine OS cells express endothelin-1 and functional endothelin A receptors, with the potential for a protumorigenic signaling loop. Increases in bone alkaline phosphatase activity are associated with osteoblastic OS lesions, and might be an epiphenomenon of active endothelin-1 signaling or excessive osteoproduction within the localized bone microenvironment. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  6. [Mechanisms of signaling associated with reactive nitrogen and oxygen in apoptosis].

    Science.gov (United States)

    Piłat, Justyna; Ługowski, Mateusz; Saczko, Jolanta; Choromańska, Anna; Chwiłkowska, Agnieszka; Banaś, Teresa; Kulbacka, Julita

    2016-05-01

    The knowledge of apoptotic mechanisms is essential in many biologic aspects related to both normal and neoplastic cells. Cell death by apoptosis is a very desirable way to eliminate unwanted cells: prevents release of the cellular content, which, in contrast to necrosis, provides no activation of inflammatory reactions. Apoptosis is a multistep process in where an extremely important role is played by caspases. Functions of caspases and their modifications are fundamental to understanding the signaling pathways responsible for regulation of apoptosis. These enzymes belong to a family of cysteine proteases that have the potential to destroy the enzymatic and structural proteins, and in the final stages of apoptosis, to lead to the disintegration of the cell. Apoptosis can be modulated by certain signaling pathway. © 2016 MEDPRESS.

  7. Local perinuclear calcium signals associated with mitosis-entry in early sea urchin embryos

    OpenAIRE

    1996-01-01

    Using calcium-sensitive dyes together with their dextran conjugates and confocal microscopy, we have looked for evidence of localized calcium signaling in the region of the nucleus before entry into mitosis, using the sea urchin egg first mitotic cell cycle as a model. Global calcium transients that appear to originate from the nuclear area are often observed just before nuclear envelope breakdown (NEB). In the absence of global increases in calcium, confocal microscopy using Calcium Green- 1...

  8. Glycine enhances muscle protein mass associated with maintaining Akt-mTOR-FOXO1 signaling and suppressing TLR4 and NOD2 signaling in piglets challenged with LPS.

    Science.gov (United States)

    Liu, Yulan; Wang, Xiuying; Wu, Huanting; Chen, Shaokui; Zhu, Huiling; Zhang, Jing; Hou, Yongqing; Hu, Chien-An Andy; Zhang, Guolong

    2016-08-01

    Pro-inflammatory cytokines play a critical role in the pathophysiology of muscle atrophy. We hypothesized that glycine exerted an anti-inflammatory effect and alleviated lipopolysaccharide (LPS)-induced muscle atrophy in piglets. Pigs were assigned to four treatments including the following: 1) nonchallenged control, 2) LPS-challenged control, 3) LPS+1.0% glycine, and 4) LPS+2.0% glycine. After receiving the control, 1.0 or 2.0% glycine-supplemented diets, piglets were treated with either saline or LPS. At 4 h after treatment with saline or LPS, blood and muscle samples were harvested. We found that 1.0 or 2.0% glycine increased protein/DNA ratio, protein content, and RNA/DNA ratio in gastrocnemius or longissimus dorsi (LD) muscles. Glycine also resulted in decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) in gastrocnemius muscle. In addition, glycine restored the phosphorylation of Akt, mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and Forkhead Box O 1 (FOXO1) in gastrocnemius or LD muscles. Furthermore, glycine resulted in decreased plasma tumor necrosis factor-α (TNF-α) concentration and muscle TNF-α mRNA abundance. Moreover, glycine resulted in decreased mRNA expresson of Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain protein 2 (NOD2), and their respective downstream molecules in gastrocnemius or LD muscles. These results indicate glycine enhances muscle protein mass under an inflammatory condition. The beneficial roles of glycine on the muscle are closely associated with maintaining Akt-mTOR-FOXO1 signaling and suppressing the activation of TLR4 and/or NOD2 signaling pathways. Copyright © 2016 the American Physiological Society.

  9. Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance.

    Science.gov (United States)

    Tubbs, Emily; Theurey, Pierre; Vial, Guillaume; Bendridi, Nadia; Bravard, Amélie; Chauvin, Marie-Agnès; Ji-Cao, Jingwei; Zoulim, Fabien; Bartosch, Birke; Ovize, Michel; Vidal, Hubert; Rieusset, Jennifer

    2014-10-01

    Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains between both organelles involved in Ca(2+) exchange, through the voltage-dependent anion channel (VDAC)-1/glucose-regulated protein 75 (Grp75)/inositol 1,4,5-triphosphate receptor (IP3R)-1 complex, and regulating energy metabolism. Whereas mitochondrial dysfunction, ER stress, and altered Ca(2+) homeostasis are associated with altered insulin signaling, the implication of MAM dysfunctions in insulin resistance is unknown. Here we validated an approach based on in situ proximity ligation assay to detect and quantify VDAC1/IP3R1 and Grp75/IP3R1 interactions at the MAM interface. We demonstrated that MAM integrity is required for insulin signaling and that induction of MAM prevented palmitate-induced alterations of insulin signaling in HuH7 cells. Disruption of MAM integrity by genetic or pharmacological inhibition of the mitochondrial MAM protein, cyclophilin D (CypD), altered insulin signaling in mouse and human primary hepatocytes and treatment of CypD knockout mice with metformin improved both insulin sensitivity and MAM integrity. Furthermore, ER-mitochondria interactions are altered in liver of both ob/ob and diet-induced insulin-resistant mice and improved by rosiglitazone treatment in the latter. Finally, increasing organelle contacts by overexpressing CypD enhanced insulin action in primary hepatocytes of diabetic mice. Collectively, our data reveal a new role of MAM integrity in hepatic insulin action and resistance, providing a novel target for the modulation of insulin action. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  10. Biphasic activation of liver regeneration-associated signals in an early stage after portal vein branch ligation

    International Nuclear Information System (INIS)

    Yokoyama, Shinya; Yokoyama, Yukihiro; Kawai, Toru; Kobayashi, Satoshi; Nagino, Masato; Oda, Koji; Nimura, Yuji; Sokabe, Masahiro

    2006-01-01

    At an early stage in liver regeneration, a variety of factors including transcriptional factors, proinflammatory cytokines, and proto-oncogenes are activated or expressed. However, these responses are affected by surgical stress in the conventional portal vein branch ligation model (PVL). We sought to determine the net activation of early regeneration-associated signals after PVL using a newly developed non-surgical stress PVL model. Male Wistar rats were assigned into two groups, a stress-PVL (sPVL) model with laparotomy and portal vein branch ligation, and a non-stress-PVL (nsPVL) one subjected to portal vein branch ligation 1 week after laparotomy in which the effects of surgical stress were subsided. The activation of transcriptional factors and expression of immediate early genes were analyzed at an early time point (within 24 h) by Western blotting and RT-PCR, respectively. A monophasic upregulation of nuclear factor-κB (NF-κB) and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) peaked at 3 h after sPVL was observed. In contrast, the expression pattern of these factors was biphasic (first peak at 0.5-1 h, second peak at 3-6 h) in nsPVL group. The expression pattern of immediate early genes showed a similar trend between sPVL and nsPVL. cDNA array analysis for the non-ligated lobe at 2 h after PVL revealed a much higher gene activation in sPVL than in nsPVL. These results indicate that previously observed activation pattern of regeneration-associated signals after PVL is significantly affected by the effect of laparotomy and our results using nsPVL model may more accurately represent liver regeneration-associated signal pattern

  11. Chloroplast biogenesis-associated nuclear genes: Control by plastid signals evolved prior to their regulation as part of photomorphogenesis.

    Directory of Open Access Journals (Sweden)

    Alison C HIlls

    2015-12-01

    Full Text Available The assembly of photosynthetically-competent chloroplasts occurs in angiosperm seedlings when first exposed to light, and is due to the control by light of photosynthesis-associated nuclear genes (PhANGs, also dependent upon plastid-to-nucleus biogenic communication signals. The relationship between light- and plastid signal-regulation of PhANGs is close but poorly understood. In contrast, many conifers green in the dark and the promoter of a pine PhANG, Lhcb, is active in the dark in tobacco. Here we show that the activity of this promoter in tobacco is sensitive to plastid photobleaching, or to the inhibition of plastid translation in the light or the dark, and the same interventions reduce expression of the native gene in pine seedlings, demonstrating classic plastid biogenic signalling in gymnosperms. Furthermore, Arabidopsis mutations causing defective plastid biogenesis suppress the effect in darkness of mutations in COP1 and DET1, repressors of photomorphogenesis, for the expression of several PhANGs but not a photosynthesis-unrelated, light-regulated gene. GLK transcriptional regulators mediate the response of LHCB but not of other tested PhANGs. We propose gain of the ability by repressors of photomorphogenesis to suppress the response of PhANG promoters to positive plastid biogenic signals in the dark to have contributed to the evolution of light control of chloroplast biogenesis.

  12. Severe Dermatomyositis Triggered by Interferon Beta-1a Therapy and Associated With Enhanced Type I Interferon Signaling

    Science.gov (United States)

    Somani, Ally-Khan; Swick, Alan R.; Cooper, Kevin D.; McCormick, Thomas S.

    2013-01-01

    Background Type I interferons (IFNs) are common therapeutics for several diseases, including viral infections and multiple sclerosis (MS). Although numerous studies have implicated type I INFs with the production of autoantibodies and the development of certain autoimmune disorders, interferon beta has not previously been described in association with dermatomyositis, to our knowledge. Previous microarray studies of muscle biopsy specimens from patients with dermatomyositis disclosed a type I IFN–induced gene expression profile. The central role of plasmacytoid dendritic cell precursors, together with increased type IIFN production, suggests a pivotal role for type I IFNs in dermatomyositis. We report a case of dermatomyositis exacerbated or induced by interferon beta therapy for MS and provide evidence that demonstrates enhanced type I IFN signaling in this patient. Observations We observed new-onset dermatomyositis in a 57-year-old patient treated with interferon beta for MS. His symptoms were exacerbated temporally by interferon beta injections. Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (a surrogate marker for cutaneous type I IFN signaling) showed increased staining that correlated temporally with interferon beta treatment and subsequent disease activity. In vitro treatment with interferon beta of peripheral blood mononuclear cells isolated from our patient revealed enhanced type I IFN signaling assessed by interferon-induced gene expression profiles. Conclusions To our knowledge, this is the first description of dermatomyositis exacerbated or induced by interferon beta treatment. Our results demonstrate enhanced type I IFN signaling following interferon beta treatment in our patient with dermatomyositis. PMID:18936398

  13. Tilt signals associated with a small eruption at Asama Volcano, Japan

    Science.gov (United States)

    Ohminato, T.

    2013-12-01

    It is well known that the acceleration input to a seismometer consists of translational acceleration and tilt-related acceleration. The lower the frequency is, the more contribution is from the tilt-related acceleration. The tilt contribution can be easily extracted from the velocity output of broadband seismometers by the following simple procedure. The roll-off of the transfer function of the broadband seismometer in the frequency range below its characteristic frequency is proportional to the square of frequency. It means that the sensor output in this frequency range is proportional to the time-derivative of the ground acceleration. The result of time integration of the signal in this frequency range is, thus proportional to the ground acceleration, which are proportional to the ground tilt. As long as we concentrate on the low enough frequency range, this simple integration procedure is equivalent to the traditional procedure of sensor-response removal followed by transfer to the tilt response On February 2, 2009, a small eruption occurred at Mt. Asama, central Japan. A broadband seismic network operated by Earthquake Research Institute, University of Tokyo, detected tilt-related signals during the eruption. According to the tilt signals that were extracted by the above mentioned procedure, an inflation started 30 minutes before the summit eruption. The inflation was followed by a rapid deflation due to the summit eruption. At the stations relatively far from the summit, while the tilt changes before the eruption were below noise level and thus were not detected, the tilt changes after the eruption were clearly detected by most of the stations around Mt. Asama. The post eruption tilt signals were oriented not to the summit but to the northwestern side of Mt. Asama. The tilt signals before and during the eruption observed at the near-summit stations are interpreted as an accumulation and release of pressure beneath the summit crater before and after the

  14. Role of IL-17A signalling in psoriasis and associated bone loss.

    Science.gov (United States)

    Uluçkan, Özge; Wagner, Erwin F

    2016-01-01

    Inflammation is a physiological reaction to tissue injury, pathogen invasion and a natural response to various stress stimuli. Innate and adaptive immune cells are activated and recruited to the site of inflammation to suppress or promote inflammation. The recruitment and activation of immune cells is modulated by cytokines and chemokines, which are regulated by transcription factors, such as AP-1 (Fos/Jun), NF-kB, NFATs and STATs. Moreover, it is now appreciated that chronic inflammation can lead to systemic effects affecting the whole organism by mechanisms which are not well understood.Here we review our recent data obtained from the analyses of psoriasis patient samples as well as from AP-1 (Fos/Jun)-dependent, genetically engineered mouse models. The deletion of two AP-1 factors JunB and c-Jun in an inducible manner in adult mice, specifically in Keratin-5 expressing tissues, leads to a psoriasis-like disease. Importantly, the epidermal proteome of the mutant mice is comparable to psoriasis patient samples. Our analyses revealed that the activation of S100A8/A9-dependent C3 complement as well as a miR-21-dependent TIMP-3/TACE pathway leading to TNF-α shedding, are causally involved in disease development.Epidermal deletion of only JunB in mice leads to chronic skin inflammation with increased levels of pro-inflammatory cytokines and multi-organ involvement. Our recent findings show that chronic skin inflammation induces bone loss through systemic elevated IL-17A signalling. This novel mechanism involves inhibition of osteoblast-mediated bone formation by reduced Wnt signalling with no effect on RANKL-dependent osteoclastic bone resorption. These data have important translational implications; blocking of IL-17A signalling, which is already approved for the treatment of psoriasis, should also be considered to prevent the adverse skeletal consequences of chronic inflammatory diseases.

  15. Sortilin Associates with Trk Receptors to Enhance Anterograde Transport and Signaling by Neurotrophins

    DEFF Research Database (Denmark)

    Vægter, Christian Bjerggaard

      Neurotrophins (NT) are neuronal growth factors essential for development and maintenance of the nervous system. They are released in two forms with opposing biological functions. The proforms induce apoptosis by engaging a death signaling complex comprising the p75NTR neurotrophin receptor...... and survival has been extensively studied in knockout mouse models. We recently generated a Sortilin knockout mouse model (Sort1-/-) and showed that the receptor is essential for p75NTR to induce death of neurons during certain stages of development and aging and upon brain injury (Jansen et al, Nat. Neurosci...

  16. PIP kinases define PI4,5P2 signaling specificity by association with effectors

    OpenAIRE

    Choi, Suyong; Thapa, Narendra; Tan, Xiaojun; Hedman, Andrew C.; Anderson, Richard A.

    2015-01-01

    Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an essential lipid messenger with roles in all eukaryotes and most aspects of human physiology. By controlling the targeting and activity of its effectors, PI4,5P2 modulates processes, such as cell migration, vesicular trafficking, cellular morphogenesis, signaling and gene expression. In cells, PI4,5P2 has a much higher concentration than other phosphoinositide species and its total content is largely unchanged in response to extracellular s...

  17. Analysis of electrical and magnetic bio-signals associated with motor performance and fatigue

    Science.gov (United States)

    Yao, Bing

    This dissertation reports findings centered principally on comprehensive research related to human bio-signals (EEG, MEG, EMG and fMRI) acquired during repetitive maximal voluntary contractions (MVC) that induced severe fatigue. Fatigue is a common experience that reduces productivity and quality of life and increases chances of injury. Although abundant information has been gained in the last several decades regarding muscular and spinal-level mechanisms of muscle fatigue, very little is known about how cortical centers control and respond to fatigue. The main purpose of this study was to examine the fatigue effects on the central nervous system by analyzing the bio-signals collected in the designed experiments. Healthy human subjects were asked to perform a series of repetitive handgrip MVCs with their dominant hand until exhaustion. Handgrip forces, electrical activity (EMG) from primary and non-primary muscles, and EEG, MEG, or fMRI signals from different locations of the brain were recorded simultaneously. The time series data were segmented into several physiologically meaningful epochs (time phases), from rest to preparation to movement execution/sustaining. A series of studies, including motor-related cortical potential (MRCP) analysis, power spectrum analysis, time-frequency (spectrogram) analysis of EEG, EEG source localization and nonlinear analysis (fractal dimension and largest Lyapunov exponent), and fMRI analysis, was applied to the data. We hypothesized that the fatigue effects would act differently on brain signals of different phases. The MRCP results showed that the negative potential (NP) related to motor task preparation only had minimal changes with fatigue. The power of all EEG frequencies did not alter significantly during the preparation phase but decreased significantly during the sustained phase of the contraction. The fractal dimension and the largest Lyapunov exponent decreased significantly during the sustained phase as fatigue

  18. Stunted Growth Caused by Blast Disease in Rice Seedlings Is Associated with Changes in Phytohormone Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Chang-Jie Jiang

    2017-09-01

    Full Text Available In response to pathogen attack, plants prioritize defense reactions generally at the expense of plant growth. In this work, we report that changes in phytohormone signaling pathways are associated with the stunted plant growth caused by blast disease in rice seedlings. Infection of rice seedlings with blast fungus Magnaporthe oryzae (race 007.0 at the four-leaf stage (three true leaves resulted in considerable inhibition of the growth of the upper uninfected distal leaves; the length of leaf blade and leaf sheath of the sixth and seventh leaf was reduced by 27 and 82%, and 88 and 72%, respectively, compared to that in the uninoculated plant control. Interestingly, cutting off the blast-infected fourth leaf blade within 2 days post inoculation (dpi significantly rescued the inhibition of leaf growth, implying that an inhibitory substance(s and/or signal was generated in the blast-infected leaves (fourth leaf and transmitted to the upper distal leaves (sixth and seventh during the 2-dpi period that induced growth inhibition. Expression analysis of marker genes for phytohormone pathways revealed acute activation of the jasmonate (JA and abscisic acid (ABA signaling pathways, and repression of auxin, gibberellic acid (GA and salicylic acid (SA signaling pathways, in the sixth leaf. The genes related to cell wall expansion were also significantly downregulated. In the blast-infected fourth leaf, JA pathway was activated within 2 dpi, followed by activation of ABA pathway 3 dpi. Further, leaf inhibition caused by blast infection was partially rescued in the rice mutant line coleoptile photomorphogenesis 2 (cpm2, which is defective in the gene encoding allene oxide cyclase (OsAOC. These results indicate that the JA signaling pathway is at least partly involved in the growth inhibition processes. Collectively, our data suggest that, upon pathogen attack, rice seedlings prioritize defense reactions against the infecting pathogen by temporarily ceasing

  19. Profiling of luteal transcriptome during prostaglandin F2-alpha treatment in buffalo cows: analysis of signaling pathways associated with luteolysis.

    Directory of Open Access Journals (Sweden)

    Kunal B Shah

    Full Text Available In several species including the buffalo cow, prostaglandin (PG F2α is the key molecule responsible for regression of corpus luteum (CL. Experiments were carried out to characterize gene expression changes in the CL tissue at various time points after administration of luteolytic dose of PGF2α in buffalo cows. Circulating progesterone levels decreased within 1 h of PGF2α treatment and evidence of apoptosis was demonstrable at 18 h post treatment. Microarray analysis indicated expression changes in several of immediate early genes and transcription factors within 3 h of treatment. Also, changes in expression of genes associated with cell to cell signaling, cytokine signaling, steroidogenesis, PG synthesis and apoptosis were observed. Analysis of various components of LH/CGR signaling in CL tissues indicated decreased LH/CGR protein expression, pCREB levels and PKA activity post PGF2α treatment. The novel finding of this study is the down regulation of CYP19A1 gene expression accompanied by decrease in expression of E2 receptors and circulating and intra luteal E2 post PGF2α treatment. Mining of microarray data revealed several differentially expressed E2 responsive genes. Since CYP19A1 gene expression is low in the bovine CL, mining of microarray data of PGF2α-treated macaques, the species with high luteal CYP19A1 expression, showed good correlation between differentially expressed E2 responsive genes between both the species. Taken together, the results of this study suggest that PGF2α interferes with luteotrophic signaling, impairs intra-luteal E2 levels and regulates various signaling pathways before the effects on structural luteolysis are manifest.

  20. Association of toll-like receptor 4 signaling pathway with steroid-induced femoral head osteonecrosis in rats.

    Science.gov (United States)

    Tian, Lei; Zhou, Dong-Sheng; Wang, Kun-Zheng; Zhang, Wei; Shi, Zhi-Bin; Fan, Li-Hong; Sun, Shui

    2014-10-01

    Osteonecrosis of the femoral head is frequently observed in patients treated with excessive corticosteroids. However, the pathogenesis of corticosteroid-induced osteonecrosis remains unclear. The purpose of this study was to investigate the role of Toll-like receptor 4 (TLR4) signaling pathway in steroid-induced femoral head osteonecrosis in rats. Male Sprague-Dawley rats were injected intramuscularly with 20 mg/kg methylprednisolone (MP) for 8 weeks, twice per week. The animals were sacrificed at 2, 4 and 8 weeks after the last MP injection, respectively, and then allocated to the 2-, 4- and 8-week model groups (n=24 each). Rats in the control group (n=12) were not given any treatment. Histopathological analysis was performed and the concentration of tartrate-resistant acid phosphatase (TRAP) in plasma was determined. The activation of osteoclasts in the femoral head was assessed by TRAP staining. The expression of TLR4, MyD88, TRAF6 and NF-κB p65 that are involved in TLR4 signaling, and MCP-1 production were detected by using real-time PCR (RT-PCR) and Western blotting. The results showed that the osteonecrosis in the femoral head was clearly observed and the concentration of TRAP in the plasma was increased in the model rats. The femoral head tissues in MP-treated rats were positive for TRAP and the intensity of TRAP staining was greater in MP-treated rats than in control rats. As compared with the control group, the mRNA expression of TLR4 signaling-related factors was enhanced significantly at 4 and 8 weeks, and the protein levels of these factors increased significantly with time. It was concluded that MP could induce the femoral head osteonecrosis in rats, which was associated with osteoclast activation via the TLR4 signaling pathway. These findings suggest that TLR4 signaling pathway plays a pivotal role in the pathogenesis of steroid-induced osteonecrosis.

  1. Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors.

    Directory of Open Access Journals (Sweden)

    Michael Lutter

    Full Text Available Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating.An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001 for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of 'binge-like' eating.These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.

  2. An Association Map on the Effect of Flavonoids on the Signaling Pathways in Colorectal Cancer.

    Science.gov (United States)

    Koosha, Sanaz; Alshawsh, Mohammed A; Looi, Chung Yeng; Seyedan, Atefehalsadat; Mohamed, Zahurin

    2016-01-01

    Colorectal cancer (CRC) is the third most common type of cancer in the world, causing thousands of deaths annually. Although chemotherapy is known to be an effective treatment to combat colon cancer, it produces severe side effects. Natural products, on the other hand, appear to generate fewer side effects than do chemotherapeutic drugs. Flavonoids are polyphenolic compounds found in various fruits and vegetables known to possess antioxidant activities, and the literature shows that several of these flavonoids have anti-CRC propertiesFlavonoids are classified into five main subclasses: flavonols, flavanones, flavones, flavan-3-ols, and flavanonols. Of these subclasses, the flavanonols have a minimum effect against CRC, whereas the flavones play an important role. The main targets for the inhibitory effect of flavonoids on CRC signaling pathways are caspase; nuclear factor kappa B; mitogen-activated protein kinase/p38; matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9; p53; β-catenin; cyclin-dependent kinase (CDK)2 and CDK4; and cyclins A, B, D, and E. In this review article, we summarize the in vitro and in vivo studies that have been performed since 2000 on the anti-CRC properties of flavonoids. We also describe the signaling pathways affected by flavonoids that have been found to be involved in CRC. Some flavonoids have the potential to be an effective alternative to chemotherapeutic drugs in the treatment of colon cancer; well-controlled clinical studies should, however, be conducted to support this proposal.

  3. Romantic love is associated with enhanced inhibitory control in an emotional stop-signal task

    Directory of Open Access Journals (Sweden)

    Sensen Song

    2016-10-01

    Full Text Available Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG, and half were single and had never been in a romantic relationship (single group, SG. Based on duration of romantic relationship (i.e., love duration, the LG were further divided into two subgroups: early stage love and longer periods of love. All participants completed an emotional Stop Signal Task (eSST, which consisted of a variety of human face stimuli representing sadness (a negative emotion, as well as neutral emotions. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in longer periods of love or SG individuals, with no significant differences between the latter two groups. Conclusions: Compared with individuals who were single, early-stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness.

  4. Romantic Love Is Associated with Enhanced Inhibitory Control in an Emotional Stop-Signal Task.

    Science.gov (United States)

    Song, Sensen; Zou, Zhiling; Song, Hongwen; Wang, Yongming; d'Oleire Uquillas, Federico; Wang, Huijun; Chen, Hong

    2016-01-01

    Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG), and half were single and had never been in a romantic relationship (single group, SG). Based on duration of romantic relationship (i.e., love duration), the LG were further divided into two subgroups: "early stage love" and "longer periods of love". All participants completed an emotional Stop Signal Task, consisting of a variety of human face stimuli displaying either sad or neutral affect. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT)] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in "longer periods of love" or SG individuals, with no significant differences between the two latter groups. Conclusion: Compared with individuals who were single, early stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness.

  5. Romantic Love Is Associated with Enhanced Inhibitory Control in an Emotional Stop-Signal Task

    Science.gov (United States)

    Song, Sensen; Zou, Zhiling; Song, Hongwen; Wang, Yongming; d’Oleire Uquillas, Federico; Wang, Huijun; Chen, Hong

    2016-01-01

    Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG), and half were single and had never been in a romantic relationship (single group, SG). Based on duration of romantic relationship (i.e., love duration), the LG were further divided into two subgroups: “early stage love” and “longer periods of love”. All participants completed an emotional Stop Signal Task, consisting of a variety of human face stimuli displaying either sad or neutral affect. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT)] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in “longer periods of love” or SG individuals, with no significant differences between the two latter groups. Conclusion: Compared with individuals who were single, early stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness. PMID:27826260

  6. Akt signaling-associated metabolic effects of dietary gold nanoparticles in Drosophila

    Science.gov (United States)

    Wang, Bin; Chen, Nan; Wei, Yingliang; Li, Jiang; Sun, Li; Wu, Jiarui; Huang, Qing; Liu, Chang; Fan, Chunhai; Song, Haiyun

    2012-08-01

    Gold nanoparticles (AuNPs) are often used as vehicles to deliver drugs or biomolecules, due to their mild effect on cell survival and proliferation. However, little is known about their effect on cellular metabolism. Here we examine the in vivo effect of AuNPs on metabolism using Drosophila as a model. Drosophila and vertebrates possess similar basic metabolic functions, and a highly conserved PI3K/Akt/mTOR signaling pathway plays a central role in the regulation of energy metabolism in both organisms. We show that dietary AuNPs enter the fat body, a key metabolic tissue in Drosophila larvae. Significantly, larvae fed with AuNP show increased lipid levels without triggering stress responses. In addition, activities of the PI3K/Akt/mTOR signaling pathway and fatty acids synthesis are increased in these larvae. This study thus reveals a novel function of AuNPs in influencing animal metabolism and suggests its potential therapeutic applications for metabolic disorders.

  7. Effects of ceftriaxone on GLT1 isoforms, xCT and associated signaling pathways in P rats exposed to ethanol.

    Science.gov (United States)

    Rao, P S S; Saternos, Hannah; Goodwani, Sunil; Sari, Youssef

    2015-07-01

    Several studies have demonstrated a correlation between extracellular glutamate concentration in the mesolimbic reward pathway and alcohol craving. Extracellular glutamate concentration is regulated by several glutamate transporters. Glial glutamate transporter 1 (GLT1) is one of them that regulates the majority of extracellular glutamate concentration. In addition, cystine/glutamate antiporter (xCT) is another transporter that regulates extracellular glutamate. We focus in this study to determine the effects of ceftriaxone, β-lactam antibiotic, on glial proteins such as GLT1 isoforms, xCT, glutamate aspartate transporter (GLAST), and several associated signaling pathways as well as ethanol intake in P rats. Additionally, to examine the onset of signaling pathways associated with GLT1 upregulation following ceftriaxone treatment, we tested 2- versus 5-day daily dosing of ceftriaxone. Ceftriaxone treatment (100 mg/kg), 2 and 5 days, resulted in about five fold reduction in ethanol intake by P rats. The reduction in ethanol intake was associated with significantly enhanced expression of GLT1, GLT1a, GLT1b, and xCT in the nucleus accumbens (NAc) and prefrontal cortex (PFC) of 5-day ceftriaxone-treated P rats. Two-day-treated P rats showed marked changes in expression of these glutamate transporters in the PFC but not in the NAc. Importantly, ceftriaxone-treated P rats (2 and 5 days) demonstrated enhanced phosphorylation of Akt and nuclear translocation of nuclear factor kappaB (NFκB) in the NAc and PFC compared to control animals. These findings demonstrate that ceftriaxone treatment induced upregulation of GLT1, GLT1 isoforms, and xCT in association with activation of the Akt-NFκB signaling pathway.

  8. Higher Education Association Lobbying: Grassroots Outreach as a Signal of Constituent Opinion

    Science.gov (United States)

    Bennett, Stacy M.

    2012-01-01

    This study sought to gain a better understanding of lobbying by the major DC-based higher education associations. To understand this phenomenon, this study looked at the lobbying tactics used by the associations and how they decide on what lobbying tactics to use. A qualitative, multiple case study approach was used with a sample comprised of…

  9. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    Science.gov (United States)

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are ...

  10. Exploration of the association rules mining technique for the signal detection of adverse drug events in spontaneous reporting systems.

    Science.gov (United States)

    Wang, Chao; Guo, Xiao-Jing; Xu, Jin-Fang; Wu, Cheng; Sun, Ya-Lin; Ye, Xiao-Fei; Qian, Wei; Ma, Xiu-Qiang; Du, Wen-Min; He, Jia

    2012-01-01

    The detection of signals of adverse drug events (ADEs) has increased because of the use of data mining algorithms in spontaneous reporting systems (SRSs). However, different data mining algorithms have different traits and conditions for application. The objective of our study was to explore the application of association rule (AR) mining in ADE signal detection and to compare its performance with that of other algorithms. Monte Carlo simulation was applied to generate drug-ADE reports randomly according to the characteristics of SRS datasets. Thousand simulated datasets were mined by AR and other algorithms. On average, 108,337 reports were generated by the Monte Carlo simulation. Based on the predefined criterion that 10% of the drug-ADE combinations were true signals, with RR equaling to 10, 4.9, 1.5, and 1.2, AR detected, on average, 284 suspected associations with a minimum support of 3 and a minimum lift of 1.2. The area under the receiver operating characteristic (ROC) curve of the AR was 0.788, which was equivalent to that shown for other algorithms. Additionally, AR was applied to reports submitted to the Shanghai SRS in 2009. Five hundred seventy combinations were detected using AR from 24,297 SRS reports, and they were compared with recognized ADEs identified by clinical experts and various other sources. AR appears to be an effective method for ADE signal detection, both in simulated and real SRS datasets. The limitations of this method exposed in our study, i.e., a non-uniform thresholds setting and redundant rules, require further research.

  11. Association of reactive oxygen species-mediated signal transduction with in vitro apoptosis sensitivity in chronic lymphocytic leukemia B cells.

    Directory of Open Access Journals (Sweden)

    Adam L Palazzo

    Full Text Available BACKGROUND: Chronic lymphocytic leukemia (CLL is a B cell malignancy with a variable clinical course and unpredictable response to therapeutic agents. Single cell network profiling (SCNP utilizing flow cytometry measures alterations in signaling biology in the context of molecular changes occurring in malignancies. In this study SCNP was used to identify proteomic profiles associated with in vitro apoptotic responsiveness of CLL B cells to fludarabine, as a basis for ultimately linking these with clinical outcome. METHODOLOGY/PRINCIPAL FINDING: SCNP was used to quantify modulated-signaling of B cell receptor (BCR network proteins and in vitro F-ara-A mediated apoptosis in 23 CLL samples. Of the modulators studied the reactive oxygen species, hydrogen peroxide (H₂O₂, a known intracellular second messenger and a general tyrosine phosphatase inhibitor stratified CLL samples into two sub-groups based on the percentage of B cells in a CLL sample with increased phosphorylation of BCR network proteins. Separately, in the same patient samples, in vitro exposure to F-ara-A also identified two sub-groups with B cells showing competence or refractoriness to apoptotic induction. Statistical analysis showed that in vitro F-ara-A apoptotic proficiency was highly associated with the proficiency of CLL B cells to undergo H₂O₂-augmented signaling. CONCLUSIONS/SIGNIFICANCE: This linkage in CLL B cells among the mechanisms governing chemotherapy-induced apoptosis increased signaling of BCR network proteins and a likely role of phosphatase activity suggests a means of stratifying patients for their response to F-ara-A based regimens. Future studies will examine the clinical applicability of these findings and also the utility of this approach in relating mechanism to function of therapeutic agents.

  12. Testing strong interaction theories

    International Nuclear Information System (INIS)

    Ellis, J.

    1979-01-01

    The author discusses possible tests of the current theories of the strong interaction, in particular, quantum chromodynamics. High energy e + e - interactions should provide an excellent means of studying the strong force. (W.D.L.)

  13. Protein-Tyrosine Kinase Signaling in the Biological Functions Associated with Sperm

    Directory of Open Access Journals (Sweden)

    Takashi W. Ijiri

    2012-01-01

    Full Text Available In sexual reproduction, two gamete cells (i.e., egg and sperm fuse (fertilization to create a newborn with a genetic identity distinct from those of the parents. In the course of these developmental processes, a variety of signal transduction events occur simultaneously in each of the two gametes, as well as in the fertilized egg/zygote/early embryo. In particular, a growing body of knowledge suggests that the tyrosine kinase Src and/or other protein-tyrosine kinases are important elements that facilitate successful implementation of the aforementioned processes in many animal species. In this paper, we summarize recent findings on the roles of protein-tyrosine phosphorylation in many sperm-related processes (from spermatogenesis to epididymal maturation, capacitation, acrosomal exocytosis, and fertilization.

  14. CYP2S1 depletion enhances colorectal cell proliferation is associated with PGE2-mediated activation of β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Chao [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China); College of Life Science, Anhui Normal University, Wuhu 241000, Anhui (China); Li, Changyuan [College of Life Science, Anhui Normal University, Wuhu 241000, Anhui (China); Li, Minle; Tong, Xuemei [Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China); Hu, Xiaowen; Yang, Xuhan [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China); Yan, Xiaomei [School of Life Sciences & Biotechnology, Shanghai JiaoTong University, Shanghai 200240 (China); He, Lin, E-mail: helinhelin@gmail.com [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China); Wan, Chunling, E-mail: clwan@sjtu.edu.cn [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030 (China)

    2015-02-15

    Colorectal epithelial cancer is one of the most common cancers in the world and its 5-year survival rate is still relatively low. Cytochrome P450 (CYP) enzymes in epithelial cells lining the alimentary tract play an important role in the oxidative metabolism of a wide range of xenobiotics, including (pro-)carcinogens and endogenous compounds. Although CYP2S1, a member of CYP family, strongly expressed in many extrahepatic tissues, the role of CYP2S1 in cancer remains unclear. To investigate whether CYP2S1 involves in colorectal carcinogenesis, cell proliferation was analyzed in HCT116 cells depleted of CYP2S1 using small hairpin interfering RNA. Our data show that CYP2S1 knockdown promotes cell proliferation through increasing the level of endogenous prostaglandin E2(PGE2). PGE2, in turn, reduces phosphorylation of β-catenin and activates β-catenin signaling, which contributes to the cell proliferation. Furthermore, CYP2S1 knockdown increase tumor growth in xenograft mouse model. In brief, these results demonstrate that CYP2S1 regulates colorectal cancer growth through associated with PGE2-mediated activation of β-catenin signaling. - Highlights: • Knockdown of CYP2S1 expression improve HCT116 cell proliferation in vitro and in vivo. • Elevate PGE2 production in CYP2S1 knockdown cell is associated with its proliferation. • Elevate PGE2 level in CYP2S1 knockdown cells enhance β-catenin accumulation. • β-catenin activate TCF/LEF and target gene expression thus promote cell proliferation.

  15. Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling

    International Nuclear Information System (INIS)

    Foster, James S; Fish, Lindsay M; Phipps, Jonathan E; Bruker, Charles T; Lewis, James M; Bell, John L; Solomon, Alan; Kestler, Daniel P

    2013-01-01

    The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines. The A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM–transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms. ODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells. The apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior

  16. BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Andreas E. Moor

    2015-12-01

    Full Text Available BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.

  17. Cocaine-associated odor cue re-exposure increases blood oxygenation level dependent signal in memory and reward regions of the maternal rat brain.

    Science.gov (United States)

    Caffrey, Martha K; Febo, Marcelo

    2014-01-01

    Cue triggered relapse during the postpartum period can negatively impact maternal care. Given the high reward value of pups in maternal rats, we designed an fMRI experiment to test whether offspring presence reduces the neural response to a cocaine associated olfactory cue. Cocaine conditioned place preference was carried out before pregnancy in the presence of two distinct odors that were paired with cocaine or saline (+Cue and -Cue). The BOLD response to +Cue and -Cue was measured in dams on postpartum days 2-4. Odor cues were delivered to dams in the absence and then the presence of pups. Our data indicate that several limbic and cognitive regions of the maternal rat brain show a greater BOLD signal response to a +Cue versus -Cue. These include dorsal striatum, prelimbic cortex, parietal cortex, habenula, bed nucleus of stria terminalis, lateral septum and the mediodorsal and the anterior thalamic nucleus. Of the aforementioned brain regions, only the parietal cortex of cocaine treated dams showed a significant modulatory effect of pup presence. In this area of the cortex, cocaine exposed maternal rats showed a greater BOLD activation in response to the +Cue in the presence than in the absence of pups. Specific regions of the cocaine exposed maternal rat brain are strongly reactive to drug associated cues. The regions implicated in cue reactivity have been previously reported in clinical imaging work, and previous work supports their role in various motivational and cognitive functions. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Meta-analysis of associations between human brain volume and intelligence differences : How strong are they and what do they mean?

    NARCIS (Netherlands)

    Pietschnig, J.; Penke, L.; Wicherts, J.M.; Zeiler, M.; Voracek, M.

    2015-01-01

    Positive associations between human intelligence and brain size have been suspected for more than 150 years. Nowadays, modern non-invasive measures of in vivo brain volume (Magnetic Resonance Imaging) make it possible to reliably assess associations with IQ. By means of a systematic review of

  19. Ovarian Germline Stem Cells (OGSCs and the Hippo Signaling Pathway Association with Physiological and Pathological Ovarian Aging in Mice

    Directory of Open Access Journals (Sweden)

    Jia Li

    2015-07-01

    Full Text Available Background: The Hippo signaling pathway plays fundamental roles in stem cell maintenance in a variety of tissues and has thus implications for stem cell biology. Key components of this recently discovered pathway have been shown to be associated with primordial follicle activation. However, whether the Hippo signaling pathway plays a role in the development of Ovarian Germline Stem Cells (OGSCs during physiological and pathological ovarian aging in mice is unknown. Methods: Mice at the age of 7 days (7D, or of 2, 10, or 20 months (2M, 10M, 20M and mice at 2M treated with TPT and CY/BUS drugs were selected as physiological and pathological ovarian aging models, respectively. Immunohistochemistry was used to assess the development of follicles, and the co-localization of genes characteristic of OGSCs with MST1, LATS2 and YAP1 was assessed by immunofluorescence, western blotting and real-time PCR methods. Results: The Hippo signal pathway and MVH/OCT4 genes were co-expressed in the mouse ovarian cortex. The level and co-localization of LATS2, MST1, MVH, and OCT4 were significantly decreased with increased age, but YAP1 was more prevalent in the mouse ovarian cortex of 2M mice than 7D mice and was not observed in 20M mice. Furthermore, YAP1, MVH, and OCT4 were gradually decreased after TPT and CY/BUS treatment, and LATS2 mRNA and protein up-regulation persisted in TPT- and CY/BUS-treated mice. However, the expression of MST1 was lower in the TPT and CY/BUS groups compared with the control group. In addition, pYAP1 protein showed the highest expression in the ovarian cortexes of 7D mice compared with 20M mice, and the value of pYAP1/YAP1 decreased from 7D to 20M. Moreover, pYAP1 decreased in the TPT- and CY/BUS-treated groups, but the value of pYAP1/YAP1 increased in these groups. Conclusion: Taken together, our results show that the Hippo signaling pathway is associated with the changes that take place in OGSCs during physiological and pathological

  20. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease

    NARCIS (Netherlands)

    Sabater-Lleal, M.; Huang, J.; Chasman, D.I.; Naitza, S.; Dehghan, A.; Johnson, A.D.; Teumer, A.; Reiner, A.P.; Folkersen, L.; Basu, S.; Rudnicka, A.R.; Trompet, S.; Mälarstig, A.; Baumert, J.; Bis, J.C.; Guo, X.; Hottenga, J.J.; Shin, S.Y.; Lopez, L.M.; Lahti, J.; Tanaka, T.; Yanek, L.R.; Oudot-Mellakh, T.; Wilson, J.F.; Navarro, P.; Huffman, J.E.; Zemunik, T.; Redline, S.; Mehra, R.; Pulanic, D.; Rudan, I.; Wright, A.F.; Kolcic, I.; Polasek, O.; Wild, S.H.; Campbell, H.; Curb, J.D.; Wallace, R.; Liu, S.; Eaton, C.B.; Becker, D.M.; Becker, L.C.; Bandinelli, S.; Räikkönen, K.; Widén, E.; Palotie, A.; Fornage, M.; Green, D.; Gross, M.; Davies, G.E.; Harris, S.E.; Liewald, D.C.; Starr, J.M.; Williams, F.M.; Grant, P.J.; Spector, T.D.; Strawbridge, R.J.; Silveira, A.; Sennblad, B.; Rivadeneira, F.; Uitterlinden, A.G.; Franco, O.H.; Hofman, A.; van Dongen, J.; Willemsen, G.; Boomsma, D.I.; Yao, J.; Swords Jenny, N.; Haritunians, T.; McKnight, B.; Lumley, T.; Taylor, K.D.; Rotter, J.I.; Psaty, B.M.; Peters, A.; Gieger, C.; Illig, T.; Grotevendt, A.; Homuth, G.; Völzke, H.; Kocher, T.; Goel, A.; Franzosi, M.G.; Seedorf, U.; Clarke, R.; Steri, M.; Tarasov, K.V.; Sanna, S.; Schlessinger, D.; Stott, D.J.; Sattar, N.; Buckley, B.M.; Rumley, A.; Lowe, G.D.; McArdle, W.L.; Chen, M.H.; Tofler, G.H.; Song, J.; Boerwinkle, E.; Folsom, A.R.; Rose, L.M.; Franco-Cereceda, A.; Teichert, M.; Ikram, M.A.; Mosley, T.H.; Bevan, S.; Dichgans, M.; Rothwell, P.M.; Sudlow, C.L.; Hopewell, J.C.; Chambers, J.C.; Saleheen, D.; Kooner, J.S.; Danesh, J.; Nelson, C.P.; Erdmann, J.; Reilly, M.P.; Kathiresan, S.; Schunkert, H.; Morange, P.E.; Ferrucci, L.; Eriksson, J.G.; Jacobs, D.; Deary, I.J.; Soranzo, N.; Witteman, J.C.; de Geus, E.J.C.; Tracy, R.P.; Hayward, C.; Koenig, W.; Cucca, F.; Jukema, J.W.; Eriksson, P.; Seshadri, S.; Markus, H.S.; Watkins, H.; Samani, N.J.; Wallaschofski, H.; Smith, N.L.; Tregouet, D.A.; Ridker, P.M.; Tang, W.; Strachan, D.P.; Hamsten, A.; O'Donnell, C.J.

    2013-01-01

    BACKGROUND-: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND

  1. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease

    NARCIS (Netherlands)

    Sabater-Lleal, M.; Huang, J.; Chasman, D.; Naitza, S.; Dehghan, A.; Johnson, A.D.; Teumer, A.; Reiner, A.P.; Folkersen, L.; Basu, S.; Rudnicka, A.R.; Trompet, S.; Malarstig, A.; Baumert, J.; Bis, J.C.; Guo, X.; Hottenga, J.J.; Shin, S.Y.; Lopez, L.M.; Lahti, J.; Tanaka, T.; Yanek, L.R.; Oudot-Mellakh, T.; Wilson, J.F.; Navarro, P.; Huffman, J.E.; Zemunik, T.; Redline, S.; Mehra, R.; Pulanic, D.; Rudan, I.; Wright, A.F.; Kolcic, I.; Polasek, O.; Wild, S.H.; Campbell, H.; Curb, J.D.; Wallace, R.; Liu, S.; Eaton, C.B.; Becker, D.M.; Becker, L.C.; Bandinelli, S.; Raikkonen, K.; Widen, E.; Palotie, A.; Fornage, M.; Green, D.; Gross, M.; Davies, G.; Harris, S.E.; Liewald, D.C.; Starr, J.M.; Williams, F.M.; Grant, P.J.; Spector, T.D.; Strawbridge, R.J.; Silveira, A.; Sennblad, B.; Rivadeneira, F.; Uitterlinden, A.G.; Franco, O.H.; Hofman, A.; Dongen, J. Van; Willemsen, G.; Boomsma, D.I.; Yao, J.; Jenny, N. Swords; Haritunians, T.; McKnight, B.; Lumley, T.; Taylor, K.D.; Rotter, J.I.; Psaty, B.M.; Peters, A.; Gieger, C.; Illig, T.; Grotevendt, A.; Homuth, G.; Volzke, H.; Kocher, T.; Goel, A.; Franzosi, M.G.; Seedorf, U.; Clarke, R.; Steri, M.; Tarasov, K.V.; Sanna, S.; Schlessinger, D.; Stott, D.J.; Sattar, N.; Buckley, B.M.; Rumley, A.; Lowe, G.D.; McArdle, W.L.; Chen, M.H.; Tofler, G.H.; Song, J.; Boerwinkle, E.; Folsom, A.R.; Teichert, M.; et al.,

    2013-01-01

    BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS:

  2. Wnt/β-catenin signaling promotes aging-associated hair graying in mice.

    Science.gov (United States)

    Zhang, Zhihui; Lei, Mingxing; Xin, Haoran; Hu, Chunyan; Yang, Tian; Xing, Yizhan; Li, Yuhong; Guo, Haiying; Lian, Xiaohua; Deng, Fang

    2017-09-19

    Canities is an obvious sign of aging in mouse and human, shown as hair graying. Melanocytes in the hair follicle show cyclic activity with hair cycling, which transitions from anagen, catagen to telogen. How the hairs turn gray during aging is not completely uncovered. Here, by using immunostaining and LacZ staining in Dct-LacZ mice, we show that β-catenin is expressed in melanocytes during hair cycling. RT-PCR, western blot and immunostaining show that β-catenin expression is significantly increased in both anagen and telogen skin of aged mice, when compared to the anagen and telogen skin of young mice, respectively. Overexpression of Wnt10b not only accelerates hair follicle to enter anagen phase, but also promotes melanocytes differentiation in young adult mice (2-month old), with increased β-catenin expression in melanocytes at the secondary hair germ and matrix region of regenerated hair follicles. Overexpression of Wnt10b also promotes melanocyte progenitor cells differentiation in vitro . Our data suggest that increased Wnt signaling promotes excessive differentiation of melanocytes, leading to exhaustion of melanocyte stem cells and eventually canities in aged mice.

  3. Valproate alters dopamine signaling in association with induction of Par-4 protein expression.

    Directory of Open Access Journals (Sweden)

    Saebom Lee

    Full Text Available Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA, a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4, an intracellular binding partner of dopamine D2 receptors (DRD2, plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.

  4. Monitoring Notch Signaling-Associated Activation of Stem Cell Niches within Injured Dental Pulp

    Directory of Open Access Journals (Sweden)

    Thimios A. Mitsiadis

    2017-05-01

    Full Text Available Dental pulp stem/progenitor cells guarantee tooth homeostasis, repair and regeneration throughout life. The decision between renewal and differentiation of these cells is influenced by physical and molecular interactions with stromal cells and extracellular matrix molecules forming the specialized microenvironment of dental pulp stem cell niches. Here we study the activation of putative pulp niches after tooth injury through the upregulation of Notch signaling pathway. Notch1, Notch2, and Notch3 molecules were used as markers of dental pulp stem/progenitor cells. Upon dental injury, Notch1 and Notch3 are detected in cells related to vascular structures suggesting a role of these proteins in the activation of specific pulpal perivascular niches. In contrast, a population of Notch2-positive cells that are actively proliferative is observed in the apical part of the pulp. Kinetics of these cells is followed up with a lipophilic DiI labeling, showing that apical pulp cells migrate toward the injury site where dynamic regenerative/repair events occur. The knowledge of the activation and regulation of dental pulp stem/progenitor cells within their niches in pathologic conditions may be helpful for the realization of innovative dental treatments in the near future.

  5. Association between regulator of G protein signaling 9-2 and body weight.

    Directory of Open Access Journals (Sweden)

    Jeffrey L Waugh

    Full Text Available Regulator of G protein signaling 9-2 (RGS9-2 is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9-2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc and observed a reduction in body weight after overexpression of RGS9-2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9-2 as a factor in regulating body weight.

  6. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

    NARCIS (Netherlands)

    Trynka, Gosia; Hunt, Karen A.; Bockett, Nicholas A.; Romanos, Jihane; Mistry, Vanisha; Szperl, Agata; Bakker, Sjoerd F.; Bardella, Maria Teresa; Bhaw-Rosun, Leena; Castillejo, Gemma; de la Concha, Emilio G.; de Almeida, Rodrigo Coutinho; Dias, Kerith-Rae M.; van Diemen, Cleo C.; Dubois, Patrick C. A.; Duerr, Richard H.; Edkins, Sarah; Franke, Lude; Fransen, Karin; Gutierrez, Javier; Heap, Graham A. R.; Hrdlickova, Barbara; Hunt, Sarah; Plaza Izurieta, Leticia; Izzo, Valentina; Joosten, Leo A. B.; Langford, Cordelia; Mazzilli, Maria Cristina; Mein, Charles A.; Midah, Vandana; Mitrovic, Mitja; Mora, Barbara; Morelli, Marinita; Nutland, Sarah; Nunez, Concepcion; Onengut-Gumuscu, Suna; Pearce, Kerra; Platteel, Mathieu; Polanco, Isabel; Potter, Simon; Ribes-Koninckx, Carmen; Ricano-Ponce, Isis; Rich, Stephen S.; Rybak, Anna; Luis Santiago, Jose; Senapati, Sabyasachi; Sood, Ajit; Szajewska, Hania; Troncone, Riccardo; Varade, Jezabel; Wallace, Chris; Wolters, Victorien M.; Zhernakova, Alexandra; Thelma, B. K.; Cukrowska, Bozena; Urcelay, Elena; Ramon Bilbao, Jose; Mearin, M. Luisa; Barisani, Donatella; Barrett, Jeffrey C.; Plagnol, Vincent; Deloukas, Panos; Wijmenga, Cisca; van Heel, David A.

    2011-01-01

    Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified

  7. Depressive symptoms in middle-aged women are more strongly associated with physical health and social support than with socioeconomic factors

    DEFF Research Database (Denmark)

    Aro, A R; Nyberg, N; Absetz, P

    2001-01-01

    The association of socioeconomic factors, health-related factors, and social support with depressive symptoms has been extensively studied. However, most epidemiological studies have focused on a few factors such as marital status, social class, and employment. In this study of middle-aged women we....... Socioeconomic, health-related, and social support factors were all measured with single items. All variables, except level of urbanization, were significantly associated with depressive symptoms in univariate analyses. Multivariate associations were examined with standard multiple regression analyses in three...

  8. Identification of bovine leukemia virus tax function associated with host cell transcription, signaling, stress response and immune response pathway by microarray-based gene expression analysis

    Directory of Open Access Journals (Sweden)

    Arainga Mariluz

    2012-03-01

    Full Text Available Abstract Background Bovine leukemia virus (BLV is associated with enzootic bovine leukosis and is closely related to human T-cell leukemia virus type I. The Tax protein of BLV is a transcriptional activator of viral replication and a key contributor to oncogenic potential. We previously identified interesting mutant forms of Tax with elevated (TaxD247G or reduced (TaxS240P transactivation effects on BLV replication and propagation. However, the effects of these mutations on functions other than transcriptional activation are unknown. In this study, to identify genes that play a role in the cascade of signal events regulated by wild-type and mutant Tax proteins, we used a large-scale host cell gene-profiling approach. Results Using a microarray containing approximately 18,400 human mRNA transcripts, we found several alterations after the expression of Tax proteins in genes involved in many cellular functions such as transcription, signal transduction, cell growth, apoptosis, stress response, and immune response, indicating that Tax protein has multiple biological effects on various cellular environments. We also found that TaxD247G strongly regulated more genes involved in transcription, signal transduction, and cell growth functions, contrary to TaxS240P, which regulated fewer genes. In addition, the expression of genes related to stress response significantly increased in the presence of TaxS240P as compared to wild-type Tax and TaxD247G. By contrast, the largest group of downregulated genes was related to immune response, and the majority of these genes belonged to the interferon family. However, no significant difference in the expression level of downregulated genes was observed among the Tax proteins. Finally, the expression of important cellular factors obtained from the human microarray results were validated at the RNA and protein levels by real-time quantitative reverse transcription-polymerase chain reaction and western blotting

  9. Expression of factors and key components associated with the PI3K signaling pathway in colon cancer.

    Science.gov (United States)

    Chen, Hua; Gao, Junyi; Du, Zhenhua; Zhang, Xuequn; Yang, Fei; Gao, Wei

    2018-04-01

    The pathophysiology of colorectal cancer (CRC) has not been fully elucidated. The dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway frequently contributes to the tumorigenesis and progression of human cancer. The aim of the present study was to explore the expression and clinical significance of a number of associated factors and key components of the PI3K signaling pathway, including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (p110α), phosphorylated protein kinase B (p-Akt) Ser473, p-mammalian target of rapamycin (mTOR) Ser2448, cyclin D1, cyclin dependent kinase (CDK)4, RELA proto-oncogene, nuclear factor-κβ subunit (p65), Ras and extracellular signal-regulated kinase (ERK)1/2 in human CRC. The expression of target proteins was detected using immunohistochemistry (IHC) in 65 CRC cases and 15 colonic adenoma cases. The association between the expression of target proteins and clinical pathological parameters was analyzed using a χ 2 test. IHC results revealed that the expression of all target proteins was significantly increased in CRC tissues compared with in colonic adenoma tissues (P0.05). Cyclin D1, CDK4 and Ras were revealed to be expressed significantly higher in poorly differentiated CRC compared with moderately differentiated CRC (Pcancer tissues with lymph node metastasis compared with cancer tissues without lymph node metastasis (P<0.05). These results suggest that the target proteins may all participate in the tumorigenesis of CRC. Furthermore, cyclin D1, CDK4, Ras, p65 and ERK1/2 may be important in the progression of CRC. The results of the present study may provide novel predictive factors and therapeutic targets for CRC.

  10. The Association of CXC Receptor 4 Mediated Signaling Pathway with Oxaliplatin-Resistant Human Colorectal Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Wen-Shih Huang

    Full Text Available The stromal cell-derived factor-1 (SDF-1/CXC receptor 4 (CXCR4 axis plays an important role in tumor angiogenesis and invasiveness in colorectal cancer (CRC progression. In addition, metastatic CRC remains one of the most difficult human malignancies to treat because of its chemoresistant behavior. However, the mechanism by which correlation occurs between CXCR4 and the clinical response of CRC to chemotherapy remains unknown. We generated chemoresistant cells with increasing doses of oxaliplatin (OXA and 5-Fluorouracil (5FU to develop resistance at a clinical dose. We found that the putative markers did not change in the parental cells, but HCT-116/OxR and HCT-116/5-FUR were more aggressive and had higher tumor growth (demonstrated by wound healing, chemotaxis assay, and a nude mice xenograft model with the use of oxaliplatin. Apoptosis induced by oxaliplatin treatment was significantly decreased in HCT-116/OxR compared to the parental cells. Moreover, HCT-116/OxR cells displayed increased levels of p-gp, p-Akt p-ERK, p-IKBβ, CXCR4, and Bcl-2, but they also significantly inhibited the apoptotic pathways when compared to the parental strain. We evaluated the molecular mechanism governing the signaling pathway associated with anti-apoptosis activity and the aggressive status of chemoresistant cells. Experiments involving specific inhibitors demonstrated that the activation of the pathways associated with CXCR4, ERK1/2 mitogen-activated protein kinase (MAPK, and phosphatidylinositol 3-kinase (PI3K/Akt is critical to the functioning of the HCT-116/OxR and HCT-116/5-FUR characteristics of chemosensitivity. These findings elucidate the mechanism of CXCR4/PI3K/Akt downstream signaling and provide strategies to inhibit CXCR4 mediated signaling pathway in order to overcome CRC's resistance to chemotherapy.

  11. The Adaptor Protein SAP Directly Associates with CD3ζ Chain and Regulates T Cell Receptor Signaling

    Science.gov (United States)

    Proust, Richard; Bertoglio, Jacques; Gesbert, Franck

    2012-01-01

    Mutations altering the gene encoding the SLAM associated protein (SAP) are responsible for the X-linked lymphoproliferative disease or XLP1. Its absence is correlated with a defective NKT cells development, a decrease in B cell functions and a reduced T cells and NK cells cytotoxic activities, thus leading to an immunodeficiency syndrome. SAP is a small 128 amino-acid long protein that is almost exclusively composed of an SH2 domain. It has been shown to interact with the CD150/SLAM family of receptors, and in a non-canonical manner with SH3 containing proteins such as Fyn, βPIX, PKCθ and Nck1. It would thus play the role of a minimal adaptor protein. It has been shown that SAP plays an important function in the activation of T cells through its interaction with the SLAM family of receptors. Therefore SAP defective T cells display a reduced activation of signaling events downstream of the TCR-CD3 complex triggering. In the present work, we evidence that SAP is a direct interactor of the CD3ζ chain. This direct interaction occurs through the first ITAM of CD3ζ, proximal to the membrane. Additionally, we show that, in the context of the TCR-CD3 signaling, an Sh-RNA mediated silencing of SAP is responsible for a decrease of several canonical T cell signaling pathways including Erk, Akt and PLCγ1 and to a reduced induction of IL-2 and IL-4 mRNA. Altogether, we show that SAP plays a central function in the T cell activation processes through a direct association with the CD3 complex. PMID:22912825

  12. Pulsed electromagnetic fields promote in vitro osteoblastogenesis through a Wnt/β-catenin signaling-associated mechanism.

    Science.gov (United States)

    Zhai, Mingming; Jing, Da; Tong, Shichao; Wu, Yan; Wang, Pan; Zeng, Zhaobin; Shen, Guanghao; Wang, Xin; Xu, Qiaoling; Luo, Erping

    2016-02-18

    Substantial evidence indicates that pulsed electromagnetic fields (PEMF) could accelerate fracture healing and enhance bone mass, whereas the unclear mechanism by which PEMF stimulation promotes osteogenesis limits its extensive clinical application. In the present study, effects and potential molecular signaling mechanisms of PEMF on in vitro osteoblasts were systematically investigated. Osteoblast-like MC3T3-E1 cells were exposed to PEMF burst (0.5, 1, 2, or 6 h/day) with 15.38 Hz at various intensities (5 Gs (0.5 mT), 10 Gs (1 mT), or 20 Gs (2 mT)) for 3 consecutive days. PEMF stimulation at 20 Gs (2 mT) for 2 h/day exhibited most prominent promotive effects on osteoblastic proliferation via Cell Counting kit-8 analyses. PEMF exposure induced well-organized cytoskeleton, and promoted formation of extracellular matrix mineralization nodules. Significantly increased proliferation-related gene expressions at the proliferation phase were observed after PEMF stimulation, including Ccnd 1 and Ccne 1. PEMF resulted in significantly increased gene and protein expressions of alkaline phosphatase and osteocalcin at the differentiation phase of osteoblasts rather than the proliferation phase via quantitative reverse transcription polymerase chain reaction and Western blotting analyses. Moreover, PEMF upregulated gene and protein expressions of collagen type 1, Runt-related transcription factor 2 and Wnt/β-catenin signaling (Wnt1, Lrp6, and β-catenin) at proliferation and differentiation phases. Together, our present findings highlight that PEMF stimulated osteoblastic functions through a Wnt/β-catenin signaling-associated mechanism and, hence, regulates downstream osteogenesis-associated gene/protein expressions. Bioelectromagnetics. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Strong-interaction nonuniversality

    International Nuclear Information System (INIS)

    Volkas, R.R.; Foot, R.; He, X.; Joshi, G.C.

    1989-01-01

    The universal QCD color theory is extended to an SU(3) 1 direct product SU(3) 2 direct product SU(3) 3 gauge theory, where quarks of the ith generation transform as triplets under SU(3)/sub i/ and singlets under the other two factors. The usual color group is then identified with the diagonal subgroup, which remains exact after symmetry breaking. The gauge bosons associated with the 16 broken generators then form two massive octets under ordinary color. The interactions between quarks and these heavy gluonlike particles are explicitly nonuniversal and thus an exploration of their physical implications allows us to shed light on the fundamental issue of strong-interaction universality. Nonuniversality and weak flavor mixing are shown to generate heavy-gluon-induced flavor-changing neutral currents. The phenomenology of these processes is studied, as they provide the major experimental constraint on the extended theory. Three symmetry-breaking scenarios are presented. The first has color breaking occurring at the weak scale, while the second and third divorce the two scales. The third model has the interesting feature of radiatively induced off-diagonal Kobayashi-Maskawa matrix elements

  14. Changes in ethylene signaling and MADS box gene expression are associated with banana finger drop.

    Science.gov (United States)

    Hubert, O; Piral, G; Galas, C; Baurens, F-C; Mbéguié-A-Mbéguié, D

    2014-06-01

    Banana finger drop was examined in ripening banana harvested at immature (iMG), early (eMG) and late mature green (lMG) stages, with contrasting ripening rates and ethylene sensitivities. Concomitantly, 11 ethylene signal transduction components (ESTC) and 6 MADS box gene expressions were comparatively studied in median (control zone, CZ) and pedicel rupture (drop zone DZ) areas in peel tissue. iMG fruit did not ripen or develop finger drop while eMG and lMG fruits displayed a similar finger drop pattern. Several ESTC and MADS box gene mRNAs were differentially induced in DZ and CZ and sequentially in eMG and lMG fruits. MaESR2, 3 and MaEIL1, MaMADS2 and MaMADS5 had a higher mRNA level in eMG and acted earlier, whereas MaERS1, MaCTR1, MaEIL3/AB266319, MaEIL4/AB266320 and MaEIL5/AB266321, MaMADS4 and to a lesser extent MaMADS2 and 5 acted later in lMG. In this fruit, MaERS1 and 3, MaCTR1, MaEIL3, 4 and MaEIL5/AB266321, and MaMADS4 were enhanced by finger drop, suggesting their specific involvement in this process. MaEIL1, MaMADS1 and 3, induced at comparable levels in DZ and CZ, are probably related to the overall fruit ripening process. These findings led us to consider that developmental cues are the predominant finger drop regulation factor. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    Science.gov (United States)

    Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W.H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; zu Schwabedissen, Henriette Meyer; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; consortium, HRGEN; den Hoed, Marcel; Loos, Ruth J.F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A.M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; Fabiola Del, Greco M.; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C.M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Leach, Irene Mateo; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C.M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R.P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I.W.; Newton-Cheh, Christopher

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD. PMID:24952745

  16. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling.

    Science.gov (United States)

    Hakim, Fahed; Wang, Yang; Zhang, Shelley X L; Zheng, Jiamao; Yolcu, Esma S; Carreras, Alba; Khalyfa, Abdelnaby; Shirwan, Haval; Almendros, Isaac; Gozal, David

    2014-03-01

    Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that sleep fragmentation promotes tumor growth and progression through proinflammatory TLR4 signaling. In the design, we compared mice that were exposed to sleep fragmentation one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis four weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that sleep fragmentation enhanced tumor size and weight compared with control mice. Increased invasiveness was apparent in sleep fragmentation tumors, which penetrated the tumor capsule into surrounding tissues, including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in sleep fragmentation tumors, where they were distributed in a relatively closer proximity to the tumor capsule compared with control mice. Although tumors were generally smaller in both MYD88(-/-) and TRIF(-/-) hosts, the more aggressive features produced by sleep fragmentation persisted. In contrast, these more aggressive features produced by sleep fragmentation were abolished completely in TLR4(-/-) mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways. ©2014 AACR

  17. Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma.

    Science.gov (United States)

    Kuromi, Teruyuki; Matsushita, Michiko; Iwasaki, Takeshi; Nonaka, Daisuke; Kuwamoto, Satoshi; Nagata, Keiko; Kato, Masako; Akizuki, Gen; Kitamura, Yukisato; Hayashi, Kazuhiko

    2017-11-01

    Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that mostly occurs in the elderly. Merkel cell polyomavirus (MCPyV) is detected in approximately 80% of MCCs and is associated with carcinogenesis. Hedgehog signaling pathway plays a role in human embryogenesis and organogenesis. In addition, reactivation of this pathway later in life can cause tumors. Twenty-nineMCPyV-positive and 21 MCPyV-negative MCCs were immunohistochemically stained with primary antibodies for hedgehog signaling (SHH, IHH, PTCH1, SMO, GLI1, GLI2, and GLI3) and evaluated using H-score. Polymerase chain reaction and sequence analysis for SHH and GLI1 exons were also performed. Expression of SHH was higher in MCPyV-positive MCCs than in MCPyV-negative MCCs (PA. Only 2 mutations with amino acid changes were detected in MCPyV-negative MCCs only: 1 missense mutation in GLI1 exon 4 and 1 nonsense mutation in SHH-3B. Expression of SHH and GLI1 may be useful prognostic markers of MCC because increased expression was associated with better prognosis. The high rate of c.576G>A silent mutation in GLI1 exon 5 was a feature of MCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. An Optimal Bahadur-Efficient Method in Detection of Sparse Signals with Applications to Pathway Analysis in Sequencing Association Studies.

    Directory of Open Access Journals (Sweden)

    Hongying Dai

    Full Text Available Next-generation sequencing data pose a severe curse of dimensionality, complicating traditional "single marker-single trait" analysis. We propose a two-stage combined p-value method for pathway analysis. The first stage is at the gene level, where we integrate effects within a gene using the Sequence Kernel Association Test (SKAT. The second stage is at the pathway level, where we perform a correlated Lancaster procedure to detect joint effects from multiple genes within a pathway. We show that the Lancaster procedure is optimal in Bahadur efficiency among all combined p-value methods. The Bahadur efficiency,[Formula: see text], compares sample sizes among different statistical tests when signals become sparse in sequencing data, i.e. ε →0. The optimal Bahadur efficiency ensures that the Lancaster procedure asymptotically requires a minimal sample size to detect sparse signals ([Formula: see text]. The Lancaster procedure can also be applied to meta-analysis. Extensive empirical assessments of exome sequencing data show that the proposed method outperforms Gene Set Enrichment Analysis (GSEA. We applied the competitive Lancaster procedure to meta-analysis data generated by the Global Lipids Genetics Consortium to identify pathways significantly associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol.

  19. An Optimal Bahadur-Efficient Method in Detection of Sparse Signals with Applications to Pathway Analysis in Sequencing Association Studies.

    Science.gov (United States)

    Dai, Hongying; Wu, Guodong; Wu, Michael; Zhi, Degui

    2016-01-01

    Next-generation sequencing data pose a severe curse of dimensionality, complicating traditional "single marker-single trait" analysis. We propose a two-stage combined p-value method for pathway analysis. The first stage is at the gene level, where we integrate effects within a gene using the Sequence Kernel Association Test (SKAT). The second stage is at the pathway level, where we perform a correlated Lancaster procedure to detect joint effects from multiple genes within a pathway. We show that the Lancaster procedure is optimal in Bahadur efficiency among all combined p-value methods. The Bahadur efficiency,[Formula: see text], compares sample sizes among different statistical tests when signals become sparse in sequencing data, i.e. ε →0. The optimal Bahadur efficiency ensures that the Lancaster procedure asymptotically requires a minimal sample size to detect sparse signals ([Formula: see text]). The Lancaster procedure can also be applied to meta-analysis. Extensive empirical assessments of exome sequencing data show that the proposed method outperforms Gene Set Enrichment Analysis (GSEA). We applied the competitive Lancaster procedure to meta-analysis data generated by the Global Lipids Genetics Consortium to identify pathways significantly associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol.

  20. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas.

    Science.gov (United States)

    Wakimoto, Hiroaki; Tanaka, Shota; Curry, William T; Loebel, Franziska; Zhao, Dan; Tateishi, Kensuke; Chen, Juxiang; Klofas, Lindsay K; Lelic, Nina; Kim, James C; Dias-Santagata, Dora; Ellisen, Leif W; Borger, Darrell R; Fendt, Sarah-Maria; Vander Heiden, Matthew G; Batchelor, Tracy T; Iafrate, A John; Cahill, Daniel P; Chi, Andrew S

    2014-06-01

    Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898-909. ©2014 AACR. ©2014 American Association for Cancer Research.

  1. Electrophysiological signals associated with fluency of different levels of processing reveal multiple contributions to recognition memory.

    Science.gov (United States)

    Li, Bingbing; Taylor, Jason R; Wang, Wei; Gao, Chuanji; Guo, Chunyan

    2017-08-01

    Processing fluency appears to influence recognition memory judgements, and the manipulation of fluency, if misattributed to an effect of prior exposure, can result in illusory memory. Although it is well established that fluency induced by masked repetition priming leads to increased familiarity, manipulations of conceptual fluency have produced conflicting results, variously affecting familiarity or recollection. Some recent studies have found that masked conceptual priming increases correct recollection (Taylor & Henson, 2012), and the magnitude of this behavioural effect correlates with analogous fMRI BOLD priming effects in brain regions associated with recollection (Taylor, Buratto, & Henson, 2013). However, the neural correlates and time-courses of masked repetition and conceptual priming were not compared directly in previous studies. The present study used event-related potentials (ERPs) to identify and compare the electrophysiological correlates of masked repetition and conceptual priming and investigate how they contribute to recognition memory. Behavioural results were consistent with previous studies: Repetition primes increased familiarity, whereas conceptual primes increased correct recollection. Masked repetition and conceptual priming also decreased the latency of late parietal component (LPC). Masked repetition priming was associated with an early P200 effect and a later parietal maximum N400 effect, whereas masked conceptual priming was only associated with a central-parietal maximum N400 effect. In addition, the topographic distributions of the N400 repetition priming and conceptual priming effects were different. These results suggest that fluency at different levels of processing is associated with different ERP components, and contributes differentially to subjective recognition memory experiences. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Seminal Plasma HIV-1 RNA Concentration Is Strongly Associated with Altered Levels of Seminal Plasma Interferon-γ, Interleukin-17, and Interleukin-5

    Science.gov (United States)

    Hoffman, Jennifer C.; Anton, Peter A.; Baldwin, Gayle Cocita; Elliott, Julie; Anisman-Posner, Deborah; Tanner, Karen; Grogan, Tristan; Elashoff, David; Sugar, Catherine; Yang, Otto O.

    2014-01-01

    Abstract Seminal plasma HIV-1 RNA level is an important determinant of the risk of HIV-1 sexual transmission. We investigated potential associations between seminal plasma cytokine levels and viral concentration in the seminal plasma of HIV-1-infected men. This was a prospective, observational study of paired blood and semen samples from 18 HIV-1 chronically infected men off antiretroviral therapy. HIV-1 RNA levels and cytokine levels in seminal plasma and blood plasma were measured and analyzed using simple linear regressions to screen for associations between cytokines and seminal plasma HIV-1 levels. Forward stepwise regression was performed to construct the final multivariate model. The median HIV-1 RNA concentrations were 4.42 log10 copies/ml (IQR 2.98, 4.70) and 2.96 log10 copies/ml (IQR 2, 4.18) in blood and seminal plasma, respectively. In stepwise multivariate linear regression analysis, blood HIV-1 RNA level (pplasma HIV-1 RNA level. After controlling for blood HIV-1 RNA level, seminal plasma HIV-1 RNA level was positively associated with interferon (IFN)-γ (p=0.03) and interleukin (IL)-17 (p=0.03) and negatively associated with IL-5 (p=0.0007) in seminal plasma. In addition to blood HIV-1 RNA level, cytokine profiles in the male genital tract are associated with HIV-1 RNA levels in semen. The Th1 and Th17 cytokines IFN-γ and IL-17 are associated with increased seminal plasma HIV-1 RNA, while the Th2 cytokine IL-5 is associated with decreased seminal plasma HIV-1 RNA. These results support the importance of genital tract immunomodulation in HIV-1 transmission. PMID:25209674

  3. Seismo-acoustic signals associated with degassing explosions recorded at Shishaldin Volcano, Alaska, 2003-2004

    Science.gov (United States)

    Petersen, T.

    2007-01-01

    In summer 2003, a Chaparral Model 2 microphone was deployed at Shishaldin Volcano, Aleutian Islands, Alaska. The pressure sensor was co-located with a short-period seismometer on the volcano’s north flank at a distance of 6.62 km from the active summit vent. The seismo-acoustic data exhibit a correlation between impulsive acoustic signals (1–2 Pa) and long-period (LP, 1–2 Hz) earthquakes. Since it last erupted in 1999, Shishaldin has been characterized by sustained seismicity consisting of many hundreds to two thousand LP events per day. The activity is accompanied by up to ∼200 m high discrete gas puffs exiting the small summit vent, but no significant eruptive activity has been confirmed. The acoustic waveforms possess similarity throughout the data set (July 2003–November 2004) indicating a repetitive source mechanism. The simplicity of the acoustic waveforms, the impulsive onsets with relatively short (∼10–20 s) gradually decaying codas and the waveform similarities suggest that the acoustic pulses are generated at the fluid–air interface within an open-vent system. SO2 measurements have revealed a low SO2 flux, suggesting a hydrothermal system with magmatic gases leaking through. This hypothesis is supported by the steady-state nature of Shishaldin’s volcanic system since 1999. Time delays between the seismic LP and infrasound onsets were acquired from a representative day of seismo-acoustic data. A simple model was used to estimate source depths. The short seismo-acoustic delay times have revealed that the seismic and acoustic sources are co-located at a depth of 240±200 m below the crater rim. This shallow depth is confirmed by resonance of the upper portion of the open conduit, which produces standing waves with f=0.3 Hz in the acoustic waveform codas. The infrasound data has allowed us to relate Shishaldin’s LP earthquakes to degassing explosions, created by gas volume ruptures from a fluid–air interface.

  4. The naive CD4+ count in HIV-1-infected patients at time of initiation of highly active antiretroviral therapy is strongly associated with the level of immunological recovery

    DEFF Research Database (Denmark)

    Michael, OG; Kirk, O; Mathiesen, Lars Reinhardt

    2002-01-01

    CD4 + count followed a triphasic pattern, reflecting an initial phase of rapid redistribution from lymphoid tissues, followed by a slow increase, partially due to an increase in naive CD4+ cell count. From Month 18 onwards, both naive and total CD4 + cell counts stabilized, although viral suppression......-infected patients. The focus was on the naive CD4 + cell time course and associations between naive CD4 + cell counts and established prognostic markers. Total and naive CD4 + cell counts were measured using flow cytometry. The HIV-RNA detection limit was 20 copies/ml. During 36 months of HAART, the total...... was sustained. There was no association between plasma viral load and the increase in naive CD4 + cell count. Importantly, baseline naive CD4 + cell count was significantly associated with the change in naive CD4 + cell count, suggesting that the naive cell count at baseline does influence the immunological...

  5. In roots of Arabidopsis thaliana, the damage-associated molecular pattern AtPep1 is a stronger elicitor of immune signalling than flg22 or the chitin heptamer.

    Directory of Open Access Journals (Sweden)

    Lorenzo Poncini

    Full Text Available Plants interpret their immediate environment through perception of small molecules. Microbe-associated molecular patterns (MAMPs such as flagellin and chitin are likely to be more abundant in the rhizosphere than plant-derived damage-associated molecular patterns (DAMPs. We investigated how the Arabidopsis thaliana root interprets MAMPs and DAMPs as danger signals. We monitored root development during exposure to increasing concentrations of the MAMPs flg22 and the chitin heptamer as well as of the DAMP AtPep1. The tissue-specific expression of defence-related genes in roots was analysed using a toolkit of promoter::YFPN lines reporting jasmonic acid (JA-, salicylic acid (SA-, ethylene (ET- and reactive oxygen species (ROS- dependent signalling. Finally, marker responses were analysed during invasion by the root pathogen Fusarium oxysporum. The DAMP AtPep1 triggered a stronger activation of the defence markers compared to flg22 and the chitin heptamer. In contrast to the tested MAMPs, AtPep1 induced SA- and JA-signalling markers in the root and caused a severe inhibition of root growth. Fungal attack resulted in a strong activation of defence genes in tissues close to the invading fungal hyphae. The results collectively suggest that AtPep1 presents a stronger danger signal to the Arabidopsis root than the MAMPs flg22 and chitin heptamer.

  6. In roots of Arabidopsis thaliana, the damage-associated molecular pattern AtPep1 is a stronger elicitor of immune signalling than flg22 or the chitin heptamer.

    Science.gov (United States)

    Poncini, Lorenzo; Wyrsch, Ines; Dénervaud Tendon, Valérie; Vorley, Thomas; Boller, Thomas; Geldner, Niko; Métraux, Jean-Pierre; Lehmann, Silke

    2017-01-01

    Plants interpret their immediate environment through perception of small molecules. Microbe-associated molecular patterns (MAMPs) such as flagellin and chitin are likely to be more abundant in the rhizosphere than plant-derived damage-associated molecular patterns (DAMPs). We investigated how the Arabidopsis thaliana root interprets MAMPs and DAMPs as danger signals. We monitored root development during exposure to increasing concentrations of the MAMPs flg22 and the chitin heptamer as well as of the DAMP AtPep1. The tissue-specific expression of defence-related genes in roots was analysed using a toolkit of promoter::YFPN lines reporting jasmonic acid (JA)-, salicylic acid (SA)-, ethylene (ET)- and reactive oxygen species (ROS)- dependent signalling. Finally, marker responses were analysed during invasion by the root pathogen Fusarium oxysporum. The DAMP AtPep1 triggered a stronger activation of the defence markers compared to flg22 and the chitin heptamer. In contrast to the tested MAMPs, AtPep1 induced SA- and JA-signalling markers in the root and caused a severe inhibition of root growth. Fungal attack resulted in a strong activation of defence genes in tissues close to the invading fungal hyphae. The results collectively suggest that AtPep1 presents a stronger danger signal to the Arabidopsis root than the MAMPs flg22 and chitin heptamer.

  7. Chronic early childhood exposure to arsenic is associated with a TNF-mediated proteomic signaling response.

    Science.gov (United States)

    Smeester, Lisa; Bommarito, Paige A; Martin, Elizabeth M; Recio-Vega, Rogelio; Gonzalez-Cortes, Tania; Olivas-Calderon, Edgar; Lantz, R Clark; Fry, Rebecca C

    2017-06-01

    Exposure to inorganic arsenic (iAs) in drinking water is a global public health concern and is associated with a range of health outcomes, including immune dysfunction. Children are a particularly sensitive population to the effects of inorganic arsenic, yet the biological mechanisms underlying adverse health outcomes are understudied. Here we used a proteomic approach to examine the effects of iAs exposure on circulating serum protein levels in a cross-sectional children's cohort in Mexico. To identify iAs-associated proteins, levels of total urinary arsenic (U-tAs) and its metabolites were determined and serum proteins assessed for differences in expression. The results indicate an enrichment of Tumor Necrosis Factor-(TNF)-regulated immune and inflammatory response proteins that displayed decreased expression levels in relation to increasing U-tAs. Notably, when analyzed in the context of the proportions of urinary arsenic metabolites in children, the most robust response was observed in relation to the monomethylated arsenicals. This study is among the first serum proteomics assessment in children exposed to iAs. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Culture shapes a mesolimbic response to signals of dominance and subordination that associates with behavior.

    Science.gov (United States)

    Freeman, Jonathan B; Rule, Nicholas O; Adams, Reginald B; Ambady, Nalini

    2009-08-01

    It has long been understood that culture shapes individuals' behavior, but how this is accomplished in the human brain has remained largely unknown. To examine this, we made use of a well-established cross-cultural difference in behavior: American culture tends to reinforce dominant behavior whereas, conversely, Japanese culture tends to reinforce subordinate behavior. In 17 Americans and 17 Japanese individuals, we assessed behavioral tendencies towards dominance versus subordination and measured neural responses using fMRI during the passive viewing of stimuli related to dominance and subordination. In Americans, dominant stimuli selectively engaged the caudate nucleus, bilaterally, and the medial prefrontal cortex (mPFC), whereas these were selectively engaged by subordinate stimuli in Japanese. Correspondingly, Americans self-reported a tendency towards more dominant behavior whereas Japanese self-reported a tendency towards more subordinate behavior. Moreover, activity in the right caudate and mPFC correlated with behavioral tendencies towards dominance versus subordination, such that stronger responses in the caudate and mPFC to dominant stimuli were associated with more dominant behavior and stronger responses in the caudate and mPFC to subordinate stimuli were associated with more subordinate behavior. The findings provide a first demonstration that culture can flexibly shape functional activity in the mesolimbic reward system, which in turn may guide behavior.

  9. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes.

    Science.gov (United States)

    Dutta, Eryn H; Behnia, Faranak; Boldogh, Istvan; Saade, George R; Taylor, Brandie D; Kacerovský, Marian; Menon, Ramkumar

    2016-02-01

    In women with preterm premature rupture of the membranes (PPROM), increased oxidative stress may accelerate premature cellular senescence, senescence-associated inflammation and proteolysis, which may predispose them to rupture. We demonstrate mechanistic differences between preterm birth (PTB) and PPROM by revealing differences in fetal membrane redox status, oxidative stress-induced damage, distinct signaling pathways and senescence activation. Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM. Fetal membranes and amniotic fluid samples were collected from women with PTB and PPROM. Molecular, biochemical and histologic markers were used to document differences in oxidative stress and antioxidant enzyme status, DNA damage, secondary signaling activation by Ras-GTPase and mitogen-activated protein kinases, and activation of senescence between membranes from the two groups. Oxidative stress was higher and antioxidant enzymes were lower in PPROM compared with PTB. PTB membranes had minimal DNA damage and showed activation of Ras-GTPase and ERK/JNK signaling pathway with minimal signs of senescence. PPROM had higher numbers of cells with DNA damage, prosenescence stress kinase (p38 MAPK) activation and signs of senescence. Samples were obtained retrospectively after delivery. The markers of senescence that we tested are specific but are not sufficient to confirm senescence as the pathology in PPROM. Oxidative stress-induced DNA damage and senescence are characteristics of fetal membranes from PPROM, compared with PTB with intact membranes. PTB and PPROM arise from distinct pathophysiologic pathways. Oxidative stress and oxidative stress-induced cellular damages are likely determinants of the mechanistic signaling pathways and phenotypic outcome. This study is supported by developmental funds to Dr R. Menon from the Department of Obstetrics and Gynecology at The University of

  10. Aliasing of the Schumann resonance background signal by sprite-associated Q-bursts

    Science.gov (United States)

    Guha, Anirban; Williams, Earle; Boldi, Robert; Sátori, Gabriella; Nagy, Tamás; Bór, József; Montanyà, Joan; Ortega, Pascal

    2017-12-01

    The Earth's naturally occurring Schumann resonances (SR) are composed of a quasi-continuous background component and a larger-amplitude, short-duration transient component, otherwise called 'Q-burst' (Ogawa et al., 1967). Sprites in the mesosphere are also known to accompany the energetic positive ground flashes that launch the Q-bursts (Boccippio et al., 1995). Spectra of the background Schumann Resonances (SR) require a natural stabilization period of ∼10-12 min for the three conspicuous modal parameters to be derived from Lorentzian fitting. Before the spectra are computed and the fitting process is initiated, the raw time series data need to be properly filtered for local cultural noise, narrow band interference as well as for large transients in the form of global Q-bursts. Mushtak and Williams (2009) describe an effective technique called Isolated Lorentzian (I-LOR), in which, the contributions from local cultural and various other noises are minimized to a great extent. An automated technique based on median filtering of time series data has been developed. These special lightning flashes are known to have greater contribution in the ELF range (below 1 kHz) compared to general negative CG strikes (Huang et al., 1999; Cummer et al., 2006). The global distributions of these Q-bursts have been studied by Huang et al. (1999) Rhode Island, USA by wave impedance methods from single station ELF measurements at Rhode Island, USA and from Japan Hobara et al. (2006). The present work aims to demonstrate the effect of Q-bursts on SR background spectra using GPS time-stamped observation of TLEs. It is observed that the Q-bursts selected for the present work do alias the background spectra over a 5-s period, though the amplitudes of these Q-bursts are far below the background threshold of 16 Core Standard Deviation (CSD) so that they do not strongly alias the background spectra of 10-12 min duration. The examination of one exceptional Q-burst shows that appreciable

  11. Childhood ADHD Is Strongly Associated with a Broad Range of Psychiatric Disorders during Adolescence: A Population-Based Birth Cohort Study

    Science.gov (United States)

    Yoshimasu, Kouichi; Barbaresi, William J.; Colligan, Robert C.; Voigt, Robert G.; Killian, Jill M.; Weaver, Amy L.; Katusic, Slavica K.

    2012-01-01

    Background: To evaluate associations between attention-deficit/hyperactivity disorder (ADHD) and comorbid psychiatric disorders using research-identified incident cases of ADHD and population-based controls. Methods: Subjects included a birth cohort of all children born 1976-1982 remaining in Rochester, MN after age five (n = 5,718). Among them we…

  12. Elevated skin autofluorescence is strongly associated with foot ulcers in patients with diabetes : a cross-sectional, observational study of Chinese subjects

    NARCIS (Netherlands)

    Hu, Hang; Han, Chun-mao; Hu, Xin-lei; Ye, Wan-lan; Huang, Wen-juan; Smit, Andries J.

    This study was designed to evaluate the association between skin autofluorescence (AF), an indicator of advanced glycation end-products (AGEs), and foot ulcers in subjects with diabetes. In this study, 195 Chinese diabetic subjects were examined. Their feet were examined regardless of whether an

  13. Diverse phosphorylation patterns of B cell receptor-associated signaling in naïve and memory human B cells revealed by phosphoflow, a powerful technique to study signaling at the single cell level

    Directory of Open Access Journals (Sweden)

    Franklin R Toapanta

    2012-10-01

    Full Text Available Following interaction with cognate antigens, B cells undergo cell activation, proliferation and differentiation. Ligation of the B cell receptor (BCR leads to the phosphorylation of BCR-associated signaling proteins within minutes of antigen binding, a process with profound consequences for the fate of the cells and development of effector immunity. Phosphoflow allows a rapid evaluation of various signaling pathways in complex heterogenous cell subsets. This novel technique was used in combination with multi-chromatic flow cytometry and fluorescent-cell barcoding to study phosphorylation of BCR-associated signaling pathways in naïve and memory human B cell subsets. Proteins of the initiation (Syk, propagation (Btk, Akt and integration (p38MAPK and Erk1/2 signaling units were studied. Switched memory (Sm CD27+ and Sm CD27- phosphorylation patterns were similar when stimulated with anti-IgA or -IgG. In contrast, naïve and unswitched memory (Um cells showed significant differences following IgM stimulation. Enhanced phosphorylation of Syk was observed in Um cells, suggesting a lower activation threshold. This is likely the result of higher amounts of IgM on the cell surface, higher pan-Syk levels and enhanced susceptibility to phosphatase inhibition. All other signaling proteins evaluated also showed some degree of enhanced phosphorylation in Um cells. Furthermore, both the PLC-γ2 and PI3K pathways were activated in Um cells, while only the PI3K pathway was activated on naïve cells. Um cells were the only ones that activated signaling pathways when stimulated with fluorescently-labeled S. Typhi and S. pneumoniae. Finally, simultaneous evaluation of signaling proteins at the single cell level (multi-phosphorylated cells revealed that interaction with gram positive and negative bacteria resulted in complex and diverse signaling patterns. Phosphoflow holds great potential to accelerate vaccine development by identifying signaling profiles in good

  14. Strong Associations Exist among Oxidative Stress and Antioxidant Biomarkers in the Circulating, Cellular and Urinary Anatomical Compartments in Guatemalan Children from the Western Highlands.

    Directory of Open Access Journals (Sweden)

    María J Soto-Méndez

    Full Text Available A series of antioxidant enzymes and non-enzymatic compounds act to protect cells from uncontrolled propagation of free radicals. It is poorly understood, though, to what extent and how their interaction is harmonized.To explore associative interactions among a battery of urinary and blood biomarkers of oxidative stress and enzymatic and non-enzymatic markers of the antioxidant defense system in children from low income households.For this cross-sectional descriptive study, urine, red cells, and plasma were sampled in 82 preschool children attending three daycare centers in Quetzaltenango Guatemala. The urinary oxidative stress biomarkers studied were F2-isoprostanes and 8-hydroxy-deoxy-guanosine. Red cell enzyme activities measured were: catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase. Circulating non-enzymatic antioxidants selected were: retinol, tocopherols, β-carotene and coenzymes Q9 and Q10.In a Spearman rank-order correlation hemi-matrix, of 55 paired combinations of the 11 biomarkers, 28 (51% were significantly correlated among each other (p ≤ 0.05, with the strongest association being retinol and tocopherols (r = 0.697, p 0.5 to ≤ 0.10. F2-isoprostanes showed the greatest number of cross-associations, having significant interactions with 8 of the 10 remaining biomarkers. Goodness-of-fit modeling improved or maintained the r value for 24 of the significant interactions and for one of the 5 borderline associations. Multiple regression backward stepwise analysis indicated that plasma retinol, β-carotene and coenzyme Q10 were independent predictors of urinary F2-isoprostanes.Numerous significant associations resulted among biomarkers of oxidation and responders to oxidation. Interesting findings were the apparent patterns of harmonious interactions among the elements of the oxidation-antioxidation systems in this population.

  15. Waveform inversion of very long period impulsive signals associated with magmatic injection beneath Kilauea Volcano, Hawaii

    Science.gov (United States)

    Ohminato, T.; Chouet, B.A.; Dawson, P.; Kedar, S.

    1998-01-01

    We use data from broadband seismometers deployed around the summit of Kilauea Volcano to quantify the mechanism associated with a transient in the flow of magma feeding the east rift eruption of the volcano. The transient is marked by rapid inflation of the Kilauea summit peaking at 22 ??rad 4.5 hours after the event onset, followed by slow deflation over a period of 3 days. Superimposed on the summit inflation is a series of sawtooth displacement pulses, each characterized by a sudden drop in amplitude lasting 5-10 s followed by an exponential recovery lasting 1-3 min. The sawtooth waveforms display almost identical shapes, suggesting a process involving the repeated activation of a fixed source. The particle motion associated with each sawtooth is almost linear, and its major swing shows compressional motion at all stations. Analyses of semblance and particle motion are consistent with a point source located 1 km beneath the northeast edge of the Halemaumau pit crater. To estimate the source mechanism, we apply a moment tensor inversion to the waveform data, assuming a point source embedded in a homogeneous half-space with compressional and shear wave velocities representative of the average medium properties at shallow depth under Kilauea. Synthetic waveforms are constructed by a superposition of impulse responses for six moment tensor components and three single force components. The origin times of individual impulses are distributed along the time axis at appropriately small, equal intervals, and their amplitudes are determined by least squares. In this inversion, the source time functions of the six tensor and three force components are determined simultaneously. We confirm the accuracy of the inversion method through a series of numerical tests. The results from the inversion show that the waveform data are well explained by a pulsating transport mechanism operating on a subhorizontal crack linking the summit reservoir to the east rift of Kilauea. The crack

  16. Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

    DEFF Research Database (Denmark)

    Browne, Brigid C.; Hochgräfe, Falko; Wu, Jianmin

    2013-01-01

    Acquired resistance to the anti‐estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen‐resistant MCF7 breast cancer cells (Tam......R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam...... into the molecular alterations associated with the tamoxifen‐resistant phenotype, and identify MARCKS as a potential biomarker of therapeutic responsiveness that may assist in stratification of patients for optimal therapy....

  17. Association between changes in electromyographic signal amplitude and abdominal muscle thickness in individuals with and without lumbopelvic pain.

    Science.gov (United States)

    Whittaker, Jackie L; McLean, Linda; Hodder, Joanne; Warner, Martin B; Stokes, Maria J

    2013-01-01

    Validation study. To investigate the association between changes in electromyographic (EMG) signal amplitude and sonographic measures of muscle thickness of 4 abdominal muscles, during 2 clinical tests, in adults with and without lumbopelvic pain. There is a trend in rehabilitation to use ultrasound imaging (USI) to determine the extent of abdominal muscle contraction. However, the literature investigating the relationship between abdominal muscle thickness change and level of activation is inconclusive and has not included clinically relevant tasks. Simultaneous recording from fine-wire EMG and USI was performed for 4 abdominal muscles, in 7 adults with lumbopelvic pain (mean ± SD age, 29.7 ± 12.0 years) and 7 adults without lumbopelvic pain (32.0 ± 10.6 years), during an active straight leg raise (ASLR) test and an abdominal drawing-in maneuver (ADIM). Cross-correlation functions and linear regression analyses were used to describe the relationship between the 2 measures. Analyses of variance were used to compare individuals with and without lumbopelvic pain, with an alpha set at .05. Across all muscles, peak cross-correlation values were low (ASLR, r = 0.28 ± 0.09; ADIM, r = 0.35 ± 0.11), and there was large variability in associated time lags (ASLR, τ = 0.69 ± 2.56 seconds; ADIM, τ = 0.53 ± 3.75 seconds). Regression analyses did not detect a systematic pattern of association between EMG signal amplitude and USI measurements, and analyses of variance revealed no differences between cohorts. These results suggest a weak relationship between EMG amplitude and abdominal muscle thickness change measured with USI during the ADIM and ASLR, and raise questions about thickness change derived from USI as a measure of muscular activity for the abdominal musculature.

  18. <strong>Project proposal:strong>

    DEFF Research Database (Denmark)

    Katajainen, Jyrki

    2007-01-01

    The Standard Template Library (STL) is a collection of generic algorithms and data structures that is part of the standard run-time environment of the C++ programming language. The STL provides four kinds of associative element containers: set, multiset, map, and multimap. In this project the goal...

  19. Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

    Science.gov (United States)

    Varani, Stefania; Gelsomino, Francesco; Bartoletti, Michele; Viale, Pierluigi; Mastroianni, Antonio; Briganti, Elisabetta; Ortolani, Patrizia; Albertini, Francesco; Calzetti, Carlo; Prati, Francesca; Cenni, Patrizia; Castellani, Gastone; Morini, Silvia; Rossini, Giada; Landini, Maria Paola; Sambri, Vittorio

    2015-01-01

    Toscana virus (TOSV) is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS) cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs) and cytokine levels in plasma and cerebrospinal fluid (CSF) from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS. PMID:26569288

  20. Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

    Directory of Open Access Journals (Sweden)

    Stefania Varani

    2015-11-01

    Full Text Available Toscana virus (TOSV is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs and cytokine levels in plasma and cerebrospinal fluid (CSF from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.

  1. Acquisition of apoptotic resistance in cadmium-induced malignant transformation: specific perturbation of JNK signal transduction pathway and associated metallothionein overexpression.

    Science.gov (United States)

    Qu, Wei; Fuquay, Richard; Sakurai, Teruaki; Waalkes, Michael P

    2006-08-01

    Prior work has shown that chronic cadmium exposed rat liver epithelial cells (CCE-LE) become malignantly transformed after protracted low level cadmium exposure. Acquisition of apoptotic resistance is common in oncogenesis and the present work explores this possibility in CCE-LE cells. CCE-LE cells were resistant to apoptosis induced by etoposide or an acute high concentration of cadmium as assessed by flow cytometry with annexin/FITC. Three key mitogen-activated protein kinases (MAPKs), namely ERK1/2, JNK1/2, and p38, were phosphorylated in CCE-LE cells after acute cadmium exposure. However, the levels of phosphorylated JNK1/2 were markedly decreased in CCE-LE cells compared to control. JNK kinase activity was also suppressed in CCE-LE cells exposed to cadmium. Epidermal growth factor (EGF), used as a positive control for stimulating JNK phosphorylation, was much less effective in CCE-LE cells than control cells. Ro318220 (Ro), a strong activator of JNK, increased phosphorylated JNK1/2 to levels similar to the cadmium-treated control cells and also enhanced apoptosis in response to cadmium in CCE-LE cells. Metallothionein (MT), which is thought to potentially inhibit apoptosis, was strongly overexpressed in CCE-LE cells. Further, in MT knockout (MT-/-) fibroblasts, JNK1/2 phosphorylation was markedly increased after cadmium exposure compared with similarly treated wild-type (MT+/+) cells. These results indicate cadmium-transformed cells acquired apoptotic resistance, which may be linked to the specific suppression of the JNK pathway and is associated with MT overexpression, which, in turn, may impact this signal transduction pathway. The acquisition of apoptotic resistance may play an important role in cadmium carcinogenesis by contributing to both tumor initiation and malignant progression.

  2. Fasting Increases Human Skeletal Muscle Net Phenylalanine Release and This Is Associated with Decreased mTOR Signaling

    Science.gov (United States)

    Vendelbo, Mikkel Holm; Møller, Andreas Buch; Christensen, Britt; Nellemann, Birgitte; Clasen, Berthil Frederik Forrest; Nair, K. Sreekumaran; Jørgensen, Jens Otto Lunde; Jessen, Niels; Møller, Niels

    2014-01-01

    Aim Fasting is characterised by profound changes in energy metabolism including progressive loss of body proteins. The underlying mechanisms are however unknown and we therefore determined the effects of a 72-hour-fast on human skeletal muscle protein metabolism and activation of mammalian target of rapamycin (mTOR), a key regulator of cell growth. Methods Eight healthy male volunteers were studied twice: in the postabsorptive state and following 72 hours of fasting. Regional muscle amino acid kinetics was measured in the forearm using amino acid tracers. Signaling to protein synthesis and breakdown were assessed in skeletal muscle biopsies obtained during non-insulin and insulin stimulated conditions on both examination days. Results Fasting significantly increased forearm net phenylalanine release and tended to decrease phenylalanine rate of disappearance. mTOR phosphorylation was decreased by ∼50% following fasting, together with reduced downstream phosphorylation of 4EBP1, ULK1 and rpS6. In addition, the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and fasting increased expression of the autophagic marker LC3B-II by ∼30%. p62 is degraded during autophagy but was increased by ∼10% during fasting making interpretation of autophagic flux problematic. MAFbx and MURF1 ubiquitin ligases remained unaltered after fasting indicating no change in protesomal protein degradation. Conclusions Our results show that during fasting increased net phenylalanine release in skeletal muscle is associated to reduced mTOR activation and concomitant decreased downstream signaling to cell growth. PMID:25020061

  3. Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

    Science.gov (United States)

    Zheng, Jialin; Ghorpade, Anuja; Niemann, Douglas; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard E.

    1999-01-01

    Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis. PMID:10482576

  4. Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling.

    Directory of Open Access Journals (Sweden)

    Mikkel Holm Vendelbo

    Full Text Available Fasting is characterised by profound changes in energy metabolism including progressive loss of body proteins. The underlying mechanisms are however unknown and we therefore determined the effects of a 72-hour-fast on human skeletal muscle protein metabolism and activation of mammalian target of rapamycin (mTOR, a key regulator of cell growth.Eight healthy male volunteers were studied twice: in the postabsorptive state and following 72 hours of fasting. Regional muscle amino acid kinetics was measured in the forearm using amino acid tracers. Signaling to protein synthesis and breakdown were assessed in skeletal muscle biopsies obtained during non-insulin and insulin stimulated conditions on both examination days.Fasting significantly increased forearm net phenylalanine release and tended to decrease phenylalanine rate of disappearance. mTOR phosphorylation was decreased by ∼50% following fasting, together with reduced downstream phosphorylation of 4EBP1, ULK1 and rpS6. In addition, the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and fasting increased expression of the autophagic marker LC3B-II by ∼30%. p62 is degraded during autophagy but was increased by ∼10% during fasting making interpretation of autophagic flux problematic. MAFbx and MURF1 ubiquitin ligases remained unaltered after fasting indicating no change in protesomal protein degradation.Our results show that during fasting increased net phenylalanine release in skeletal muscle is associated to reduced mTOR activation and concomitant decreased downstream signaling to cell growth.

  5. Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia.

    Science.gov (United States)

    Norris, J W; Pombo, M; Shirley, E; Blevins, G; Tablin, F

    2015-01-01

    Two congenital bleeding diatheses have been identified in Thoroughbred horses: Glanzmann thrombasthenia (GT) and a second, novel diathesis associated with abnormal platelet function in response to collagen and thrombin stimulation. Platelet dysfunction in horses with this second thrombasthenia results from a secretory defect. Two affected and 6 clinically normal horses. Ex vivo study. Washed platelets were examined for (1) expression of the αIIb-β3 integrin; (2) fibrinogen binding capacity in response to ADP and thrombin; (3) secretion of dense and α-granules; (4) activation of the mammalian target of rapamycin (mTOR)-protein kinase B (AKT) signaling pathway; and (5) cellular distribution of phosphatidylinositol-4-phosphate-3-kinase, class 2B (PIK3C2B) and SH2 containing inositol-5'-phosphatase 1 (SHIP1). Platelets from affected horses expressed normal amounts of αIIb-β3 integrin and bound fibrinogen normally in response to ADP, but bound 80% less fibrinogen in response to thrombin. α-granules only released 50% as much Factor V as control platelets, but dense granules released their contents normally. Protein kinase B (AKT) phosphorylation was reduced after thrombin activation, but mTOR Complex 2 (mTORC2) and phosphoinositide-dependent kinase 1 (PDK1) signaling were normal. SH2-containing inositol-5'-phosphatase 1 (SHIP1) did not localize to the cytoskeleton of affected platelets and was decreased overall consistent with reduced AKT phosphorylation. Defects in fibrinogen binding, granule secretion, and signal transduction are unique to this thrombasthenia, which we designate as atypical equine thrombasthenia. Copyright © The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

  6. Regular treadmill exercise prevents sleep deprivation-induced disruption of synaptic plasticity and associated signaling cascade in the dentate gyrus.

    Science.gov (United States)

    Zagaar, Munder; Dao, An; Alhaider, Ibrahim; Alkadhi, Karim

    2013-09-01

    Evidence suggests that regular exercise can protect against learning and memory impairment in the presence of insults such as sleep deprivation. The dentate gyrus (DG) area of the hippocampus is a key staging area for learning and memory processes and is particularly sensitive to sleep deprivation. The purpose of this study was to determine the effect of regular exercise on early-phase long-term potentiation (E-LTP) and its signaling cascade in the presence of sleep deprivation. Rats were exposed to 4 weeks of regular treadmill exercise then subsequently sleep-deprived for 24h using the modified multiple platform model before experimentation. We tested the effects of exercise and/or sleep deprivation using electrophysiological recording in the DG to measure synaptic plasticity; and Western blot analysis to quantify the levels of key signaling proteins related to E-LTP. Regular exercise prevented the sleep deprivation-induced impairment of E-LTP in the DG area as well as the sleep deprivation-associated decrease in basal protein levels of phosphorylated and total α calcium/calmodulin-dependent protein kinase II (P/total-CaMKII) and brain-derived neurotrophic factor (BDNF). High frequency stimulation (HFS) to the DG area was used to model learning stimuli and increased the P-CaMKII and BDNF levels in normal animals: yet failed to change these levels in sleep-deprived rats. However, HFS in control and sleep-deprived rats increased the levels of the phosphatase calcineurin. In contrast, exercise increased BDNF and P-CaMKII levels in exercised/sleep-deprived rats. Regular exercise appears to exert a protective effect against sleep deprivation-induced spatial memory impairment by inducing hippocampal signaling cascades that positively modulate basal and stimulated levels of key effectors such as P-CaMKII and BDNF, while attenuating increases in the protein phosphatase calcineurin. © 2013.

  7. Nine supramolecular assemblies from 5,7-dimethyl-1,8-naphthyridine-2-amine and carboxylic acids by strong classical H-bonds and other noncovalent associations

    Science.gov (United States)

    Ding, Aihua; Jin, Shouwen; Jin, Shide; Guo, Ming; Liu, Hui; Guo, Jianzhong; Wang, Daqi

    2017-12-01

    This article demonstrates 5,7-dimethyl-1,8-naphthyridine-2-amine based organic salt formation in nine crystalline solids 1-9, in which the carboxylates have been integrated. Addition of equivalents of the COOH to the solution of 5,7-dimethyl-1,8-naphthyridine-2-amine generates the singly protonated cationic species which direct the carboxylates. The nine compounds crystallize as their organic salts with the COOH proton transferred to the aromatic N of the 5,7-dimethyl-1,8-naphthyridine-2-amine. All salts have been characterized by IR, mp, EA and XRD technique. The major driving force in 1-9 is the classical H-bonds from 5,7-dimethyl-1,8-naphthyridine-2-amine and the acids, here the Nsbnd H⋯O H-bonds were found in all salts. Other extensive non-covalent interactions also exhibit great functions in space association of the molecular counterparts in relevant crystals. Except 4, all salts had the CHsbnd O, or CH3sbnd O interactions or both. Except 9, the common R22 (8) graph set has been observed in all salts due to the H-bonds and the non-covalent associations. For the synergistic interactions of the classical H-bonds and the various non-covalent associations, the salts displayed 1D-3D structures.

  8. Community-Level Sanitation Coverage More Strongly Associated with Child Growth and Household Drinking Water Quality than Access to a Private Toilet in Rural Mali

    Science.gov (United States)

    2017-01-01

    Sanitation access can provide positive externalities; for example, safe disposal of feces by one household prevents disease transmission to households nearby. However, little empirical evidence exists to characterize the potential health benefits from sanitation externalities. This study investigated the effect of community sanitation coverage versus individual household sanitation access on child health and drinking water quality. Using a census of 121 villages in rural Mali, we analyzed the association of community latrine coverage (defined by a 200 m radius surrounding a household) and individual household latrine ownership with child growth and household stored water quality. Child height-for-age had a significant and positive linear relationship with community latrine coverage, while child weight-for-age and household water quality had nonlinear relationships that leveled off above 60% coverage (p water quality were not associated with individual household latrine ownership. The relationship between community latrine coverage and child height was strongest among households without a latrine; for these households, each 10% increase in latrine coverage was associated with a 0.031 (p-value = 0.040) increase in height-for-age z-score. In this study, the level of sanitation access of surrounding households was more important than private latrine access for protecting water quality and child health. PMID:28514143

  9. Suicidal Ideation Is Associated with Altered Variability of Fingertip Photo-Plethysmogram Signal in Depressed Patients

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    Ahsan H. Khandoker

    2017-07-01

    Full Text Available Physiological and psychological underpinnings of suicidal behavior remain ill-defined and lessen timely diagnostic identification of this subgroup of patients. Arterial stiffness is associated with autonomic dysregulation and may be linked to major depressive disorder (MDD. The aim of this study was to investigate the association between arterial stiffness by photo-plethysmogram (PPG in MDD with and without suicidal ideation (SI by applying multiscale tone entropy (T-E variability analysis. Sixty-one 10-min PPG recordings were analyzed from 29 control, 16 MDD patients with (MDDSI+ and 16 patients without SI (MDDSI−. MDD was based on a psychiatric evaluation and the Mini-International Neuropsychiatric Interview (MINI. Severity of depression was assessed using the Hamilton Depression Rating Scale (HAM-D. PPG features included peak (systole, trough (diastole, pulse wave amplitude (PWA, pulse transit time (PTT and pulse wave velocity (PWV. Tone (Diastole at all lags and Tone (PWA at lags 8, 9, and 10 were found to be significantly different between the MDDSI+ and MDDSI− group. However, Tone (PWA at all lags and Tone (PTT at scales 3–10 were also significantly different between the MDDSI+ and CONT group. In contrast, Entropy (Systole, Entropy (Diastole and Tone (Diastole were significantly different between MDDSI− and CONT groups. The suicidal score was also positively correlated (r = 0.39 ~ 0.47; p < 0.05 with systolic and diastolic entropy values at lags 2–10. Multivariate logistic regression analysis and leave-one-out cross-validation were performed to study the effectiveness of multi-lag T–E features in predicting SI risk. The accuracy of predicting SI was 93.33% in classifying MDDSI+ and MDDSI− with diastolic T-E and lag between 2 and 10. After including anthropometric variables (Age, body mass index, and Waist Circumference, that accuracy increased to 96.67% for MDDSI+/− classification. Our findings suggest that tone

  10. Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.

    Science.gov (United States)

    Li, Qi; Lee, Cheng Hiang; Peters, Lauren A; Mastropaolo, Lucas A; Thoeni, Cornelia; Elkadri, Abdul; Schwerd, Tobias; Zhu, Jun; Zhang, Bin; Zhao, Yongzhong; Hao, Ke; Dinarzo, Antonio; Hoffman, Gabriel; Kidd, Brian A; Murchie, Ryan; Al Adham, Ziad; Guo, Conghui; Kotlarz, Daniel; Cutz, Ernest; Walters, Thomas D; Shouval, Dror S; Curran, Mark; Dobrin, Radu; Brodmerkel, Carrie; Snapper, Scott B; Klein, Christoph; Brumell, John H; Hu, Mingjing; Nanan, Ralph; Snanter-Nanan, Brigitte; Wong, Melanie; Le Deist, Francoise; Haddad, Elie; Roifman, Chaim M; Deslandres, Colette; Griffiths, Anne M; Gaskin, Kevin J; Uhlig, Holm H; Schadt, Eric E; Muise, Aleixo M

    2016-05-01

    Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-κB. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores. In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22

  11. Variation in regulator of G-protein signaling 17 gene (RGS17 is associated with multiple substance dependence diagnoses

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    Zhang Huiping

    2012-05-01

    Full Text Available Abstract Background RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence. Methods The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs was examined with four substance dependence diagnoses (alcohol (AD, cocaine (CD, opioid (OD or marijuana (MjD] in 1,905 African Americans (AAs: 1,562 cases and 343 controls and 1,332 European Americans (EAs: 981 cases and 351 controls. Analyses were performed using both χ2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses. Results Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003≤Pempirical≤0.037. The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005≤Pempirical≤0.019. This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P = 0.002 and non-significantly lower mRNA expression levels of RGS17 in CEU subjects (P = 0.185. No RGS20 SNPs were associated with any of the four dependence traits in either population. Conclusions This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations.

  12. Particle Radiation signals the Expression of Genes in stress-associated Pathways

    Science.gov (United States)

    Blakely, E.; Chang, P.; Bjornstad, K.; Dosanjh, M.; Cherbonnel, C.; Rosen, C.

    The explosive development of microarray screening methods has propelled genome research in a variety of biological systems allowing investigators to examine large-scale alterations in gene expression for research in toxicology pathology and therapy The radiation environment in space is complex and encompasses a variety of highly energetic and charged particles Estimation of biological responses after exposure to these types of radiation is important for NASA in their plans for long-term manned space missions Instead of using the 10 000 gene arrays that are in the marketplace we have chosen to examine particle radiation-induced changes in gene expression using a focused DNA microarray system to study the expression of about 100 genes specifically associated with both the upstream and downstream aspects of the TP53 stress-responsive pathway Genes that are regulated by TP53 include functional clusters that are implicated in cell cycle arrest apoptosis and DNA repair A cultured human lens epithelial cell model Blakely et al IOVS 41 3808 2000 was used for these studies Additional human normal and radiosensitive fibroblast cell lines have also been examined Lens cells were grown on matrix-coated substrate and exposed to 55 MeV u protons at the 88 cyclotron in LBNL or 1 GeV u Iron ions at the NASA Space Radiation Laboratory The other cells lines were grown on conventional tissue culture plasticware RNA and proteins were harvested at different times after irradiation RNA was isolated from sham-treated or select irradiated populations

  13. Galvanic interpretation of self-potential signals associated withmicrobial sulfate-reduction

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    Williams, Kenneth H.; Hubbard, Susan S.; Banfield, Jillian F.

    2007-05-02

    We have evaluated the usefulness of the self-potential (SP)geophysical method to track the onset and location of microbialsulfate-reduction in saturated sediments during organic carbon amendment.Following stimulation of sulfate-reducing bacteria (SRB) by addition oflactate, anomalous voltages exceeding 600 mV correlated in space and timewith the accumulation of dissolved sulfide. Abiotic experiments in whichthe sulfide concentration at the measurement electrode was systematicallyvaried showed a positive correlation between the magnitude of the SPanomaly and differences in the half-cell potential associated with themeasurement and reference electrodes. Thus, we infer that the SPanomaliesresulted from electrochemical differences that developedbetween sulfide-rich regions and areas having higher oxidation potential.In neither experiment did generation of an SP anomaly require thepresence of an in situ electronic conductor, as is required by othermodels. These findings emphasize the importance of incorporation ofelectrochemical effects at electrode surfaces in interpretation of SPdata from geophysical studies. We conclude that SP measurements provide aminimally invasive means for monitoring stimulated sulfate-reductionwithin saturated sediments.

  14. Endogenous proteolytic cleavage of disease-associated prion protein to produce C2 fragments is strongly cell- and tissue-dependent.

    Science.gov (United States)

    Dron, Michel; Moudjou, Mohammed; Chapuis, Jérôme; Salamat, Muhammad Khalid Farooq; Bernard, Julie; Cronier, Sabrina; Langevin, Christelle; Laude, Hubert

    2010-04-02

    The abnormally folded form of the prion protein (PrP(Sc)) accumulating in nervous and lymphoid tissues of prion-infected individuals can be naturally cleaved to generate a N-terminal-truncated fragment called C2. Information about the identity of the cellular proteases involved in this process and its possible role in prion biology has remained limited and controversial. We investigated PrP(Sc) N-terminal trimming in different cell lines and primary cultured nerve cells, and in the brain and spleen tissue from transgenic mice infected by ovine and mouse prions. We found the following: (i) the full-length to C2 ratio varies considerably depending on the infected cell or tissue. Thus, in primary neurons and brain tissue, PrP(Sc) accumulated predominantly as untrimmed species, whereas efficient trimming occurred in Rov and MovS cells, and in spleen tissue. (ii) Although C2 is generally considered to be the counterpart of the PrP(Sc) proteinase K-resistant core, the N termini of the fragments cleaved in vivo and in vitro can actually differ, as evidenced by a different reactivity toward the Pc248 anti-octarepeat antibody. (iii) In lysosome-impaired cells, the ratio of full-length versus C2 species dramatically increased, yet efficient prion propagation could occur. Moreover, cathepsin but not calpain inhibitors markedly inhibited C2 formation, and in vitro cleavage by cathepsins B and L produced PrP(Sc) fragments lacking the Pc248 epitope, strongly arguing for the primary involvement of acidic hydrolases of the endolysosomal compartment. These findings have implications on the molecular analysis of PrP(Sc) and cell pathogenesis of prion infection.

  15. Endogenous Proteolytic Cleavage of Disease-associated Prion Protein to Produce C2 Fragments Is Strongly Cell- and Tissue-dependent*

    Science.gov (United States)

    Dron, Michel; Moudjou, Mohammed; Chapuis, Jérôme; Salamat, Muhammad Khalid Farooq; Bernard, Julie; Cronier, Sabrina; Langevin, Christelle; Laude, Hubert

    2010-01-01

    The abnormally folded form of the prion protein (PrPSc) accumulating in nervous and lymphoid tissues of prion-infected individuals can be naturally cleaved to generate a N-terminal-truncated fragment called C2. Information about the identity of the cellular proteases involved in this process and its possible role in prion biology has remained limited and controversial. We investigated PrPSc N-terminal trimming in different cell lines and primary cultured nerve cells, and in the brain and spleen tissue from transgenic mice infected by ovine and mouse prions. We found the following: (i) the full-length to C2 ratio varies considerably depending on the infected cell or tissue. Thus, in primary neurons and brain tissue, PrPSc accumulated predominantly as untrimmed species, whereas efficient trimming occurred in Rov and MovS cells, and in spleen tissue. (ii) Although C2 is generally considered to be the counterpart of the PrPSc proteinase K-resistant core, the N termini of the fragments cleaved in vivo and in vitro can actually differ, as evidenced by a different reactivity toward the Pc248 anti-octarepeat antibody. (iii) In lysosome-impaired cells, the ratio of full-length versus C2 species dramatically increased, yet efficient prion propagation could occur. Moreover, cathepsin but not calpain inhibitors markedly inhibited C2 formation, and in vitro cleavage by cathepsins B and L produced PrPSc fragments lacking the Pc248 epitope, strongly arguing for the primary involvement of acidic hydrolases of the endolysosomal compartment. These findings have implications on the molecular analysis of PrPSc and cell pathogenesis of prion infection. PMID:20154089

  16. Unusual seismic signals associated with the activity at Galeras volcano, Colombia, from July 1992 to September 1994

    Directory of Open Access Journals (Sweden)

    L. Narvàez M.

    1996-06-01

    Full Text Available After the emplacement of a lava dome at Galeras volcano in 1991, seven eruptions occurred from July 16, 1992, to September 23, 1994, six of which were preceded by quasi-monochromatic, long-duration seismic events with slowly decaying coda named «tornillos» (screws. The dominant frequencies of these unusual seismic signals are related to source characteristics and show temporal changes, diminishing and then tending to stabilize before an eruption. At the same time, the accumulated number and the duration of these signals increase several days prior to the eruption. The increase in the duration of the tornillo events and the decline of the dominant frequencies both suggest an increasing impedance contrast between the surrounding solid material and the fluid. These characteristics may be associated with an increase in the free gas phase in the magma produced by saturation of volatiles due to cooling, crystallization and partial solidification of the column of magma plugging the conduits. The solidified magma can contribute to sealing the conduits and preventing free gas escape, with consequent generation of overpressure. An eruption is initiated when the overpressure exceeds the resistance strength of the solid material.

  17. Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling.

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    Yunhai Luo

    2014-07-01

    Full Text Available Genome maintenance in germ cells is critical for fertility and the stable propagation of species. While mechanisms of meiotic DNA repair and chromosome behavior are well-characterized, the same is not true for primordial germ cells (PGCs, which arise and propagate during very early stages of mammalian development. Fanconi anemia (FA, a genomic instability syndrome that includes hypogonadism and testicular failure phenotypes, is caused by mutations in genes encoding a complex of proteins involved in repair of DNA lesions associated with DNA replication. The signaling mechanisms underlying hypogonadism and testicular failure in FA patients or mouse models are unknown. We conducted genetic studies to show that hypogonadism of Fancm mutant mice is a result of reduced proliferation, but not apoptosis, of PGCs, resulting in reduced germ cells in neonates of both sexes. Progressive loss of germ cells in adult males also occurs, overlaid with an elevated level of meiotic DNA damage. Genetic studies indicated that ATM-p53-p21 signaling is partially responsible for the germ cell deficiency.

  18. Cyanidin Chloride inhibits ovariectomy-induced osteoporosis by suppressing RANKL-mediated osteoclastogenesis and associated signaling pathways.

    Science.gov (United States)

    Cheng, Jianwen; Zhou, Lin; Liu, Qian; Tickner, Jennifer; Tan, Zhen; Li, Xiaofeng; Liu, Mei; Lin, Xixi; Wang, Tao; Pavlos, Nathan J; Zhao, Jinmin; Xu, Jiake

    2018-03-01

    Over-production and activation of osteoclasts is a common feature of osteolytic conditions such as osteoporosis, tumor-associated osteolysis, and inflammatory bone erosion. Cyanidin Chloride, a subclass of anthocyanin, displays antioxidant and anti-carcinogenesis properties, but its role in osteoclastic bone resorption and osteoporosis is not well understood. In this study, we showed that Cyanidin Chloride inhibits osteoclast formation, hydroxyapatite resorption, and receptor activator of NF-κB ligand (RANKL)-induced osteoclast marker gene expression; including ctr, ctsk, and trap. Further investigation revealed that Cyanidin Chloride inhibits RANKL-induced NF-κB activation, suppresses the degradation of IκB-α and attenuates the phosphorylation of extracellular signal-regulated kinases (ERK). In addition, Cyanidin Chloride abrogated RANKL-induced calcium oscillations, the activation of nuclear factor of activated T cells calcineurin-dependent 1 (NFATc1), and the expression of c-Fos. Further, we showed that Cyanidin Chloride protects against ovariectomy-induced bone loss in vivo. Together our findings suggest that Cyanidin Chloride is capable of inhibiting osteoclast formation, hydroxyapatite resorption and RANKL-induced signal pathways in vitro and OVX-induced bone loss in vivo, and thus might have therapeutic potential for osteolytic diseases. © 2017 Wiley Periodicals, Inc.

  19. Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling.

    Science.gov (United States)

    Tikhanovich, Irina; Kuravi, Sudhakiranmayi; Artigues, Antonio; Villar, Maria T; Dorko, Kenneth; Nawabi, Atta; Roberts, Benjamin; Weinman, Steven A

    2015-09-04

    Arginine methylation is a common post-translational modification, but its role in regulating protein function is poorly understood. This study demonstrates that, TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase involved in innate immune signaling, is regulated by reversible arginine methylation in a range of primary and cultured cells. Under basal conditions, TRAF6 is methylated by the methyltransferase PRMT1, and this inhibits its ubiquitin ligase activity, reducing activation of toll-like receptor signaling. In response to toll-like receptor ligands, TRAF6 is demethylated by the Jumonji domain protein JMJD6. Demethylation is required for maximal activation of NF-κB. Loss of JMJD6 leads to reduced response, and loss of PRMT1 leads to basal pathway activation with subsequent desensitization to ligands. In human primary cells, variations in the PRMT1/JMJD6 ratio significantly correlate with TRAF6 methylation, basal activation of NF-κB, and magnitude of response to LPS. Reversible arginine methylation of TRAF6 by the opposing effects of PRMT1 and JMJD6 is, therefore, a novel mechanism for regulation of innate immune pathways. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. First and second trimester gestational weight gains are most strongly associated with cord blood levels of hormones at delivery important for glycemic control and somatic growth.

    Science.gov (United States)

    Rifas-Shiman, Sheryl L; Fleisch, Abby; Hivert, Marie-France; Mantzoros, Christos; Gillman, Matthew W; Oken, Emily

    2017-04-01

    Excessive gestational weight gain (GWG) during pregnancy is associated with adverse outcomes for mothers and offspring. Early, mid, and late pregnancy GWGs have different associations with fetal growth and later life adiposity, but associations with cord blood hormones, which might predict later health, are not well studied. In 978 pregnant women from the pre-birth Project Viva cohort, we calculated trimester-specific GWG using clinically recorded prenatal weights. Outcomes were levels of umbilical cord blood hormones related to fetal and postnatal growth. We used linear regression models adjusted for maternal race/ethnicity, pre-pregnancy BMI, parity, education, pregnancy smoking status and child sex; 2nd and 3rd trimester models were additionally adjusted for GWG in prior trimesters. Mean±SD pre-pregnancy BMI was 24.9±5.5kg/m 2 , 30% were non-white, and 63% were college graduates. Mean±SD cord blood hormone levels were insulin-like growth factor [IGF]-1 (56.4±24.3ng/mL), IGF-2 (408.5±92.7ng/mL), IGFBP-3 (1084±318ng/mL), insulin (6.5±7.2 uU/mL), C-peptide (1.0±0.6ng/mL), leptin (9.0±6.6ng/mL) and adiponectin (28.7±6.8μg/mL). Mean±SD 1st, 2nd and 3rd trimester GWG rates were 0.22±0.22, 0.49±0.19 and 0.46±0.22kg/wk. Greater 1st trimester GWG (per 0.2kg/wk) was associated with higher insulin (0.5 uU/mL; 95% CI 0.1, 0.9) and C-peptide (0.06ng/mL; 95% CI 0.02, 0.09) and lower adiponectin (-0.4μg/mL; 95% CI -0.9, 0.0). Greater 2nd trimester GWG (per 0.2kg/wk) was associated with higher IGF-1 (2.3ng/mL; 95% CI 0.6, 4.0), IGF-2 (7.9ng/mL; 95% CI 1.2, 14.6), IGFBP-3 (41.6ng/mL; 95% CI 19.4, 63.7) and leptin (0.9ng/mL; 0.4, 1.4). 3rd trimester GWG was not associated with cord blood hormones. 1st trimester weight gain appears to matter more for cord blood hormones related to offspring glucose/insulin regulation, whereas 2nd trimester gain matters more for hormones related to growth and adiposity. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Is podoplanin expression associated with transforming growth factor-β signaling in odontogenic cysts and tumors?

    Science.gov (United States)

    Etemad-Moghadam, Shahroo; Alaeddini, Mojgan

    2018-03-26

    Induction of podoplanin by transforming growth factor-β (TGF-β) has been shown in a number of lesions but not in odontogenic tumors (OTs). We evaluated the association between these markers in OTs for the first time and compared their expression among the different neoplasms. Immunohistochemistry using monoclonal antibody against podoplanin and TGF-β was performed on 76 odontogenic cysts and tumors. Spearman's correlation coefficient, Kruskal-Wallis, and Mann-Whitney U tests followed by adjustment with Bonferroni were used for statistical analysis (P < .05). A significant difference in podoplanin expression was found among the lesions consisting of solid ameloblastomas, adenomatoid odontogenic tumors, ameloblastic fibromas, odontogenic myxomas (OMs), odontogenic keratocysts, and calcifying odontogenic cysts. Significant differences were observed only between OMs and each of the other neoplasms. Podoplanin immunostaining in the connective tissue was absent in most lesions. TGF-β was significantly different among the study sample but not between the lesions in paired comparisons. None of the studied OTs showed significant correlations between podoplanin-TGF-β, in either the epithelium or the stroma. These markers were also descriptively reported in calcifying epithelial odontogenic tumors. The inductive effect of TGF-β on podoplanin seems to be limited, if any, in odontogenic lesions. Podoplanin appears to play a role in some aspects of OTs with epithelial or mixed origins. Despite the possible participation of podoplanin in tumorigenesis, it may not necessarily be involved in the aggressive behavior of OTs. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Estrogenic gper signaling regulates mir144 expression in cancer cells and cancer-associated fibroblasts (cafs)

    Science.gov (United States)

    Vivacqua, Adele; De Marco, Paola; Santolla, Maria Francesca; Cirillo, Francesca; Pellegrino, Michele; Panno, Maria Luisa; Abonante, Sergio; Maggiolini, Marcello

    2015-01-01

    MicroRNAs (miRNAs) are small non coding RNA molecules that play a crucial role in several pathophysiological conditions, including cancer. The stimulation of hormone-sensitive tumors by estrogens are mediated by estrogen receptor (ER)α and G protein estrogen receptor (GPER). Previous studies have reported that ERα regulates miRNA expression, while this ability of GPER remains to be elucidated. Here, we demonstrate that in SkBr3 breast cancer and HepG2 hepatocarcinoma cells, 17β-estradiol (E2) and the selective GPER ligand G-1 induce miR144 expression through GPER and the involvement of the PI3K/ERK1/2/Elk1 transduction pathway. Moreover, we show that E2 and G-1 down-regulate through miR144 the onco-suppressor Runx1 and increase cell cycle progression. The capability of E2 and G-1 in triggering the induction of miR144 and the down-regulation of Runx1 was also confirmed in cancer-associated fibroblasts (CAFs) that are main components of the tumor microenvironment driving cancer progression. Further confirming these results, Runx1 protein levels were found decreased in tumor xenografts upon G-1 treatment. On the basis of our findings miR144 and Runx1 may be included among the oncotargets of GPER action. Moreover, the present data provide new insights regarding the ability of estrogens to trigger the GPER/miR144/Runx1 transduction pathway toward the stimulation of cancer progression. PMID:26030000

  3. Exercise associated hormonal signals as powerful determinants of an effective fat mass loss.

    Science.gov (United States)

    Bajer, B; Vlcek, M; Galusova, A; Imrich, R; Penesova, A

    2015-07-01

    Obesity management for achieving an effective weight loss includes dietary modification and exercise [resistance (strength), endurance (cardiovascular) or intervals training (high-intensity intermittent exercise)]. Regular exercise acutely increases fat oxidation, which induces loss of fat mass and increases energy expenditure. Moreover, it has a positive effect on the physical (improved insulin sensitivity, lipid profile, etc.) and mental health (mood, cognition, memory, sleep, etc.). Endocrine responses to muscle actions are affected by many factors, including the exercise muscle groups (lower and upper body), load/volume, time-under tension, and rest-period intervals between sets, training status, gender, and age. The aim of this review is to summarize, evaluate, and clarify the literature data focusing on the endocrine responses to different types of exercise, including the frequency, intensity, and type of movement with regard to the fat loss strategies. Many studies have investigated anabolic [growth hormone, insulin-like growth factor-1 (IGF-1), testosterone] and gluco- and appetite- regulatory (insulin, cortisol, ghrelin) hormone responses and adaptations of skeletal muscles to exercise. Muscle tissue is a critical endocrine organ, playing important role in the regulation of several physiological and metabolic events. Moreover, we are also describing the response of some other substances to exercise, such as myokines [irisin, apelin, brain-derived neurotrophic factor (BDNF), myostatin, and fibroblast growth factor 21 (FGF21)]. It is proposed that reducing intra-abdominal fat mass and increasing cardiorespiratory fitness through improving nutritional quality, reducing sedentary behavior, and increase the participation in physical activity/exercise, might be associated with clinical benefits, sometimes even in the absence of weight loss.

  4. The Plant Actin Cytoskeleton Responds to Signals from Microbe-Associated Molecular Patterns

    Energy Technology Data Exchange (ETDEWEB)

    Henty-Ridilla, Jessica L.; Shimono, Masaki; Li, Jiejie; Chang, Jeff H.; Day, Brad; Staiger, Christopher J.; Zhou, Jian-Min

    2013-04-04

    Plants are constantly exposed to a large and diverse array of microbes; however, most plants are immune to the majority of potential invaders and susceptible to only a small subset of pathogens. The cytoskeleton comprises a dynamic intracellular framework that responds rapidly to biotic stresses and supports numerous fundamental cellular processes including vesicle trafficking, endocytosis and the spatial distribution of organelles and protein complexes. For years, the actin cytoskeleton has been assumed to play a role in plant innate immunity against fungi and oomycetes, based largely on static images and pharmacological studies. To date, however, there is little evidence that the host-cell actin cytoskeleton participates in responses to phytopathogenic bacteria. Here, we quantified the spatiotemporal changes in host-cell cytoskeletal architecture during the immune response to pathogenic and non-pathogenic strains of Pseudomonas syringae pv. tomato DC3000. Two distinct changes to host cytoskeletal arrays were observed that correspond to distinct phases of plant-bacterial interactions i.e. the perception of microbe-associated molecular patterns (MAMPs) during pattern-triggered immunity (PTI) and perturbations by effector proteins during effector-triggered susceptibility (ETS). We demonstrate that an immediate increase in actin filament abundance is a conserved and novel component of PTI. Notably, treatment of leaves with a MAMP peptide mimic was sufficient to elicit a rapid change in actin organization in epidermal cells, and this actin response required the host-cell MAMP receptor kinase complex, including FLS2, BAK1 and BIK1. Finally, we found that actin polymerization is necessary for the increase in actin filament density and that blocking this increase with the actin-disrupting drug latrunculin B leads to enhanced susceptibility of host plants to pathogenic and non-pathogenic bacteria.

  5. Performing high-level sport is strongly associated with urinary incontinence in elite athletes: a comparative study of 372 elite female athletes and 372 controls.

    Science.gov (United States)

    Carvalhais, Alice; Natal Jorge, Renato; Bø, Kari

    2017-06-22

    To evaluate the prevalence of urinary incontinence (UI) in female elite athletes compared with controls and to investigate potential risk factors for UI among elite athletes. This cross-sectional study included 372 elite athletes (athletes group, AG) and 372 age-matched controls (control group, CG). The median age was low (19 years) and the vast majority were nulliparous. Potential risk factors, including clinical, demographic and sports practice characteristics, were collected by using a questionnaire. The International Consultation on Urinary Incontinence Questionnaire-Urinary Incontinence-Short Form was applied to estimate the prevalence of UI. OR with 95% CIs were used to estimate the association with UI. The final model was adjusted for constipation, family history of UI and history of urinary infection. The prevalence of UI was 29.6% and 13.4% in AG and CG, respectively (psport (adjusted (adj) OR=3.31; 95% CI 2.20 to 4.97), family history of UI (adj OR=1.54; 95% CI 1.04 to 2.29), history of urinary infection (adj OR=1.53; 95% CI 1.05 to 2.23) and constipation (adj OR=1.79; 95% CI 1.07 to 2.98) were associated with UI. The prevalence of UI among Portuguese female elite athletes is high and the odds of UI were three times higher than in controls. Also, constipation, family history of UI and history of urinary infections were significantly associated with UI. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. General parenting styles are not strongly associated with fruit and vegetable intake and social-environmental correlates among 11-year-old children in four countries in Europe.

    Science.gov (United States)

    De Bourdeaudhuij, I; Te Velde, S J; Maes, L; Pérez-Rodrigo, C; de Almeida, M D V; Brug, J

    2009-02-01

    To investigate whether fruit and vegetable (F&V) intake in 11-year-olds, and social-environmental correlates of F&V intake such as parental modelling and encouragement, family food rules and home availability, differ according to general parenting styles in Belgium, The Netherlands, Portugal and Spain. Cross-sectional study. Primary schools in four countries. Pupils and one of their parents completed questionnaires to measure F&V intake, related social-environmental correlates and general parenting styles. The sample size was 4555 (49.3 % boys); 1180 for Belgium, 883 for The Netherlands, 1515 for Portugal and 977 for Spain. Parenting styles were divided into authoritative, authoritarian, indulgent and neglectful. No differences were found in F&V intake across parenting styles and only very few significant differences in social-environmental correlates. The authoritarian (more parental encouragement and more demands to eat fruit) and the authoritative (more availability of fruit and vegetables) parenting styles resulted in more favourable correlates. Despite earlier studies suggesting that general parenting styles are associated with health behaviours in children, the present study suggests that this association is weak to non-existent for F&V intakes in four different European countries.

  7. Strong association between non alcoholic fatty liver disease (NAFLD and low 25(OH vitamin D levels in an adult population with normal serum liver enzymes

    Directory of Open Access Journals (Sweden)

    Pozzilli Paolo

    2011-07-01

    Full Text Available Abstract Background Hypovitaminosis D has been recently recognized as a worldwide epidemic. Since vitamin D exerts significant metabolic activities, comprising free fatty acids (FFA flux regulation from the periphery to the liver, its deficiency may promote fat deposition into the hepatocytes. Aim of our study was to test the hypothesis of a direct association between hypovitaminosis D and the presence of NAFLD in subjects with various degree of insulin-resistance and related metabolic disorders. Methods We studied 262 consecutive subjects referred to the Diabetes and Metabolic Diseases clinics for metabolic evaluation. NAFLD (non-alcoholic fatty liver disease was diagnosed by upper abdomen ultrasonography, metabolic syndrome was identified according to the Third Report of National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATPIII modified criteria. Insulin-resistance was evaluated by means of HOMA-IR. Fatty-Liver-Index, a recently identified correlate of NAFLD, was also estimated. Serum 25(OHvitamin D was measured by colorimetric method. Results Patients with NAFLD (n = 162,61.8% had reduced serum 25(OH vitamin D levels compared to subjects without NAFLD (14.8 ± 9.2 vs 20.5 ± 9.7 ng/ml, p Conclusions Low 25(OHvitamin D levels are associated with the presence of NAFLD independently from metabolic syndrome, diabetes and insulin-resistance profile.

  8. Two missense mutations in melanocortin 1 receptor (MC1R) are strongly associated with dark ventral coat color in reindeer (Rangifer tarandus).

    Science.gov (United States)

    Våge, D I; Nieminen, M; Anderson, D G; Røed, K H

    2014-10-01

    The protein-coding region of melanocortin 1 receptor (MC1R) was sequenced to identify potential variation affecting coat color in reindeer (Rangifer tarandus). A T→C sequence variation at nucleotide position 218 (c.218T>C) causing an amino acid (aa) change from methionine to threonine at aa position 73 (p.Met73Thr) was identified. In addition, a T→G sequence variation was found at nucleotide position 839 (c.839T>G), causing phenylalanine to be exchanged by cysteine at aa position 280 (p.Phe280Cys). The two sequence variants (c.218C and c.839G) were found to be closely associated with a darker belly coat compared with animals not having any of these two variants. The aa acid change p.Met73Thr affects the same position as p.Met73Lys previously reported to give constitutive activation of MC1R in black sheep (Ovis aries), whereas p.Phe280Cys is identical to one of two variants previously reported to be associated with dark coat color in Arctic fox (Alopex lagopus), supporting that the two variants found in reindeer are functional. The complete absence of Thr73 and Cys280 among the 51 wild reindeer analyzed provides some evidence that these variants are more common in the domestic herds. © 2014 Stichting International Foundation for Animal Genetics.

  9. Endoplasmic Reticulum-Mitochondria Communication Through Ca2+Signaling: The Importance of Mitochondria-Associated Membranes (MAMs).

    Science.gov (United States)

    Marchi, Saverio; Bittremieux, Mart; Missiroli, Sonia; Morganti, Claudia; Patergnani, Simone; Sbano, Luigi; Rimessi, Alessandro; Kerkhofs, Martijn; Parys, Jan B; Bultynck, Geert; Giorgi, Carlotta; Pinton, Paolo

    2017-01-01

    The execution of proper Ca 2+ signaling requires close apposition between the endoplasmic reticulum (ER) and mitochondria. Hence, Ca 2+ released from the ER is "quasi-synaptically" transferred to mitochondrial matrix, where Ca 2+ stimulates mitochondrial ATP synthesis by activating the tricarboxylic acid (TCA) cycle. However, when the Ca 2+ transfer is excessive and sustained, mitochondrial Ca 2+ overload induces apoptosis by opening the mitochondrial permeability transition pore. A large number of regulatory proteins reside at mitochondria-associated ER membranes (MAMs) to maintain the optimal distance between the organelles and to coordinate the functionality of both ER and mitochondrial Ca 2+ transporters or channels. In this chapter, we discuss the different pathways involved in the regulation of ER-mitochondria Ca 2+ flux and describe the activities of the various Ca 2+ players based on their primary intra-organelle localization.

  10. Association of the leucine-7 to proline-7 variation in the signal sequence of neuropeptide Y with major depression

    DEFF Research Database (Denmark)

    Koefoed, Pernille; Woldbye, David P. D.; Hansen, Thomas v. O.

    2012-01-01

    disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro. Results: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5 n = 593; p = 0.009; odds ratio, OR: 1......Objective: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide...... sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression. Method: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric...

  11. Strongly Correlated Topological Insulators

    Science.gov (United States)

    2016-02-03

    Strongly Correlated Topological Insulators In the past year, the grant was used for work in the field of topological phases, with emphasis on finding...surface of topological insulators. In the past 3 years, we have started a new direction, that of fractional topological insulators. These are materials...in which a topologically nontrivial quasi-flat band is fractionally filled and then subject to strong interactions. The views, opinions and/or

  12. A strong association between biologically active testosterone and leptin in non-obese men and women is lost with increasing (central) adiposity.

    Science.gov (United States)

    Söderberg, S; Olsson, T; Eliasson, M; Johnson, O; Brismar, K; Carlström, K; Ahrén, B

    2001-01-01

    In both humans and rodents, males have lower levels of leptin than females at any level of adiposity. Experimental data support the idea that testosterone exerts a negative influence on leptin levels. There are, however, major inconsistencies in available data concerning the possible association between androgenicity and leptin in humans. Reasons could be the influence of androgenicity on leptin production being dependent on body composition, and incomplete measures of biologically active testosterone levels. In the present study we have characterized the relationship between biologically active testosterone and leptin after careful stratification for gender and adiposity. Healthy subjects (n=158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) population were studied with a cross-sectional design. Anthropometric measurements (body mass index (BMI) and waist circumference) and oral glucose tolerance tests were performed. Circulating levels of leptin, insulin, testosterone, androstenedione, sex hormone-binding globulin (SHBG) and insulin-like growth factor-1 (IGF-1) were measured by radioimmunoassays or microparticle enzyme immunoassays. Apparent concentrations of free testosterone and non-SHBG-bound testosterone were calculated. After adjustments for age, BMI and insulin, leptin levels were inversely correlated to testosterone levels in non-obese men (r=-0.56, Ptestosterone correlated in a positive manner in non-obese women (r=0.59, Plow waist circumference (r=-0.59, Plow levels of biologically active testosterone and SHBG in men with low and medium waist circumference, insulin in men with high waist circumference, high levels of testosterone and insulin in non-obese women, and BMI in obese women. We conclude that low leptin levels are associated with androgenicity in non-obese men and women and that the direction of this association is dependent on gender and body fat

  13. Nuclear detection of Y-box protein-1 (YB-1) closely associates with progesterone receptor negativity and is a strong adverse survival factor in human breast cancer

    International Nuclear Information System (INIS)

    Dahl, Edgar; Dunn, Sandra E; Mertens, Peter R; En-Nia, Abdelaziz; Wiesmann, Frank; Krings, Renate; Djudjaj, Sonja; Breuer, Elisabeth; Fuchs, Thomas; Wild, Peter J; Hartmann, Arndt

    2009-01-01

    Y-box binding protein-1 (YB-1) is the prototypic member of the cold shock protein family that fulfills numerous cellular functions. In the nucleus YB-1 protein orchestrates transcription of proliferation-related genes, whereas in the cytoplasm it associates with mRNA and directs translation. In human tumor entities, such as breast, lung and prostate cancer, cellular YB-1 expression indicates poor clinical outcome, suggesting that YB-1 is an attractive marker to predict patients' prognosis and, potentially, is suitable to individualize treatment protocols. Given these predictive qualities of YB-1 detection we sought to establish a highly specific monoclonal antibody (Mab) for diagnostic testing and its characterization towards outcome prediction (relapse-free and overall survival). Hybridoma cell generation was carried out with recombinant YB-1 protein as immunogen and Mab characterization was performed using immunoblotting and ELISA with recombinant and tagged YB-1 proteins, as well as immunohistochemistry of healthy and breast cancer specimens. Breast tumor tissue array staining results were analyzed for correlations with receptor expression and outcome parameters. YB-1-specific Mab F-E2G5 associates with conformational binding epitopes mapping to two domains within the N-terminal half of the protein and detects nuclear YB-1 protein by immunohistochemistry in paraffin-embedded breast cancer tissues. Prognostic evaluation of Mab F-E2G5 was performed by immunohistochemistry of a human breast cancer tissue microarray comprising 179 invasive breast cancers, 8 ductal carcinoma in situ and 37 normal breast tissue samples. Nuclear YB-1 detection in human breast cancer cells was associated with poor overall survival (p = 0.0046). We observed a close correlation between nuclear YB-1 detection and absence of progesterone receptor expression (p = 0.002), indicating that nuclear YB-1 detection marks a specific subgroup of breast cancer. Likely due to limitation of sample

  14. Nuclear detection of Y-box protein-1 (YB-1 closely associates with progesterone receptor negativity and is a strong adverse survival factor in human breast cancer

    Directory of Open Access Journals (Sweden)

    Wild Peter J

    2009-11-01

    Full Text Available Abstract Background Y-box binding protein-1 (YB-1 is the prototypic member of the cold shock protein family that fulfills numerous cellular functions. In the nucleus YB-1 protein orchestrates transcription of proliferation-related genes, whereas in the cytoplasm it associates with mRNA and directs translation. In human tumor entities, such as breast, lung and prostate cancer, cellular YB-1 expression indicates poor clinical outcome, suggesting that YB-1 is an attractive marker to predict patients' prognosis and, potentially, is suitable to individualize treatment protocols. Given these predictive qualities of YB-1 detection we sought to establish a highly specific monoclonal antibody (Mab for diagnostic testing and its characterization towards outcome prediction (relapse-free and overall survival. Methods Hybridoma cell generation was carried out with recombinant YB-1 protein as immunogen and Mab characterization was performed using immunoblotting and ELISA with recombinant and tagged YB-1 proteins, as well as immunohistochemistry of healthy and breast cancer specimens. Breast tumor tissue array staining results were analyzed for correlations with receptor expression and outcome parameters. Results YB-1-specific Mab F-E2G5 associates with conformational binding epitopes mapping to two domains within the N-terminal half of the protein and detects nuclear YB-1 protein by immunohistochemistry in paraffin-embedded breast cancer tissues. Prognostic evaluation of Mab F-E2G5 was performed by immunohistochemistry of a human breast cancer tissue microarray comprising 179 invasive breast cancers, 8 ductal carcinoma in situ and 37 normal breast tissue samples. Nuclear YB-1 detection in human breast cancer cells was associated with poor overall survival (p = 0.0046. We observed a close correlation between nuclear YB-1 detection and absence of progesterone receptor expression (p = 0.002, indicating that nuclear YB-1 detection marks a specific subgroup of

  15. Strong Cosmic Censorship

    Science.gov (United States)

    Isenberg, James

    2017-01-01

    The Hawking-Penrose theorems tell us that solutions of Einstein's equations are generally singular, in the sense of the incompleteness of causal geodesics (the paths of physical observers). These singularities might be marked by the blowup of curvature and therefore crushing tidal forces, or by the breakdown of physical determinism. Penrose has conjectured (in his `Strong Cosmic Censorship Conjecture`) that it is generically unbounded curvature that causes singularities, rather than causal breakdown. The verification that ``AVTD behavior'' (marked by the domination of time derivatives over space derivatives) is generically present in a family of solutions has proven to be a useful tool for studying model versions of Strong Cosmic Censorship in that family. I discuss some of the history of Strong Cosmic Censorship, and then discuss what is known about AVTD behavior and Strong Cosmic Censorship in families of solutions defined by varying degrees of isometry, and discuss recent results which we believe will extend this knowledge and provide new support for Strong Cosmic Censorship. I also comment on some of the recent work on ``Weak Null Singularities'', and how this relates to Strong Cosmic Censorship.

  16. The naive CD4+ count in HIV-1-infected patients at time of initiation of highly active antiretroviral therapy is strongly associated with the level of immunological recovery

    DEFF Research Database (Denmark)

    Michael, OG; Kirk, O; Mathiesen, Lars Reinhardt

    2002-01-01

    Current antiretroviral therapy can induce considerable, sustained viral suppression followed by immunological recovery, in which naive CD4 + cells are important. Long-term immunological recovery was investigated during the first 3 y of highly active antiretroviral therapy (HAART) in 210 HIV-1......-infected patients. The focus was on the naive CD4 + cell time course and associations between naive CD4 + cell counts and established prognostic markers. Total and naive CD4 + cell counts were measured using flow cytometry. The HIV-RNA detection limit was 20 copies/ml. During 36 months of HAART, the total...... CD4 + count followed a triphasic pattern, reflecting an initial phase of rapid redistribution from lymphoid tissues, followed by a slow increase, partially due to an increase in naive CD4+ cell count. From Month 18 onwards, both naive and total CD4 + cell counts stabilized, although viral suppression...

  17. Community-Level Sanitation Coverage More Strongly Associated with Child Growth and Household Drinking Water Quality than Access to a Private Toilet in Rural Mali.

    Science.gov (United States)

    Harris, Michael; Alzua, Maria Laura; Osbert, Nicolas; Pickering, Amy

    2017-06-20

    Sanitation access can provide positive externalities; for example, safe disposal of feces by one household prevents disease transmission to households nearby. However, little empirical evidence exists to characterize the potential health benefits from sanitation externalities. This study investigated the effect of community sanitation coverage versus individual household sanitation access on child health and drinking water quality. Using a census of 121 villages in rural Mali, we analyzed the association of community latrine coverage (defined by a 200 m radius surrounding a household) and individual household latrine ownership with child growth and household stored water quality. Child height-for-age had a significant and positive linear relationship with community latrine coverage, while child weight-for-age and household water quality had nonlinear relationships that leveled off above 60% coverage (p sanitation access of surrounding households was more important than private latrine access for protecting water quality and child health.

  18. Growth of L-band scintillation at anomaly crest station in association with strong TEC gradient: A study covering wide solar activity period

    Science.gov (United States)

    Pathak, K.; Devi, M.; Barbara, A. K.; Zahan, Y.

    2018-01-01

    The paper aims at to study the sources associated with growth of L band scintillation over Guwahati, an Appleton anomaly region. Starting with the analysis of diurnal and seasonal characteristic features of scintillation from a minimum sunspot number (Rz) of 10 to a maximum of 140, the paper shows that scintillations are more likely to develop during high solar activity period. It also highlights the explosive increase in occurrence of scintillation from post sunset to pre midnight hours in vernal equinoctial months when the background TEC is 50% more than on a normal day, accompanied by enhanced TEC decay rate. The role of equatorial anomaly effects through EXB drift processes are brought into discussion as possible sources on the growth of small scale irregularities leading to such scintillations.

  19. Violence against women is strongly associated with suicide attempts: evidence from the WHO multi-country study on women's health and domestic violence against women.

    Science.gov (United States)

    Devries, Karen; Watts, Charlotte; Yoshihama, Mieko; Kiss, Ligia; Schraiber, Lilia Blima; Deyessa, Negussie; Heise, Lori; Durand, Julia; Mbwambo, Jessie; Jansen, Henrica; Berhane, Yemane; Ellsberg, Mary; Garcia-Moreno, Claudia

    2011-07-01

    Suicidal behaviours are one of the most important contributors to the global burden of disease among women, but little is known about prevalence and modifiable risk factors in low and middle income countries. We use data from the WHO multi-country study on women's health and domestic violence against women to examine the prevalence of suicidal thoughts and attempts, and relationships between suicide attempts and mental health status, child sexual abuse, partner violence and other variables. Population representative cross-sectional household surveys were conducted from 2000-2003 in 13 provincial (more rural) and city (urban) sites in Brazil, Ethiopia, Japan, Namibia, Peru, Samoa, Serbia, Thailand and Tanzania. 20967 women aged 15-49 years participated. Prevalence of lifetime suicide attempts, lifetime suicidal thoughts, and suicidal thoughts in the past four weeks were calculated, and multivariate logistic regression models were fit to examine factors associated with suicide attempts in each site. Prevalence of lifetime suicide attempts ranged from 0.8% (Tanzania) to 12.0% (Peru city); lifetime thoughts of suicide from 7.2% (Tanzania province) to 29.0% (Peru province), and thoughts in the past four weeks from 1.9% (Serbia) to 13.6% (Peru province). 25-50% of women with suicidal thoughts in the past four weeks had also visited a health worker in that time. The most consistent risk factors for suicide attempts after adjusting for probable common mental health disorders were: intimate partner violence, non-partner physical violence, ever being divorced, separated or widowed, childhood sexual abuse and having a mother who had experienced intimate partner violence. Mental health policies and services must recognise the consistent relationship between violence and suicidality in women in low and middle income countries. Training health sector workers to recognize and respond to the consequences of violence may substantially reduce the health burden associated with

  20. Expression pattern of Wnt signaling components in the adult intestine.

    NARCIS (Netherlands)

    Gregorieff, A.; Pinto, D.; Begthel, H.; Destree, O.; Kielman, M.; Clevers, J.C.

    2005-01-01

    BACKGROUND & AIMS: In the intestine, the canonical Wnt signaling cascade plays a crucial role in driving the proliferation of epithelial cells. Furthermore, aberrant activation of Wnt signaling is strongly associated with the development of colorectal cancer. Despite this evidence, little is known

  1. Strong Double Higgs Production at the LHC

    CERN Document Server

    Contino, Roberto; Moretti, Mauro; Piccinini, Fulvio; Rattazzi, Riccardo

    2010-01-01

    The hierarchy problem and the electroweak data, together, provide a plausible motivation for considering a light Higgs emerging as a pseudo-Goldstone boson from a strongly-coupled sector. In that scenario, the rates for Higgs production and decay differ significantly from those in the Standard Model. However, one genuine strong coupling signature is the growth with energy of the scattering amplitudes among the Goldstone bosons, the longitudinally polarized vector bosons as well as the Higgs boson itself. The rate for double Higgs production in vector boson fusion is thus enhanced with respect to its negligible rate in the SM. We study that reaction in pp collisions, where the production of two Higgs bosons at high pT is associated with the emission of two forward jets. We concentrate on the decay mode hh -> WW^(*)WW^(*) and study the semi-leptonic decay chains of the W's with 2, 3 or 4 leptons in the final states. While the 3 lepton final states are the most relevant and can lead to a 3 sigma signal significa...

  2. Urinary pH Levels are Strongly Associated with Bladder Recurrence After Nephroureterectomy in Upper Tract Urothelial Carcinoma Patients with a Smoking History.

    Science.gov (United States)

    Ide, Hiroki; Kikuchi, Eiji; Hagiwara, Masayuki; Hayakawa, Nozomi; Hongo, Hiroshi; Miyajima, Akira; Oya, Mototsugu

    2016-12-01

    Aromatic amines, well-known bladder carcinogens, derived from cigarette smoke are activated by acidic urine. We herein determined whether urinary pH levels are associated with bladder recurrence in upper tract urothelial carcinoma patients with a positive smoking history. A total of 256 upper tract urothelial carcinoma patients who were surgically treated at our institution between 1990 and 2013 were included. Urinary pH levels were defined as the median of at least two consecutive measurements within 1 month of surgery. Ninety-six patients (37.5 %) had pH pH ≥5.5, and urinary pH levels were identified as one of the significant predictors for bladder recurrence in univariate but not multivariate Cox regression analysis in overall. In patients with a positive smoking history among those without a history of bladder tumor (N = 110), the 5-year bladder recurrence-free survival rate was 52.5 % in patients with pH ≥5.5, which was significantly higher than that in those with pH pH pH pH for urine alkalization may prevent bladder recurrence.

  3. High-dimensional analysis of the aging immune system: verification of age-associated differences in immune signaling responses in healthy donors.

    Science.gov (United States)

    Longo, Diane M; Louie, Brent; Ptacek, Jason; Friedland, Greg; Evensen, Erik; Putta, Santosh; Atallah, Michelle; Spellmeyer, David; Wang, Ena; Pos, Zoltan; Marincola, Francesco M; Schaeffer, Andrea; Lukac, Suzanne; Railkar, Radha; Beals, Chan R; Cesano, Alessandra; Carayannopoulos, Leonidas N; Hawtin, Rachael E

    2014-06-21

    Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors. In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)]. Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets. These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies.

  4. Dietary pattern associated with selenoprotein P and MRI-derived body fat volumes, liver signal intensity, and metabolic disorders.

    Science.gov (United States)

    di Giuseppe, Romina; Plachta-Danielzik, Sandra; Koch, Manja; Nöthlings, Ute; Schlesinger, Sabrina; Borggrefe, Jan; Both, Marcus; Müller, Hans-Peter; Kassubek, Jan; Jacobs, Gunnar; Lieb, Wolfgang

    2018-02-14

    The association of complex dietary patterns with circulating selenoprotein P (SELENOP) levels in humans is unknown. In a general population sample, we aimed to identify a dietary pattern explaining inter-individual variation in circulating SELENOP concentrations and to study this pattern in relation to prevalent diabetes, metabolic syndrome (MetS), MRI-determined total volumes of visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, and liver signal intensity/fatty liver disease. In this cross-sectional study, serum SELENOP levels were measured in 853 individuals. In a subsample of 553 participants, whole-body MRI was performed to assess body fat distribution and liver fat. Dietary intake was assessed by a self-administered food frequency questionnaire and the dietary pattern identified using reduced-rank regression (RRR). Multivariable linear and logistic regressions were used to investigate associations between dietary pattern score and metabolic traits. Characterized by high intake of fruit, vegetables and antioxidant beverages, the RRR-derived dietary pattern displayed inverse associations with VAT, SAT, MetS, and prevalent diabetes in multivariable-adjusted restricted cubic splines. Each unit increase in dietary pattern score was associated with 31% higher SELENOP levels, 12% lower VAT (95% CI: - 19%; - 5%), 13% (95% CI: - 20%; - 6%) lower SAT values and 46% (95% CI: 27%; 60%) and 53% (95% CI: 22%; 72%) lower odds of having MetS or diabetes, respectively. No meaningful relations were observed between the dietary pattern and liver traits. Our observations propose diet-related regulation in SELENOP levels and that the identified dietary pattern is inversely related to VAT, SAT, MetS, and prevalent diabetes.

  5. Strong conservation of rhoptry-associated-protein-1 (RAP-1) locus organization and sequence among Babesia isolates infecting sheep from China (Babesia motasi-like phylogenetic group).

    Science.gov (United States)

    Niu, Qingli; Valentin, Charlotte; Bonsergent, Claire; Malandrin, Laurence

    2014-12-01

    Rhoptry-associated-protein 1 (RAP-1) is considered as a potential vaccine candidate due to its involvement in red blood cell invasion by parasites in the genus Babesia. We examined its value as a vaccine candidate by studying RAP-1 conservation in isolates of Babesia sp. BQ1 Ningxian, Babesia sp. Tianzhu and Babesia sp. Hebei, responsible for ovine babesiosis in different regions of China. The rap-1 locus in these isolates has very similar features to those described for Babesia sp. BQ1 Lintan, another Chinese isolate also in the B. motasi-like phylogenetic group, namely the presence of three types of rap-1 genes (rap-1a, rap-1b and rap-1c), multiple conserved rap-1b copies (5) interspaced with more or less variable rap-1a copies (6), and the 3' localization of one rap-1c. The isolates Babesia sp. Tianzhu, Babesia sp. BQ1 Lintan and Ningxian were almost identical (average nucleotide identity of 99.9%) over a putative locus of about 31 Kb, including the intergenic regions. Babesia sp. Hebei showed a similar locus organization but differed in the rap-1 locus sequence, for each gene and intergenic region, with an average nucleotide identity of 78%. Our results are in agreement with 18S rDNA phylogenetic studies performed on these isolates. However, in extremely closely related isolates the rap-1 locus seems more conserved (99.9%) than the 18S rDNA (98.7%), whereas in still closely related isolates the identities are much lower (78%) compared with the 18S rDNA (97.7%). The particularities of the rap-1 locus in terms of evolution, phylogeny, diagnosis and vaccine development are discussed. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Cocaine-Induced Behavioral Sensitization Is Associated With Changes in the Expression of Endocannabinoid and Glutamatergic Signaling Systems in the Mouse Prefrontal Cortex

    Science.gov (United States)

    Blanco, Eduardo; Pavón, Francisco J.; Palomino, Ana; Luque-Rojas, María Jesús; Serrano, Antonia; Rivera, Patricia; Bilbao, Ainhoa; Alen, Francisco; Vida, Margarita; Suárez, Juan

    2015-01-01

    Background: Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. Methods: We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. Results: Although acute cocaine (10mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic

  7. Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex.

    Science.gov (United States)

    Blanco, Eduardo; Pavón, Francisco J; Palomino, Ana; Luque-Rojas, María Jesús; Serrano, Antonia; Rivera, Patricia; Bilbao, Ainhoa; Alen, Francisco; Vida, Margarita; Suárez, Juan; Rodríguez de Fonseca, Fernando

    2014-10-31

    Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. Although acute cocaine (10 mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20 mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10 mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An

  8. Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology.

    Science.gov (United States)

    Betz, Charles; Stracka, Daniele; Prescianotto-Baschong, Cristina; Frieden, Maud; Demaurex, Nicolas; Hall, Michael N

    2013-07-30

    The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75-voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism.

  9. mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology

    Science.gov (United States)

    Betz, Charles; Stracka, Daniele; Prescianotto-Baschong, Cristina; Frieden, Maud; Demaurex, Nicolas; Hall, Michael N.

    2013-01-01

    The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75–voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism. PMID:23852728

  10. Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase.

    Directory of Open Access Journals (Sweden)

    Shuangxi Li

    2016-06-01

    Full Text Available Hedgehog (Hh signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR-family protein Smoothened (Smo. Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail. We find that CL-II phosphorylation is promoted by protein kinase A (PKA-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo.

  11. Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase.

    Science.gov (United States)

    Li, Shuangxi; Li, Shuang; Han, Yuhong; Tong, Chao; Wang, Bing; Chen, Yongbin; Jiang, Jin

    2016-06-01

    Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR)-family protein Smoothened (Smo). Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish)/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail). We find that CL-II phosphorylation is promoted by protein kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo.

  12. Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase

    Science.gov (United States)

    Tong, Chao; Wang, Bing; Chen, Yongbin; Jiang, Jin

    2016-01-01

    Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR)-family protein Smoothened (Smo). Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish)/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail). We find that CL-II phosphorylation is promoted by protein kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo. PMID:27280464

  13. IGFBP-3 Interacts with the Vitamin D Receptor in Insulin Signaling Associated with Obesity in Visceral Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Inmaculada Moreno-Santos

    2017-11-01

    Full Text Available Adipose tissue has traditionally only been considered as an energy storage organ. Nevertheless, the importance of this tissue in systemic physiology and, especially, in systemic inflammation has been highlighted in recent years. Adipose tissue expresses proteins related to vitamin D (VD metabolism, and it has been proposed that it can act as a VD storage tissue. The active form of VD, 1,25-dihydroxyvitamin D3 (1,25(OH2D3, is able to modify adipocyte and adipose tissue physiology via the VD receptor (VDR, decreasing the expression of pro-inflammatory cytokines in adipose tissue. Moreover, VD deficiency and VDR has been reported to be associated with obesity and diabetes. However, the results of the different studies are not conclusive. Insulin growth binding proteins (IGFBPs have been identified in adipose tissue, but their roles are poorly understood. Therefore, the objective of this study was to analyze the plasma levels of VD and the gene expression of VDR in the adipose tissue of subjects with morbid obesity (MO and with different degrees of insulin resistance (IR, as well as the functionality of direct interaction between IGFBP-3 and VDR, which could explain its inhibitory role in adipogenesis. Our results show a novel role of the VD system in the regulation and activation of IGFBP-3 in visceral adipose tissue (VAT of patients with MO, as a new and alternative mechanism proposed in the insulin signaling associated with obesity.

  14. Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth

    Science.gov (United States)

    Deloulme, Jean-Christophe; Gory-Fauré, Sylvie; Mauconduit, Franck; Chauvet, Sophie; Jonckheere, Julie; Boulan, Benoit; Mire, Erik; Xue, Jing; Jany, Marion; Maucler, Caroline; Deparis, Agathe A.; Montigon, Olivier; Daoust, Alexia; Barbier, Emmanuel L.; Bosc, Christophe; Deglon, Nicole; Brocard, Jacques; Denarier, Eric; Le Brun, Isabelle; Pernet-Gallay, Karin; Vilgrain, Isabelle; Robinson, Phillip J.; Lahrech, Hana; Mann, Fanny; Andrieux, Annie

    2015-01-01

    Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts. PMID:26037503

  15. Strong Arcwise Connectedness

    OpenAIRE

    Espinoza, Benjamin; Gartside, Paul; Kovan-Bakan, Merve; Mamatelashvili, Ana

    2012-01-01

    A space is `n-strong arc connected' (n-sac) if for any n points in the space there is an arc in the space visiting them in order. A space is omega-strong arc connected (omega-sac) if it is n-sac for all n. We study these properties in finite graphs, regular continua, and rational continua. There are no 4-sac graphs, but there are 3-sac graphs and graphs which are 2-sac but not 3-sac. For every n there is an n-sac regular continuum, but no regular continuum is omega-sac. There is an omega-sac ...

  16. Abortion: Strong's counterexamples fail

    DEFF Research Database (Denmark)

    Di Nucci, Ezio

    2009-01-01

    This paper shows that the counterexamples proposed by Strong in 2008 in the Journal of Medical Ethics to Marquis's argument against abortion fail. Strong's basic idea is that there are cases--for example, terminally ill patients--where killing an adult human being is prima facie seriously morally......'s scenarios have some valuable future or admitted that killing them is not seriously morally wrong. Finally, if "valuable future" is interpreted as referring to objective standards, one ends up with implausible and unpalatable moral claims....

  17. Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression

    Science.gov (United States)

    2011-01-01

    Background SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN protein levels co-exist with active autocrine TGF-β signaling in cancer cells is yet to be understood. Results In this study, we found elevated SKI and SnoN protein levels in a panel of melanoma cell lines, as compared to normal melanocytes. There was no correlation between SKI protein content and the capacity of melanoma cells to invade Matrigel™, to form subcutaneous tumors, or to metastasize to bone after intracardiac inoculation into nude mice. Nor did we find a correlation between SKI expression and histopathological staging of human melanoma. TGF-β induced a rapid and dose-dependent degradation of SKI protein, associated with SMAD3/4 specific transcriptional response and induction of pro-metastatic target genes, partially prevented by pharmacologic blockade of proteasome activity. SKI knockdown in 1205Lu melanoma cells did not alter their invasive capacity or transcriptional responses to TGF-β, and did not allow p21 expression in response to TGF-β or reveal any growth inhibitory activity of TGF-β. Conclusions Despite high expression in melanoma cells, the role of SKI in melanoma remains elusive: SKI does not efficiently interfere with the pro-oncogenic activities of TGF-β, unless stabilized by proteasome blockade. Its highly labile nature makes it an unlikely target for therapeutic intervention. PMID:21211030

  18. A strong comeback

    International Nuclear Information System (INIS)

    Marier, D.

    1992-01-01

    This article presents the results of a financial rankings survey which show a strong economic activity in the independent energy industry. The topics of the article include advisor turnover, overseas banks, and the increase in public offerings. The article identifies the top project finance investors for new projects and restructurings and rankings for lenders

  19. Neurodevelopmental alterations and seizures developed by mouse model of infantile hypophosphatasia are associated with purinergic signalling deregulation

    Science.gov (United States)

    Sebastián-Serrano, Álvaro; Engel, Tobias; de Diego-García, Laura; Olivos-Oré, Luis A.; Arribas-Blázquez, Marina; Martínez-Frailes, Carlos; Pérez-Díaz, Carmen; Millán, José Luis; Artalejo, Antonio R.; Miras-Portugal, María Teresa; Henshall, David C.; Díaz-Hernández, Miguel

    2016-01-01

    Hypomorphic mutations in the gene encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme, ALPL in human or Akp2 in mice, cause hypophosphatasia (HPP), an inherited metabolic bone disease also characterized by spontaneous seizures. Initially, these seizures were attributed to the impairment of GABAergic neurotransmission caused by altered vitamin B6 (vit-B6) metabolism. However, clinical cases in human newborns and adults whose convulsions are refractory to pro-GABAergic drugs but controlled by the vit-B6 administration, suggest that other factors are involved. Here, to evaluate whether neurodevelopmental alterations are underlying the seizures associated to HPP, we performed morphological and functional characterization of postnatal homozygous TNAP null mice, a model of HPP. These analyses revealed that TNAP deficient mice present an increased proliferation of neural precursors, an altered neuronal morphology, and an augmented neuronal activity. We found that these alterations were associated with a partial downregulation of the purinergic P2X7 receptor (P2X7R). Even though deficient P2X7R mice present similar neurodevelopmental alterations, they do not develop neonatal seizures. Accordingly, we found that the additional blockage of P2X7R prevent convulsions and extend the lifespan of mice lacking TNAP. In agreement with these findings, we also found that exogenous administration of ATP or TNAP antagonists induced seizures in adult wild-type mice by activating P2X7R. Finally, our results also indicate that the anticonvulsive effects attributed to vit-B6 may be due to its capacity to block P2X7R. Altogether, these findings suggest that the purinergic signalling regulates the neurodevelopmental alteration and the neonatal seizures associated to HPP. PMID:27466191

  20. LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways.

    Science.gov (United States)

    Kumar, Jitender; Swanberg, Maria; McGuigan, Fiona; Callreus, Mattias; Gerdhem, Paul; Akesson, Kristina

    2011-09-01

    Osteoporosis is a common complex disorder in postmenopausal women leading to changes in the micro-architecture of bone and increased risk of fracture. Members of the low-density lipoprotein receptor-related protein (LRP) gene family regulates the development and physiology of bone through the Wnt/β-catenin (Wnt) pathway that in turn cross-talks with the bone morphogenetic protein (BMP) pathway. In two cohorts of Swedish women: OPRA (n=1002; age 75 years) and PEAK-25 (n=1005; age 25 years), eleven single nucleotide polymorphisms (SNPs) from Wnt pathway genes (LRP4; LRP5; G protein-coupled receptor 177, GPR177) were analyzed for association with Bone Mineral Density (BMD), rate of bone loss, hip geometry, quantitative ultrasound and fracture. Additionally, interaction of LRP4 with LRP5, GPR177 and BMP2 were analyzed. LRP4 (rs6485702) was associated with higher total body (TB) and lumbar spine (LS) BMD in the PEAK-25 cohort (p=0.006 and 0.005 respectively), and interaction was observed with LRP5 (p=0.007) and BMP2 (p=0.004) for TB BMD. LRP4 also showed significant interaction with LRP5 for femoral neck (FN) and LS BMD in this cohort. In the OPRA cohort, LRP4 polymorphisms were associated with significantly lower fracture incidence overall (p=0.008-0.001) and fewer hip fractures (rs3816614, p=0.006). Significant interaction in the OPRA cohort was observed for LRP4 with BMP2 and GPR177 for FN BMD as well as for rate of bone loss at TB and FN (p=0.007-0.0001). In conclusion, LRP4 and interaction between LRP4 and genes in the Wnt and BMP signaling pathways modulate bone phenotypes including peak bone mass and fracture, the clinical endpoint of osteoporosis. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. RBPJ, the major transcriptional effector of Notch signaling, remains associated with chromatin throughout mitosis, suggesting a role in mitotic bookmarking.

    Science.gov (United States)

    Lake, Robert J; Tsai, Pei-Fang; Choi, Inchan; Won, Kyoung-Jae; Fan, Hua-Ying

    2014-03-01

    Mechanisms that maintain transcriptional memory through cell division are important to maintain cell identity, and sequence-specific transcription factors that remain associated with mitotic chromatin are emerging as key players in transcriptional memory propagation. Here, we show that the major transcriptional effector of Notch signaling, RBPJ, is retained on mitotic chromatin, and that this mitotic chromatin association is mediated through the direct association of RBPJ with DNA. We further demonstrate that RBPJ binds directly to nucleosomal DNA in vitro, with a preference for sites close to the entry/exit position of the nucleosomal DNA. Genome-wide analysis in the murine embryonal-carcinoma cell line F9 revealed that roughly 60% of the sites occupied by RBPJ in asynchronous cells were also occupied in mitotic cells. Among them, we found that a fraction of RBPJ occupancy sites shifted between interphase and mitosis, suggesting that RBPJ can be retained on mitotic chromatin by sliding on DNA rather than disengaging from chromatin during mitotic chromatin condensation. We propose that RBPJ can function as a mitotic bookmark, marking genes for efficient transcriptional activation or repression upon mitotic exit. Strikingly, we found that sites of RBPJ occupancy were enriched for CTCF-binding motifs in addition to RBPJ-binding motifs, and that RBPJ and CTCF interact. Given that CTCF regulates transcription and bridges long-range chromatin interactions, our results raise the intriguing hypothesis that by collaborating with CTCF, RBPJ may participate in establishing chromatin domains and/or long-range chromatin interactions that could be propagated through cell division to maintain gene expression programs.

  2. RBPJ, the major transcriptional effector of Notch signaling, remains associated with chromatin throughout mitosis, suggesting a role in mitotic bookmarking.

    Directory of Open Access Journals (Sweden)

    Robert J Lake

    2014-03-01

    Full Text Available Mechanisms that maintain transcriptional memory through cell division are important to maintain cell identity, and sequence-specific transcription factors that remain associated with mitotic chromatin are emerging as key players in transcriptional memory propagation. Here, we show that the major transcriptional effector of Notch signaling, RBPJ, is retained on mitotic chromatin, and that this mitotic chromatin association is mediated through the direct association of RBPJ with DNA. We further demonstrate that RBPJ binds directly to nucleosomal DNA in vitro, with a preference for sites close to the entry/exit position of the nucleosomal DNA. Genome-wide analysis in the murine embryonal-carcinoma cell line F9 revealed that roughly 60% of the sites occupied by RBPJ in asynchronous cells were also occupied in mitotic cells. Among them, we found that a fraction of RBPJ occupancy sites shifted between interphase and mitosis, suggesting that RBPJ can be retained on mitotic chromatin by sliding on DNA rather than disengaging from chromatin during mitotic chromatin condensation. We propose that RBPJ can function as a mitotic bookmark, marking genes for efficient transcriptional activation or repression upon mitotic exit. Strikingly, we found that sites of RBPJ occupancy were enriched for CTCF-binding motifs in addition to RBPJ-binding motifs, and that RBPJ and CTCF interact. Given that CTCF regulates transcription and bridges long-range chromatin interactions, our results raise the intriguing hypothesis that by collaborating with CTCF, RBPJ may participate in establishing chromatin domains and/or long-range chromatin interactions that could be propagated through cell division to maintain gene expression programs.

  3. Cardiomyocyte-targeted overexpression of the coxsackie-adenovirus receptor causes a cardiomyopathy in association with beta-catenin signaling.

    Science.gov (United States)

    Caruso, Laura; Yuen, Stella; Smith, Julie; Husain, Mansoor; Opavsky, Mary Anne

    2010-06-01

    The coxsackie-adenovirus receptor (CAR) is an adhesion molecule found at the intercalated disc of cardiomyocytes in association with other adherens and tight junction proteins. CAR expression is increased at cardiomyocyte junctions in patients with heart failure. It is not known what contribution elevated CAR expression makes to cardiac pathology. We generated a binary transgenic mouse enabling cardiac-restricted doxycycline-regulated expression of Flag-tagged murine CAR (mCAR(+)/alpha MtTA(+) mice). Myocardial CAR levels were increased 6-fold in mCAR(+)/alpha MtTA(+) mice, localizing to intercalated discs and sarcolemma. Well at birth, mCAR(+)/alpha MtTA(+) mice developed a severe cardiomyopathy and died by 4 weeks. Cardiomyocyte hypertrophy was evident at 1 week, with increased heart:body weight ratios by 3 weeks. Disorganization and degeneration of cardiomyocytes were evident with disrupted adherens junctions. Doxycycline administration turned off transgene expression and rescued mice from the development of the cardiomyopathic phenotype. In CAR-overexpressing mCAR(+)/alpha MtTA(+) mice, adherens junction proteins were abnormally expressed. N-cadherin protein levels were 83% lower in mCAR(+)/alpha MtTA(+) hearts vs controls at 1 week, with levels subsequently increased above controls at 3 weeks. beta-catenin expression was 90% and 135% above controls at 1 and 3 weeks, respectively. Nuclear translocation of beta-catenin in cardiomyocytes of mCAR(+)/alpha MtTA(+) mice was associated with increased c-myc RNA, a target of active beta-catenin known to be associated with cardiac hypertrophy. Our study is the first to demonstrate that increased CAR expression can induce a cardiomyopathy and supports a model whereby the pathogenesis is determined by CAR stimulated beta-catenin signaling, and/or disruption of the adherens junction. (c) 2010 Elsevier Ltd. All rights reserved.

  4. Acylcarnitines as markers of exercise-associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons.

    Science.gov (United States)

    Zhang, Jie; Light, Alan R; Hoppel, Charles L; Campbell, Caitlin; Chandler, Carol J; Burnett, Dustin J; Souza, Elaine C; Casazza, Gretchen A; Hughen, Ronald W; Keim, Nancy L; Newman, John W; Hunter, Gary R; Fernandez, Jose R; Garvey, W Timothy; Harper, Mary-Ellen; Fiehn, Oliver; Adams, Sean H

    2017-01-01

    that a weight-loss/fitness intervention alters plasma xenometabolites [i.e. cis-3,4-methylene-heptanoylcarnitine and γ-butyrobetaine (a co-metabolite possibly derived in part from gut bacteria)], suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered whether acylcarnitine metabolites signal to muscle-innervating afferents; palmitoylcarnitine at concentrations as low as 1-10 μm activated a subset (∼2.5-5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as signals of exertion to short-loop somatosensory-motor circuits or to the brain. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

  5. Strong Electroweak Symmetry Breaking

    CERN Document Server

    Grinstein, Benjamin

    2011-01-01

    Models of spontaneous breaking of electroweak symmetry by a strong interaction do not have fine tuning/hierarchy problem. They are conceptually elegant and use the only mechanism of spontaneous breaking of a gauge symmetry that is known to occur in nature. The simplest model, minimal technicolor with extended technicolor interactions, is appealing because one can calculate by scaling up from QCD. But it is ruled out on many counts: inappropriately low quark and lepton masses (or excessive FCNC), bad electroweak data fits, light scalar and vector states, etc. However, nature may not choose the minimal model and then we are stuck: except possibly through lattice simulations, we are unable to compute and test the models. In the LHC era it therefore makes sense to abandon specific models (of strong EW breaking) and concentrate on generic features that may indicate discovery. The Technicolor Straw Man is not a model but a parametrized search strategy inspired by a remarkable generic feature of walking technicolor,...

  6. Emerging ST121/agr4 community-associated methicillin-resistant Staphylococcus aureus (MRSA with strong adhesin and cytolytic activities: trigger for MRSA pneumonia and fatal aspiration pneumonia in an influenza-infected elderly

    Directory of Open Access Journals (Sweden)

    T.-W. Wan

    2016-09-01

    Full Text Available The pathogenesis of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA pneumonia in influenza-infected elderly individuals has not yet been elucidated in detail. In the present study, a 92-year-old man infected with influenza developed CA-MRSA pneumonia. His CA-MRSA was an emerging type, originated in ST121/agr4 S. aureus, with diversities of Panton–Valentine leucocidin (PVL−/spat5110/SCCmecV+ versus PVL+/spat159(etc./SCCmec−, but with common virulence potentials of strong adhesin and cytolytic activities. Resistance to erythromycin/clindamycin (inducible-type and gentamicin was detected. Pneumonia improved with the administration of levofloxacin, but with the subsequent development of fatal aspiration pneumonia. Hence, characteristic CA-MRSA with strong adhesin and cytolytic activities triggered influenza-related sequential complications.

  7. Black carbon exposure more strongly associated with census tract poverty compared to household income among US black, white, and Latino working class adults in Boston, MA (2003–2010)

    International Nuclear Information System (INIS)

    Krieger, Nancy; Waterman, Pamela D.; Gryparis, Alexandros; Coull, Brent A.

    2014-01-01

    We investigated the association of individual-level ambient exposure to black carbon (spatiotemporal model-based estimate for latitude and longitude of residential address) with individual, household, and census tract socioeconomic measures among a study sample comprised of 1757 US urban working class white, black and Latino adults (age 25–64) recruited for two studies conducted in Boston, MA (2003–2004; 2008–2010). Controlling for age, study, and exam date, the estimated average annual black carbon exposure for the year prior to study enrollment at the participants' residential address was directly associated with census tract poverty (beta = 0.373; 95% confidence interval (CI) 0.322, 0.423) but not with annual household income or education; null associations with race/ethnicity became significant only after controlling for socioeconomic position. - Highlights: • The study included 1757 black, Latino, and white working class adults in Boston, MA. • Census tract poverty was associated with annual average black carbon exposure. • Annual household income was not associated with black carbon exposure. • Individual-level education was not associated with black carbon exposure. • The observed socioeconomic patterns varied by race/ethnicity. - In a US multiethnic urban working adult population, exposure to black carbon was more strongly associated with census tract as compared to household- or individual-level socioeconomic measures

  8. Plasmons in strong superconductors

    International Nuclear Information System (INIS)

    Baldo, M.; Ducoin, C.

    2011-01-01

    We present a study of the possible plasmon excitations that can occur in systems where strong superconductivity is present. In these systems the plasmon energy is comparable to or smaller than the pairing gap. As a prototype of these systems we consider the proton component of Neutron Star matter just below the crust when electron screening is not taken into account. For the realistic case we consider in detail the different aspects of the elementary excitations when the proton, electron components are considered within the Random-Phase Approximation generalized to the superfluid case, while the influence of the neutron component is considered only at qualitative level. Electron screening plays a major role in modifying the proton spectrum and spectral function. At the same time the electron plasmon is strongly modified and damped by the indirect coupling with the superfluid proton component, even at moderately low values of the gap. The excitation spectrum shows the interplay of the different components and their relevance for each excitation modes. The results are relevant for neutrino physics and thermodynamical processes in neutron stars. If electron screening is neglected, the spectral properties of the proton component show some resemblance with the physical situation in high-T c superconductors, and we briefly discuss similarities and differences in this connection. In a general prospect, the results of the study emphasize the role of Coulomb interaction in strong superconductors.

  9. Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Masahiro Suzuki

    Full Text Available It has been suggested that prolonged inflammatory bowel diseases (IBD may lead to colitis-associated carcinogenesis (CAC. We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2 expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.

  10. Diabetic cognitive dysfunction is associated with increased bile acids in liver and activation of bile acid signaling in intestine.

    Science.gov (United States)

    Wang, Xue; Wang, Fangyu; Zhang, Yidan; Xiong, Hui; Zhang, Yanjun; Zhuang, Pengwei; Zhang, Youcai

    2018-05-01

    Impaired regulation of bile acid (BA) homeostasis has been suggested to be associated with adverse metabolic consequences. However, whether BA homeostasis is altered in diabetes-induced cognitive dysfunction (DCD) remains unknown. In the present study, mice were divided into four groups, namely normal control (NC) group, high-fat diet (HFD) group, diabetes without cognitive dysfunction (unDCD) group, and DCD group. Compared to HFD mice, the concentration of total BAs in liver was higher in unDCD and DCD mice, due to increased intestinal BA absorption. DCD mice tended to have higher BA concentrations in both liver and ileum than unDCD mice. Consequently, DCD mice had increased basolateral BA efflux (Ostα, Ostβ, and Mrp4) and decreased BA synthesis (Cyp7a1, Cyp8b1, and Cyp7b1) in the liver as well as activated Fxr-Fgf15 signaling in the ileum. DCD mice also had increased BA hydroxylation (Cyp3a11) and BA sulfation (Sult2a1) in the liver compared to HFD mice. Furthermore, the bacterial community composition was altered in the cecum of DCD mice, characterized with a marked increase in Defferribacteres and Candidatus Saccharibacteria. In summary, the present study provides the first comprehensive analysis of BA homeostasis in DCD mice, and revealed a potential role of BAs in DCD development. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Lorenzo Falchi

    2016-02-01

    Full Text Available The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology of these agents, as well as clinical experience regarding their use for the treatment of patients with CLL. Our foci will be both the most common and the most clinically significant toxicities associated with these drugs.

  12. Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway.

    Science.gov (United States)

    Bizzozero, L; Cazzato, D; Cervia, D; Assi, E; Simbari, F; Pagni, F; De Palma, C; Monno, A; Verdelli, C; Querini, P R; Russo, V; Clementi, E; Perrotta, C

    2014-04-01

    Melanoma is a rapidly growing and highly metastatic cancer with high mortality rates, for which a resolutive treatment is lacking. Identification of novel therapeutic strategies and biomarkers of tumour stage is thus of particular relevance. We report here on a novel biomarker and possible candidate therapeutic target, the sphingolipid metabolising enzyme acid sphingomyelinase (A-SMase). A-SMase expression correlates inversely with tumour stage in human melanoma biopsies. Studies in a mouse model of melanoma and on cell lines derived from mouse and human melanomas demonstrated that A-SMase levels of expression actually determine the malignant phenotype of melanoma cells in terms of pigmentation, tumour progression, invasiveness and metastatic ability. The action of A-SMase is mediated by the activation of the extracellular signal-regulated kinase, the subsequent proteasomal degradation of the Microphtalmia-associated transcription factor (Mitf) and inhibition of cyclin-dependent kinase 2, Bcl-2 and c-Met, downstream targets of Mitf involved in tumour cell proliferation, survival and metastatisation.

  13. δ-opioid receptor and somatostatin receptor-4 heterodimerization: possible implications in modulation of pain associated signaling.

    Directory of Open Access Journals (Sweden)

    Rishi K Somvanshi

    Full Text Available Pain relief is the principal action of opioids. Somatostatin (SST, a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4. In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.

  14. Coronin 2A (CRN5) expression is associated with colorectal adenoma-adenocarcinoma sequence and oncogenic signalling

    International Nuclear Information System (INIS)

    Rastetter, Raphael H.; Blömacher, Margit; Drebber, Uta; Marko, Marija; Behrens, Juliane; Solga, Roxana; Hojeili, Sarah; Bhattacharya, Kurchi; Wunderlich, Claudia M.; Wunderlich, F. Thomas; Odenthal, Margarete; Ziemann, Anja; Eichinger, Ludwig; Clemen, Christoph S.

    2015-01-01

    Coronin proteins are known as regulators of actin-based cellular processes, and some of them are associated with the malignant progression of human cancer. Here, we show that expression of coronin 2A is up-regulated in human colon carcinoma. This study included 26 human colon tumour specimens and 9 normal controls. Expression and localisation of coronin 2A was studied by immunohistochemistry, immunofluorescence imaging, cell fractionation, and immunoblotting. Functional roles of coronin 2A were analysed by over-expression and knock-down of the protein. Protein interactions were studied by co-immunoprecipitation and pull-down experiments, mass spectrometry analyses, and in vitro kinase and methylation assays. Histopathological investigation revealed that the expression of coronin 2A in colon tumour cells is up-regulated during the adenoma-adenocarcinoma progression. At the subcellular level, coronin 2A localised to multiple compartments, i.e. F-actin stress fibres, the front of lamellipodia, focal adhesions, and the nuclei. Over-expression of coronin 2A led to a reduction of F-actin stress fibres and elevated cell migration velocity. We identified two novel direct coronin 2A interaction partners. The interaction of coronin 2A with MAPK14 (mitogen activated protein kinase 14 or MAP kinase p38α) led to phosphorylation of coronin 2A and also to activation of the MAPK14 pathway. Moreover, coronin 2A interacted with PRMT5 (protein arginine N-methyltransferase 5), which modulates the sensitivity of tumour cells to TRAIL-induced cell death. We show that increased expression of coronin 2A is associated with the malignant phenotype of human colon carcinoma. Moreover, we linked coronin 2A to MAPK14 and PRMT5 signalling pathways involved in tumour progression. The online version of this article (doi:10.1186/s12885-015-1645-7) contains supplementary material, which is available to authorized users

  15. Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging

    Directory of Open Access Journals (Sweden)

    Caroline eMenard

    2014-05-01

    Full Text Available The LOU/C/Jall (LOU rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6-42 months were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn, an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non obese aging

  16. A Point Mutation in Suppressor of Cytokine Signalling 2 (Socs2 Increases the Susceptibility to Inflammation of the Mammary Gland while Associated with Higher Body Weight and Size and Higher Milk Production in a Sheep Model.

    Directory of Open Access Journals (Sweden)

    Rachel Rupp

    2015-12-01

    Full Text Available Mastitis is an infectious disease mainly caused by bacteria invading the mammary gland. Genetic control of susceptibility to mastitis has been widely evidenced in dairy ruminants, but the genetic basis and underlying mechanisms are still largely unknown. We describe the discovery, fine mapping and functional characterization of a genetic variant associated with elevated milk leukocytes count, or SCC, as a proxy for mastitis. After implementing genome-wide association studies, we identified a major QTL associated with SCC on ovine chromosome 3. Fine mapping of the region, using full sequencing with 12X coverage in three animals, provided one strong candidate SNP that mapped to the coding sequence of a highly conserved gene, suppressor of cytokine signalling 2 (Socs2. The frequency of the SNP associated with increased SCC was 21.7% and the Socs2 genotype explained 12% of the variance of the trait. The point mutation induces the p.R96C substitution in the SH2 functional domain of SOCS2 i.e. the binding site of the protein to various ligands, as well-established for the growth hormone receptor GHR. Using surface plasmon resonance we showed that the p.R96C point mutation completely abrogates SOCS2 binding affinity for the phosphopeptide of GHR. Additionally, the size, weight and milk production in p.R96C homozygote sheep, were significantly increased by 24%, 18%, and 4.4%, respectively, when compared to wild type sheep, supporting the view that the point mutation causes a loss of SOCS2 functional activity. Altogether these results provide strong evidence for a causal mutation controlling SCC in sheep and highlight the major role of SOCS2 as a tradeoff between the host's inflammatory response to mammary infections, and body growth and milk production, which are all mediated by the JAK/STAT signaling pathway.

  17. Motor Skill Learning Is Associated with Phase-Dependent Modifications in the Striatal cAMP/PKA/DARPP-32 Signaling Pathway in Rodents.

    Directory of Open Access Journals (Sweden)

    Yu Qian

    Full Text Available Abundant evidence points to a key role of dopamine in motor skill learning, although the underlying cellular and molecular mechanisms are still poorly understood. Here, we used a skilled-reaching paradigm to first examine changes in the expression of the plasticity-related gene Arc to map activity in cortico-striatal circuitry during different phases of motor skill learning in young animals. In the early phase, Arc mRNA was significantly induced in the medial prefrontal cortex (mPFC, cingulate cortex, primary motor cortex, and striatum. In the late phase, expression of Arc did not change in most regions, except in the mPFC and dorsal striatum. In the second series of experiments, we studied the learning-induced changes in the phosphorylation state of dopamine and cAMP-regulated phosphoprotein, 32k Da (DARPP-32. Western blot analysis of the phosphorylation state of DARPP-32 and its downstream target cAMP response element-binding protein (CREB in the striatum revealed that the early, but not late, phase of motor skill learning was associated with increased levels of phospho-Thr34-DARPP-32 and phospho-Ser133-CREB. Finally, we used the DARPP-32 knock-in mice with a point mutation in the Thr34 regulatory site (i.e., protein kinase A site to test the significance of this pathway in motor skill learning. In accordance with our hypothesis, inhibition of DARPP-32 activity at the Thr34 regulatory site strongly attenuated the motor learning rate and skilled reaching performance of mice. These findings suggest that the cAMP/PKA/DARPP-32 signaling pathway is critically involved in the acquisition of novel motor skills, and also demonstrate a dynamic shift in the contribution of cortico-striatal circuitry during different phases of motor skill learning.

  18. Multimodal signalling in estrildid finches: song, dance and colour are associated with different ecological and life-history traits.

    Science.gov (United States)

    Gomes, A C R; Funghi, C; Soma, M; Sorenson, M D; Cardoso, G C

    2017-07-01

    Sexual traits (e.g. visual ornaments, acoustic signals, courtship behaviour) are often displayed together as multimodal signals. Some hypotheses predict joint evolution of different sexual signals (e.g. to increase the efficiency of communication) or that different signals trade off with each other (e.g. due to limited resources). Alternatively, multiple signals may evolve independently for different functions, or to communicate different information (multiple message hypothesis). We evaluated these hypotheses with a comparative study in the family Estrildidae, one of the largest songbird radiations, and one that includes many model species for research in sexual selection and communication. We found little evidence for either joint evolution or trade-offs between song and colour ornamentation. Some negative correlations between dance repertoire and song traits may suggest a functional compromise, but generally courtship dance also evolved independently from other signals. Instead of correlated evolution, we found that song, dance and colour are each related to different socio-ecological traits. Song complexity evolved together with ecological generalism, song performance with investment in reproduction, dance with commonness and habitat type, whereas colour ornamentation was shown previously to correlate mostly with gregariousness. We conclude that multimodal signals evolve in response to various socio-ecological traits, suggesting the accumulation of distinct signalling functions. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  19. Strong-coupling approximations

    International Nuclear Information System (INIS)

    Abbott, R.B.

    1984-03-01

    Standard path-integral techniques such as instanton calculations give good answers for weak-coupling problems, but become unreliable for strong-coupling. Here we consider a method of replacing the original potential by a suitably chosen harmonic oscillator potential. Physically this is motivated by the fact that potential barriers below the level of the ground-state energy of a quantum-mechanical system have little effect. Numerically, results are good, both for quantum-mechanical problems and for massive phi 4 field theory in 1 + 1 dimensions. 9 references, 6 figures

  20. Strong interaction and QFD

    International Nuclear Information System (INIS)

    Ebata, T.

    1981-01-01

    With an assumed weak multiplet structure for bosonic hadrons, which is consistent with the ΔI = 1/2 rule, it is shown that the strong interaction effective hamiltonian is compatible with the weak SU(2) x U(1) gauge transformation. Especially the rho-meson transforms as a triplet under SU(2)sub(w), and this is the origin of the rho-photon analogy. It is also shown that the existence of the non-vanishing Cabibbo angle is a necessary condition for the absence of the exotic hadrons. (orig.)

  1. Diagnosis of complications associated with acute cholecystitis using computed tomography and diffusion-weighted imaging with background body signal suppression/T2 image fusion

    Science.gov (United States)

    Tomizawa, Minoru; Shinozaki, Fuminobu; Tanaka, Satomi; Sunaoshi, Takafumi; Kano, Daisuke; Sugiyama, Eriko; Shite, Misaki; Haga, Ryouta; Fukamizu, Yoshiya; Fujita, Toshiyuki; Kagayama, Satoshi; Hasegawa, Rumiko; Shirai, Yoshinori; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

    2017-01-01

    In a clinical setting, it is important to diagnose complications of acute cholecystitis accurately. Diffusion-weighted whole body imaging with background body signal suppression/T2-weighted image fusion (DWIBS/T2) provides high signal intensity with a strong contrast against surrounding tissues in anatomical settings. In the present study, patients who were being treated for acute cholecystitis and underwent DWIBS/T2 in the National Hospital Organization Shimoshizu Hospital between December 2012 and August 2015 were enrolled. A total of 10 men and 4 women underwent DWIBS/T2. Records, including DWIBS/T2 and computed tomography (CT) imaging, were retrospectively analyzed for patients with acute cholecystitis. CT images revealed thickened gallbladder walls in patients with acute cholecystitis, and high signal intensity was observed in DWIBS/T2 images for the thickened gallbladder wall. Inflammation of the pericholecystic space and the liver resulted in high intensity signals with DWIBS/T2 imaging, whereas CT imaging revealed a low-density area in the cholecystic space. Plain CT scanning identified a low-density area in the liver, which became more obvious with contrast-enhanced CT. DWIBS/T2 imaging showed the inflammation of the liver and pericholesyctic space as an area of high signal intensity. Detectability of inflammation of the pericholecystic space and the liver was the same for DWIBS/T2 and CT, which suggests that DWIBS/T2 has the same sensitivity as CT scanning for the diagnosis of complicated acute cholecystitis. However, the strong contrast shown by DWIBS/T2 allows for easier evaluation of acute cholecystitis than CT scanning. PMID:28672993

  2. Strong Coupling Holography

    CERN Document Server

    Dvali, Gia

    2009-01-01

    We show that whenever a 4-dimensional theory with N particle species emerges as a consistent low energy description of a 3-brane embedded in an asymptotically-flat (4+d)-dimensional space, the holographic scale of high-dimensional gravity sets the strong coupling scale of the 4D theory. This connection persists in the limit in which gravity can be consistently decoupled. We demonstrate this effect for orbifold planes, as well as for the solitonic branes and string theoretic D-branes. In all cases the emergence of a 4D strong coupling scale from bulk holography is a persistent phenomenon. The effect turns out to be insensitive even to such extreme deformations of the brane action that seemingly shield 4D theory from the bulk gravity effects. A well understood example of such deformation is given by large 4D Einstein term in the 3-brane action, which is known to suppress the strength of 5D gravity at short distances and change the 5D Newton's law into the four-dimensional one. Nevertheless, we observe that the ...

  3. Novel ST-MUSIC-based spectral analysis for detection of ULF geomagnetic signals anomalies associated with seismic events in Mexico

    Directory of Open Access Journals (Sweden)

    Omar Chavez

    2016-05-01

    Full Text Available Recently, the analysis of ultra-low-frequency (ULF geomagnetic signals in order to detect seismic anomalies has been reported in several works. Yet, they, although having promising results, present problems for their detection since these anomalies are generally too much weak and embedded in high noise levels. In this work, a short-time multiple signal classification (ST-MUSIC, which is a technique with high-frequency resolution and noise immunity, is proposed for the detection of seismic anomalies in the ULF geomagnetic signals. Besides, the energy (E of geomagnetic signals processed by ST-MUSIC is also presented as a complementary parameter to measure the fluctuations between seismic activity and seismic calm period. The usefulness and effectiveness of the proposal are demonstrated through the analysis of a synthetic signal and five real signals with earthquakes. The analysed ULF geomagnetic signals have been obtained using a tri-axial fluxgate magnetometer at the Juriquilla station, which is localized in Queretaro, Mexico (geographic coordinates: longitude 100.45° E and latitude 20.70° N. The results obtained show the detection of seismic perturbations before, during, and after the main shock, making the proposal a suitable tool for detecting seismic precursors.

  4. Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans.

    Science.gov (United States)

    Ceko, Marta; Milenkovic, Nevena; le Coutre, Philipp; Westermann, Jörg; Lewin, Gary R

    2014-07-01

    The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRβ, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  5. Endogenous sulfur dioxide regulates hippocampal neuron apoptosis in developing epileptic rats and is associated with the PERK signaling pathway.

    Science.gov (United States)

    Niu, Manman; Han, Ying; Li, Qinrui; Zhang, Jing

    2018-02-05

    Epilepsy is among the most common neurological diseases in children. Recurrent seizures can result in hippocampal damage and seriously impair learning and memory functions in children. However, the mechanisms underlying epilepsy-related brain injury are unclear. Neuronal apoptosis is among the most common neuropathological manifestations of brain injury. Endogenous sulfur dioxide (SO 2 ) has been shown to be involved in seizures and related neuron apoptosis. However, the role of endogenous SO 2 in epilepsy remains unclear. This study assessed whether endogenous SO 2 is involved in epilepsy and its underlying mechanisms. Using a rat epilepsy model induced by an intraperitoneal injection of kainic acid (KA), we found that hippocampal neuron apoptosis was induced in epileptic rats, and the SO 2 content and aspartate aminotransferase (AAT) activity in the plasma were increased compared to those in the control group. However, the inhibition of SO 2 production by l-aspartate-β-hydroxamate (HDX) can subvert this response 72h after an epileptic seizure. No difference in apoptosis was observed 7 d after the epileptic seizure in the KA and KA+HDX groups. The protein expression levels of AAT2, glucose-regulated protein 78 (GRP78), pancreatic eIF2 kinase-like ER kinase (PERK) and phospho-PERK (p-PERK) were remarkably elevated in the hippocampi of the epileptic rats, while the HDX treatment was capable of reversing this process 7 d after the epileptic seizure. These results indicate that the inhibition of endogenous SO 2 production can alleviate neuronal apoptosis and is associated with the PERK signaling pathway during the initial stages after epileptic seizure, but inhibiting SO 2 production only delayed the occurrence of apoptosis and did not prevent neuronal apoptosis in the epileptic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Cinnamon counteracts the negative effects of a high fat/high fructose diet on behavior, brain insulin signaling and Alzheimer-associated changes

    Science.gov (United States)

    Insulin resistance leads to memory impairment. Cinnamon (CN) improves whole body insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling, and Alzheimer-associated gene expression in the brain were measured in male Wistar rats fed a high fat/high fructose...

  7. Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

    Science.gov (United States)

    Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induce...

  8. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

    DEFF Research Database (Denmark)

    Zeng, Chenjie; Guo, Xingyi; Long, Jirong

    2016-01-01

    carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS...