WorldWideScience

Sample records for related signaling molecules

  1. Acupuncture Alters Expression of Insulin Signaling Related Molecules and Improves Insulin Resistance in OLETF Rats

    Directory of Open Access Journals (Sweden)

    Xin-Yu Huang

    2016-01-01

    Full Text Available To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6, Zusanli (ST36, and Sanyinjiao (SP6; in contrast, acupuncture to Shenshu (BL23 was administered perpendicularly. For Neiguan (PC6 and Zusanli (ST36, needles were connected to an electroacupuncture (EA apparatus. Fasting blood glucose (FPG was measured by glucose oxidase method. Plasma fasting insulin (FINS and serum C peptide (C-P were determined by ELISA. Protein and mRNA expressions of insulin signaling molecules were determined by Western blot and real-time RT-PCR, respectively. OLETF rats exhibit increased levels of FPG, FINS, C-P, and homeostasis model assessment-estimated insulin resistance (HOMA-IR, which were effectively decreased by acupuncture treatment. mRNA expressions of several insulin signaling related molecules IRS1, IRS2, Akt2, aPKCζ, and GLUT4 were decreased in OLETF rats compared to SD controls. Expression of these molecules was restored back to normal levels upon acupuncture administration. PI3K-p85α was increased in OLETF rats; this increase was also reversed by acupuncture treatment. Acupuncture improves insulin resistance in OLETF rats, possibly via regulating expression of key insulin signaling related molecules.

  2. Unilateral vestibular deafferentation-induced changes in calcium signaling-related molecules in the rat vestibular nuclear complex.

    Science.gov (United States)

    Masumura, Chisako; Horii, Arata; Mitani, Kenji; Kitahara, Tadashi; Uno, Atsuhiko; Kubo, Takeshi

    2007-03-23

    Inquiries into the neurochemical mechanisms of vestibular compensation, a model of lesion-induced neuronal plasticity, reveal the involvement of both voltage-gated Ca(2+) channels (VGCC) and intracellular Ca(2+) signaling. Indeed, our previous microarray analysis showed an up-regulation of some calcium signaling-related genes such as the alpha2 subunit of L-type calcium channels, calcineurin, and plasma membrane Ca(2+) ATPase 1 (PMCA1) in the ipsilateral vestibular nuclear complex (VNC) following unilateral vestibular deafferentation (UVD). To further elucidate the role of calcium signaling-related molecules in vestibular compensation, we used a quantitative real-time polymerase chain reaction (PCR) method to confirm the microarray results and investigated changes in expression of these molecules at various stages of compensation (6 h to 2 weeks after UVD). We also investigated the changes in gene expression during Bechterew's phenomenon and the effects of a calcineurin inhibitor on vestibular compensation. Real-time PCR showed that genes for the alpha2 subunit of VGCC, PMCA2, and calcineurin were transiently up-regulated 6 h after UVD in ipsilateral VNC. A subsequent UVD, which induced Bechterew's phenomenon, reproduced a complete mirror image of the changes in gene expressions of PMCA2 and calcineurin seen in the initial UVD, while the alpha2 subunit of VGCC gene had a trend to increase in VNC ipsilateral to the second lesion. Pre-treatment by FK506, a calcineurin inhibitor, decelerated the vestibular compensation in a dose-dependent manner. Although it is still uncertain whether these changes in gene expression are causally related to the molecular mechanisms of vestibular compensation, this observation suggests that after increasing the Ca(2+) influx into the ipsilateral VNC neurons via up-regulated VGCC, calcineurin may be involved in their synaptic plasticity. Conversely, an up-regulation of PMCA2, a brain-specific Ca(2+) pump, would increase an efflux of Ca

  3. Chronic Stress Decreases Basal Levels of Memory-Related Signaling Molecules in Area CA1 of At-Risk (Subclinical) Model of Alzheimer's Disease.

    Science.gov (United States)

    Alkadhi, Karim A; Tran, Trinh T

    2015-08-01

    An important factor that may affect the severity and time of onset of Alzheimer's disease (AD) is chronic stress. Epidemiological studies report that chronically stressed individuals are at an increased risk for developing AD. The purpose of this study was to reveal whether chronic psychosocial stress could hasten the appearance of AD symptoms including changes in basal levels of cognition-related signaling molecules in subjects who are at risk for the disease. We investigated the effect of chronic psychosocial stress on basal levels of memory-related signaling molecules in area CA1 of subclinical rat model of AD. The subclinical symptomless rat model of AD was induced by osmotic pump continuous intracerebroventricular (ICV) infusion of 160 pmol/day Aβ1-42 for 14 days. Rats were chronically stressed using the psychosocial stress intruder model. Western blot analysis of basal protein levels of important signaling molecules in hippocampal area CA1 showed no significant difference between the subclinical AD rat model and control rat. Following six weeks of psychosocial stress, molecular analysis showed that subclinical animals subjected to stress have significantly reduced basal levels of p-CaMKII and decreased p-CaMKII/t-CaMKII ratio as well as decreased basal levels of p-CREB, total CREB, and BDNF. The present results suggest that these changes in basal levels of signaling molecules may be responsible for impaired learning, memory, and LTP in this rat model, which support the proposition that chronic stress may accelerate the emergence of AD in susceptible individuals.

  4. Carbon Monoxide: An Essential Signalling Molecule

    Science.gov (United States)

    Mann, Brian E.

    Carbon monoxide (CO), like nitric oxide (NO), is an essential signalling molecule in humans. It is active in the cardiovascular system as a vasodilator. In addition, CO possesses anti-inflammatory, anti-apoptotic and anti-proliferative properties and protects tissues from hypoxia and reperfusion injury. Some of its applications in animal models include suppression of organ graft rejection and safeguarding the heart during reperfusion after cardiopulmonary bypass surgery. CO also suppresses arteriosclerotic lesions following angioplasty, reverses established pulmonary hypertension and mitigates the development of post-operative ileus in the murine small intestine and the development of cerebral malaria in mice as well as graft-induced intimal hyperplasia in pigs. There have been several clinical trials using air-CO mixtures for the treatment of lung-, heart-, kidney- and abdominal-related diseases. This review examines the research involving the development of classes of compounds (with particular emphasis on metal carbonyls) that release CO, which could be used in clinically relevant conditions. The review is drawn not only from published papers in the chemical literature but also from the extensive biological literature and patents on CO-releasing molecules (CO-RMs).

  5. Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats.

    Science.gov (United States)

    Chaalal, Amina; Poirier, Roseline; Blum, David; Laroche, Serge; Enderlin, Valérie

    2018-05-23

    Hypothyroidism is a condition that becomes more prevalent with age. Patients with untreated hypothyroidism have consistently reported symptoms of severe cognitive impairments. In patients suffering hypothyroidism, thyroid hormone supplementation offers the prospect to alleviate the cognitive consequences of hypothyroidism; however, the therapeutic value of TH supplementation remains at present uncertain and the link between cellular modifications associated with hypothyroidism and neurodegeneration remains to be elucidated. In the present study, we therefore evaluated the molecular and behavioral consequences of T3 hormone replacement in an animal model of hypothyroidism. We have previously reported that the antithyroid molecule propylthiouracil (PTU) given in the drinking water favors cerebral atrophy, brain neuroinflammation, Aβ production, Tau hyperphosphorylation, and altered plasticity-related cell-signaling pathways in the hippocampus in association with hippocampal-dependent spatial memory deficits. In the present study, our aim was to explore, in this model, the effect of hippocampal T3 signaling normalization on various molecular mechanisms involved in learning and memory that goes awry under conditions of hypothyroidism and to evaluate its potential for recovery of hippocampal-dependent memory deficits. We report that T3 supplementation can alleviate hippocampal-dependent memory impairments displayed by hypothyroid rats and normalize key markers of thyroid status in the hippocampus, of neuroinflammation, Aβ production, and of cell-signaling pathways known to be involved in synaptic plasticity and memory function. Together, these findings suggest that normalization of hippocampal T3 signaling is sufficient to reverse molecular and cognitive dysfunctions associated with hypothyroidism.

  6. Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

    Science.gov (United States)

    Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

    2010-03-01

    Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.

  7. Impact of exogenous lipase supplementation on growth, intestinal function, mucosal immune and physical barrier, and related signaling molecules mRNA expression of young grass carp (Ctenopharyngodon idella).

    Science.gov (United States)

    Liu, Sen; Feng, Lin; Jiang, Wei-Dan; Liu, Yang; Jiang, Jun; Wu, Pei; Zeng, Yun-Yun; Xu, Shu-De; Kuang, Sheng-Yao; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Zhou, Xiao-Qiu

    2016-08-01

    This study investigated the effects of exogenous lipase supplementation on the growth performance, intestinal growth and function, immune response and physical barrier function, and related signaling molecules mRNA expression of young grass carp (Ctenopharyngodon idella). A total of 450 grass carp (255.02 ± 0.34 g) were fed five diets for 60 days. There were 5 dietary treatments that included a normal protein and lipid diet containing 30% crude protein (CP) with 5% ether extract (EE), and the low-protein and high-lipid diets (28% CP, 6% EE) supplemented with graded levels of exogenous lipase supplementation activity at 0, 1193, 2560 and 3730 U/kg diet. The results indicated that compared with a normal protein and lipid diet (30% CP, 5% EE), a low-protein and high-lipid diet (28% CP, 6% EE) (un-supplemented lipase) improved lysozyme activities and complement component 3 contents in the distal intestine (DI), interleukin 10 mRNA expression in the proximal intestine (PI), and glutathione S-transferases activity and glutathione content in the intestine of young grass carp. In addition, in low-protein and high-lipid diets, optimal exogenous lipase supplementation significantly increased acid phosphatase (ACP) activities and complement component 3 (C3) contents (P exogenous lipase supplementation significantly decreased reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC) contents (P exogenous lipase supplementation significantly elevated the mRNA levels of tight junction proteins (Occludin, zonula occludens 1, Claudin b, Claudin c and Claudin 3) (P exogenous lipase supplementation improved growth, intestinal growth and function, intestinal immunity, physical barrier, and regulated the mRNA expression of related signal molecules of fish. The optimal level of exogenous lipase supplementation in young grass carp (255-771 g) was estimated to be 1193 U kg(-1) diet. Copyright © 2016. Published by Elsevier Ltd.

  8. Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1)*

    Science.gov (United States)

    Zhuo, You; Yang, Jeong-Yeh; Moremen, Kelley W.; Prestegard, James H.

    2016-01-01

    Human carcinoembryonic antigen-related cell adhesion molecule 1 (C?/Au: EACAM1) is a cell-surface signaling molecule involved in cell adhesion, proliferation, and immune response. It is also implicated in cancer angiogenesis, progression, and metastasis. This diverse set of effects likely arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other molecules. Its N-terminal Ig variable (IgV) domain has been suggested to be a principal player in these interactions. Previous crystal structures of the β-sandwich-like IgV domain have been produced using Escherichia coli-expressed material, which lacks native glycosylation. These have led to distinctly different proposals for dimer interfaces, one involving interactions of ABED β-strands and the other involving GFCC′C″ β-strands, with the former burying one prominent glycosylation site. These structures raise questions as to which form may exist in solution and what the effect of glycosylation may have on this form. Here, we use NMR cross-correlation measurements to examine the effect of glycosylation on CEACAM1-IgV dimerization and use residual dipolar coupling (RDC) measurements to characterize the solution structure of the non-glycosylated form. Our findings demonstrate that even addition of a single N-linked GlcNAc at potential glycosylation sites inhibits dimer formation. Surprisingly, RDC data collected on E. coli expressed material in solution indicate that a dimer using the non-glycosylated GFCC′C″ interface is preferred even in the absence of glycosylation. The results open new questions about what other factors may facilitate dimerization of CEACAM1 in vivo, and what roles glycosylation may play in heterophylic interactions. PMID:27471271

  9. Inside-out signaling promotes dynamic changes in the carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) oligomeric state to control its cell adhesion properties.

    Science.gov (United States)

    Patel, Prerna C; Lee, Hannah S W; Ming, Aaron Y K; Rath, Arianna; Deber, Charles M; Yip, Christopher M; Rocheleau, Jonathan V; Gray-Owen, Scott D

    2013-10-11

    Cell-cell contacts are fundamental to multicellular organisms and are subject to exquisite levels of control. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) can engage in both cis-homophilic (parallel) oligomerization and trans-homophilic (anti-parallel) binding. In this study, we establish that the CEACAM1 transmembrane domain has a propensity to form cis-dimers via the transmembrane-embedded (432)GXXXG(436) motif and that this basal state is overcome when activated calmodulin binds to the CEACAM1 cytoplasmic domain. Although mutation of the (432)GXXXG(436) motif reduced CEACAM1 oligomerization, it did not affect surface localization of the receptor or influence CEACAM1-dependent cellular invasion by the pathogenic Neisseria. The mutation did, however, have a striking effect on CEACAM1-dependent cellular aggregation, increasing both the kinetics of cell-cell association and the size of cellular aggregates formed. CEACAM1 association with tyrosine kinase c-Src and tyrosine phosphatases SHP-1 and SHP-2 was not affected by the (432)GXXXG(436) mutation, consistent with their association with the monomeric form of wild type CEACAM1. Collectively, our results establish that a dynamic oligomer-to-monomer shift in surface-expressed CEACAM1 facilitates trans-homophilic binding and downstream effector signaling.

  10. Threonine modulates immune response, antioxidant status and gene expressions of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream (Megalobrama amblycephala).

    Science.gov (United States)

    Habte-Tsion, Habte-Michael; Ren, Mingchun; Liu, Bo; Ge, Xianping; Xie, Jun; Chen, Ruli

    2016-04-01

    A 9-week feeding trial was conducted to investigate the effects of graded dietary threonine (Thr) levels (0.58-2.58%) on the hematological parameters, immune response, antioxidant status and hepatopancreatic gene expression of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream. For this purpose, 3 tanks were randomly arranged and assigned to each experimental diet. Fish were fed with their respective diet to apparent satiation 4 times daily. The results indicated that white blood cell, red blood cell and haemoglobin significantly responded to graded dietary Thr levels, while hematocrit didn't. Complement components (C3 and C4), total iron-binding capacity (TIBC), immunoglobulin M (IgM), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) increased with increasing dietary Thr levels up to 1.58-2.08% and thereafter tended to decrease. Dietary Thr regulated the gene expressions of Cu/Zn-SOD, Mn-SOD and CAT, GPx1, glutathione S-transferase mu (GST), nuclear factor erythroid 2-related factor 2 (Nrf2), heat shock protein-70 (Hsp70), tumor necrosis factor-alpha (TNF-α), apolipoprotein A-I (ApoA1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and fructose-bisphosphate aldolase B (ALDOB); while the gene expression of peroxiredoxin II (PrxII) was not significantly modified by graded Thr levels. These genes are involved in different functions including antioxidant, immune, and defense responses, energy metabolism and protein synthesis. Therefore, this study could provide a new molecular tool for studies in fish immunonutrition and shed light on the regulatory mechanisms that dietary Thr improved the antioxidant and immune capacities of fish. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Signal transduction by the major histocompatibility complex class I molecule

    DEFF Research Database (Denmark)

    Pedersen, A E; Skov, Svend; Bregenholt, S

    1999-01-01

    Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell...... and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems....

  12. Identification and quantitation of signal molecule-dependent protein phosphorylation

    KAUST Repository

    Groen, Arnoud J.; Thomas, Ludivine; Lilley, Kathryn S.; Marondedze, Claudius

    2013-01-01

    in combination with phosphopeptide enrichment by titanium dioxide (TiO2) and their identification by MS is described. This workflow can be used to gain insights into the role of signalling molecules such as cyclic nucleotides on regulatory networks through

  13. Role of chrysin on expression of insulin signaling molecules

    Directory of Open Access Journals (Sweden)

    Kottireddy Satyanarayana

    2015-01-01

    Full Text Available Background: Currently available drugs are unsuccessful for the treatment of tye-2 diabetes due to their adverseside-effects. Hence, a search for novel drugs, especially ofplant origin, continues. Chrysin (5,7-dihydroxyflavone is a flavonoid, natural component of traditional medicinal herbs, present in honey, propolis and many plant extracts that hasbeen used in traditional medicine around the world to treat numerous ailments. Objective: The present study was aimed to identify the protective role of chrysin on the expression of insulin-signaling molecules in the skeletal muscle of high fat and sucrose-induced type-2 diabetic adult male rats. Materials and Methods: The oral effective dose of chrysin (100 mg/kg body weight was given once a day until the end of the study (30 days post-induction of diabetes to high fat diet-induced diabetic rats.At the end of the experimental period, fasting blood glucose, oral glucose tolerance, serum lipid profile, lipid peroxidation (LPO and free radical generation, as well as the levels of insulin signaling molecules and tissue glycogen in the gastrocnemius muscle were assessed. Results: Diabetic rats showed impaired glucose tolerance and impairment in insulin signaling molecules (IR, IRS-1, p-IRS-1Tyr 632 , p- Akt Thr308 , glucose transporter subtype 4 [GLUT4] proteins and glycogen concentration. Serum insulin, lipid profile, LPO and free radical generation were found to be increased in diabetic control rats.The treatment with chrysin normalized the altered levels of blood glucose, serum insulin, lipid profile, LPO and insulin signaling molecules as well as GLUT4 proteins. Conclusion: Our present findings indicate that chrysin improves glycemic control through activation of insulin signal transduction in the gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic male rats.

  14. TSH Receptor Signaling Abrogation by a Novel Small Molecule.

    Science.gov (United States)

    Latif, Rauf; Realubit, Ronald B; Karan, Charles; Mezei, Mihaly; Davies, Terry F

    2016-01-01

    Pathological activation of the thyroid-stimulating hormone receptor (TSHR) is caused by thyroid-stimulating antibodies in patients with Graves' disease (GD) or by somatic and rare genomic mutations that enhance constitutive activation of the receptor influencing both G protein and non-G protein signaling. Potential selective small molecule antagonists represent novel therapeutic compounds for abrogation of such abnormal TSHR signaling. In this study, we describe the identification and in vitro characterization of a novel small molecule antagonist by high-throughput screening (HTS). The identification of the TSHR antagonist was performed using a transcription-based TSH-inhibition bioassay. TSHR-expressing CHO cells, which also expressed a luciferase-tagged CRE response element, were optimized using bovine TSH as the activator, in a 384 well plate format, which had a Z score of 0.3-0.6. Using this HTS assay, we screened a diverse library of ~80,000 compounds at a final concentration of 16.7 μM. The selection criteria for a positive hit were based on a mean signal threshold of ≥50% inhibition of control TSH stimulation. The screening resulted in 450 positive hits giving a hit ratio of 0.56%. A secondary confirmation screen against TSH and forskolin - a post receptor activator of adenylyl cyclase - confirmed one TSHR-specific candidate antagonist molecule (named VA-K-14). This lead molecule had an IC 50 of 12.3 μM and a unique chemical structure. A parallel analysis for cell viability indicated that the lead inhibitor was non-cytotoxic at its effective concentrations. In silico docking studies performed using a TSHR transmembrane model showed the hydrophobic contact locations and the possible mode of inhibition of TSHR signaling. Furthermore, this molecule was capable of inhibiting TSHR stimulation by GD patient sera and monoclonal-stimulating TSHR antibodies. In conclusion, we report the identification of a novel small molecule TSHR inhibitor, which has the

  15. Gram-Negative Bacterial Sensors for Eukaryotic Signal Molecules

    Directory of Open Access Journals (Sweden)

    Olivier Lesouhaitier

    2009-09-01

    Full Text Available Ample evidence exists showing that eukaryotic signal molecules synthesized and released by the host can activate the virulence of opportunistic pathogens. The sensitivity of prokaryotes to host signal molecules requires the presence of bacterial sensors. These prokaryotic sensors, or receptors, have a double function: stereospecific recognition in a complex environment and transduction of the message in order to initiate bacterial physiological modifications. As messengers are generally unable to freely cross the bacterial membrane, they require either the presence of sensors anchored in the membrane or transporters allowing direct recognition inside the bacterial cytoplasm. Since the discovery of quorum sensing, it was established that the production of virulence factors by bacteria is tightly growth-phase regulated. It is now obvious that expression of bacterial virulence is also controlled by detection of the eukaryotic messengers released in the micro-environment as endocrine or neuro-endocrine modulators. In the presence of host physiological stress many eukaryotic factors are released and detected by Gram-negative bacteria which in return rapidly adapt their physiology. For instance, Pseudomonas aeruginosa can bind elements of the host immune system such as interferon-γ and dynorphin and then through quorum sensing circuitry enhance its virulence. Escherichia coli sensitivity to the neurohormones of the catecholamines family appears relayed by a recently identified bacterial adrenergic receptor. In the present review, we will describe the mechanisms by which various eukaryotic signal molecules produced by host may activate Gram-negative bacteria virulence. Particular attention will be paid to Pseudomonas, a genus whose representative species, P. aeruginosa, is a common opportunistic pathogen. The discussion will be particularly focused on the pivotal role played by these new types of pathogen sensors from the sensing to the transduction

  16. Signaling lymphocytic activation molecules Slam and cancers: friends or foes?

    Science.gov (United States)

    Fouquet, Gregory; Marcq, Ingrid; Debuysscher, Véronique; Bayry, Jagadeesh; Rabbind Singh, Amrathlal; Bengrine, Abderrahmane; Nguyen-Khac, Eric; Naassila, Mickael; Bouhlal, Hicham

    2018-03-23

    Signaling Lymphocytic Activation Molecules (SLAM) family receptors are initially described in immune cells. These receptors recruit both activating and inhibitory SH2 domain containing proteins through their Immunoreceptor Tyrosine based Switch Motifs (ITSMs). Accumulating evidence suggest that the members of this family are intimately involved in different physiological and pathophysiological events such as regulation of immune responses and entry pathways of certain viruses. Recently, other functions of SLAM, principally in the pathophysiology of neoplastic transformations have also been deciphered. These new findings may prompt SLAM to be considered as new tumor markers, diagnostic tools or potential therapeutic targets for controlling the tumor progression. In this review, we summarize the major observations describing the implications and features of SLAM in oncology and discuss the therapeutic potential attributed to these molecules.

  17. Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

    Science.gov (United States)

    Voronkov, Andrey; Krauss, Stefan

    2012-01-01

    Wnt/β-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/β-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, β-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where β-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where β-catenin levels are regulated and the nucleus where β-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of β-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular β- catenin levels. However, β-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/β-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of β-catenin at its various locations provides alternative points for therapeutic interventions. PMID:23016862

  18. Losing the Warning Signal: Drought Compromises the Cross-Talk of Signaling Molecules in Quercus ilex Exposed to Ozone

    Directory of Open Access Journals (Sweden)

    Lorenzo Cotrozzi

    2017-06-01

    Full Text Available Understanding the interactions between drought and acute ozone (O3 stress in terms of signaling molecules and cell death would improve the predictions of plant responses to climate change. The aim was to investigate whether drought stress influences the responses of plants to acute episodes of O3 exposure. In this study, the behavior of 84 Mediterranean evergreen Quercus ilex plants was evaluated in terms of cross-talk responses among signaling molecules. Half of the sample was subjected to drought (20% of the effective daily evapotranspiration, for 15 days and was later exposed to an acute O3 exposure (200 nL L-1 for 5 h. First, our results indicate that in well-water conditions, O3 induced a signaling pathway specific to O3-sensitive behavior. Second, different trends and consequently different roles of phytohormones and signaling molecules (ethylene, ET; abscisic acid, ABA; salycilic acid, SA and jasmonic acid, JA were observed in relation to water stress and O3. A spatial and functional correlation between these signaling molecules was observed in modulating O3-induced responses in well-watered plants. In contrast, in drought-stressed plants, these compounds were not involved either in O3-induced signaling mechanisms or in leaf senescence (a response observed in water-stressed plants before the O3-exposure. Third, these differences were ascribable to the fact that in drought conditions, most defense processes induced by O3 were compromised and/or altered. Our results highlight how Q. ilex plants suffering from water deprivation respond differently to an acute O3 episode compared to well-watered plants, and suggest new effect to be considered in plant responses to environmental changes. This poses the serious question as to whether or not multiple high-magnitude O3 events (as predicted can change these cross-talk responses, thus opening it up possible further investigations.

  19. Identification and quantitation of signal molecule-dependent protein phosphorylation

    KAUST Repository

    Groen, Arnoud J.

    2013-09-03

    Phosphoproteomics is a fast-growing field that aims at characterizing phosphorylated proteins in a cell or a tissue at a given time. Phosphorylation of proteins is an important regulatory mechanism in many cellular processes. Gel-free phosphoproteome technique involving enrichment of phosphopeptide coupled with mass spectrometry has proven to be invaluable to detect and characterize phosphorylated proteins. In this chapter, a gel-free quantitative approach involving 15N metabolic labelling in combination with phosphopeptide enrichment by titanium dioxide (TiO2) and their identification by MS is described. This workflow can be used to gain insights into the role of signalling molecules such as cyclic nucleotides on regulatory networks through the identification and quantification of responsive phospho(proteins). © Springer Science+Business Media New York 2013.

  20. Electron attachment to indole and related molecules

    Energy Technology Data Exchange (ETDEWEB)

    Modelli, Alberto, E-mail: alberto.modelli@unibo.it [Dipartimento di Chimica “G. Ciamician”, Universitá di Bologna, via Selmi 2, 40126 Bologna (Italy); Centro Interdipartimentale di Ricerca in Scienze Ambientali (CIRSA), Universitá di Bologna, via S. Alberto 163, 48123 Ravenna (Italy); Jones, Derek, E-mail: d.jones@isof.cnr.it [ISOF, Istituto per la Sintesi Organica e la Fotoreattività, C.N.R., via Gobetti 101, 40129 Bologna (Italy); Pshenichnyuk, Stanislav A., E-mail: sapsh@anrb.ru [Institute of Molecule and Crystal Physics, Ufa Research Centre, Russian Academy of Sciences, Prospekt Oktyabrya 151, 450075 Ufa (Russian Federation)

    2013-11-14

    Gas-phase formation of temporary negative ion states via resonance attachment of low-energy (0–6 eV) electrons into vacant molecular orbitals of indoline (I), indene (II), indole (III), 2-methylen-1,3,3-trimethylindoline (IV), and 2,3,3-trimethyl-indolenine (V) was investigated for the first time by electron transmission spectroscopy (ETS). The description of their empty-level structures was supported by density functional theory and Hartree-Fock calculations, using empirically calibrated linear equations to scale the calculated virtual orbital energies. Dissociative electron attachment spectroscopy (DEAS) was used to measure the fragment anion yields generated through dissociative decay channels of the parent molecular anions of compounds I-V, detected with a mass filter as a function of the incident electron energy in the 0–14 eV energy range. The vertical and adiabatic electron affinities were evaluated at the B3LYP/6-31+G(d) level as the anion/neutral total energy difference. The same theoretical method is also used for evaluation of the thermodynamic energy thresholds for production of the negative fragments observed in the DEA spectra. The loss of a hydrogen atom from the parent molecular anion ([M-H]{sup −}) provides the most intense signal in compounds I-IV. The gas-phase DEAS data can provide support for biochemical reaction mechanisms in vivo involving initial hydrogen abstraction from the nitrogen atom of the indole moiety, present in a variety of biologically important molecules.

  1. Caffeine and REM sleep deprivation: Effect on basal levels of signaling molecules in area CA1.

    Science.gov (United States)

    Alkadhi, Karim A; Alhaider, Ibrahim A

    2016-03-01

    We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treated with caffeine in drinking water (0.3g/l) for four weeks before they were REM sleep-deprived for 24h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylated- and total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. DMPD: Regulation of cytokine signaling by SOCS family molecules. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14644140 Regulation of cytokine signaling by SOCS family molecules. Fujimoto M, Nak...a T. Trends Immunol. 2003 Dec;24(12):659-66. (.png) (.svg) (.html) (.csml) Show Regulation of cytokine signaling by SOCS family... molecules. PubmedID 14644140 Title Regulation of cytokine signaling by SOCS family molec

  3. Comparative gel-based phosphoproteomics in response to signaling molecules

    KAUST Repository

    Marondedze, Claudius; Lilley, Kathryn S.; Thomas, Ludivine

    2013-01-01

    The gel-based proteomics approach is a valuable technique for studying the characteristics of proteins. This technique has diverse applications ranging from analysis of a single protein to the study of the total cellular proteins. Further, protein quality and to some extent distribution can be first assessed by means of one-dimensional gel electrophoresis and then more informatively, for comparative analysis, using the two-dimensional gel electrophoresis technique. Here, we describe how to take advantage of the availability of fluorescent dyes to stain for a selective class of proteins on the same gel for the detection of both phospho- and total proteomes. This enables the co-detection of phosphoproteins as well as total proteins from the same gel and is accomplished by utilizing two different fluorescent stains, the ProQ-Diamond, which stains only phosphorylated proteins, and Sypro Ruby, which stains the entire subset of proteins. This workflow can be applied to gain insights into the regulatory mechanisms induced by signaling molecules such as cyclic nucleotides through the quantification and subsequent identification of responsive phospho- and total proteins. © Springer Science+Business Media New York 2013.

  4. Comparative gel-based phosphoproteomics in response to signaling molecules

    KAUST Repository

    Marondedze, Claudius

    2013-09-03

    The gel-based proteomics approach is a valuable technique for studying the characteristics of proteins. This technique has diverse applications ranging from analysis of a single protein to the study of the total cellular proteins. Further, protein quality and to some extent distribution can be first assessed by means of one-dimensional gel electrophoresis and then more informatively, for comparative analysis, using the two-dimensional gel electrophoresis technique. Here, we describe how to take advantage of the availability of fluorescent dyes to stain for a selective class of proteins on the same gel for the detection of both phospho- and total proteomes. This enables the co-detection of phosphoproteins as well as total proteins from the same gel and is accomplished by utilizing two different fluorescent stains, the ProQ-Diamond, which stains only phosphorylated proteins, and Sypro Ruby, which stains the entire subset of proteins. This workflow can be applied to gain insights into the regulatory mechanisms induced by signaling molecules such as cyclic nucleotides through the quantification and subsequent identification of responsive phospho- and total proteins. © Springer Science+Business Media New York 2013.

  5. Intercellular communication in Helicobacter pylori: luxS is essential for the production of an extracellular signaling molecule.

    Science.gov (United States)

    Forsyth, M H; Cover, T L

    2000-06-01

    Individual bacteria of numerous species can communicate and coordinate their actions via the production, release, and detection of extracellular signaling molecules. In this study, we used the Vibrio harveyi luminescence bioassay to determine whether Helicobacter pylori produces such a factor. Cell-free conditioned media from H. pylori strains 60190 and 26695 each induced >100-fold-greater luminescence in V. harveyi than did sterile culture medium. The H. pylori signaling molecule had a molecular mass of 100-fold-greater luminescence in the V. harveyi bioassay than did conditioned medium from either mutant strain. Production of the signaling molecule was restored in an H. pylori luxS null mutant strain by complementation with a single intact copy of luxS placed in a heterologous site on the chromosome. In addition, Escherichia coli DH5alpha produced autoinducer activity following the introduction of an intact copy of luxS from H. pylori. Production of the signaling molecule by H. pylori was growth phase dependent, with maximal production occurring in the mid-exponential phase of growth. Transcription of H. pylori vacA also was growth phase dependent, but this phenomenon was not dependent on luxS activity. These data indicate that H. pylori produces an extracellular signaling molecule related to AI-2 from V. harveyi. We speculate that this signaling molecule may play a role in regulating H. pylori gene expression.

  6. Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling.

    Science.gov (United States)

    Sheremet, Michael; Kapoor, Shobhna; Schröder, Peter; Kumar, Kamal; Ziegler, Slava; Waldmann, Herbert

    2017-09-19

    Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small-molecule modulators of Wnt-related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone-derived β-lactone as the key intermediate that was transformed into a δ-lactone appended to the D-ring of the steroidal scaffold. This natural-product-inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase-independent manner. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Expression of SMAD signal transduction molecules in the pancreas

    DEFF Research Database (Denmark)

    Brorson, Michael; Hougaard, D.; Nielsen, Jens Høiriis

    2001-01-01

    Members of the TGF-beta superfamily of cytokines have been implicated in pancreatic cancer, pancreatitis and in regulation and differentiation of pancreatic endocrine and exocrine cells. Different TGF-beta members signal through phosphorylation of different signal transduction proteins, which eve...

  8. Detection, Characterization, and Biological Effect of Quorum-Sensing Signaling Molecules in Peanut-Nodulating Bradyrhizobia

    Directory of Open Access Journals (Sweden)

    Walter Giordano

    2012-03-01

    Full Text Available Bacteria of the genus Bradyrhizobium are able to establish a symbiotic relationship with peanut (Arachis hypogaea root cells and to fix atmospheric nitrogen by converting it to nitrogenous compounds. Quorum sensing (QS is a cell-cell communication mechanism employed by a variety of bacterial species to coordinate behavior at a community level through regulation of gene expression. The QS process depends on bacterial production of various signaling molecules, among which the N-acylhomoserine lactones (AHLs are most commonly used by Gram-negative bacteria. Some previous reports have shown the production of QS signaling molecules by various rhizobia, but little is known regarding mechanisms of communication among peanut-nodulating strains. The aims of this study were to identify and characterize QS signals produced by peanut-nodulating bradyrhizobial strains and to evaluate their effects on processes related to cell interaction. Detection of AHLs in 53 rhizobial strains was performed using the biosensor strains Agrobacterium tumefaciens NTL4 (pZLR4 and Chromobacterium violaceum CV026 for AHLs with long and short acyl chains, respectively. None of the strains screened were found to produce AHLs with short acyl chains, but 14 strains produced AHLs with long acyl chains. These 14 AHL-producing strains were further studied by quantification of β-galactosidase activity levels (AHL-like inducer activity in NTL4 (pZLR4. Strains displaying moderate to high levels of AHL-like inducer activity were subjected to chemical identification of signaling molecules by high-performance liquid chromatography coupled to mass spectrometry (LC-MS/MS. For each AHL-producing strain, we found at least four different AHLs, corresponding to N-hexanoyl-DL-homoserine lactone (C6, N-(3-oxodecanoyl-L-homoserine lactone (3OC10, N-(3-oxododecanoyl-L-homoserine lactone (3OC12, and N-(3-oxotetradecanoyl-L-homoserine lactone (3OC14. Biological roles of 3OC10, 3OC12, and 3OC14 AHLs

  9. Agrobacterium tumefaciens responses to plant-derived signaling molecules

    Science.gov (United States)

    Subramoni, Sujatha; Nathoo, Naeem; Klimov, Eugene; Yuan, Ze-Chun

    2014-01-01

    As a special phytopathogen, Agrobacterium tumefaciens infects a wide range of plant hosts and causes plant tumors also known as crown galls. The complexity of Agrobacterium–plant interaction has been studied for several decades. Agrobacterium pathogenicity is largely attributed to its evolved capabilities of precise recognition and response to plant-derived chemical signals. Agrobacterium perceives plant-derived signals to activate its virulence genes, which are responsible for transferring and integrating its Transferred DNA (T-DNA) from its Tumor-inducing (Ti) plasmid into the plant nucleus. The expression of T-DNA in plant hosts leads to the production of a large amount of indole-3-acetic acid (IAA), cytokinin (CK), and opines. IAA and CK stimulate plant growth, resulting in tumor formation. Agrobacterium utilizes opines as nutrient sources as well as signals in order to activate its quorum sensing (QS) to further promote virulence and opine metabolism. Intriguingly, Agrobacterium also recognizes plant-derived signals including γ-amino butyric acid and salicylic acid (SA) to activate quorum quenching that reduces the level of QS signals, thereby avoiding the elicitation of plant defense and preserving energy. In addition, Agrobacterium hijacks plant-derived signals including SA, IAA, and ethylene to down-regulate its virulence genes located on the Ti plasmid. Moreover, certain metabolites from corn (Zea mays) also inhibit the expression of Agrobacterium virulence genes. Here we outline the responses of Agrobacterium to major plant-derived signals that impact Agrobacterium–plant interactions. PMID:25071805

  10. Agrobacterium tumefaciens responses to plant-derived signaling molecules

    Directory of Open Access Journals (Sweden)

    Sujatha eSubramoni

    2014-07-01

    Full Text Available As a special phytopathogen, Agrobacterium tumefaciens infects a wide range of plant hosts and causes plant tumors also known as crown galls. The complexity of Agrobacterium-plant interaction has been studied for several decades. Agrobacterium pathogenicity is largely attributed to its evolved capabilities of precise recognition and response to plant-derived chemical signals. Agrobacterium perceives plant-derived signals to activate its virulence genes, which are responsible for transferring and integrating its T-DNA (Transferred DNA from its Tumour-inducing (Ti plasmid into the plant nucleus. The expression of T-DNA in plant hosts leads to the production of a large amount of indole-3-acetic acid (IAA, cytokinin (CK and opines. IAA and CK stimulate plant growth, resulting in tumor formation. Agrobacterium utilizes opines as nutrient sources as well as signals in order to activate its quorum sensing (QS to further promote virulence and opine metabolism. Intriguingly, Agrobacterium also recognizes plant-derived signals including -amino butyric acid (GABA and salicylic acid (SA to activate quorum quenching that reduces the level of QS signals, thereby avoiding the elicitation of plant defense and preserving energy. In addition, Agrobacterium hijacks plant-derived signals including SA, IAA, and ethylene (ET to down-regulate its virulence genes located on the Ti plasmid. Moreover, certain metabolites from corn (Zea mays also inhibit the expression of Agrobacterium virulence genes. Here we outline the responses of Agrobacterium to major plant-derived signals that impact Agrobacterium-plant interactions.

  11. Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival.

    Science.gov (United States)

    Pišlar, Anja; Perišić Nanut, Milica; Kos, Janko

    2015-12-01

    Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Gap junction modulation by extracellular signaling molecules: the thymus model

    Directory of Open Access Journals (Sweden)

    Alves L.A.

    2000-01-01

    Full Text Available Gap junctions are intercellular channels which connect adjacent cells and allow direct exchange of molecules of low molecular weight between them. Such a communication has been described as fundamental in many systems due to its importance in coordination, proliferation and differentiation. Recently, it has been shown that gap junctional intercellular communication (GJIC can be modulated by several extracellular soluble factors such as classical hormones, neurotransmitters, interleukins, growth factors and some paracrine substances. Herein, we discuss some aspects of the general modulation of GJIC by extracellular messenger molecules and more particularly the regulation of such communication in the thymus gland. Additionally, we discuss recent data concerning the study of different neuropeptides and hormones in the modulation of GJIC in thymic epithelial cells. We also suggest that the thymus may be viewed as a model to study the modulation of gap junction communication by different extracellular messengers involved in non-classical circuits, since this organ is under bidirectional neuroimmunoendocrine control.

  13. Organometallics and related molecules for energy conversion

    CERN Document Server

    Wong, Wai-Yeung

    2015-01-01

    This book presents a critical perspective of the applications of organometallic compounds (including those with metal or metalloid elements) and other related metal complexes as versatile functional materials in the transformation of light into electricity (solar energy conversion) and electricity into light (light generation in light emitting diode), in the reduction of carbon dioxide to useful chemicals, as well as in the safe and efficient production and utilization of hydrogen, which serves as an energy storage medium (i.e. energy carrier). This book focuses on recent research developmen

  14. Role of the DIP Molecules in DCC Signaling

    Science.gov (United States)

    1999-09-01

    to policies of applicable Federal Law 45 CFR 46. N/A In conducting research utilizing recombinant DNA technology , the investigator(s) adhered to...for 1 h, then with 0.1 mg/ml of proteinase K, 0.1% SDS at 50’C Ihle, 1995; Fraser and Evan, 1996). These molecules overnight. Samples were extracted ...incubated with 20 yg/ml of anti-DCC antibody diluted in PBS-0.1% saponin for 1 h, washed with PBS, blocked Western blotting with 5% normal donkey serum for 1

  15. Study in Mice Links Key Signaling Molecule to Underlying Cause of Osteogenesis Imperfecta

    Science.gov (United States)

    ... Links Key Signaling Molecule to Underlying Cause of Osteogenesis Imperfecta By Kirstie Saltsman, Ph.D. | September 5, 2014 Vertebra from a mouse engineered to have osteogenesis imperfecta (upper panel). Following eight weeks of treatment with ...

  16. Methods for the selective detection of alkyne-presenting molecules and related compositions and systems

    Science.gov (United States)

    Valdez, Carlos A.; Vu, Alexander K.

    2017-10-17

    Provided herein are methods for selectively detecting an alkyne-presenting molecule in a sample and related detection reagents, compositions, methods and systems. The methods include contacting a detection reagent with the sample for a time and under a condition to allow binding of the detection reagent to the one or more alkyne-presenting molecules possibly present in the matrix to the detection reagent. The detection reagent includes an organic label moiety presenting an azide group. The binding of the azide group to the alkyne-presenting molecules results in emission of a signal from the organic label moiety.

  17. All-optical signal processing at 10 GHz using a photonic crystal molecule

    Energy Technology Data Exchange (ETDEWEB)

    Combrié, Sylvain; Lehoucq, Gaëlle; Junay, Alexandra; De Rossi, Alfredo, E-mail: alfredo.derossi@thalesgroup.com [Thales Research and Technology, 1 Avenue A. Fresnel, 91767 Palaiseau (France); Malaguti, Stefania; Bellanca, Gaetano; Trillo, Stefano [Department of Engineering, Università di Ferrara, v. Saragat 1, 44122 Ferrara (Italy); Ménager, Loic [Thales Systèmes Aeroportés, 2 Av. Gay Lussac, 78851 Elancourt (France); Peter Reithmaier, Johann [Institute of Nanostructure Technologies and Analytics, CINSaT, University of Kassel, Heinrich-Plett-Str. 40, 34132 Kassel (Germany)

    2013-11-04

    We report on 10 GHz operation of an all-optical gate based on an Indium Phosphide Photonic Crystal Molecule. Wavelength conversion and all-optical mixing of microwave signals are demonstrated using the 2 mW output of a mode locked diode laser. The spectral separation of the optical pump and signal is crucial in suppressing optical cross-talk.

  18. Influences of excluded volume of molecules on signaling processes on the biomembrane.

    Directory of Open Access Journals (Sweden)

    Masashi Fujii

    Full Text Available We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i monotonically increasing; ii increasing then decreasing in a bell-shaped curve; or iii increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor.

  19. Global analysis of small molecule binding to related protein targets.

    Directory of Open Access Journals (Sweden)

    Felix A Kruger

    2012-01-01

    Full Text Available We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity.

  20. Posttranslational protein S-palmitoylation and the compartmentalization of signaling molecules in neurons

    Directory of Open Access Journals (Sweden)

    SEAN I PATTERSON

    2002-01-01

    Full Text Available Protein domains play a fundamental role in the spatial and temporal organization of intracellular signaling systems. While protein phosphorylation has long been known to modify the interactions that underlie this organization, the dynamic cycling of lipids should now be included amongst the posttranslational processes determining specificity in signal transduction. The characteristics of this process are reminiscent of the properties of protein and lipid phosphorylation in determining compartmentalization through SH2 or PH domains. Recent studies have confirmed the functional importance of protein S-palmitoylation in the compartmentalization of signaling molecules that support normal physiological function in cell division and apoptosis, and synaptic transmission and neurite outgrowth. In neurons, S-palmitoylation and targeting of proteins to rafts are regulated differentially in development by a number of processes, including some related to synaptogenesis and synaptic plasticity. Alterations in the S-palmitoylation state of proteins substantially affect their cellular function, raising the possibility of new therapeutic targets in cancer and nervous system injury and disease.

  1. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    International Nuclear Information System (INIS)

    Kim, Kyung-Chang; Kim, Hyeon Guk; Roh, Tae-Young; Park, Jihwan; Jung, Kyung-Min; Lee, Joo-Shil; Choi, Sang-Yun; Kim, Sung Soon; Choi, Byeong-Sun

    2011-01-01

    Research highlights: → CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. → CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. → HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. → H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. → HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56 Lck , ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56 Lck , ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.

  2. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung-Chang [National Institute of Health, Chungbuk (Korea, Republic of); School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Hyeon Guk [National Institute of Health, Chungbuk (Korea, Republic of); Roh, Tae-Young [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Park, Jihwan [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Jung, Kyung-Min; Lee, Joo-Shil [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Sang-Yun [School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Sung Soon [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Byeong-Sun, E-mail: byeongsun@korea.kr [National Institute of Health, Chungbuk (Korea, Republic of)

    2011-01-14

    Research highlights: {yields} CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. {yields} CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. {yields} HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. {yields} H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. {yields} HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56{sup Lck}, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56{sup Lck}, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new

  3. Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-cadherin

    DEFF Research Database (Denmark)

    Hansen, S M; Berezin, V; Bock, E

    2008-01-01

    Formation of appropriate neural circuits depends on a complex interplay between extracellular guiding cues and intracellular signaling events that result in alterations of cytoskeletal dynamics and a neurite growth response. Surface-expressed cell adhesion molecules (CAMs) interact with the surro......Formation of appropriate neural circuits depends on a complex interplay between extracellular guiding cues and intracellular signaling events that result in alterations of cytoskeletal dynamics and a neurite growth response. Surface-expressed cell adhesion molecules (CAMs) interact...... extracellular guidance cues to intracellular events and thereby regulating neurite outgrowth. In this review, we focus on two CAMs, the neural cell adhesion molecule (NCAM) and N-cadherin, and their ability to mediate signaling associated with a neurite outgrowth response. In particular, we will focus on direct...

  4. Legume receptors perceive the rhizobial lipochitin oligosaccharide signal molecules by direct binding

    DEFF Research Database (Denmark)

    Broghammer, Angelique; Krusell, Lene; Blaise, Mickael

    2012-01-01

    Lipochitin oligosaccharides called Nod factors function as primary rhizobial signal molecules triggering legumes to develop new plant organs: root nodules that host the bacteria as nitrogen-fixing bacteroids. Here, we show that the Lotus japonicus Nod factor receptor 5 (NFR5) and Nod factor recep...

  5. A density-dependent switch drives stochastic clustering and polarization of signaling molecules.

    Directory of Open Access Journals (Sweden)

    Alexandra Jilkine

    2011-11-01

    Full Text Available Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered "off" state is desired? And, what limits the spread of clusters when an "on" state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the "neutral drift polarity model." Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization.

  6. Identification of Quorum Sensing Signal Molecule of Lactobacillus delbrueckii subsp. bulgaricus.

    Science.gov (United States)

    Pang, Xiaoyang; Liu, Cuiping; Lyu, Pengcheng; Zhang, Shuwen; Liu, Lu; Lu, Jing; Ma, Changlu; Lv, Jiaping

    2016-12-14

    Many bacteria in nature use quorum sensing (QS) to regulate gene expression. The quorum sensing system plays critical roles in the adaptation of bacteria to the surrounding environment. Previous studies have shown that during high-density fermentation, the autolysis of lactic acid bacteria was regulated by the QS system, and the two-component system (TCS, LBUL_RS00115/LBUL_RS00110) is involved in the autolysis of Lactobacillus delbrueckii subsp. bulgaricus. However, the QS signal molecule, which regulates this pathway, has not been identified. In this study, we compared the genome of Lactobacillus bulgaricus ATCC BAA-365 with the locus of seven lactobacillus QS systems; the position of the QS signal molecule of Lactobacillus bulgaricus ATCC BAA-365 was predicted by bioinformatics tool. Its function was identified by in vitro experiments. Construction of TCS mutant by gene knockout of LBUL_RS00115 confirmed that the signal molecule regulates the density of the flora by the TCS (LBUL_RS00115/LBUL_RS00110). This study indicated that quorum quenching and inhibition based on the signal molecule might serve as an approach to reduce the rate of autolysis of LAB and increase the number of live bacteria in fermentation.

  7. Bacteroides species produce Vibrio harveyi autoinducer 2-related molecules.

    Science.gov (United States)

    Antunes, Luis Caetano Martha; Ferreira, Lívia Queiroz; Ferreira, Eliane Oliveira; Miranda, Karla Rodrigues; Avelar, Kátia Eliane Santos; Domingues, Regina Maria Cavalcanti Pilotto; Ferreira, Maria Candida de Souza

    2005-10-01

    Quorum sensing is a density-dependent gene regulation mechanism that has been described in many bacterial species in the last decades. Bacteria that use quorum sensing as part of their gene regulation circuits produce molecules called autoinducers that accumulate in the environment and activate target genes in a quorum-dependent way. Some specific clues led us to hypothesize that Bacteroides species can produce autoinducers and possess a quorum sensing system. First, Bacteroides are anaerobic bacteria that are frequently involved in polymicrobial infections. These infections often involve Pseudomonas aeruginosa and Staphylococcus aureus, two of the best understood examples of bacteria that employ quorum sensing systems as part of their pathogenesis. Also, studies have detected the presence of a quorum sensing gene involved in the production of autoinducers in Porphyromonas gingivalis, a species closely related to the Bacteroides genus. These and other evidences prompted us to investigate if Bacteroides strains could produce autoinducer molecules that could be detected by a Vibrio harveyi reporter system. In this paper, we show that supernatants of B. fragilis, B. vulgatus and B. distasonis strains are able to stimulate the V. harveyi quorum sensing system 2. Also, we were able to demonstrate that the stimulation detected is due to the production of autoinducer molecules and not the growth of reporter strains after addition of supernatant. Moreover, the phenomenon observed does not seem to represent the degradation of repressors possibly present in the culture medium used. We could also amplify bands from some of the strains tested using primers designed to the luxS gene of Escherichia coli. Altogether, our results show that B. fragilis, B. vulgatus and B. distasonis (but possibly some other species) can produce V. harveyi autoinducer 2-related molecules. However, the role of such molecules in the biology of these organisms remains unknown.

  8. Role of signaling lymphocytic activation molecule in T helper cell responses

    Directory of Open Access Journals (Sweden)

    Jan E. de Vries

    1998-01-01

    Full Text Available Signaling lymphocytic activation molecule (SLAM; CDw150 is a 70 kDa glycoprotein. Signaling lymphocytic activation molecule is constitutively expressed on memory T cells, CD56+ T cells, a subset of T cell receptor γδ+ cells, immature thymocytes and, at low levels, on a proportion of peripheral blood B cells. Signaling lymphocytic activation molecule is rapidly upregulated on all T and B cells after activation. Engagement of SLAM by F(ab’2 fragments of an anti-SLAM monoclonal antibody (mAb A12 enhances antigen-specific T cell proliferation. In addition, mAb A12 was directly mitogenic for T cell clones and activated T cells. T cell proliferation induced by mAb A12 is independent of interleukin (IL-2, IL-4, IL-12 and IL-15, but is cyclosporin A sensitive. Ligation of SLAM during antigen-specific T cell proliferation resulted in upregulation of interferon (IFN-γ production, even by allergen-specific T helper cell (Th 2 clones, whereas the levels of IL-4 and IL-5 production were only marginally affected. The mAb A12 was unable to induce IL-4 and IL-5 production by Th1 clones. Co-stimulation of skin-derived Der P1-specific Th2 cells from patients with atopic dermatitis via SLAM resulted in the generation of a population of IFN-γ-producing cells, thereby reverting their phenotype to a Th0 pattern. Signaling lymphocytic activation molecule is a high-affinity self ligand mediating homophilic cell interaction. In addition, soluble SLAM enhances both T and B cell proliferation. Collectively, these data indicate that SLAM molecules act both as receptors and ligands that are not only involved in T cell expansion but also drive the expanding T cells during immune responses into the Th0/Th1 pathway. This suggests that signaling through SLAM plays a role in directing Th0/Th1 development.

  9. Detecting and characterizing N-acyl-homoserine lactone signal molecules by thin-layer chromatography

    Science.gov (United States)

    Shaw, Paul D.; Ping, Gao; Daly, Sean L.; Cha, Chung; Cronan, John E.; Rinehart, Kenneth L.; Farrand, Stephen K.

    1997-01-01

    Many Gram-negative bacteria regulate gene expression in response to their population size by sensing the level of acyl-homoserine lactone signal molecules which they produce and liberate to the environment. We have developed an assay for these signals that couples separation by thin-layer chromatography with detection using Agrobacterium tumefaciens harboring lacZ fused to a gene that is regulated by autoinduction. With the exception of N-butanoyl-l-homoserine lactone, the reporter detected acyl-homoserine lactones with 3-oxo-, 3-hydroxy-, and 3-unsubstituted side chains of all lengths tested. The intensity of the response was proportional to the amount of the signal molecule chromatographed. Each of the 3-oxo- and the 3-unsubstituted derivatives migrated with a unique mobility. Using the assay, we showed that some bacteria produce as many as five detectable signal molecules. Structures could be assigned tentatively on the basis of mobility and spot shape. The dominant species produced by Pseudomonas syringae pv. tabaci chromatographed with the properties of N-(3-oxohexanoyl)-l-homoserine lactone, a structure that was confirmed by mass spectrometry. An isolate of Pseudomonas fluorescens produced five detectable species, three of which had novel chromatographic properties. These were identified as the 3-hydroxy- forms of N-hexanoyl-, N-octanoyl-, and N-decanoyl-l-homoserine lactone. The assay can be used to screen cultures of bacteria for acyl-homoserine lactones, for quantifying the amounts of these molecules produced, and as an analytical and preparative aid in determining the structures of these signal molecules. PMID:9177164

  10. Small Molecules Affect Human Dental Pulp Stem Cell Properties Via Multiple Signaling Pathways

    Science.gov (United States)

    Al-Habib, Mey; Yu, Zongdong

    2013-01-01

    One fundamental issue regarding stem cells for regenerative medicine is the maintenance of stem cell stemness. The purpose of the study was to test whether small molecules can enhance stem cell properties of mesenchymal stem cells (MSCs) derived from human dental pulp (hDPSCs), which have potential for multiple clinical applications. We identified the effects of small molecules (Pluripotin (SC1), 6-bromoindirubin-3-oxime and rapamycin) on the maintenance of hDPSC properties in vitro and the mechanisms involved in exerting the effects. Primary cultures of hDPSCs were exposed to optimal concentrations of these small molecules. Treated hDPSCs were analyzed for their proliferation, the expression levels of pluripotent and MSC markers, differentiation capacities, and intracellular signaling activations. We found that small molecule treatments decreased cell proliferation and increased the expression of STRO-1, NANOG, OCT4, and SOX2, while diminishing cell differentiation into odonto/osteogenic, adipogenic, and neurogenic lineages in vitro. These effects involved Ras-GAP-, ERK1/2-, and mTOR-signaling pathways, which may preserve the cell self-renewal capacity, while suppressing differentiation. We conclude that small molecules appear to enhance the immature state of hDPSCs in culture, which may be used as a strategy for adult stem cell maintenance and extend their capacity for regenerative applications. PMID:23573877

  11. Cross-kingdom signalling: exploitation of bacterial quorum sensing molecules by the green seaweed Ulva.

    Science.gov (United States)

    Joint, Ian; Tait, Karen; Wheeler, Glen

    2007-07-29

    The green seaweed Ulva has been shown to detect signal molecules produced by bacteria. Biofilms that release N-acylhomoserine lactones (AHLs) attract zoospores--the motile reproductive stages of Ulva. The evidence for AHL involvement is based on several independent lines of evidence, including the observation that zoospores are attracted to wild-type bacteria that produce AHLs but are not attracted to mutants that do not produce signal molecules. Synthetic AHL also attracts zoospores and the attraction is lost in the presence of autoinducer inactivation (AiiA) protein. The mechanism of attraction is not chemotactic but involves chemokinesis. When zoospores detect AHLs, the swimming rate is reduced and this results in accumulation of cells at the source of the AHL. It has been demonstrated that the detection of AHLs results in calcium influx into the zoospore. This is the first example of a calcium signalling event in a eukaryote in response to bacterial quorum sensing molecules. The role of AHLs in the ecology of Ulva is discussed. It is probable that AHLs act as cues for the settlement of zoospores, rather than being directly involved as a signalling mechanism.

  12. Concentration-related response potentiometric titrations to study the interaction of small molecules with large biomolecules.

    Science.gov (United States)

    Hamidi-Asl, Ezat; Daems, Devin; De Wael, Karolien; Van Camp, Guy; Nagels, Luc J

    2014-12-16

    In the present paper, the utility of a special potentiometric titration approach for recognition and calculation of biomolecule/small-molecule interactions is reported. This approach is fast, sensitive, reproducible, and inexpensive in comparison to the other methods for the determination of the association constant values (Ka) and the interaction energies (ΔG). The potentiometric titration measurement is based on the use of a classical polymeric membrane indicator electrode in a solution of the small-molecule ligand. The biomolecule is used as a titrant. The potential is measured versus a reference electrode and transformed into a concentration-related signal over the entire concentration interval, also at low concentrations, where the millivolt (y-axis) versus log canalyte (x-axis) potentiometric calibration curve is not linear. In the procedure, Ka is calculated for the interaction of cocaine with a cocaine binding aptamer and with an anticocaine antibody. To study the selectivity and cross-reactivity, other oligonucleotides and aptamers are tested, as well as other small ligand molecules such as tetrakis(4-chlorophenyl)borate, metergoline, lidocaine, and bromhexine. The calculated Ka compared favorably to the value reported in the literature using surface plasmon resonance. The potentiometric titration approach called "concentration-related response potentiometry" is used to study molecular interaction for seven macromolecular target molecules and four small-molecule ligands.

  13. ZAP-70 and p72syk are signaling response elements through MHC class II molecules

    DEFF Research Database (Denmark)

    Kanner, S B; Grosmaire, L S; Blake, J

    1995-01-01

    Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization...... of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA...... by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family...

  14. Signaling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line

    DEFF Research Database (Denmark)

    Holland, J; Owens, T

    1997-01-01

    Intercellular adhesion molecule 1 (ICAM-1) (CD54) is an adhesion molecule of the immunoglobulin superfamily. The interaction between ICAM-1 on B lymphocytes and leukocyte function-associated antigen 1 on T cells plays a major role in several aspects of the immune response, including T-dependent B...... cell activation. While it was originally believed that ICAM-1 played a purely adhesive role, recent evidence suggests that it can itself transduce biochemical signals. We demonstrate that cross-linking of ICAM-1 results in the up-regulation of class II major histocompatibility complex, and we...... investigate the biochemical mechanism for the signaling role of ICAM-1. We show that cross-linking of ICAM-1 on the B lymphoma line A20 induces an increase in tyrosine phosphorylation of several cellular proteins, including the Src family kinase p53/p56(lyn). In vitro kinase assays showed that Lyn kinase...

  15. Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1.

    Directory of Open Access Journals (Sweden)

    Pamela Y Ting

    Full Text Available Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML. Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC50 values below 10 μM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function.

  16. Biosurfactants: promising bioactive molecules for oral-related health applications.

    Science.gov (United States)

    Elshikh, Mohamed; Marchant, Roger; Banat, Ibrahim M

    2016-09-01

    Biosurfactants are naturally produced molecules that demonstrate potentially useful properties such as the ability to reduce surface tensions between different phases. Besides having similar properties to their artificial chemical counterparts, they are regarded as environmental friendly, biodegradable and less toxic, which make them desirable candidates for downstream applications. The structure-activity-related properties of the biosurfactants which are directly correlated with potency of the biosurfactants as antimicrobial agents, the ability of the biosurfactants to alter surface energies and their ability to increase bioavailability are particularly what attract researchers to exploit their potential use in the oral-related health applications. Current research into biosurfactant indicates significant future potential for use in cosmetic and therapeutic oral hygiene product formulations and related medical device treatments. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. Discovery of novel small molecule activators of β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Folkert Verkaar

    Full Text Available Wnt/β-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/β-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed bona fide activators of β-catenin signaling. The compounds stabilized cytoplasmic β-catenin and activated β-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate β-catenin signaling has yet to be determined, several key regulators of Wnt/β-catenin signaling, including glycogen synthase kinase 3 and Frizzled receptors, were excluded as the molecular target. The compounds displayed remarkable selectivity, as they only induced β-catenin signaling in a human osteosarcoma U2OS cell line and not in a variety of other cell lines examined. Our data indicate that differences in cellular Wnt/β-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/β-catenin signaling.

  18. Sleep staging with movement-related signals.

    Science.gov (United States)

    Jansen, B H; Shankar, K

    1993-05-01

    Body movement related signals (i.e., activity due to postural changes and the ballistocardiac effort) were recorded from six normal volunteers using the static-charge-sensitive bed (SCSB). Visual sleep staging was performed on the basis of simultaneously recorded EEG, EMG and EOG signals. A statistical classification technique was used to determine if reliable sleep staging could be performed using only the SCSB signal. A classification rate of between 52% and 75% was obtained for sleep staging in the five conventional sleep stages and the awake state. These rates improved from 78% to 89% for classification between awake, REM and non-REM sleep and from 86% to 98% for awake versus asleep classification.

  19. Functional network of glycan-related molecules: Glyco-Net in Glycoconjugate Data Bank

    Directory of Open Access Journals (Sweden)

    Miura Nobuaki

    2010-06-01

    Full Text Available Abstract Background Glycans are involved in a wide range of biological process, and they play an essential role in functions such as cell differentiation, cell adhesion, pathogen-host recognition, toxin-receptor interactions, signal transduction, cancer metastasis, and immune responses. Elucidating pathways related to post-translational modifications (PTMs such as glycosylation are of growing importance in post-genome science and technology. Graphical networks describing the relationships among glycan-related molecules, including genes, proteins, lipids and various biological events are considered extremely valuable and convenient tools for the systematic investigation of PTMs. However, there is no database which dynamically draws functional networks related to glycans. Description We have created a database called Glyco-Net http://www.glycoconjugate.jp/functions/, with many binary relationships among glycan-related molecules. Using search results, we can dynamically draw figures of the functional relationships among these components with nodes and arrows. A certain molecule or event corresponds to a node in the network figures, and the relationship between the molecule and the event are indicated by arrows. Since all components are treated equally, an arrow is also a node. Conclusions In this paper, we describe our new database, Glyco-Net, which is the first database to dynamically show networks of the functional profiles of glycan related molecules. The graphical networks will assist in the understanding of the role of the PTMs. In addition, since various kinds of bio-objects such as genes, proteins, and inhibitors are equally treated in Glyco-Net, we can obtain a large amount of information on the PTMs.

  20. Small Molecule Modulator of p53 Signaling Pathway: Application for Radiosensitizing or Radioprotection Agents

    International Nuclear Information System (INIS)

    Oh, Sang Taek; Cho, Mun Ju; Gwak, Jung Sug; Ryu, Min Jung; Song, Jie Young; Yun, Yeon Sook

    2009-01-01

    The tumor suppressor p53 is key molecule to protect the cell against genotoxic stress and..the most frequently mutated..protein..in cancer cells. Lack of functional p53..is accompanied by high rate of genomic instability, rapid tumor progression, resistance to anticancer therapy, and increased angiogenesis. In response to DNA damage, p53 protein rapidly accumulated through attenuated proteolysis and is also activated as transcription factor. Activated p53 up-regulates target genes involved in cell cycle arrest and/or apoptosis and then lead to suppression of malignant transformation and the maintenance of genomic integrity. Chemical genetics is a new technology to uncover the signaling networks that regulated biological phenotype using exogenous reagents such as small molecules. Analogous to classical forward genetic screens in model organism, this approach makes use of high throughput, phenotypic assay to identify small molecules that disrupt gene product function in a way that alters a phenotype of interest. Recently, interesting small molecules were identified from cell based high throughput screening and its target protein or mechanism of action were identified by various methods including affinity chromatography, protein array profiling, mRNA or phage display, transcription profiling, and RNA interference

  1. Small Molecule Modulator of p53 Signaling Pathway: Application for Radiosensitizing or Radioprotection Agents

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Sang Taek; Cho, Mun Ju; Gwak, Jung Sug; Ryu, Min Jung [PharmacoGenomics Research Center, Inje University, Busan (Korea, Republic of); Song, Jie Young; Yun, Yeon Sook [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    The tumor suppressor p53 is key molecule to protect the cell against genotoxic stress and..the most frequently mutated..protein..in cancer cells. Lack of functional p53..is accompanied by high rate of genomic instability, rapid tumor progression, resistance to anticancer therapy, and increased angiogenesis. In response to DNA damage, p53 protein rapidly accumulated through attenuated proteolysis and is also activated as transcription factor. Activated p53 up-regulates target genes involved in cell cycle arrest and/or apoptosis and then lead to suppression of malignant transformation and the maintenance of genomic integrity. Chemical genetics is a new technology to uncover the signaling networks that regulated biological phenotype using exogenous reagents such as small molecules. Analogous to classical forward genetic screens in model organism, this approach makes use of high throughput, phenotypic assay to identify small molecules that disrupt gene product function in a way that alters a phenotype of interest. Recently, interesting small molecules were identified from cell based high throughput screening and its target protein or mechanism of action were identified by various methods including affinity chromatography, protein array profiling, mRNA or phage display, transcription profiling, and RNA interference.

  2. Control of Biofilms with the Fatty Acid Signaling Molecule cis-2-Decenoic Acid

    Directory of Open Access Journals (Sweden)

    Cláudia N. H. Marques

    2015-11-01

    Full Text Available Biofilms are complex communities of microorganisms in organized structures attached to surfaces. Importantly, biofilms are a major cause of bacterial infections in humans, and remain one of the most significant challenges to modern medical practice. Unfortunately, conventional therapies have shown to be inadequate in the treatment of most chronic biofilm infections based on the extraordinary innate tolerance of biofilms to antibiotics. Antagonists of quorum sensing signaling molecules have been used as means to control biofilms. QS and other cell-cell communication molecules are able to revert biofilm tolerance, prevent biofilm formation and disrupt fully developed biofilms, albeit with restricted effectiveness. Recently however, it has been demonstrated that Pseudomonas aeruginosa produces a small messenger molecule cis-2-decenoic acid (cis-DA that shows significant promise as an effective adjunctive to antimicrobial treatment of biofilms. This molecule is responsible for induction of the native biofilm dispersion response in a range of Gram-negative and Gram-positive bacteria and in yeast, and has been shown to reverse persistence, increase microbial metabolic activity and significantly enhance the cidal effects of conventional antimicrobial agents. In this manuscript, the use of cis-2-decenoic acid as a novel agent for biofilm control is discussed. Stimulating the biofilm dispersion response as a novel antimicrobial strategy holds significant promise for enhanced treatment of infections and in the prevention of biofilm formation.

  3. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

    Directory of Open Access Journals (Sweden)

    Tertia D Purves-Tyson

    receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence.

  4. Ocean acidification affects marine chemical communication by changing structure and function of peptide signalling molecules.

    Science.gov (United States)

    Roggatz, Christina C; Lorch, Mark; Hardege, Jörg D; Benoit, David M

    2016-12-01

    Ocean acidification is a global challenge that faces marine organisms in the near future with a predicted rapid drop in pH of up to 0.4 units by the end of this century. Effects of the change in ocean carbon chemistry and pH on the development, growth and fitness of marine animals are well documented. Recent evidence also suggests that a range of chemically mediated behaviours and interactions in marine fish and invertebrates will be affected. Marine animals use chemical cues, for example, to detect predators, for settlement, homing and reproduction. But, while effects of high CO 2 conditions on these behaviours are described across many species, little is known about the underlying mechanisms, particularly in invertebrates. Here, we investigate the direct influence of future oceanic pH conditions on the structure and function of three peptide signalling molecules with an interdisciplinary combination of methods. NMR spectroscopy and quantum chemical calculations were used to assess the direct molecular influence of pH on the peptide cues, and we tested the functionality of the cues in different pH conditions using behavioural bioassays with shore crabs (Carcinus maenas) as a model system. We found that peptide signalling cues are susceptible to protonation in future pH conditions, which will alter their overall charge. We also show that structure and electrostatic properties important for receptor binding differ significantly between the peptide forms present today and the protonated signalling peptides likely to be dominating in future oceans. The bioassays suggest an impaired functionality of the signalling peptides at low pH. Physiological changes due to high CO 2 conditions were found to play a less significant role in influencing the investigated behaviour. From our results, we conclude that the change of charge, structure and consequently function of signalling molecules presents one possible mechanism to explain altered behaviour under future oceanic p

  5. Interleukin 4 signals through two related pathways.

    Science.gov (United States)

    Pernis, A; Witthuhn, B; Keegan, A D; Nelms, K; Garfein, E; Ihle, J N; Paul, W E; Pierce, J H; Rothman, P

    1995-08-15

    The interleukin 4 (IL-4) signaling pathway involves activation, by tyrosine phosphorylation, of two distinct substrates, a signal-transducing factor (STF-IL4) and the IL-4-induced phosphotyrosine substrate (4PS). It is not known whether the IL-4-mediated activation of these substrates occurs via related or distinct signaling pathways. We report that 32D cells, an IL-3-dependent myeloid progenitor cell line in which no phosphorylated 4PS is found, activate high levels of STF-IL4 in response to IL-4. Consistent with the known requirement for 4PS or insulin receptor substrate 1 (IRS-1) in IL-4-mediated mitogenesis, activation of STF-IL4 in 32D cells is not sufficient for IL-4-inducible c-myc expression. In addition, we have examined the ability of 32D cells transfected with different truncation mutants of the human IL-4 receptor to activate Jak-3 kinase and STF-IL4 in response to human IL-4. As in the case of 4PS/IRS-1, we have found that activation of both Jak-3 and STF-IL4 requires the presence of the IL-4 receptor region comprising aa 437-557. The finding that the same region of the IL-4 receptor is required for the induction of both 4PS/IRS-1 and STF-IL4 suggests that the IL-4-stimulated activation of these two substrates might involve common factors.

  6. Cross Talk between H2O2 and Interacting Signal Molecules under Plant Stress Response

    Science.gov (United States)

    Saxena, Ina; Srikanth, Sandhya; Chen, Zhong

    2016-01-01

    It is well established that oxidative stress is an important cause of cellular damage. During stress conditions, plants have evolved regulatory mechanisms to adapt to various environmental stresses. One of the consequences of stress is an increase in the cellular concentration of reactive oxygen species, which is subsequently converted to H2O2. H2O2 is continuously produced as the byproduct of oxidative plant aerobic metabolism. Organelles with a high oxidizing metabolic activity or with an intense rate of electron flow, such as chloroplasts, mitochondria, or peroxisomes are major sources of H2O2 production. H2O2 acts as a versatile molecule because of its dual role in cells. Under normal conditions, H2O2 immerges as an important factor during many biological processes. It has been established that it acts as a secondary messenger in signal transduction networks. In this review, we discuss potential roles of H2O2 and other signaling molecules during various stress responses. PMID:27200043

  7. Nitric oxide in denitrification - an elusive signal molecule emitted from soil

    Science.gov (United States)

    Bakken, L. R.; Frostegard, A.

    2010-12-01

    Soils emit variable amounts of NO and N2O, with environmental consequences (atmosphere chemistry and global warming). Nitrification was for some time considered the main source of NO emission, but several investigations have indicated that denitrification may be a potent source as well. However, strong emission of NO from denitrifying organisms is in some conflict with common understanding of the role of NO in the regulation of denitrification, as based on paradigm model strains. NO appears to be an important signal molecule for denitrifying organisms by exerting a positive feedback on the expression of the genes coding for denitrification. On the other hand, a careful control of the NO concentrations at nanomolar concentrations has long been considered an essential fitness character for denitrifying organisms, since micromolar concentrations of NO is toxic to many organisms. For the same reason, organisms lacking genes encoding NO reductase (NOR) have been considered unfit for denitrification. This view is challenged by isolation of organisms whose primary product of denitrification is NO, either because they lack the genes for NO reductase, or because their synthesis of the denitrification proteome is extremely unbalanced, resulting in transient NO accumulation to micromolar concentrations when grown in pure culture. Such paralyzing NO concentrations are probably never reached in natural environments, however, due to diffusion and NO-absorption by adjacent organisms, be it by NOR or other NO scavenging enzymes. Hypothetically, the production of NO by denitrifying organisms may be an advantage by fending off nearby competitors. We have embarked on a comparative study of denitrification phenotypes regarding their denitrification gene expression and control of NO and N2O concentrations in response to anoxic spells. This includes model strains (Paracoccus denitrificans and Agrobacterium tumefaciens) and recently isolated strains within several genera. Some are found

  8. Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.

    Science.gov (United States)

    Hyde, Thomas M; Lipska, Barbara K; Ali, Towhid; Mathew, Shiny V; Law, Amanda J; Metitiri, Ochuko E; Straub, Richard E; Ye, Tianzhang; Colantuoni, Carlo; Herman, Mary M; Bigelow, Llewellyn B; Weinberger, Daniel R; Kleinman, Joel E

    2011-07-27

    GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.

  9. Hydrogen molecules and hydrogen-related defects in crystalline silicon

    Science.gov (United States)

    Fukata, N.; Sasaki, S.; Murakami, K.; Ishioka, K.; Nakamura, K. G.; Kitajima, M.; Fujimura, S.; Kikuchi, J.; Haneda, H.

    1997-09-01

    We have found that hydrogen exists in molecular form in crystalline silicon treated with hydrogen atoms in the downstream of a hydrogen plasma. The vibrational Raman line of hydrogen molecules is observed at 4158 cm-1 for silicon samples hydrogenated between 180 and 500 °C. The assignment of the Raman line is confirmed by its isotope shift to 2990 cm-1 for silicon treated with deuterium atoms. The Raman intensity has a maximum for hydrogenation at 400 °C. The vibrational Raman line of the hydrogen molecules is broad and asymmetric. It consists of at least two components, possibly arising from hydrogen molecules in different occupation sites in crystalline silicon. The rotational Raman line of hydrogen molecules is observed at 590 cm-1. The Raman band of Si-H stretching is observed for hydrogenation temperatures between 100 and 500 °C and the intensity has a maximum for hydrogenation at 250 °C.

  10. Activation of stress signaling molecules in bat brain during arousal from hibernation.

    Science.gov (United States)

    Lee, Moonyong; Choi, Inho; Park, Kyoungsook

    2002-08-01

    Induction of glucose-regulated proteins (GRPs) is a ubiquitous intracellular response to stresses such as hypoxia, glucose starvation and acidosis. The induction of GRPs offers some protection against these stresses in vitro, but the specific role of GRPs in vivo remains unclear. Hibernating bats present a good in vivo model to address this question. The bats must overcome local high oxygen demand in tissue by severe metabolic stress during arousal thermogenesis. We used brain tissue of a temperate bat Rhinolopus ferrumequinum to investigate GRP induction by high metabolic oxygen demand and to identify associated signaling molecules. We found that during 30 min of arousal, oxygen consumption increased from nearly zero to 11.9/kg/h, which was about 8.7-fold higher than its active resting metabolic rate. During this time, body temperature rose from 7 degrees C to 35 degrees C, and levels of TNF-alpha and lactate in brain tissue increased 2-2.5-fold, indicating a high risk of oxygen shortage. Concomitantly, levels of GRP75, GRP78 and GRP94 increased 1.5-1.7-fold. At the same time, c-Jun N-terminal protein kinase (JNK) activity increased 6.4-fold, and extracellular signal-regulated protein kinase (ERK) activity decreased to a similar degree (6.1-fold). p38 MAPK activity was very low and remained unchanged during arousal. In addition, survival signaling molecules protein kinase B (Akt) and protein kinase C (PKC) were activated 3- and 5-fold, respectively, during arousal. Taken together, our results showed that bat brain undergoes high oxygen demand during arousal from hibernation. Up-regulation of GRP proteins and activation of JNK, PKCgamma and Akt may be critical for neuroprotection and the survival of bats during the repeated process.

  11. Endothelial juxtaposition of distinct adult stem cells activates angiogenesis signaling molecules in endothelial cells.

    Science.gov (United States)

    Mohammadi, Elham; Nassiri, Seyed Mahdi; Rahbarghazi, Reza; Siavashi, Vahid; Araghi, Atefeh

    2015-12-01

    Efficacy of therapeutic angiogenesis needs a comprehensive understanding of endothelial cell (EC) function and biological factors and cells that interplay with ECs. Stem cells are considered the key components of pro- and anti-angiogenic milieu in a wide variety of physiopathological states, and interactions of EC-stem cells have been the subject of controversy in recent years. In this study, the potential effects of three tissue-specific adult stem cells, namely rat marrow-derived mesenchymal stem cells (rBMSCs), rat adipose-derived stem cells (rADSCs) and rat muscle-derived satellite cells (rSCs), on the endothelial activation of key angiogenic signaling molecules, including VEGF, Ang-2, VEGFR-2, Tie-2, and Tie2-pho, were investigated. Human umbilical vein endothelial cells (HUVECs) and rat lung microvascular endothelial cells (RLMECs) were cocultured with the stem cells or incubated with the stem cell-derived conditioned media on Matrigel. Following HUVEC-stem cell coculture, CD31-positive ECs were flow sorted and subjected to western blotting to analyze potential changes in the expression of the pro-angiogenic signaling molecules. Elongation and co-alignment of the stem cells were seen along the EC tubes in the EC-stem cell cocultures on Matrigel, with cell-to-cell dye communication in the EC-rBMSC cocultures. Moreover, rBMSCs and rADSCs significantly improved endothelial tubulogenesis in both juxtacrine and paracrine manners. These two latter stem cells dynamically up-regulated VEGF, Ang-2, VREGR-2, and Tie-2 but down-regulated Tie2-pho and the Tie2-pho/Tie-2 ratio in HUVECs. Induction of pro-angiogenic signaling in ECs by marrow- and adipose-derived MSCs further indicates the significance of stem cell milieu in angiogenesis dynamics.

  12. Modulation of Hippocampal Neural Plasticity by Glucose-Related Signaling

    Directory of Open Access Journals (Sweden)

    Marco Mainardi

    2015-01-01

    Full Text Available Hormones and peptides involved in glucose homeostasis are emerging as important modulators of neural plasticity. In this regard, increasing evidence shows that molecules such as insulin, insulin-like growth factor-I, glucagon-like peptide-1, and ghrelin impact on the function of the hippocampus, which is a key area for learning and memory. Indeed, all these factors affect fundamental hippocampal properties including synaptic plasticity (i.e., synapse potentiation and depression, structural plasticity (i.e., dynamics of dendritic spines, and adult neurogenesis, thus leading to modifications in cognitive performance. Here, we review the main mechanisms underlying the effects of glucose metabolism on hippocampal physiology. In particular, we discuss the role of these signals in the modulation of cognitive functions and their potential implications in dysmetabolism-related cognitive decline.

  13. Endocannabinoids and the processing of value-related signals

    Directory of Open Access Journals (Sweden)

    Miriam eMelis

    2012-02-01

    Full Text Available Endocannabinoids serve as retrograde signaling molecules at many synapses within the CNS, particularly GABAergic and glutamatergic synapses. Synapses onto midbrain dopamine (DA neurons in the ventral tegmental area (VTA make no exception to this rule. In fact, the effects of cannabinoids on dopamine transmission as well as DA-related behaviors are generally exerted through the modulation of inhibitory and excitatory afferents impinging onto DA neurons. Endocannabinoids, by regulating different forms of synaptic plasticity in the VTA, provide a critical modulation of the DA neuron output and, ultimately, of the systems driving and regulating motivated behaviors. Because DA cells exhibit diverse states of activity, which crucially depend on their intrinsic properties and afferent drive, the understanding of the role played by endocannabinoids in synaptic modulations is critical for their overall functions. Particularly, endocannabinoids by selectively inhibiting afferent activity may alter the functional states of DA neurons and potentiate the responsiveness of the reward system to phasic DA.

  14. Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.

    OpenAIRE

    Nishimura, R; Li, W; Kashishian, A; Mondino, A; Zhou, M; Cooper, J; Schlessinger, J

    1993-01-01

    Autophosphorylation sites of growth factor receptors with tyrosine kinase activity function as specific binding sites for Src homology 2 (SH2) domains of signaling molecules. This interaction appears to be a crucial step in a mechanism by which receptor tyrosine kinases relay signals to downstream signaling pathways. Nck is a widely expressed protein consisting exclusively of SH2 and SH3 domains, the overexpression of which causes cell transformation. It has been shown that various growth fac...

  15. Nitrogen modulation of legume root architecture signaling pathways involves phytohormones and small regulatory molecules.

    Science.gov (United States)

    Mohd-Radzman, Nadiatul A; Djordjevic, Michael A; Imin, Nijat

    2013-10-01

    Nitrogen, particularly nitrate is an important yield determinant for crops. However, current agricultural practice with excessive fertilizer usage has detrimental effects on the environment. Therefore, legumes have been suggested as a sustainable alternative for replenishing soil nitrogen. Legumes can uniquely form nitrogen-fixing nodules through symbiotic interaction with specialized soil bacteria. Legumes possess a highly plastic root system which modulates its architecture according to the nitrogen availability in the soil. Understanding how legumes regulate root development in response to nitrogen availability is an important step to improving root architecture. The nitrogen-mediated root development pathway starts with sensing soil nitrogen level followed by subsequent signal transduction pathways involving phytohormones, microRNAs and regulatory peptides that collectively modulate the growth and shape of the root system. This review focuses on the current understanding of nitrogen-mediated legume root architecture including local and systemic regulations by different N-sources and the modulations by phytohormones and small regulatory molecules.

  16. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling

    DEFF Research Database (Denmark)

    Zecchini, Silvia; Bombardelli, Lorenzo; Decio, Alessandra

    2011-01-01

    glycoprotein involved in brain development and plasticity, in EOC. NCAM is absent from normal ovarian epithelium but becomes highly expressed in a subset of human EOC, in which NCAM expression is associated with high tumour grade, suggesting a causal role in cancer aggressiveness. We demonstrate that NCAM......Epithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which mainly disseminates to organs of the peritoneal cavity, an event mediated by molecular mechanisms that remain elusive. Here, we investigated the expression and functional role of neural cell adhesion molecule (NCAM), a cell surface...... stimulates EOC cell migration and invasion in vitro and promotes metastatic dissemination in mice. This pro-malignant function of NCAM is mediated by its interaction with fibroblast growth factor receptor (FGFR). Indeed, not only FGFR signalling is required for NCAM-induced EOC cell motility, but targeting...

  17. Effects of gelling agent and extracellular signaling molecules on the culturability of marine bacteria

    DEFF Research Database (Denmark)

    Rygaard, Anita Mac; Schmidt Thøgersen, Mariane; Nielsen, Kristian Fog

    2017-01-01

    Only 1 % of marine bacteria are currently culturable using standard laboratory procedures and this is a major obstacle for our understanding of the biology of marine microorganisms and for the discovery of novel microbial natural products. Therefore, the purpose of the present study was to invest......Only 1 % of marine bacteria are currently culturable using standard laboratory procedures and this is a major obstacle for our understanding of the biology of marine microorganisms and for the discovery of novel microbial natural products. Therefore, the purpose of the present study...... was to investigate if improved cultivation conditions, including the use of an alternative gelling agent, and supplementation with signaling molecules, could improve the culturability of bacteria from seawater. Substituting agar with gellan gum improved viable counts 3 – 40-fold, depending on medium composition...

  18. Synemin acts as a regulator of signalling molecules during skeletal muscle hypertrophy.

    Science.gov (United States)

    Li, Zhenlin; Parlakian, Ara; Coletti, Dario; Alonso-Martin, Sonia; Hourdé, Christophe; Joanne, Pierre; Gao-Li, Jacqueline; Blanc, Jocelyne; Ferry, Arnaud; Paulin, Denise; Xue, Zhigang; Agbulut, Onnik

    2014-11-01

    Synemin, a type IV intermediate filament (IF) protein, forms a bridge between IFs and cellular membranes. As an A-kinase-anchoring protein, it also provides temporal and spatial targeting of protein kinase A (PKA). However, little is known about its functional roles in either process. To better understand its functions in muscle tissue, we generated synemin-deficient (Synm(-) (/-)) mice. Synm(-) (/-) mice displayed normal development and fertility but showed a mild degeneration and regeneration phenotype in myofibres and defects in sarcolemma membranes. Following mechanical overload, Synm(-) (/-) mice muscles showed a higher hypertrophic capacity with increased maximal force and fatigue resistance compared with control mice. At the molecular level, increased remodelling capacity was accompanied by decreased myostatin (also known as GDF8) and atrogin (also known as FBXO32) expression, and increased follistatin expression. Furthermore, the activity of muscle-mass control molecules (the PKA RIIα subunit, p70S6K and CREB1) was increased in mutant mice. Finally, analysis of muscle satellite cell behaviour suggested that the absence of synemin could affect the balance between self-renewal and differentiation of these cells. Taken together, our results show that synemin is necessary to maintain membrane integrity and regulates signalling molecules during muscle hypertrophy. © 2014. Published by The Company of Biologists Ltd.

  19. Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

    Directory of Open Access Journals (Sweden)

    Siar CH

    2010-10-01

    Full Text Available Abstract Background Notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified. Method Tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1 expression. Results Both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I. Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members. Conclusions Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage.

  20. Information flow during gene activation by signaling molecules: ethylene transduction in Arabidopsis cells as a study system

    Directory of Open Access Journals (Sweden)

    Díaz José

    2009-05-01

    Full Text Available Abstract Background We study root cells from the model plant Arabidopsis thaliana and the communication channel conformed by the ethylene signal transduction pathway. A basic equation taken from our previous work relates the probability of expression of the gene ERF1 to the concentration of ethylene. Results The above equation is used to compute the Shannon entropy (H or degree of uncertainty that the genetic machinery has during the decoding of the message encoded by the ethylene specific receptors embedded in the endoplasmic reticulum membrane and transmitted into the nucleus by the ethylene signaling pathway. We show that the amount of information associated with the expression of the master gene ERF1 (Ethylene Response Factor 1 can be computed. Then we examine the system response to sinusoidal input signals with varying frequencies to determine if the cell can distinguish between different regimes of information flow from the environment. Our results demonstrate that the amount of information managed by the root cell can be correlated with the frequency of the input signal. Conclusion The ethylene signaling pathway cuts off very low and very high frequencies, allowing a window of frequency response in which the nucleus reads the incoming message as a sinusoidal input. Out of this window the nucleus reads the input message as an approximately non-varying one. From this frequency response analysis we estimate: a the gain of the system during the synthesis of the protein ERF1 (~-5.6 dB; b the rate of information transfer (0.003 bits during the transport of each new ERF1 molecule into the nucleus and c the time of synthesis of each new ERF1 molecule (~21.3 s. Finally, we demonstrate that in the case of the system of a single master gene (ERF1 and a single slave gene (HLS1, the total Shannon entropy is completely determined by the uncertainty associated with the expression of the master gene. A second proposition shows that the Shannon entropy

  1. Interaction of plant cell signaling molecules, salicylic acid and jasmonic acid, with the mitochondria of Helicoverpa armigera.

    Science.gov (United States)

    Akbar, S M D; Sharma, H C; Jayalakshmi, S K; Sreeramulu, K

    2012-02-01

    The cotton bollworm, Helicoverpa armigera is a polyphagous pest in Asia, Africa, and the Mediterranean Europe. Salicylic acid (SA) and jasmonic acid (JA) are the cell signaling molecules produced in response to insect attack in plants. The effect of these signaling molecules was investigated on the oxidative phosphorylation and oxidative stress of H. armigera. SA significantly inhibited the state III and state IV respiration, respiratory control index (RCI), respiratory complexes I and II, induced mitochondrial swelling, and cytochrome c release in vitro. Under in vivo conditions, SA induced state IV respiration as well as oxidative stress in time- and dose-dependent manner, and also inhibited the larval growth. In contrast, JA did not affect the mitochondrial respiration and oxidative stress. SA affected the growth and development of H. armigera, in addition to its function as signaling molecules involved in both local defense reactions at feeding sites and the induction of systemic acquired resistance in plants.

  2. Applying Statistical and Complex Network Methods to Explore the Key Signaling Molecules of Acupuncture Regulating Neuroendocrine-Immune Network

    Directory of Open Access Journals (Sweden)

    Kuo Zhang

    2018-01-01

    Full Text Available The mechanisms of acupuncture are still unclear. In order to reveal the regulatory effect of manual acupuncture (MA on the neuroendocrine-immune (NEI network and identify the key signaling molecules during MA modulating NEI network, we used a rat complete Freund’s adjuvant (CFA model to observe the analgesic and anti-inflammatory effect of MA, and, what is more, we used statistical and complex network methods to analyze the data about the expression of 55 common signaling molecules of NEI network in ST36 (Zusanli acupoint, and serum and hind foot pad tissue. The results indicate that MA had significant analgesic, anti-inflammatory effects on CFA rats; the key signaling molecules may play a key role during MA regulating NEI network, but further research is needed.

  3. Discovering Small Molecule Inhibitors Targeted to Ligand-Stimulated RAGE-DIAPH1 Signaling Transduction

    Science.gov (United States)

    Pan, Jinhong

    The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of the RAGE cytoplasmic tail (ctRAGE) with intracellular effector, such as diaphanous 1 (DIAPH1), to initiate signal transduction cascades. ctRAGE is essential for RAGE-ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE is over-expressed in diseased tissues of most RAGE-associated pathogenic conditions, such as complications of Alzheimer's diseases, diabetes, vascular diseases, inflammation, cancers and neurodegeneration. They are the major diseases affecting a large population worldwide. RAGE can function as a biomarker or drug target for these diseases. The cytoplasmic tail of RAGE can be used as a drug target to inhibit RAGE-induced intracellular signaling by small molecule inhibitors to treat RAGE-associated diseases. We developed a high throughput screening assay with which we probed a small molecule library of 58,000 compounds to find that 777 small molecules displayed 50% inhibition and 97 compounds demonstrated dose-dependent inhibition of the binding of ctRAGE-DIAPH1. Eventually, there were 13 compounds which displayed dose-dependent inhibition of ctRAGE binding to DIAPH1 and direct binding to ctRAGE analyzed by 15N HSQC-NMR and native tryptophan fluorescence titration experiments; thus, they were

  4. Hydrogen molecules and hydrogen-related defects in crystalline silicon

    OpenAIRE

    Fukata, N.; Sasak, S.; Murakami, K.; Ishioka, K.; Nakamura, K. G.; Kitajima, M.; Fujimura, S.; Kikuchi, J.; Haneda, H.

    1997-01-01

    We have found that hydrogen exists in molecular form in crystalline silicon treated with hydrogen atoms in the downstream of a hydrogen plasma. The vibrational Raman line of hydrogen molecules is observed at 4158cm-1 for silicon samples hydrogenated between 180 and 500 °C. The assignment of the Raman line is confirmed by its isotope shift to 2990cm-1 for silicon treated with deuterium atoms. The Raman intensity has a maximum for hydrogenation at 400 °C. The vibrational Raman line of the hydro...

  5. Adenosine as a signaling molecule in the retina: biochemical and developmental aspects

    Directory of Open Access Journals (Sweden)

    ROBERTO PAES-DE-CARVALHO

    2002-09-01

    Full Text Available The nucleoside adenosine plays an important role as a neurotransmitter or neuromodulator in the central nervous system, including the retina. In the present paper we review compelling evidence showing that adenosine is a signaling molecule in the developing retina. In the chick retina, adenosine transporters are present since early stages of development before the appearance of adenosine A1 receptors modulating dopamine-dependent adenylate cyclase activity or A2 receptors that directly activate the enzyme. Experiments using retinal cell cultures revealed that adenosine is taken up by specific cell populations that when stimulated by depolarization or neurotransmitters such as dopamine or glutamate, release the nucleoside through calcium-dependent transporter-mediated mechanisms. The presence of adenosine in the extracellular medium and the long-term activation of adenosine receptors is able to regulate the survival of retinal neurons and blocks glutamate excitoxicity. Thus, adenosine besides working as a neurotransmitter or neuromodulator in the mature retina, is considered as an important signaling molecule during retinal development having important functions such as regulation of neuronal survival and differentiation.O nucleosídeo adenosina apresenta um importante papel como neurotransmissor ou neuromodulador no sistema nervoso central, inclusive na retina. Neste artigo apresentamos uma revisão das evidências que mostram que a adenosina é uma molécula sinalizadora na retina em desenvolvimento. Na retina de pinto, transportadores de adenosina estão presentes desde estágios precoces do desenvolvimento, antes do aparecimento dos receptores A1 que modulam a atividade adenilato ciclase dependente de dopamina ou dos receptores A2 que ativam diretamente a enzima. Experimentos usando culturas de células de retina revelaram que a adenosina é captada por populações celulares específicas que, quando estimuladas por despolarização ou por

  6. Co-ordinate regulation of distinct host cell signalling pathways by multifunctional enteropathogenic Escherichia coli effector molecules.

    Science.gov (United States)

    Kenny, Brendan; Ellis, Sarah; Leard, Alan D; Warawa, Jonathan; Mellor, Harry; Jepson, Mark A

    2002-05-01

    Enteropathogenic Escherichia coli (EPEC) is a major cause of paediatric diarrhoea and a model for the family of attaching and effacing (A/E) pathogens. A/E pathogens encode a type III secretion system to transfer effector proteins into host cells. The EPEC Tir effector protein acts as a receptor for the bacterial surface protein intimin and is involved in the formation of Cdc42-independent, actin-rich pedestal structures beneath the adhered bacteria. In this paper, we demonstrate that EPEC binding to HeLa cells also induces Tir-independent, cytoskeletal rearrangement evidenced by the early, transient formation of filopodia-like structures at sites of infection. Filopodia formation is dependent on expression of the EPEC Map effector molecule - a protein that targets mitochondria and induces their dysfunction. We show that Map-induced filopodia formation is independent of mitochondrial targeting and is abolished by cellular expression of the Cdc42 inhibitory WASP-CRIB domain, demonstrating that Map has at least two distinct functions in host cells. The transient nature of the filopodia is related to an ability of EPEC to downregulate Map-induced cell signalling that, like pedestal formation, was dependent on both Tir and intimin proteins. The ability of Tir to downregulate filopodia was impaired by disrupting a putative GTPase-activating protein (GAP) motif, suggesting that Tir may possess such a function, with its interaction with intimin triggering this activity. Furthermore, we also found that Map-induced cell signalling inhibits pedestal formation, revealing that the cellular effects of Tir and Map must be co-ordinately regulated during infection. Possible implications of the multifunctional nature of EPEC effector molecules in pathogenesis are discussed.

  7. Hydrogen sulfide in plants: from dissipation of excess sulfur to signaling molecule.

    Science.gov (United States)

    Calderwood, Alexander; Kopriva, Stanislav

    2014-09-15

    Sulfur is essential in all organisms for the synthesis of amino acids cysteine and methionine and as an active component of numerous co-factors and prosthetic groups. However, only plants, algae, fungi, and some prokaryotes are capable of using the abundant inorganic source of sulfur, sulfate. Plants take sulfate up, reduce it, and assimilate into organic compounds with cysteine being the first product of the pathway and a donor of reduced sulfur for synthesis of other S-containing compounds. Cysteine is formed in a reaction between sulfide, derived from reduction of sulfite and an activated amino acid acceptor, O-acetylserine. Sulfide is thus an important intermediate in sulfur metabolism, but numerous other functions in plants has been revealed. Hydrogen sulfide can serve as an alternative source of sulfur for plants, which may be significant in anaerobic conditions of waterlogged soils. On the other hand, emissions of hydrogen sulfide have been detected from many plant species. Since the amount of H2S discharged correlated with sulfate supply to the plants, the emissions were considered a mechanism for dissipation of excess sulfur. Significant hydrogen sulfide emissions were also observed in plants infected with pathogens, particularly with fungi. H2S thus seems to be part of the widely discussed sulfur-induced-resistance/sulfur-enhanced-defense. Recently, however, more evidence has emerged for a role for H2S in regulation and signaling. Sulfide stabilizes the cysteine synthase complex, increasing so the synthesis of its acceptor O-acetylserine. H2S has been implicating in regulation of plant stress response, particularly draught stress. There are more and more examples of processes regulated by H2S in plants being discovered, and hydrogen sulfide is emerging as an important signaling molecule, similar to its role in the animal and human world. How similar the functions, and homeostasis of H2S are in these diverse organisms, however, remains to be elucidated

  8. Identification of small molecule compounds that inhibit the HIF-1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Sun Yi

    2009-12-01

    Full Text Available Abstract Background Hypoxia-inducible factor-1 (HIF-1 is the major hypoxia-regulated transcription factor that regulates cellular responses to low oxygen environments. HIF-1 is composed of two subunits: hypoxia-inducible HIF-1α and constitutively-expressed HIF-1β. During hypoxic conditions, HIF-1α heterodimerizes with HIF-1β and translocates to the nucleus where the HIF-1 complex binds to the hypoxia-response element (HRE and activates expression of target genes implicated in cell growth and survival. HIF-1α protein expression is elevated in many solid tumors, including those of the cervix and brain, where cells that are the greatest distance from blood vessels, and therefore the most hypoxic, express the highest levels of HIF-1α. Therapeutic blockade of the HIF-1 signaling pathway in cancer cells therefore provides an attractive strategy for development of anticancer drugs. To identify small molecule inhibitors of the HIF-1 pathway, we have developed a cell-based reporter gene assay and screened a large compound library by using a quantitative high-throughput screening (qHTS approach. Results The assay is based upon a β-lactamase reporter under the control of a HRE. We have screened approximate 73,000 compounds by qHTS, with each compound tested over a range of seven to fifteen concentrations. After qHTS we have rapidly identified three novel structural series of HIF-1 pathway Inhibitors. Selected compounds in these series were also confirmed as inhibitors in a HRE β-lactamase reporter gene assay induced by low oxygen and in a VEGF secretion assay. Three of the four selected compounds tested showed significant inhibition of hypoxia-induced HIF-1α accumulation by western blot analysis. Conclusion The use of β-lactamase reporter gene assays, in combination with qHTS, enabled the rapid identification and prioritization of inhibitors specific to the hypoxia induced signaling pathway.

  9. Nitrogen modulation of legume root architecture signalling pathways involves phytohormones and small regulatory molecules

    Directory of Open Access Journals (Sweden)

    Nadiatul Akmal Mohd-Radzman

    2013-10-01

    Full Text Available Nitrogen, particularly nitrate is an important yield determinant for crops. However, current agricultural practice with excessive fertilizer usage has detrimental effects on the environment. Therefore, legumes have been suggested as a sustainable alternative for replenishing soil nitrogen. Legumes can uniquely form nitrogen-fixing nodules through symbiotic interaction with specialized soil bacteria. Legumes possess a highly plastic root system which modulates its architecture according to the nitrogen availability in the soil. Understanding how legumes regulate root development in response to nitrogen availability is an important step to improving root architecture. The nitrogen-mediated root development pathway starts with sensing soil nitrogen level followed by subsequent signal transduction pathways involving phytohormones, microRNAs and regulatory peptides that collectively modulate the growth and shape of the root system. This review focuses on the current understanding of nitrogen-mediated legume root architecture including local and systemic regulations by different N-sources and the modulations by phytohormones and small regulatory molecules.

  10. Unfolding Role of a Danger Molecule Adenosine Signaling in Modulation of Microbial Infection and Host Cell Response

    Directory of Open Access Journals (Sweden)

    Jaden S. Lee

    2018-01-01

    Full Text Available Ectonucleotidases CD39 and CD73, specific nucleotide metabolizing enzymes located on the surface of the host, can convert a pro-inflammatory environment driven by a danger molecule extracellular-ATP to an adenosine-mediated anti-inflammatory milieu. Accordingly, CD39/CD73 signaling has been strongly implicated in modulating the intensity, duration, and composition of purinergic danger signals delivered to host. Recent studies have eluted potential roles for CD39 and CD73 in selective triggering of a variety of host immune cells and molecules in the presence of pathogenic microorganisms or microbial virulence molecules. Growing evidence also suggests that CD39 and CD73 present complimentary, but likely differential, actions against pathogens to shape the course and severity of microbial infection as well as the associated immune response. Similarly, adenosine receptors A2A and A2B have been proposed to be major immunomodulators of adenosine signaling during chronic inflammatory conditions induced by opportunistic pathogens, such as oral colonizer Porphyromonas gingivalis. Therefore, we here review the recent studies that demonstrate how complex network of molecules in the extracellular adenosine signaling machinery and their interactions can reshape immune responses and may also be targeted by opportunistic pathogens to establish successful colonization in human mucosal tissues and modulate the host immune response.

  11. Pseudomonas aeruginosa quorum-sensing signal molecules interfere with dendritic cell-induced T-cell proliferation

    DEFF Research Database (Denmark)

    Skindersø, Mette Elena; Zeuthen, Louise; Pedersen, Susanne Brix

    2009-01-01

    Pseudomonas aeruginosa releases a wide array of toxins and tissue-degrading enzymes. Production of these malicious virulence factors is controlled by interbacterial communication in a process known as quorum sensing. An increasing body of evidence reveals that the bacterial signal molecule N-(3-o...

  12. Serine/threonine phosphatase tapp2cs might be served as an early signal molecule for water stress in wheat

    International Nuclear Information System (INIS)

    Song, K. H.; Tian, W. L.; Hou, B. Z.; Guo, J. X.; Mei, X. R.; Li, Y. Z.

    2015-01-01

    Much progress has been made towards understanding the role of serine/threonine phosphatases type 2C (PP2Cs) in abscisic acid (ABA) signaling transduction. However, how the negative regulator, PP2Cs, responds to plant water loss remains unclear. Here, we used a series of relative soil moisture (RSM: 85 percentage (well watered), 65 percentage (moderate stress), 45 percentage (severe stress) potted winter wheat (Triticum aestivum L.) and the detached leaves to detect ABA levels and transcripts of PP2Cs, including PP2C40, PP2C45, PP2C59 and PP2C6 as well as the core downstream signals of ABA, including ABF, SnRK2.4 and SnRK2.5. The results showed that the continual loss of water led to a consistent increase in ABA levels, and that the mRNA expression levels of PP2Cs were dependent on plant water condition. PP2Cs expression could be induced by a slight loss of water, and inhibited under severe loss of water. These results were further confirmed by the transcripts of ABF, SnRK2.4 and SnRK2.5. Furthermore, in slight loss of water, 100 μM exogenous ABA could promote PP2Cs expression; in severe loss of water, it inhibited PP2Cs expression. In conclusion, ABA accumulation is controlled by water condition and the PP2C expression is dependent on plant water condition, suggesting that PP2Cs might be served as an early signal molecule for water stress in wheat. (author)

  13. Chromosomal Rainbows detect Oncogenic Rearrangements of Signaling Molecules in Thyroid Tumors

    Energy Technology Data Exchange (ETDEWEB)

    O' Brien, Benjamin; Jossart, Gregg H.; Ito, Yuko; Greulich-Bode, Karin M.; Weier, Jingly F.; Munne, Santiago; Clark, Orlo H.; Weier, Heinz-Ulrich G.

    2010-08-19

    Altered signal transduction can be considered a hallmark of many solid tumors. In thyroid cancers the receptor tyrosine kinase (rtk) genes NTRK1 (Online Mendelian Inheritance in Man = OMIM *191315, also known as 'TRKA'), RET ('Rearranged during Transfection protooncogene', OMIM *164761) and MET (OMIM *164860) have been reported as activated, rearranged or overexpressed. In many cases, a combination of cytogenetic and molecular techniques allows elucidation of cellular changes that initiate tumor development and progression. While the mechanisms leading to overexpression of the rtk MET gene remain largely unknown, a variety of chromosomal rearrangements of the RET or NTKR1 gene could be demonstrated in thyroid cancer. Abnormal expressions in these tumors seem to follow a similar pattern: the rearrangement translocates the 3'-end of the rtk gene including the entire catalytic domain to an expressed gene leading to a chimeric RNA and protein with kinase activity. Our research was prompted by an increasing number of reports describing translocations involving ret and previously unknown translocation partners. We developed a high resolution technique based on fluorescence in situ hybridization (FISH) to allow rapid screening for cytogenetic rearrangements which complements conventional chromosome banding analysis. Our technique applies simultaneous hybridization of numerous probes labeled with different reporter molecules which are distributed along the target chromosome allowing the detection of cytogenetic changes at near megabase-pair (Mbp) resolution. Here, we report our results using a probe set specific for human chromosome 10, which is altered in a significant portion of human thyroid cancers (TC's). While rendering accurate information about the cytogenetic location of rearranged elements, our multi-locus, multi-color analysis was developed primarily to overcome limitations of whole chromosome painting (WCP) and chromosome banding

  14. Adhesion molecules

    CERN Document Server

    Preedy, Victor R

    2016-01-01

    This book covers the structure and classification of adhesion molecules in relation to signaling pathways and gene expression. It discusses immunohistochemical localization, neutrophil migration, and junctional, functional, and inflammatory adhesion molecules in pathologies such as leukocyte decompression sickness and ischemia reperfusion injury. Highlighting the medical applications of current research, chapters cover diabetes, obesity, and metabolic syndrome; hypoxia; kidney disease; smoking, atrial fibrillation, and heart disease, the brain and dementia; and tumor proliferation. Finally, it looks at molecular imaging and bioinformatics, high-throughput technologies, and chemotherapy.

  15. The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression.

    Science.gov (United States)

    Patsoukis, Nikolaos; Bardhan, Kankana; Weaver, Jessica D; Sari, Duygu; Torres-Gomez, Alvaro; Li, Lequn; Strauss, Laura; Lafuente, Esther M; Boussiotis, Vassiliki A

    2017-08-22

    Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1-interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM-lamellipodin (MRL) class of adaptor molecules. Through its various domains, RIAM is a critical node of signal integration for activation of T cells, recruits monomeric and polymerized actin to drive actin remodeling and cytoskeletal reorganization, and promotes inside-out integrin signaling in T cells. As a regulator of inside-out integrin activation, RIAM affects multiple functions of innate and adaptive immunity. The effects of RIAM on cytoskeletal reorganization and integrin activation have implications in cell migration and trafficking of cancer cells. We provide an overview of the structure and interactions of RIAM, and we discuss the implications of RIAM functions in innate and adaptive immunity and cancer. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  16. Dopamine signaling in reward-related behaviors.

    Science.gov (United States)

    Baik, Ja-Hyun

    2013-01-01

    Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  17. Dopamine Signaling in reward-related behaviors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun eBaik

    2013-10-01

    Full Text Available Dopamine (DA regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  18. Task-related signal decrease on functional magnetic resonance imaging

    International Nuclear Information System (INIS)

    Hara, Yoshie; Nakamura, Mitsugu; Tamaki, Norihiko; Tamura, Shogo; Kitamura, Junji

    2001-01-01

    An atypical pattern of signal change was identified on functional magnetic resonance (fMR) imaging in pathologic patients. Three normal volunteers and 34 patients with pathologic lesions near the primary motor cortex underwent fMR imaging with echo-planar imaging while performing a hand motor task. Signal intensities were evaluated with the z-score method, and the time course and changes of the signal intensity were calculated. Nine of the 34 patients with pathologic lesions displayed a significant task-related signal reduction in motor-related areas. They also presented a conventional task-related signal increase in other motor-related areas. The time courses of the increase and decrease were the inverse of each other. There was no significant difference between rates of signal increase and decrease. Our findings suggest that this atypical signal decrease is clinically significant, and that impaired vascular reactivity and altered oxygen metabolism could contribute to the task-related signal reduction. Brain areas showing such task-related signal decrease should be preserved at surgery. (author)

  19. MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors

    DEFF Research Database (Denmark)

    Odum, Niels; Kanner, S B; Ledbetter, J A

    1993-01-01

    MHC class II-positive T cells are found in tissues involved in autoimmune and infectious disorders. Because stimulation of class II molecules by mAb or bacterial superantigens induces protein tyrosine phosphorylation through activation of PTK3 in T cells, we hypothesized that class II signals play...... tyrosine phosphorylation of specific substrates including PLC-gamma 1. Combined stimulation of IL-2R and class II molecules had an additive effect on tyrosine phosphorylation. Pretreatment of T cells with a protein tyrosine kinase inhibitor, herbimycin A, inhibited IL-2 and class II-induced proliferation...... a regulatory function in T cell activation. Here, we show that cross-linking HLA-DR and -DP but not -DQ molecules by immobilized mAb enhanced proliferative T cell responses to IL-2. In contrast, class II stimulation had no effect on IL-4-induced proliferation. The costimulatory effect was most pronounced...

  20. High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling.

    Science.gov (United States)

    Burns, Michael C; Howes, Jennifer E; Sun, Qi; Little, Andrew J; Camper, DeMarco V; Abbott, Jason R; Phan, Jason; Lee, Taekyu; Waterson, Alex G; Rossanese, Olivia W; Fesik, Stephen W

    2018-05-01

    K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS). We have previously reported on the discovery of small molecules that bind to SOS1, activate SOS-mediated nucleotide exchange on RAS, and paradoxically inhibit ERK phosphorylation (Burns et al., PNAS, 2014). Here, we describe the discovery of additional, structurally diverse small molecules that also bind to SOS1 in the same pocket and elicit similar biological effects. We tested >160,000 compounds in a fluorescence-based assay to assess their effects on SOS-mediated nucleotide exchange. X-Ray structures revealed that these small molecules bind to the CDC25 domain of SOS1. Compounds that elicited high levels of nucleotide exchange activity in vitro increased RAS-GTP levels in cells, and inhibited phospho ERK levels at higher treatment concentrations. The identification of structurally diverse SOS1 binding ligands may assist in the discovery of new molecules designed to target RAS-driven tumors. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Degradation of Bacterial Quorum Sensing Signaling Molecules by the Microscopic Yeast Trichosporon loubieri Isolated from Tropical Wetland Waters

    Directory of Open Access Journals (Sweden)

    Cheng-Siang Wong

    2013-09-01

    Full Text Available Proteobacteria produce N-acylhomoserine lactones as signaling molecules, which will bind to their cognate receptor and activate quorum sensing-mediated phenotypes in a population-dependent manner. Although quorum sensing signaling molecules can be degraded by bacteria or fungi, there is no reported work on the degradation of such molecules by basidiomycetous yeast. By using a minimal growth medium containing N-3-oxohexanoylhomoserine lactone as the sole source of carbon, a wetland water sample from Malaysia was enriched for microbial strains that can degrade N-acylhomoserine lactones, and consequently, a basidiomycetous yeast strain WW1C was isolated. Morphological phenotype and molecular analyses confirmed that WW1C was a strain of Trichosporon loubieri. We showed that WW1C degraded AHLs with N-acyl side chains ranging from 4 to 10 carbons in length, with or without oxo group substitutions at the C3 position. Re-lactonisation bioassays revealed that WW1C degraded AHLs via a lactonase activity. To the best of our knowledge, this is the first report of degradation of N-acyl-homoserine lactones and utilization of N-3-oxohexanoylhomoserine as carbon and nitrogen source for growth by basidiomycetous yeast from tropical wetland water; and the degradation of bacterial quorum sensing molecules by an eukaryotic yeast.

  2. Correlating the vibrational spectra of structurally related molecules: A spectroscopic measure of similarity.

    Science.gov (United States)

    Tao, Yunwen; Zou, Wenli; Cremer, Dieter; Kraka, Elfi

    2018-03-05

    Using catastrophe theory and the concept of a mutation path, an algorithm is developed that leads to the direct correlation of the normal vibrational modes of two structurally related molecules. The mutation path is defined by weighted incremental changes in mass and geometry of the molecules in question, which are successively applied to mutate a molecule into a structurally related molecule and thus continuously converting their normal vibrational spectra from one into the other. Correlation diagrams are generated that accurately relate the normal vibrational modes to each other by utilizing mode-mode overlap criteria and resolving allowed and avoided crossings of vibrational eigenstates. The limitations of normal mode correlation, however, foster the correlation of local vibrational modes, which offer a novel vibrational measure of similarity. It will be shown how this will open new avenues for chemical studies. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling.

    Science.gov (United States)

    Wang, Hongzhong; Zou, Xinle; Wei, Zhuang; Wu, Yuan; Li, Rongxia; Zeng, Rong; Chen, Zhengjun; Liao, Kan

    2015-01-01

    The primary cilium is composed of an axoneme that protrudes from the cell surface, a basal body beneath the membrane and a transition neck in between. It is a sensory organelle on the plasma membrane, involved in mediating extracellular signals. In the transition neck region of the cilium, the microtubules change from triplet to doublet microtubules. This region also contains the transition fibres that crosslink the axoneme with the membrane and the necklace proteins that regulate molecules being transported into and out of the cilium. In this protein-enriched, complex area it is important to maintain the correct assembly of all of these proteins. Here, through immunofluorescent staining and protein isolation, we identify the molecular chaperone Hsp90α clustered at the periciliary base. At the transition neck region, phosphorylated Hsp90α forms a stable ring around the axoneme. Heat shock treatment causes Hsp90α to dissipate and induces resorption of cilia. We further identify that Hsp90α at the transition neck region represents a signalling platform on which IRS-1 interacts with intracellular downstream signalling molecules involved in IGF-1 receptor signalling. © 2015. Published by The Company of Biologists Ltd.

  4. From signal to form: Nod factor as a morhogenetic signal molecule to induce symbiotic responses in legume root hairs

    NARCIS (Netherlands)

    Esseling, J.J.

    2004-01-01

    In this thesis, research is presented which contributes to a better understanding of nod factor (NF) induced signalling in Iegume root hairs, leading to a successful symbiosis. We mainly use root hairs of the model Iegume Medicago truncatula ('barrel medic') as an experimental system. In the

  5. Quorum sensing signaling molecules produced by reference and emerging soft-rot bacteria (Dickeya and Pectobacterium spp..

    Directory of Open Access Journals (Sweden)

    Alexandre Crépin

    Full Text Available Several small diffusible molecules are involved in bacterial quorum sensing and virulence. The production of autoinducers-1 and -2, quinolone, indole and γ-amino butyrate signaling molecules was investigated in a set of soft-rot bacteria belonging to six Dickeya or Pectobacterium species including recent or emerging potato isolates.Using bacterial biosensors, immunoassay, and chromatographic analysis, we showed that soft-rot bacteria have the common ability to produce transiently during their exponential phase of growth the N-3-oxo-hexanoyl- or the N-3-oxo-octanoyl-l-homoserine lactones and a molecule of the autoinducer-2 family. Dickeya spp. produced in addition the indole-3-acetic acid in tryptophan-rich conditions. All these signaling molecules have been identified for the first time in the novel Dickeya solani species. In contrast, quinolone and γ-amino butyrate signals were not identified and the corresponding synthases are not present in the available genomes of soft-rot bacteria. To determine if the variations of signal production according to growth phase could result from expression modifications of the corresponding synthase gene, the respective mRNA levels were estimated by reverse transcriptase-PCR. While the N-acyl-homoserine lactone production is systematically correlated to the synthase expression, that of the autoinducer-2 follows the expression of an enzyme upstream in the activated methyl cycle and providing its precursor, rather than the expression of its own synthase.Despite sharing the S-adenosylmethionine precursor, no strong link was detected between the production kinetics or metabolic pathways of autoinducers-1 and -2. In contrast, the signaling pathway of autoinducer-2 seems to be switched off by the indole-3-acetic acid pathway under tryptophan control. It therefore appears that the two genera of soft-rot bacteria have similarities but also differences in the mechanisms of communication via the diffusible molecules

  6. Quorum Sensing Signaling Molecules Produced by Reference and Emerging Soft-Rot Bacteria (Dickeya and Pectobacterium spp.)

    Science.gov (United States)

    Crépin, Alexandre; Barbey, Corinne; Beury-Cirou, Amélie; Hélias, Valérie; Taupin, Laure; Reverchon, Sylvie; Nasser, William; Faure, Denis; Dufour, Alain; Orange, Nicole; Feuilloley, Marc; Heurlier, Karin; Burini, Jean-François; Latour, Xavier

    2012-01-01

    Background Several small diffusible molecules are involved in bacterial quorum sensing and virulence. The production of autoinducers-1 and -2, quinolone, indole and γ-amino butyrate signaling molecules was investigated in a set of soft-rot bacteria belonging to six Dickeya or Pectobacterium species including recent or emerging potato isolates. Methodology/Principal Findings Using bacterial biosensors, immunoassay, and chromatographic analysis, we showed that soft-rot bacteria have the common ability to produce transiently during their exponential phase of growth the N-3-oxo-hexanoyl- or the N-3-oxo-octanoyl-l-homoserine lactones and a molecule of the autoinducer-2 family. Dickeya spp. produced in addition the indole-3-acetic acid in tryptophan-rich conditions. All these signaling molecules have been identified for the first time in the novel Dickeya solani species. In contrast, quinolone and γ-amino butyrate signals were not identified and the corresponding synthases are not present in the available genomes of soft-rot bacteria. To determine if the variations of signal production according to growth phase could result from expression modifications of the corresponding synthase gene, the respective mRNA levels were estimated by reverse transcriptase-PCR. While the N-acyl-homoserine lactone production is systematically correlated to the synthase expression, that of the autoinducer-2 follows the expression of an enzyme upstream in the activated methyl cycle and providing its precursor, rather than the expression of its own synthase. Conclusions/Significance Despite sharing the S-adenosylmethionine precursor, no strong link was detected between the production kinetics or metabolic pathways of autoinducers-1 and -2. In contrast, the signaling pathway of autoinducer-2 seems to be switched off by the indole-3-acetic acid pathway under tryptophan control. It therefore appears that the two genera of soft-rot bacteria have similarities but also differences in the

  7. Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.

    Science.gov (United States)

    Nishimura, R; Li, W; Kashishian, A; Mondino, A; Zhou, M; Cooper, J; Schlessinger, J

    1993-11-01

    Autophosphorylation sites of growth factor receptors with tyrosine kinase activity function as specific binding sites for Src homology 2 (SH2) domains of signaling molecules. This interaction appears to be a crucial step in a mechanism by which receptor tyrosine kinases relay signals to downstream signaling pathways. Nck is a widely expressed protein consisting exclusively of SH2 and SH3 domains, the overexpression of which causes cell transformation. It has been shown that various growth factors stimulate the phosphorylation of Nck and its association with autophosphorylated growth factor receptors. A panel of platelet-derived growth factor (PDGF) receptor mutations at tyrosine residues has been used to identify the Nck binding site. Here we show that mutation at Tyr-751 of the PDGF beta-receptor eliminates Nck binding both in vitro and in living cells. Moreover, the Y751F PDGF receptor mutant failed to mediate PDGF-stimulated phosphorylation of Nck in intact cells. A phosphorylated Tyr-751 is also required for binding of phosphatidylinositol-3 kinase to the PDGF receptor. Hence, the SH2 domains of p85 and Nck share a binding site in the PDGF receptor. Competition experiments with different phosphopeptides derived from the PDGF receptor suggest that binding of Nck and p85 is influenced by different residues around Tyr-751. Thus, a single tyrosine autophosphorylation site is able to link the PDGF receptor to two distinct SH2 domain-containing signaling molecules.

  8. Time signal filtering by relative neighborhood graph localized linear approximation

    DEFF Research Database (Denmark)

    Sørensen, John Aasted

    1994-01-01

    A time signal filtering algorithm based on the relative neighborhood graph (RNG) used for localization of linear filters is proposed. The filter is constructed from a training signal during two stages. During the first stage an RNG is constructed. During the second stage, localized linear filters...

  9. Role of Ethylene and Its Cross Talk with Other Signaling Molecules in Plant Responses to Heavy Metal Stress1

    Science.gov (United States)

    Thao, Nguyen Phuong; Khan, M. Iqbal R.; Thu, Nguyen Binh Anh; Hoang, Xuan Lan Thi; Asgher, Mohd; Khan, Nafees A.; Tran, Lam-Son Phan

    2015-01-01

    Excessive heavy metals (HMs) in agricultural lands cause toxicities to plants, resulting in declines in crop productivity. Recent advances in ethylene biology research have established that ethylene is not only responsible for many important physiological activities in plants but also plays a pivotal role in HM stress tolerance. The manipulation of ethylene in plants to cope with HM stress through various approaches targeting either ethylene biosynthesis or the ethylene signaling pathway has brought promising outcomes. This review covers ethylene production and signal transduction in plant responses to HM stress, cross talk between ethylene and other signaling molecules under adverse HM stress conditions, and approaches to modify ethylene action to improve HM tolerance. From our current understanding about ethylene and its regulatory activities, it is believed that the optimization of endogenous ethylene levels in plants under HM stress would pave the way for developing transgenic crops with improved HM tolerance. PMID:26246451

  10. Role of Mitochondrial Reactive Oxygen Species in the Activation of Cellular Signals, Molecules, and Function

    DEFF Research Database (Denmark)

    Indo, Hiroko P.; Hawkins, Clare L; Nakanishi, Ikuo

    2017-01-01

    -κB) and GATA signaling pathways. We have also reviewed the effects of ROS on the activation of MMP and HIF. There is significant evidence to support the hypothesis that mitochondrial superoxide can initiate signaling pathways following transport into the cytosol. In this study, we provide evidence of TATA...

  11. Inhibition of receptor tyrosine kinase signalling by small molecule agonist of T-cell protein tyrosine phosphatase

    International Nuclear Information System (INIS)

    Mattila, Elina; Marttila, Heidi; Sahlberg, Niko; Kohonen, Pekka; Tähtinen, Siri; Halonen, Pasi; Perälä, Merja; Ivaska, Johanna

    2010-01-01

    T-cell protein tyrosine phosphatase (TCPTP/TC45) is a ubiquitously expressed intra-cellular non-receptor protein tyrosine phosphatase involved in the negative regulation of several cancer relevant cellular signalling pathways. We have previously shown that interaction between the α-cytoplasmic tail of α1β1 integrin and TCPTP activates TCPTP by disrupting an inhibitory intra-molecular bond in TCPTP. Thus, inhibition of the regulatory interaction in TCPTP is a desirable strategy for TCPTP activation and attenuation of oncogenic RTK signalling. However, this is challenging with low molecular weight compounds. We developed a high-throughput compatible assay to analyse activity of recombinant TCPTP in vitro. Using this assay we have screened 64280 small molecules to identify novel agonists for TCPTP. Dose-dependent response to TCPTP agonist was performed using the in vitro assay. Inhibition effects and specificity of TCPTP agonists were evaluated using TCPTP expressing and null mouse embryonic fibroblasts. Western blot analysis was used to evaluate attenuation of PDGFRβ and EGFR phosphorylation. Inhibition of VEGF signalling was analysed with VEGF-induced endothelial cell sprouting assays. From the screen we identified six TCPTP agonists. Two compounds competed with α1-cytoplasmic domain for binding to TCPTP, suggesting that they activate TCPTP similar to α1-cyt by disrupting the intra-molecular bond in TCPTP. Importantly, one of the compounds (spermidine) displayed specificity towards TCPTP in cells, since TCPTP -/- cells were 43-fold more resistant to the compound than TCPTP expressing cells. This compound attenuates PDGFRβ and VEGFR2 signalling in cells in a TCPTP-dependent manner and functions as a negative regulator of EGFR phosphorylation in cancer cells. In this study we showed that small molecules mimicking TCPTP-α1 interaction can be used as TCPTP agonists. These data provide the first proof-of-concept description of the use of high-throughput screening

  12. Dissecting Repulsive Guidance Molecule/Neogenin function and signaling during neural development

    NARCIS (Netherlands)

    van den Heuvel, D.M.A.

    2013-01-01

    During neural development a series of precisely ordered cellular processes acts to establish a functional brain comprising millions of neurons and many more neuronal connections. Neogenin and its repulsive guidance molecule (RGM) ligands contribute to neuronal network formation by inducing axon

  13. Enhanced NMR signal detection of imino protons in RNA molecules containing 3' dangling nucleotides

    International Nuclear Information System (INIS)

    Amborski, Andrew N.; Johnson, Philip E.

    2008-01-01

    We present a method for improving the quality of nuclear magnetic resonance (NMR) spectra involving exchangeable protons near the base of the stem of RNA hairpin molecules. NMR spectra of five different RNA hairpins were compared. These hairpins consisted of a native RNA structure and four molecules each having different unpaired, or dangling, nucleotides at the 3' end. NMR experiments were acquired in water for each construct and the quality of the imino proton spectral regions were examined. The imino resonances near the base of the stem of the wild type RNA structure were not observed due to breathing motions. However, a significant increase in spectral quality for molecules with dangling 3' adenosine or guanosine nucleotides was observed, with imino protons detected in these constructs that were not observed in the wild type construct. A modest improvement in spectral quality was seen for the construct with a 3' unpaired uridine, whereas no significant improvement was observed for a 3' unpaired cytidine. This improvement in NMR spectral quality mirrors the increased thermodynamic stability observed for 3' unpaired nucleotides which is dependant on the stacking interactions of these nucleotides against the base of the stem. The use of a dangling 3' adenosine nucleotide represents an easy method to significantly improve the quality of NMR spectra of RNA molecules

  14. The mouse tumor cell lines EL4 and RMA display mosaic expression of NK-related and certain other surface molecules and appear to have a common origin.

    Science.gov (United States)

    Gays, F; Unnikrishnan, M; Shrestha, S; Fraser, K P; Brown, A R; Tristram, C M; Chrzanowska-Lightowlers, Z M; Brooks, C G

    2000-05-15

    As a potential means for facilitating studies of NK cell-related molecules, we examined the expression of these molecules on a range of mouse tumor cell lines. Of the lines we initially examined, only EL4 and RMA expressed such molecules, both lines expressing several members of the Ly49 and NKRP1 families. Unexpectedly, several of the NK-related molecules, together with certain other molecules including CD2, CD3, CD4, CD32, and CD44, were often expressed in a mosaic manner, even on freshly derived clones, indicating frequent switching in expression. In each case examined, switching was controlled at the mRNA level, with expression of CD3zeta determining expression of the entire CD3-TCR complex. Each of the variable molecules was expressed independently, with the exception that CD3 was restricted to cells that also expressed CD2. Treatment with drugs that affect DNA methylation and histone acetylation could augment the expression of at least some of the variable molecules. The striking phenotypic similarity between EL4 and RMA led us to examine the state of their TCRbeta genes. Both lines had identical rearrangements on both chromosomes, indicating that RMA is in fact a subline of EL4. Overall, these findings suggest that EL4 is an NK-T cell tumor that may have retained a genetic mechanism that permits the variable expression of a restricted group of molecules involved in recognition and signaling.

  15. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

    Science.gov (United States)

    Mistry, Pragnesh; Laird, Michelle H. W.; Schwarz, Ryan S.; Greene, Shannon; Dyson, Tristan; Snyder, Greg A.; Xiao, Tsan Sam; Chauhan, Jay; Fletcher, Steven; Toshchakov, Vladimir Y.; MacKerell, Alexander D.; Vogel, Stefanie N.

    2015-01-01

    Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein–protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. PMID:25870276

  16. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity

    Institute of Scientific and Technical Information of China (English)

    Hui Wang; Rui-Yun Peng

    2016-01-01

    With key roles in essential brain functions ranging from the long-term potentiation (LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor (NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca2+,postsynaptic density 95 (PSD-95),calcium/calmodulin-dependent protein kinase Ⅱ (CaMK Ⅱ),protein kinase A (PKA),mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.

  17. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

    Directory of Open Access Journals (Sweden)

    Takanobu Nagata

    Full Text Available Myocardial ischemia reperfusion injury (IRI adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS-3, an intrinsic negative feedback regulator of the Janus kinase (JAK-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO. The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1 was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

  18. Lactate in the brain: from metabolic end-product to signalling molecule

    KAUST Repository

    Magistretti, Pierre J.

    2018-03-08

    Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the \\'homeostatic tone\\' of the nervous system.

  19. Deletion of the signalling molecule synthase ScbA has pleiotropic effects on secondary metabolite biosynthesis, morphological differentiation and primary metabolism in Streptomyces coelicolor A3(2)

    NARCIS (Netherlands)

    D'Alia, Davide; Eggle, D.; Nieselt, K.; Hu, W.-S.; Breitling, R.; Takano, E.

    2011-01-01

    Streptomycetes have high biotechnological relevance as producers of diverse metabolites widely used in medical and agricultural applications. The biosynthesis of these metabolites is controlled by signalling molecules, gamma-butyrolactones, that act as bacterial hormones. In Streptomyces coelicolor,

  20. High throughput screening for small molecule enhancers of the interferon signaling pathway to drive next-generation antiviral drug discovery.

    Directory of Open Access Journals (Sweden)

    Dhara A Patel

    Full Text Available Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE activity in a fully automated and robust format (Z'>0.7. Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity was manifest by other members of this drug class and was independent of cytotoxic or topoisomerase inhibitory effects as well as endogenous IFN signaling or production. We also observed that this compound conferred a consequent increase in IFN-stimulated gene (ISG expression and a significant antiviral effect using a similar dose-range in a cell-culture system inoculated with encephalomyocarditis virus (EMCV. The antiviral effect was also found at compound concentrations below the ones observed for cytotoxicity. Taken together, our results provide proof of concept for using activators of components of the IFN signaling pathway to improve IFN efficacy and antiviral immune defense as well as a validated HTS approach to identify

  1. Isolation and molecular characterization of biofouling bacteria and profiling of quorum sensing signal molecules from membrane bioreactor activated sludge.

    Science.gov (United States)

    Lade, Harshad; Paul, Diby; Kweon, Ji Hyang

    2014-02-04

    The formation of biofilm in a membrane bioreactor depends on the production of various signaling molecules like N-acyl homoserine lactones (AHLs). In the present study, a total of 200 bacterial strains were isolated from membrane bioreactor activated sludge and screened for AHLs production using two biosensor systems, Chromobacterium violaceum CV026 and Agrobacterium tumefaciens A136. A correlation between AHLs production and biofilm formation has been made among screened AHLs producing strains. The 16S rRNA gene sequence analysis revealed the dominance of Aeromonas and Enterobacter sp. in AHLs production; however few a species of Serratia, Leclercia, Pseudomonas, Klebsiella, Raoultella and Citrobacter were also identified. The chromatographic characterization of sludge extract showed the presence of a broad range of quorum sensing signal molecules. Further identification of sludge AHLs by thin layer chromatography bioassay and high performance liquid chromatography confirms the presence of C4-HSL, C6-HSL, C8-HSL, 3-oxo-C8-HSL, C10-HSL, C12-HSL, 3-oxo-C12-HSL and C14-HSL. The occurrence of AHLs in sludge extract and dominance of Aeromonas and Enterobacter sp. in activated sludge suggests the key role of these bacterial strains in AHLs production and thereby membrane fouling.

  2. Differential Signaling and Sugar Exchanges in Response to Avirulent Pathogen- and Symbiont-Derived Molecules in Tobacco Cells

    Directory of Open Access Journals (Sweden)

    Carole Pfister

    2017-11-01

    Full Text Available Plants interact with microbes whose ultimate aim is to exploit plant carbohydrates for their reproduction. Plant–microbe interactions (PMIs are classified according to the nature of their trophic exchanges: while mutualistic microbes trade nutrients with plants, pathogens unilaterally divert carbohydrates. The early responses following microbe recognition and the subsequent control of plant sugar distribution are still poorly understood. To further decipher PMI functionality, we used tobacco cells treated with microbial molecules mimicking pathogenic or mutualistic PMIs, namely cryptogein, a defense elicitor, and chitotetrasaccharide (CO4, which is secreted by mycorrhizal fungi. CO4 was perceived by tobacco cells and triggered widespread transient signaling components such as a sharp cytosolic Ca2+ elevation, NtrbohD-dependent H2O2 production, and MAP kinase activation. These CO4-induced events differed from those induced by cryptogein, i.e., sustained events leading to cell death. Furthermore, cryptogein treatment inhibited glucose and sucrose uptake but not fructose uptake, and promoted the expression of NtSUT and NtSWEET sugar transporters, whereas CO4 had no effect on sugar uptake and only a slight effect on NtSWEET2B expression. Our results suggest that microbial molecules induce different signaling responses that reflect microbial lifestyle and the subsequent outcome of the interaction.

  3. Isolation and Molecular Characterization of Biofouling Bacteria and Profiling of Quorum Sensing Signal Molecules from Membrane Bioreactor Activated Sludge

    Directory of Open Access Journals (Sweden)

    Harshad Lade

    2014-02-01

    Full Text Available The formation of biofilm in a membrane bioreactor depends on the production of various signaling molecules like N-acyl homoserine lactones (AHLs. In the present study, a total of 200 bacterial strains were isolated from membrane bioreactor activated sludge and screened for AHLs production using two biosensor systems, Chromobacterium violaceum CV026 and Agrobacterium tumefaciens A136. A correlation between AHLs production and biofilm formation has been made among screened AHLs producing strains. The 16S rRNA gene sequence analysis revealed the dominance of Aeromonas and Enterobacter sp. in AHLs production; however few a species of Serratia, Leclercia, Pseudomonas, Klebsiella, Raoultella and Citrobacter were also identified. The chromatographic characterization of sludge extract showed the presence of a broad range of quorum sensing signal molecules. Further identification of sludge AHLs by thin layer chromatography bioassay and high performance liquid chromatography confirms the presence of C4-HSL, C6-HSL, C8-HSL, 3-oxo-C8-HSL, C10-HSL, C12-HSL, 3-oxo-C12-HSL and C14-HSL. The occurrence of AHLs in sludge extract and dominance of Aeromonas and Enterobacter sp. in activated sludge suggests the key role of these bacterial strains in AHLs production and thereby membrane fouling.

  4. Quorum sensing signal molecules (acylated homoserine lactones) in Gram-negative fish pathogenic bacteria

    DEFF Research Database (Denmark)

    Bruhn, Jesper Bartholin; Dalsgaard, Inger; Nielsen, K.F.

    2005-01-01

    The aim of the present study was to investigate the production of quorum sensing signals (specifically acylated homoserine lactones, AHLs) among a selection of strains of Gram-negative fish bacterial pathogens. These signals are involved in the regulation of virulence factors in some human...... salmonicida and Vibrio splendidus were also positive. Aeromonas species produced N-butanoyl homoserine lactone (BHL) and N-hexanoyl homoserine lactone (HHL) and 1 additional product, whereas N-3-oxo-hexanoyl homoserine lactone (OHHL) and HHL were detected in Vibrio salmonicida. N-3-oxo-octanoyl homoserine...... lactone (OOHL) and N-3-octanoyl homoserine lactone (OHL) were detected in Y. ruckeii. AHLs were not detected from strains of Photobacterium damselae, Flavobacterium psychrophilum or Moritella viscosa. AHLs were extracted from fish infected with Y. ruckeri but not from fish infected with A. salmonicida...

  5. Analysis of rotation-vibration relative equilibria on the example of a tetrahedral four atom molecule

    NARCIS (Netherlands)

    Efstathiou, K; Sadovskii, DA; Zhilinskii, BI

    2004-01-01

    We study relative equilibria ( RE) of a nonrigid molecule, which vibrates about a well-defined equilibrium configuration and rotates as a whole. Our analysis unifies the theory of rotational and vibrational RE. We rely on the detailed study of the symmetry group action on the initial and reduced

  6. Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents

    Science.gov (United States)

    Guo, Min; Gamby, Sonja; Zheng, Yue; Sintim, Herman O.

    2013-01-01

    Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules. PMID:23994835

  7. The Relation between Structure and Quantum Interference in Single Molecule Junctions

    DEFF Research Database (Denmark)

    Markussen, Troels; Stadler, Robert; Thygesen, Kristian Sommer

    2010-01-01

    Quantum interference (QI) of electron pathways has recently attracted increased interest as an enabling tool for single-molecule electronic devices. Although various molecular systems have been shown to exhibit QI effects and a number of methods have been proposed for its analysis, simple...... guidelines linking the molecular structure to QI effects in the phase-coherent transport regime have until now been lacking. In the present work we demonstrate that QI in aromatic molecules is intimately related to the topology of the molecule’s π system and establish a simple graphical scheme to predict...

  8. Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119

    DEFF Research Database (Denmark)

    Hassing, Helle A; Fares, Suzan; Larsen, Olav

    2016-01-01

    for 2h with the 2-MAG-lipase inhibitor JZL84 doubled the constitutive activity, indicating that endogenous lipids contribute to the apparent constitutive activity. Finally, besides being an agonist, AR231453 acted as a positive allosteric modulator of OEA and increased its potency by 54-fold at 100nM AR......231453. Our studies uncovering broad and biased signaling, masked constitutive activity by endogenous MAGs, and ago-allosteric properties of synthetic ligands may explain why many GPR119 drug-discovery programs have failed so far....

  9. Enhancement of single-molecule fluorescence signals by colloidal silver nanoparticles in studies of protein translation.

    Science.gov (United States)

    Bharill, Shashank; Chen, Chunlai; Stevens, Benjamin; Kaur, Jaskiran; Smilansky, Zeev; Mandecki, Wlodek; Gryczynski, Ignacy; Gryczynski, Zygmunt; Cooperman, Barry S; Goldman, Yale E

    2011-01-25

    Metal-enhanced fluorescence (MEF) increased total photon emission of Cy3- and Cy5-labeled ribosomal initiation complexes near 50 nm silver particles 4- and 5.5-fold, respectively. Fluorescence intensity fluctuations above shot noise, at 0.1-5 Hz, were greater on silver particles. Overall signal-to-noise ratio was similar or slightly improved near the particles. Proximity to silver particles did not compromise ribosome function, as measured by codon-dependent binding of fluorescent tRNA, dynamics of fluorescence resonance energy transfer between adjacent tRNAs in the ribosome, and tRNA translocation induced by elongation factor G.

  10. Enhancement of Single Molecule Fluorescence Signals by Colloidal Silver Nanoparticles in Studies of Protein Translation

    Science.gov (United States)

    Bharill, Shashank; Chen, Chunlai; Stevens, Benjamin; Kaur, Jaskiran; Smilansky, Zeev; Mandecki, Wlodek; Gryczynski, Ignacy; Gryczynski, Zygmunt; Cooperman, Barry S.; Goldman, Yale E.

    2011-01-01

    Metal enhanced fluorescence (MEF) increased total photon emission of Cy3- and Cy5-labeled ribosomal initiation complexes near 50 nm silver particles 4- and 5.5-fold respectively. Fluorescence intensity fluctuations above shot noise, at 0.1 – 5 Hz, were greater on silver particles. Overall signal to noise ratio was similar or slightly improved near the particles. Proximity to silver particles did not compromise ribosome function, as measured by codon-dependent binding of fluorescent tRNA, dynamics of fluorescence resonance energy transfer between adjacent tRNAs in the ribosome, and tRNA translocation induced by elongation factor G. PMID:21158483

  11. The Therapeutic Effect of the Antitumor Drug 11 Beta and Related Molecules on Polycystic Kidney Disease

    Science.gov (United States)

    2017-10-01

    models (Somlo, Yale). Preparation work to assemble a collection of probes specific for oxidative stress genes and other PKD specific genes (as part... Worked : 6 Contribution to Project: Performance of experiments including those related to mitochondrial biology in vivo and unfolded protein...1 AWARD NUMBER: W81XWH-15-1-0364 TITLE: THE THERAPEUTIC EFFECT OF THE ANTITUMOR DRUG 11 BETA AND RELATED MOLECULES ON POLYYSTIC KIDNEY DISEASE

  12. CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Deaglio, Silvia; Capobianco, Andrea; Bergui, Luciana; Dürig, Jan; Morabito, Fortunato; Dührsen, Ulrich; Malavasi, Fabio

    2003-09-15

    The prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by Ca2+ fluxes and by a markedly increased proliferation. The unsuitability of CD38 to perform as a receptor is obviated through close interaction with the B-cell-receptor (BCR) complex and CD19. On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein. Finally, CD38 signaling in IL-2-treated B-CLL cells prolonged survival and induced the appearance of plasmablasts, providing a pathogenetic hypothesis for the occurrence of Richter syndrome.

  13. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways.

    Directory of Open Access Journals (Sweden)

    John Midkiff

    Full Text Available The ability of the pathogenic yeast Candida albicans to interconvert between budded and hyphal growth states, herein termed the budded-to-hyphal transition (BHT, is important for C. albicans development and virulence. The BHT is under the control of multiple cell signaling pathways that respond to external stimuli, including nutrient availability, high temperature, and pH. Previous studies identified 21 small molecules that could inhibit the C. albicans BHT in response to carbon limitation in Spider media. However, the studies herein show that the BHT inhibitors had varying efficacies in other hyphal-inducing media, reflecting their varying abilities to block signaling pathways associated with the different media. Chemical epistasis analyses suggest that most, but not all, of the BHT inhibitors were acting through either the Efg1 or Cph1 signaling pathways. Notably, the BHT inhibitor clozapine, a FDA-approved drug used to treat atypical schizophrenia by inhibiting G-protein-coupled dopamine receptors in the brain, and several of its functional analogs were shown to act at the level of the Gpr1 G-protein-coupled receptor. These studies are the first step in determining the target and mechanism of action of these BHT inhibitors, which may have therapeutic anti-fungal utility in the future.

  14. Single-molecule tracking of small GTPase Rac1 uncovers spatial regulation of membrane translocation and mechanism for polarized signaling

    Science.gov (United States)

    Das, Sulagna; Yin, Taofei; Yang, Qingfen; Zhang, Jingqiao; Wu, Yi I.; Yu, Ji

    2015-01-01

    Polarized Rac1 signaling is a hallmark of many cellular functions, including cell adhesion, motility, and cell division. The two steps of Rac1 activation are its translocation to the plasma membrane and the exchange of nucleotide from GDP to GTP. It is, however, unclear whether these two processes are regulated independent of each other and what their respective roles are in polarization of Rac1 signaling. We designed a single-particle tracking (SPT) method to quantitatively analyze the kinetics of Rac1 membrane translocation in living cells. We found that the rate of Rac1 translocation was significantly elevated in protrusions during cell spreading on collagen. Furthermore, combining FRET sensor imaging with SPT measurements in the same cell, the recruitment of Rac1 was found to be polarized to an extent similar to that of the nucleotide exchange process. Statistical analysis of single-molecule trajectories and optogenetic manipulation of membrane lipids revealed that Rac1 membrane translocation precedes nucleotide exchange, and is governed primarily by interactions with phospholipids, particularly PI(3,4,5)P3, instead of protein factors. Overall, the study highlights the significance of membrane translocation in spatial Rac1 signaling, which is in addition to the traditional view focusing primarily on GEF distribution and exchange reaction. PMID:25561548

  15. Building interpersonal trust within organizations: A relational signaling approach

    NARCIS (Netherlands)

    Six, F.E.

    2007-01-01

    This article develops the foundations for a theory of interpersonal trust-building based on relational signalling theory (RST). RST is based on the assumptions that rationality is bounded through framing, that preferences are partially determined by altruism (through a distinction between foreground

  16. Cytokinins and auxin communicate nitrogen availability as long-distance signal molecules in pineapple (Ananas comosus).

    Science.gov (United States)

    Tamaki, Vívian; Mercier, Helenice

    2007-11-01

    This work aimed at identifying a possible role of phytohormones in long-distance (root-shoot) signaling under nitrogen deficiency. Three-months old pineapple plants were transferred from Murashige and Skoog (MS) medium to nitrogen-free MS (-N). During the first 24h on -N, 20 plants were harvested every 4h. After 30 days in -N, the remaining plants were transferred back to regular MS (+N) and 20 plants harvested every 4h for the first 24h. Following the harvests, endogenous levels of nitrate (NO(3)(-)), indole-3-acetic acid (IAA), isopentenyladenine (iP), isopentenyladenine riboside (iPR), zeatin (Z) and zeatin riboside (ZR) were analyzed in roots and leaves. In N-starved plants, the NO(3)(-) level dropped by 20% in roots between the first (4h) and the second harvest (8h). In leaves a reduction of 20% was found 4h later. Accumulation of IAA peaked in leaves at 16h. In roots, the accumulation of IAA only started at 16h while the leaf content was already in decline, which suggests that the hormone might have traveled from the leaves to the roots, communicating N-shortage. The contents of the four cytokinins were generally low in both, shoot and roots, and remained almost unchanged during the 24h of analysis. After N re-supply, roots showed a NO(3)(-) peak at 8h whereas the foliar concentration increased 4h later. Hormone levels in roots climaxed at 8h, this coinciding with the highest NO(3)(-) concentration. In leaf tissue, a dramatic accumulation was only observed for Z and ZR, and the peak was seen 4h later than in roots, suggesting that Z-type cytokinins might have traveled from the roots to the leaves. These findings provide evidence that there is a signaling pathway for N availability in pineapple plants, communicated upwards through cytokinins (N-supplemented plants) and downwards through auxin (N-starved plants).

  17. Radioresistance-related signaling pathways in nasopharyngeal carcinoma cells

    International Nuclear Information System (INIS)

    Guo Ya; Zhu Xiaodong; Qu Song; Su Fang; Wang Qi; Zhang Wei

    2011-01-01

    Objective: To study the difference of gene expression profile between the radioresistant human nasopharyngeal carcinoma cell line CNE-2R and CNE-2, and to screen the signaling pathway associated with radioresistance of nasopharyngeal carcinoma. Methods: The radioresistant nasopharyngeal carcinoma cell line CNE-2R was constructed from the original cell line CNE-2. CNE-2R and CNE-2 cells were cultured and administered with 60 Co γ-ray irradiation at the dose of 400 cGy for 15 times. Human-6v 3.0 whole genome expression profile was used to screen the differentially expressed genes. Bioinformatic analysis was used to identify the pathways related to radioresistance. Results: The number of the differentially expressed genes that were found in these 2 experiments was 374. The Kegg pathway and Biocarta pathway analysis of the differentially expressed genes showed the biological importance of Toll-like receptor signaling pathway and IL-1 R-mediated signal transduction pathway to the radioresistance of the CNE-2R cells and the significant differences of 13 genes in these 2 pathways,including JUN, MYD88, CCL5, CXCL10, STAT1, LY96, FOS, CCL3, IL-6, IL-8, IL-1α, IL-1β, and IRAK2 (t=13.47-66.57, P<0.05). Conclusions: Toll-like receptor signaling pathway and IL-1R-mediated signal transduction pathway might be related to the occurrence of radioresistance. (authors)

  18. Gaseous signalling molecule SO2 via Hippo‑MST pathway to improve myocardial fibrosis of diabetic rats.

    Science.gov (United States)

    Liu, Maojun; Liu, Shengquan; Tan, Wenting; Tang, Fen; Long, Junrong; Li, Zining; Liang, Biao; Chu, Chun; Yang, Jun

    2017-12-01

    Recent studies have indicated the existence of an endogenous sulfur dioxide (SO2)‑generating system in the cardiovascular system. The present study aimed to discuss the function and regulatory mechanism of gaseous signal molecule SO2 in inhibiting apoptosis and endoplasmic reticulum stress (ERS) via the Hippo‑MST signaling pathway to improve myocardial fibrosis of diabetic rats. A total of 40 male Sprague‑Dawley rats were randomly divided into four groups (10 rats per group): Normal control group (control group), diabetic rats group [streptozotocin (STZ) group], SO2 intervention group (STZ+SO2 group) and diabetes mellitus rats treated with L‑Aspartic acid β‑hydroxamate (HDX) group (HDX group). Diabetic rats models were established by intra‑peritoneal injection of STZ (40 mg/kg) Following model establishment, intra‑peritoneal injection of Na2SO3/NaHSO3 solution (0.54 mmol/kg) was administered in the STZ+SO2 group, and HDX solution (25 mg/kg/week) was administered in the HDX group. A total of 4 weeks later, echocardiography was performed to evaluate rats' cardiac function; Masson staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and transmission electron microscopy examinations were performed to observe myocardial morphological changes. ELISA was employed to determine the SO2 content. Western blot analysis was performed to detect the expression of proteins associated with apoptosis, ERS and the Hippo‑MST signalling pathway. Compared with the control group, the STZ group and HDX group had a disordered arrangement of myocardial cells with apparent myocardial fibrosis, and echocardiography indicated that the cardiac function was lowered, there was an obvious increase of apoptosis in myocardial tissue, the expression levels of apoptosis‑associated protein B‑cell lymphoma associated protein X, caspase‑3 and caspase‑9 were upregulated, and Bcl‑2 expression was downregulated. The expression of ERS and Hippo

  19. Real-time single-molecule co-immunoprecipitation analyses reveal cancer-specific Ras signalling dynamics

    Science.gov (United States)

    Lee, Hong-Won; Kyung, Taeyoon; Yoo, Janghyun; Kim, Tackhoon; Chung, Chaeuk; Ryu, Ji Young; Lee, Hanki; Park, Kihyun; Lee, Sangkyu; Jones, Walton D.; Lim, Dae-Sik; Hyeon, Changbong; Do Heo, Won; Yoon, Tae-Young

    2013-01-01

    Co-immunoprecipitation (co-IP) has become a standard technique, but its protein-band output provides only static, qualitative information about protein–protein interactions. Here we demonstrate a real-time single-molecule co-IP technique that generates real-time videos of individual protein–protein interactions as they occur in unpurified cell extracts. By analysing single Ras–Raf interactions with a 50-ms time resolution, we have observed transient intermediates of the protein–protein interaction and determined all the essential kinetic rates. Using this technique, we have quantified the active fraction of native Ras proteins in xenograft tumours, normal tissue and cancer cell lines. We demonstrate that the oncogenic Ras mutations selectively increase the active-Ras fraction by one order of magnitude, without affecting total Ras levels or single-molecule signalling kinetics. Our approach allows us to probe the previously hidden, dynamic aspects of weak protein–protein interactions. It also suggests a path forward towards precision molecular diagnostics at the protein–protein interaction level. PMID:23422673

  20. Molecule-binding dependent assembly of split aptamer and γ-cyclodextrin: A sensitive excimer signaling approach for aptamer biosensors

    International Nuclear Information System (INIS)

    Jin, Fen; Lian, Yan; Li, Jishan; Zheng, Jing; Hu, Yaping; Liu, Jinhua; Huang, Jin; Yang, Ronghua

    2013-01-01

    Graphical abstract: Adenosine-binding aptamer was splitted into two fragments P2 and P3 which labeled pyrene molecules, mainly produce monomer signal. γ-CD cavity brings P2 and P3 in close proximity, allowing for weak excimer emission. In the presence of target, P2 and P3 are expected to bind ATP and form an aptamer/target complex, leads to large increase of the pyrene excimer fluorescence. -- Highlights: •We assembled split aptamer and γ-cyclodextrin fluorescence biosensors for ATP detection. •The biosensor increased quantum yield and emission lifetime of the excimer. •Time-resolved fluorescence is effective for ATP assay in complicated environment. -- Abstract: A highly sensitive and selective fluorescence aptamer biosensors for the determination of adenosine triphosphate (ATP) was developed. Binding of a target with splitting aptamers labeled with pyrene molecules form stable pyrene dimer in the γ-cyclodextrin (γ-CD) cavity, yielding a strong excimer emission. We have found that inclusion of pyrene dimer in γ-cyclodextrin cavity not only exhibits additive increases in quantum yield and emission lifetime of the excimer, but also facilitates target-induced fusion of the splitting aptamers to form the aptamer/target complex. As proof-of-principle, the approach was applied to fluorescence detection of adenosine triphosphate. With an anti-ATP aptamer, the approach exhibits excimer fluorescence response toward ATP with a maximum signal-to-background ratio of 32.1 and remarkably low detection limit of 80 nM ATP in buffer solution. Moreover, due to the additive fluorescence lifetime of excimer induced by γ-cyclodextrin, time-resolved measurements could be conveniently used to detect as low as 0.5 μM ATP in blood serum quantitatively

  1. Simultaneous search for symmetry-related molecules in cross-rotation functions

    International Nuclear Information System (INIS)

    Yeates, T.O.

    1989-01-01

    In a typical cross-rotation function, the Patterson function of a single search molecule is compared with an observed Patterson function, which contains a set of symmetry-related intramolecular vector sets. In principle, it is better to search for the symmetry-related molecules simultaneously, and Nordman has reported success with an algorithm of this type. In this paper, the differences between the ordinary search and a simultaneous search are investigated, and it is shown that the combined presence of crystallographic symmetry and approximate symmetry of a search model may lead to significant bias in conventional rotation functions. The nature and magnitude of this symmetry bias are discussed. An efficient algorithm is derived for generating a modified unbiased cross-rotation function map from conventional rotation functions. Two examples are described that demonstrate improvement in the quality of the rotation function maps and the ability to obtain physically meaningful correlation coefficients. (orig.)

  2. Combinations of SNPs Related to Signal Transduction in Bipolar Disorder

    DEFF Research Database (Denmark)

    Koefoed, Pernille; Andreassen, Ole A; Bennike, Bente

    2011-01-01

    of complex diseases, it may be useful to look at combinations of genotypes. Genes related to signal transmission, e.g., ion channel genes, may be of interest in this respect in the context of bipolar disorder. In the present study, we analysed 803 SNPs in 55 genes related to aspects of signal transmission...... and calculated all combinations of three genotypes from the 3×803 SNP genotypes for 1355 controls and 607 patients with bipolar disorder. Four clusters of patient-specific combinations were identified. Permutation tests indicated that some of these combinations might be related to bipolar disorder. The WTCCC...... in the clusters in the two datasets. The present analyses of the combinations of SNP genotypes support a role for both genetic heterogeneity and interactions in the genetic architecture of bipolar disorder....

  3. Expanding signaling-molecule wavefront model of cell polarization in the Drosophila wing primordium.

    Science.gov (United States)

    Wortman, Juliana C; Nahmad, Marcos; Zhang, Peng Cheng; Lander, Arthur D; Yu, Clare C

    2017-07-01

    In developing tissues, cell polarization and proliferation are regulated by morphogens and signaling pathways. Cells throughout the Drosophila wing primordium typically show subcellular localization of the unconventional myosin Dachs on the distal side of cells (nearest the center of the disc). Dachs localization depends on the spatial distribution of bonds between the protocadherins Fat (Ft) and Dachsous (Ds), which form heterodimers between adjacent cells; and the Golgi kinase Four-jointed (Fj), which affects the binding affinities of Ft and Ds. The Fj concentration forms a linear gradient while the Ds concentration is roughly uniform throughout most of the wing pouch with a steep transition region that propagates from the center to the edge of the pouch during the third larval instar. Although the Fj gradient is an important cue for polarization, it is unclear how the polarization is affected by cell division and the expanding Ds transition region, both of which can alter the distribution of Ft-Ds heterodimers around the cell periphery. We have developed a computational model to address these questions. In our model, the binding affinity of Ft and Ds depends on phosphorylation by Fj. We assume that the asymmetry of the Ft-Ds bond distribution around the cell periphery defines the polarization, with greater asymmetry promoting cell proliferation. Our model predicts that this asymmetry is greatest in the radially-expanding transition region that leaves polarized cells in its wake. These cells naturally retain their bond distribution asymmetry after division by rapidly replenishing Ft-Ds bonds at new cell-cell interfaces. Thus we predict that the distal localization of Dachs in cells throughout the pouch requires the movement of the Ds transition region and the simple presence, rather than any specific spatial pattern, of Fj.

  4. Reciprocal upregulation of Notch signaling molecules in hematopoietic progenitor and mesenchymal stromal cells

    Directory of Open Access Journals (Sweden)

    Kikuchi Y

    2011-01-01

    Full Text Available Although mesenchymal stem cells (MSCs play pivotal supportive roles in hematopoiesis, how they interact with hematopoietic stem cells (HSCs is not well understood. We investigated the interaction between HSCs and surrogate MSCs (C3H10T1/2 stromal cells, focusing on the molecular events induced by cell contact of these bipartite populations. C3H10T1/2 is a mesenchymal stromal cell line that can be induced to differentiate into preadipocytes (A54 and myoblasts (M1601. The stromal cell derivatives were cocultured with murine HSCs (Lineage-Sca1+, and gene expression profiles in stromal cells and HSCs were compared before and after the coculture. HSCs gave rise to cobblestone areas only on A54 cells, with ninefold more progenitors than on M1601 or undifferentiated C3H10T1/2 cells. Microarray-based screening and a quantitative reverse transcriptase directed-polymerase chain reaction showed that the levels of Notch ligands (Jagged1 and Delta-like 3 were increased in A54 cells upon interaction with HSCs. On the other hand, the expression of Notch1 and Hes1 was upregulated in the HSCs cocultured with A54 cells. A transwell assay revealed that the reciprocal upregulation was dependent on cell-to-cell contact. The result suggested that in the hematopoietic niche, HSCs help MSCs to produce Notch ligands, and in turn, MSCs help HSCs to express Notch receptor. Such a reciprocal upregulation would reinforce the downstream signaling to determine the fate of hematopoietic cell lineage. Clarification of the initiating events on cell contact should lead to the identification of specific molecular targets to facilitate HSC engraftment in transplantation therapy.

  5. Activation of CO2 and Related Small Molecules by Neopentyl-Derivatized Uranium Complexes

    OpenAIRE

    Schmidt, Anna-Corina

    2015-01-01

    The world´s concern about the environment has continued to intensify as the effects of greenhouse gases or complicated work-up and disposal of radioactive substances become more obvious and profound. Unsurprisingly, the number of publications related to the solution of these issues has greatly increased in the last 15 years. Thus, a basic understanding of the specific properties and behavior of small molecules is crucial for the reduction of greenhouse gases, which may be realized through act...

  6. Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling

    International Nuclear Information System (INIS)

    Singhal, Sharad S.; Singh, Sharda P.; Singhal, Preeti; Horne, David; Singhal, Jyotsana; Awasthi, Sanjay

    2015-01-01

    4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase (JNK) and caspase-3 activation. Cells exposed to mild, transient heat or oxidative stress acquire the capacity to exclude intracellular 4HNE at a faster rate by inducing GSTA4-4 which conjugates 4HNE to glutathione (GSH), and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4HNE (GS-HNE). The balance between formation and exclusion promotes different cellular processes — higher concentrations of 4HNE promote apoptosis; whereas, lower concentrations promote proliferation. In this article, we provide a brief summary of the cellular effects of 4HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTA4-4. Taken together, 4HNE is a key signaling molecule and that GSTs being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article. - Highlights: • GSTs are the major

  7. Multivalent adhesion molecule 7 clusters act as signaling platform for host cellular GTPase activation and facilitate epithelial barrier dysfunction.

    Directory of Open Access Journals (Sweden)

    Jenson Lim

    2014-09-01

    Full Text Available Vibrio parahaemolyticus is an emerging bacterial pathogen which colonizes the gastrointestinal tract and can cause severe enteritis and bacteraemia. During infection, V. parahaemolyticus primarily attaches to the small intestine, where it causes extensive tissue damage and compromises epithelial barrier integrity. We have previously described that Multivalent Adhesion Molecule (MAM 7 contributes to initial attachment of V. parahaemolyticus to epithelial cells. Here we show that the bacterial adhesin, through multivalent interactions between surface-induced adhesin clusters and phosphatidic acid lipids in the host cell membrane, induces activation of the small GTPase RhoA and actin rearrangements in host cells. In infection studies with V. parahaemolyticus we further demonstrate that adhesin-triggered activation of the ROCK/LIMK signaling axis is sufficient to redistribute tight junction proteins, leading to a loss of epithelial barrier function. Taken together, these findings show an unprecedented mechanism by which an adhesin acts as assembly platform for a host cellular signaling pathway, which ultimately facilitates breaching of the epithelial barrier by a bacterial pathogen.

  8. Expression analysis of taste signal transduction molecules in the fungiform and circumvallate papillae of the rhesus macaque, Macaca mulatta.

    Directory of Open Access Journals (Sweden)

    Yoshiro Ishimaru

    Full Text Available The molecular mechanisms of the mammalian gustatory system have been examined in many studies using rodents as model organisms. In this study, we examined the mRNA expression of molecules involved in taste signal transduction in the fungiform papillae (FuP and circumvallate papillae (CvP of the rhesus macaque, Macaca mulatta, using in situ hybridization. TAS1R1, TAS1R2, TAS2Rs, and PKD1L3 were exclusively expressed in different subsets of taste receptor cells (TRCs in the FuP and CvP. This finding suggests that TRCs sensing different basic taste modalities are mutually segregated in macaque taste buds. Individual TAS2Rs exhibited a variety of expression patterns in terms of the apparent level of expression and the number of TRCs expressing these genes, as in the case of human TAS2Rs. GNAT3, but not GNA14, was expressed in TRCs of FuP, whereas GNA14 was expressed in a small population of TRCs of CvP, which were distinct from GNAT3- or TAS1R2-positive TRCs. These results demonstrate similarities and differences between primates and rodents in the expression profiles of genes involved in taste signal transduction.

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

    Energy Technology Data Exchange (ETDEWEB)

    Zawawi, M.S.F. [Universiti Sains Malaysia (USM) (Malaysia); Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); Dharmapatni, A.A.S.S.K.; Cantley, M.D. [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); McHugh, K.P. [University of Florida, College of Dentistry, Fl (United States); Haynes, D.R. [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); Crotti, T.N., E-mail: tania.crotti@adelaide.edu.au [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia)

    2012-10-19

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

  10. Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling.

    Science.gov (United States)

    Singhal, Sharad S; Singh, Sharda P; Singhal, Preeti; Horne, David; Singhal, Jyotsana; Awasthi, Sanjay

    2015-12-15

    4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase (JNK) and caspase-3 activation. Cells exposed to mild, transient heat or oxidative stress acquire the capacity to exclude intracellular 4HNE at a faster rate by inducing GSTA4-4 which conjugates 4HNE to glutathione (GSH), and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4HNE (GS-HNE). The balance between formation and exclusion promotes different cellular processes - higher concentrations of 4HNE promote apoptosis; whereas, lower concentrations promote proliferation. In this article, we provide a brief summary of the cellular effects of 4HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTA4-4. Taken together, 4HNE is a key signaling molecule and that GSTs being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article. Copyright © 2015 Elsevier Inc. All rights

  11. Variants of Insulin-Signaling Inhibitor Genes in Type 2 Diabetes and Related Metabolic Abnormalities

    Directory of Open Access Journals (Sweden)

    Carlo de Lorenzo

    2013-01-01

    Full Text Available Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis.

  12. ROS-related redox regulation and signaling in plants.

    Science.gov (United States)

    Noctor, Graham; Reichheld, Jean-Philippe; Foyer, Christine H

    2017-07-18

    As sessile oxygenic organisms with a plastic developmental programme, plants are uniquely positioned to exploit reactive oxygen species (ROS) as powerful signals. Plants harbor numerous ROS-generating pathways, and these oxidants and related redox-active compounds have become tightly embedded into plant function and development during the course of evolution. One dominant view of ROS-removing systems sees them as beneficial antioxidants battling to keep damaging ROS below dangerous levels. However, it is now established that ROS are a necessary part of subcellular and intercellular communication in plants and that some of their signaling functions require ROS-metabolizing systems. For these reasons, it is suggested that "ROS processing systems" would be a more accurate term than "antioxidative systems" to describe cellular components that are most likely to interact with ROS and, in doing so, transmit oxidative signals. Within this framework, our update provides an overview of the complexity and compartmentation of ROS production and removal. We place particular emphasis on the importance of ROS-interacting systems such as the complex cellular thiol network in the redox regulation of phytohormone signaling pathways that are crucial for plant development and defense against external threats. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Indole, a Signaling Molecule Produced by the Gut Microbiota, Negatively Impacts Emotional Behaviors in Rats

    Directory of Open Access Journals (Sweden)

    Mathilde Jaglin

    2018-04-01

    Full Text Available Gut microbiota produces a wide and diverse array of metabolites that are an integral part of the host metabolome. The emergence of the gut microbiome-brain axis concept has prompted investigations on the role of gut microbiota dysbioses in the pathophysiology of brain diseases. Specifically, the search for microbe-related metabolomic signatures in human patients and animal models of psychiatric disorders has pointed out the importance of the microbial metabolism of aromatic amino acids. Here, we investigated the effect of indole on brain and behavior in rats. Indole is produced by gut microbiota from tryptophan, through the tryptophanase enzyme encoded by the tnaA gene. First, we mimicked an acute and high overproduction of indole by injecting this compound in the cecum of conventional rats. This treatment led to a dramatic decrease of motor activity. The neurodepressant oxidized derivatives of indole, oxindole and isatin, accumulated in the brain. In addition, increase in eye blinking frequency and in c-Fos protein expression in the dorsal vagal complex denoted a vagus nerve activation. Second, we mimicked a chronic and moderate overproduction of indole by colonizing germ-free rats with the indole-producing bacterial species Escherichia coli. We compared emotional behaviors of these rats with those of germ-free rats colonized with a genetically-engineered counterpart strain unable to produce indole. Rats overproducing indole displayed higher helplessness in the tail suspension test, and enhanced anxiety-like behavior in the novelty, elevated plus maze and open-field tests. Vagus nerve activation was suggested by an increase in eye blinking frequency. However, unlike the conventional rats dosed with a high amount of indole, the motor activity was not altered and neither oxindole nor isatin could be detected in the brain. Further studies are required for a comprehensive understanding of the mechanisms supporting indole effects on emotional

  14. Indole, a Signaling Molecule Produced by the Gut Microbiota, Negatively Impacts Emotional Behaviors in Rats

    Science.gov (United States)

    Jaglin, Mathilde; Rhimi, Moez; Philippe, Catherine; Pons, Nicolas; Bruneau, Aurélia; Goustard, Bénédicte; Daugé, Valérie; Maguin, Emmanuelle; Naudon, Laurent; Rabot, Sylvie

    2018-01-01

    Gut microbiota produces a wide and diverse array of metabolites that are an integral part of the host metabolome. The emergence of the gut microbiome-brain axis concept has prompted investigations on the role of gut microbiota dysbioses in the pathophysiology of brain diseases. Specifically, the search for microbe-related metabolomic signatures in human patients and animal models of psychiatric disorders has pointed out the importance of the microbial metabolism of aromatic amino acids. Here, we investigated the effect of indole on brain and behavior in rats. Indole is produced by gut microbiota from tryptophan, through the tryptophanase enzyme encoded by the tnaA gene. First, we mimicked an acute and high overproduction of indole by injecting this compound in the cecum of conventional rats. This treatment led to a dramatic decrease of motor activity. The neurodepressant oxidized derivatives of indole, oxindole and isatin, accumulated in the brain. In addition, increase in eye blinking frequency and in c-Fos protein expression in the dorsal vagal complex denoted a vagus nerve activation. Second, we mimicked a chronic and moderate overproduction of indole by colonizing germ-free rats with the indole-producing bacterial species Escherichia coli. We compared emotional behaviors of these rats with those of germ-free rats colonized with a genetically-engineered counterpart strain unable to produce indole. Rats overproducing indole displayed higher helplessness in the tail suspension test, and enhanced anxiety-like behavior in the novelty, elevated plus maze and open-field tests. Vagus nerve activation was suggested by an increase in eye blinking frequency. However, unlike the conventional rats dosed with a high amount of indole, the motor activity was not altered and neither oxindole nor isatin could be detected in the brain. Further studies are required for a comprehensive understanding of the mechanisms supporting indole effects on emotional behaviors. As our findings

  15. Snore related signals processing in a private cloud computing system.

    Science.gov (United States)

    Qian, Kun; Guo, Jian; Xu, Huijie; Zhu, Zhaomeng; Zhang, Gongxuan

    2014-09-01

    Snore related signals (SRS) have been demonstrated to carry important information about the obstruction site and degree in the upper airway of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) patients in recent years. To make this acoustic signal analysis method more accurate and robust, big SRS data processing is inevitable. As an emerging concept and technology, cloud computing has motivated numerous researchers and engineers to exploit applications both in academic and industry field, which could have an ability to implement a huge blue print in biomedical engineering. Considering the security and transferring requirement of biomedical data, we designed a system based on private cloud computing to process SRS. Then we set the comparable experiments of processing a 5-hour audio recording of an OSAHS patient by a personal computer, a server and a private cloud computing system to demonstrate the efficiency of the infrastructure we proposed.

  16. Clinical development of galunisertib (LY2157299 monohydrate, a small molecule inhibitor of transforming growth factor-beta signaling pathway

    Directory of Open Access Journals (Sweden)

    Herbertz S

    2015-08-01

    Full Text Available Stephan Herbertz,1 J Scott Sawyer,2 Anja J Stauber,2 Ivelina Gueorguieva,3 Kyla E Driscoll,4 Shawn T Estrem,2 Ann L Cleverly,3 Durisala Desaiah,2 Susan C Guba,2 Karim A Benhadji,2 Christopher A Slapak,2 Michael M Lahn21Lilly Deutschland GmbH, Bad Homburg, Germany; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK; 4Lilly Research Laboratories, Eli Lilly and Company, New York, NY, USA Abstract: Transforming growth factor-beta (TGF-β signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab

  17. A small diffusible signal molecule is responsible for the global control of virulence and exoenzyme production in the plant pathogen Erwinia carotovora.

    Science.gov (United States)

    Pirhonen, M; Flego, D; Heikinheimo, R; Palva, E T

    1993-06-01

    Virulence of the plant pathogen Erwinia carotovora subsp. carotovora is dependent on the production and secretion of a complex arsenal of plant cell wall-degrading enzymes. Production of these exoenzymes is controlled by a global regulatory mechanism. A virulent mutants in one of the regulatory loci, expI, show a pleiotropic defect in the growth phase-dependent transcriptional activation of exoenzyme gene expression. The expI gene encodes a 26 kDa polypeptide that is structurally and functionally related to the luxI gene product of Vibrio fischeri. Functional similarity of expI and luxI has been demonstrated by reciprocal genetic complementation experiments. LuxI controls bioluminescence in V.fischeri in a growth phase-dependent manner by directing the synthesis of the diffusible autoinducer, N-(3-oxohexanoyl) homoserine lactone. E.c. subsp. carotovora expI+ strains or Escherichia coli harboring the cloned expI gene excrete a small diffusible signal molecule that complements the expI mutation of Erwinia as well as a luxI mutation of V.fischeri. This extracellular complementation can also be achieved by E.coli harboring the luxI gene from V.fischeri or by adding the synthetic V.fischeri autoinducer. Both the production of the plant tissue-macerating exoenzymes and the ability of the bacteria to propagate in planta are restored in expI mutants by autoinducer addition. These data suggest that the same signal molecule is employed in control of such diverse processes as virulence in a plant pathogen and bioluminescence in a marine bacterium, and may represent a general mechanism by which bacteria modulate gene expression in response to changing environmental conditions.

  18. [Controlling effect of bushen huatan compound on the insulin signal conducting molecule inside ovaries in polycystic ovary syndrome model rats].

    Science.gov (United States)

    Liang, Chen; Cong, Jing; Chang, Hui

    2011-12-01

    To study the effects of Bushen Huatan Compound (BHC) on the glycolipid metabolism and the expressions of the insulin signal conducting molecules inside ovaries in polycystic ovary syndrome (PCOS) model rats. Female Wistar rats were subcutaneously injected with 2.5 mg/kg testosterone propionate (Their female offspring were randomly divided into the medication group and the model group, 10 in each.) or neutral tea oil of the same dose (Ten female offspring was taken as the control group.) on the 16th day of pregnancy, once daily, for 3 successive days. BHC was given to rats in the medication group by gastrogavage, while equal volume of distilled water was given to rats in the model group and the control group by gastrogavage, both once daily for 20 successive days. The body weight and ovary weight were weighed to calculate the ratio of wet fat weight/body weight. The blood glucose levels were detected at 0, 0.5, 1, and 2 h using oral glucose tolerance test (OGTT). The serum concentrations of high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), fasting blood glucose (FBG), and insulin were detected to calculate homeostasis model assessment of insulin resistance (HOMA-IR). The expressions of protein kinase B (AKT2), glycogen synthase kinase-3beta (GSK3beta), glucose transporter-4 (GLUT4), extracellular signal regulated kinase-1 (ERK1) protein, P-AKT2, P-GSK3beta, and P-ERK1 in ovaries were detected using Western blot. Compared with the control group, the ratio of wet fat weight/ body weight, the blood glucose levels at 0.5 and 2 h in OGTT, and HOMA-IR all obviously increased, and the HDL-C level obviously decreased in the model group (P < 0.05). Compared with the model group, the ratio of wet fat weight/body weight and the blood glucose levels at 2 h in OGTT obviously decreased, and the HDL-C level obviously increased in the medication group (P < 0.05). The expressions of AKT2, P-AKT2, GSK3beta, P-GSK3beta, GLUT4, and ERK1 in the ovary tissue were obviously

  19. Common RNA replication signals exist among group 2 coronaviruses: evidence for in vivo recombination between animal and human coronavius molecules

    International Nuclear Information System (INIS)

    Wu, H.-Y.; Guy, James S.; Yoo, Dongwan; Vlasak, Reinhard; Urbach, Ena; Brian, David A.

    2003-01-01

    5' and 3' UTR sequences on the coronavirus genome are known to carry cis-acting elements for DI RNA replication and presumably also virus genome replication. 5' UTR-adjacent coding sequences are also thought to harbor cis-acting elements. Here we have determined the 5' UTR and adjacent 289-nt sequences, and 3' UTR sequences, for six group 2 coronaviruses and have compared them to each other and to three previously reported group 2 members. Extensive regions of highly similar UTR sequences were found but small regions of divergence were also found indicating group 2 coronaviruses could be subdivided into those that are bovine coronavirus (BCoV)-like (BCoV, human respiratory coronavirus-OC43, human enteric coronavirus, porcine hemagglutinating encephalomyelitis virus, and equine coronavirus) and those that are murine hepatitis virus (MHV)-like (A59, 2, and JHM strains of MHV, puffinosis virus, and rat sialodacryoadenitis virus). The 3' UTRs of BCoV and MHV have been previously shown to be interchangeable. Here, a reporter-containing BCoV DI RNA was shown to be replicated by all five BCoV-like helper viruses and by MHV-H2 (a human cell-adapted MHV strain), a representative of the MHV-like subgroup, demonstrating group 2 common 5' and 3' replication signaling elements. BCoV DI RNA, furthermore, acquired the leader of HCoV-OC43 by leader switching, demonstrating for the first time in vivo recombination between animal and human coronavirus molecules. These results indicate that common replication signaling elements exist among group 2 coronaviruses despite a two-cluster pattern within the group and imply there could exist a high potential for recombination among group members

  20. Structure and thermodynamics of effector molecule binding to the nitrogen signal transduction PII protein GlnZ from Azospirillum brasilense.

    Science.gov (United States)

    Truan, Daphné; Bjelić, Saša; Li, Xiao-Dan; Winkler, Fritz K

    2014-07-29

    The trimeric PII signal transduction proteins regulate the function of a variety of target proteins predominantly involved in nitrogen metabolism. ATP, ADP and 2-oxoglutarate (2-OG) are key effector molecules influencing PII binding to targets. Studies of PII proteins have established that the 20-residue T-loop plays a central role in effector sensing and target binding. However, the specific effects of effector binding on T-loop conformation have remained poorly documented. We present eight crystal structures of the Azospirillum brasilense PII protein GlnZ, six of which are cocrystallized and liganded with ADP or ATP. We find that interaction with the diphosphate moiety of bound ADP constrains the N-terminal part of the T-loop in a characteristic way that is maintained in ADP-promoted complexes with target proteins. In contrast, the interactions with the triphosphate moiety in ATP complexes are much more variable and no single predominant interaction mode is apparent except for the ternary MgATP/2-OG complex. These conclusions can be extended to most investigated PII proteins of the GlnB/GlnK subfamily. Unlike reported for other PII proteins, microcalorimetry reveals no cooperativity between the three binding sites of GlnZ trimers for any of the three effectors under carefully controlled experimental conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Meat and Livestock Association Plenary Lecture 2005. Oocyte signalling molecules and their effects on reproduction in ruminants.

    Science.gov (United States)

    McNatty, Kenneth P; Lawrence, Stephen; Groome, Nigel P; Meerasahib, Mohammed F; Hudson, Norma L; Whiting, Lynda; Heath, Derek A; Juengel, Jennifer L

    2006-01-01

    Sheep (Ovis aries) are a highly diverse species, with more than 900 different breeds that vary significantly in their physiological characteristics, including ovulation rate and fecundity. From examination of inherited patterns of ovulation rate, several breeds have been identified with point mutations in two growth factor genes that are expressed in oocytes. Currently, five different point mutations have been identified in the BMP15 (GDF9b) gene and one in GDF9. Animals heterozygous for the GDF9 and/or the BMP15 mutations have higher ovulation rates than their wild-type counterparts. In contrast, those homozygous for any of the aforementioned BMP15 or GDF9 mutations are sterile owing to arrested follicular development. In bovine and ovine ovaries, GDF9 was expressed exclusively in oocytes throughout follicular growth from the primordial stage of development, whereas in sheep BMP15 was expressed exclusively in oocytes from the primary stage: no data for the ontogeny of BMP15 expression are currently available for cattle. In vitro, ovine growth differentiation factor 9 (oGDF9) has no effect on (3)H-thymidine incorporation by either bovine or ovine granulosa cells, whereas ovine bone morphogenetic protein 15 (oBMP15) has modest (1.2- to 1.6-fold; P reproduction in mammals, including rodents, humans and ruminants. Moreover, in vivo manipulation of these oocyte signalling molecules provides new opportunities for the management of the fertility of ruminants.

  2. Viking relativity experiment: Verification of signal retardation by solar gravity

    International Nuclear Information System (INIS)

    Reasenberg, R.D.; Shapiro, I.I.; MacNeil, P.E.; Goldstein, R.B.; Breidenthal, J.C.; Brenkle, J.P.; Cain, D.L.; Kaufman, T.M.; Komarek, T.A.; Zygielbaum, A.I.

    1979-01-01

    Analysis of 14 months of data obtained from radio ranging to the Viking spacecraft verified, to an estimated accuracy of 0.1%, the prediction of the general theory of relativity that the round-trip times of light signals traveling between the Earth and Mars are increased by the direct effect of solar gravity. The correspondig value for the metric parameter γ is 1.000 +- 0.002, where the quoted uncertainty, twice the formal standard deviation, allows for possible systematic errors

  3. CD54/intercellular adhesion molecule 1 and major histocompatibility complex II signaling induces B cells to express interleukin 2 receptors and complements help provided through CD40 ligation

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    We have examined signaling roles for CD54 intercellular adhesion molecule 1 and major histocompatibility complex (MHC) II as contact ligands during T help for B cell activation. We used a T helper 1 (Th1)-dependent helper system that was previously shown to be contact as well as interleukin 2 (IL-2......) dependent to demonstrate the relative roles of CD54, MHC II, and CD40 signaling in the events leading to the induction of B cell proliferation and responsiveness to IL-2. Paraformaldehyde-fixed activated Th1-induced expression of IL-2R alpha, IL-2R beta, and B7, and upregulated MHC II and CD54 on B cells...... resulted in the upregulated expression of MHC II and of CD54 and B7, respectively, analogous to the effect of fixed activated Th1 cells. B7 expression was further enhanced by co-cross-linking CD54 and MHC II. Cross-linking of CD40 achieved comparable effects. Strikingly, cross-linking ligation of CD54...

  4. Detection of the quorum sensing signal molecule N-Dodecanoyl-DL-homoserine lactone below 1 nanomolarconcentrations using surface enhanced Raman spectroscopy

    DEFF Research Database (Denmark)

    Claussen, Anetta; Abdali, Salim; Berg, Rolf W.

    2013-01-01

    suitable tool for in situ measurements of low Acyl-Homoserine Lactone (AHL) concentrations in biofilms containing QS bacteria. Signal molecules communicate information about their environment and coordinate certain physiological activities in QS systems that exist in many bacteria. SERS enables detection...

  5. Effects of Obesity and Obesity-Related Molecules on Canine Mammary Gland Tumors.

    Science.gov (United States)

    Lim, H-Y; Im, K-S; Kim, N-H; Kim, H-W; Shin, J-I; Yhee, J-Y; Sur, J-H

    2015-11-01

    Obesity can affect the clinical course of a number of diseases, including breast cancer in women and mammary gland tumors in female dogs, via the secretion of various cytokines and hormones. The objective of this study was to examine the expression patterns of obesity-related molecules such as aromatase, leptin, and insulin-like growth factor 1 receptor (IGF-1 R) in canine mammary carcinomas (CMCs) on the basis of the body condition score (BCS). Comparative analyses of the expression of these molecules, together with prognostic factors for CMCs, including hormone receptors (HRs; estrogen and progesterone receptors), lymphatic invasion, central necrosis of the tumor, and histologic grade, were performed on 56 CMCs. The mean age of CMC onset was lower in the overweight or obese group (8.7 ± 1.9 years) than in the lean or ideal body weight group (10.4 ± 2.7 years). The proportion of poorly differentiated (grade III) tumors was significantly higher in the overweight or obese female dogs. Aromatase expression was significantly higher in the overweight or obese group and was correlated with the expression of HRs (P = .025). These findings suggest that overweight or obese status might affect the development and behavior of CMCs by tumor-adipocyte interactions and increased HR-related tumor growth. © The Author(s) 2015.

  6. Attending Weak Signals: The Prevention of Work-related Illnesses

    Directory of Open Access Journals (Sweden)

    Roy Liff

    2017-06-01

    Full Text Available This article examines the characteristics of communication among managers, human resource (HR experts, and occupational health care specialists, as they deal with such informal information as weak signals in the prevention of work-related illnesses, using a theoretical framework in which the prevention of work-related illness is analogous to theory on crisis management. This is a qualitative study in which individual and focus-group interviews were conducted in a Swedish context with occupational health care specialists, managers, and HR experts. The results suggest that organizational solutions have failed and continue to fail at controlling workers’ health problems, although the main difficulty is not in identifying the ‘right’ individually oriented weak signals. Rather, it is upper management’s reliance on formal information (e.g., statistics and surveys – because of the difficulty in supplementing it with informal information (e.g., rumors and gossip – that makes it difficult to improve traditional health and safety work

  7. Analysis of two potential long-distance signaling molecules, LjCLE-RS1/2 and jasmonic acid, in a hypernodulating mutant too much love.

    Science.gov (United States)

    Magori, Shimpei; Kawaguchi, Masayoshi

    2010-04-01

    Legume plants tightly control the number and development of root nodules. This is partly regulated by a long-distance signaling known as auto-regulation of nodulation (AON). AON signaling involves at least two potential long-distance signals: root-derived signal and shoot-derived signal. However, their molecular characteristics and the mode of action remain unclear. In our recent study, we isolated a novel Lotus japonicus hypernodulating mutant too much love (tml). Based on several grafting experiments, we concluded that its causative gene TML functions as a receptor of the shoot-derived signal. This finding prompted us to ask how the candidates of the long-distance signal molecules, LjCLE-RS1/2 and jasmonic acid (JA), are affected in tml mutants. Expression analysis revealed that rapid induction of LjCLE-RS1/2 upon rhizobial inoculation is still intact in tml, supporting that TML plays a role in reception of the shoot-derived signal but not in generation of the root-derived signal. Furthermore, physiological analysis showed that JA, a candidate of the shoot-derived signal, can suppress tml hypernodulation. Therefore, contrary to the previous report, JA might not be a component of AON signaling.

  8. Invariance of molecular charge transport upon changes of extended molecule size and several related issues

    Directory of Open Access Journals (Sweden)

    Ioan Bâldea

    2016-03-01

    Full Text Available As a sanity test for the theoretical method employed, studies on (steady-state charge transport through molecular devices usually confine themselves to check whether the method in question satisfies the charge conservation. Another important test of the theory’s correctness is to check that the computed current does not depend on the choice of the central region (also referred to as the “extended molecule”. This work addresses this issue and demonstrates that the relevant transport and transport-related properties are indeed invariant upon changing the size of the extended molecule, when the embedded molecule can be described within a general single-particle picture (namely, a second-quantized Hamiltonian bilinear in the creation and annihilation operators. It is also demonstrates that the invariance of nonequilibrium properties is exhibited by the exact results but not by those computed approximately within ubiquitous wide- and flat-band limits (WBL and FBL, respectively. To exemplify the limitations of the latter, the phenomenon of negative differential resistance (NDR is considered. It is shown that the exactly computed current may exhibit a substantial NDR, while the NDR effect is absent or drastically suppressed within the WBL and FBL approximations. The analysis done in conjunction with the WBLs and FBLs reveals why general studies on nonequilibrium properties require a more elaborate theoretical than studies on linear response properties (e.g., ohmic conductance and thermopower at zero temperature. Furthermore, examples are presented that demonstrate that treating parts of electrodes adjacent to the embedded molecule and the remaining semi-infinite electrodes at different levels of theory (which is exactly what most NEGF-DFT approaches do is a procedure that yields spurious structures in nonlinear ranges of current–voltage curves.

  9. Inhibition of Dengue Virus Replication by a Class of Small-Molecule Compounds That Antagonize Dopamine Receptor D4 and Downstream Mitogen-Activated Protein Kinase Signaling

    Science.gov (United States)

    Smith, Jessica L.; Stein, David A.; Shum, David; Fischer, Matthew A.; Radu, Constantin; Bhinder, Bhavneet; Djaballah, Hakim; Nelson, Jay A.; Früh, Klaus

    2014-01-01

    ABSTRACT Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. To date, no vaccines or antiviral therapeutics have been approved for combating DENV-associated disease. In this paper, we describe a class of tricyclic small-molecule compounds—dihydrodibenzothiepines (DHBTs), identified through high-throughput screening—with potent inhibitory activity against DENV serotype 2. SKI-417616, a highly active representative of this class, displayed activity against all four serotypes of DENV, as well as against a related flavivirus, West Nile virus (WNV), and an alphavirus, Sindbis virus (SINV). This compound was characterized to determine its mechanism of antiviral activity. Investigation of the stage of the viral life cycle affected revealed that an early event in the life cycle is inhibited. Due to the structural similarity of the DHBTs to known antagonists of the dopamine and serotonin receptors, we explored the roles of two of these receptors, serotonin receptor 2A (5HTR2A) and the D4 dopamine receptor (DRD4), in DENV infection. Antagonism of DRD4 and subsequent downstream phosphorylation of epidermal growth factor receptor (EGFR)-related kinase (ERK) were found to impact DENV infection negatively, and blockade of signaling through this network was confirmed as the mechanism of anti-DENV activity for this class of compounds. IMPORTANCE The dengue viruses are mosquito-borne, reemerging human pathogens that are the etiological agents of a spectrum of febrile diseases. Currently, there are no approved therapeutic treatments for dengue-associated disease, nor is there a vaccine. This study identifies a small molecule, SKI-417616, with potent anti-dengue virus activity. Further analysis revealed that SKI-417616 acts through antagonism of the host cell dopamine D4 receptor and subsequent repression of the ERK phosphorylation pathway. These results suggest that SKI-417616, or other

  10. Electronic Transport in Single-Stranded DNA Molecule Related to Huntington's Disease

    Science.gov (United States)

    Sarmento, R. G.; Silva, R. N. O.; Madeira, M. P.; Frazão, N. F.; Sousa, J. O.; Macedo-Filho, A.

    2018-04-01

    We report a numerical analysis of the electronic transport in single chain DNA molecule consisting of 182 nucleotides. The DNA chains studied were extracted from a segment of the human chromosome 4p16.3, which were modified by expansion of CAG (cytosine-adenine-guanine) triplet repeats to mimics Huntington's disease. The mutated DNA chains were connected between two platinum electrodes to analyze the relationship between charge propagation in the molecule and Huntington's disease. The computations were performed within a tight-binding model, together with a transfer matrix technique, to investigate the current-voltage (I-V) of 23 types of DNA sequence and compare them with the distributions of the related CAG repeat numbers with the disease. All DNA sequences studied have a characteristic behavior of a semiconductor. In addition, the results showed a direct correlation between the current-voltage curves and the distributions of the CAG repeat numbers, suggesting possible applications in the development of DNA-based biosensors for molecular diagnostics.

  11. Solid state proton spin-lattice relaxation in four structurally related organic molecules

    International Nuclear Information System (INIS)

    Beckmann, Peter A.; Burbank, Kendra S.; Lau, Matty M.W.; Ree, Jessica N.; Weber, Tracy L.

    2003-01-01

    We report and interpret the temperature dependence of the proton spin-lattice relaxation rate at 8.50 and 22.5 MHz in four polycrystalline solids composed of structurally related molecules: 2-ethylanthracene, 2-t-butylanthracene, 2-ethylanthraquinone, and 2-t-butylanthraquinone. We have been unable to grow single crystals and therefore do not know the crystal structures. Hence, we use the NMR relaxometry data to make predictions about the solid state structures. As expected, we are able to conclude that the ethyl groups do not reorient in the solid state but that the t-butyl groups do. The anthraquinones have a ''simpler'' structure than the anthracenes. The best dynamical models suggest that there is a unique crystallographic site for the t-butyl groups in 2-t-butylanthraquinone and two sites, each with half the molecules, for the ethyl groups in 2-ethylanthraquinone. There are also two sites in 2-ethylanthracene, but with unequal weights, suggesting four sites in the unit cell with lower symmetry than the two anthraquinones. Finally, the observed relaxation rate data in 2-t-butylanthracene is very complex and its interpretation demonstrates the uniqueness problem that arises in interpreting relaxometry data without the knowledge of the crystal structure

  12. Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Mary E Irwin

    Full Text Available The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+ALL is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI that target BCR/ABL, such as imatinib, have improved treatment of Ph(+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2 is expressed in ~30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+ALL as compared to just 4.8% of Ph(-ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM. Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM. Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.

  13. Recent host range expansion of canine distemper virus and variation in its receptor, the signaling lymphocyte activation molecule, in carnivores.

    Science.gov (United States)

    Ohishi, Kazue; Suzuki, Rintaro; Maeda, Taro; Tsuda, Miwako; Abe, Erika; Yoshida, Takao; Endo, Yasuyuki; Okamura, Maki; Nagamine, Takashi; Yamamoto, Hanae; Ueda, Miya; Maruyama, Tadashi

    2014-07-01

    The signaling lymphocyte activation molecule (SLAM) is a receptor for morbilliviruses. To understand the recent host range expansion of canine distemper virus (CDV) in carnivores, we determined the nucleotide sequences of SLAMs of various carnivores and generated three-dimensional homology SLAM models. Thirty-four amino acid residues were found for the candidates binding to CDV on the interface of the carnivore SLAMs. SLAM of the domestic dog (Canis lupus familiaris) were similar to those of other members of the suborder Caniformia, indicating that the animals in this group have similar sensitivity to dog CDV. However, they were different at nine positions from those of felids. Among the nine residues, four of domestic cat (Felis catus) SLAM (72, 76, 82, and 129) and three of lion (Panthera leo persica) SLAM (72, 82, and 129) were associated with charge alterations, suggesting that the felid interfaces have lower affinities to dog CDV. Only the residue at 76 was different between domestic cat and lion SLAM interfaces. The domestic cat SLAM had threonine at 76, whereas the lion SLAM had arginine, a positively charged residue like that of the dog SLAM. The cat SLAM with threonine is likely to have lower affinity to CDV-H and to confer higher resistance against dog CDV. Thus, the four residues (72, 76, 82, and 129) on carnivore SLAMs are important for the determination of affinity and sensitivity with CDV. Additionally, the CDV-H protein of felid strains had a substitution of histidine for tyrosine at 549 of dog CDV-H and may have higher affinity to lion SLAM. Three-dimensional model construction is a new risk assessment method of morbillivirus infectivity. Because the method is applicable to animals that have no information about virus infection, it is especially useful for morbillivirus risk assessment and wildlife conservation.

  14. Age-Related Changes in Electroencephalographic Signal Complexity

    Science.gov (United States)

    Zappasodi, Filippo; Marzetti, Laura; Olejarczyk, Elzbieta; Tecchio, Franca; Pizzella, Vittorio

    2015-01-01

    The study of active and healthy aging is a primary focus for social and neuroscientific communities. Here, we move a step forward in assessing electrophysiological neuronal activity changes in the brain with healthy aging. To this end, electroencephalographic (EEG) resting state activity was acquired in 40 healthy subjects (age 16–85). We evaluated Fractal Dimension (FD) according to the Higuchi algorithm, a measure which quantifies the presence of statistical similarity at different scales in temporal fluctuations of EEG signals. Our results showed that FD increases from age twenty to age fifty and then decreases. The curve that best fits the changes in FD values across age over the whole sample is a parabola, with the vertex located around age fifty. Moreover, FD changes are site specific, with interhemispheric FD asymmetry being pronounced in elderly individuals in the frontal and central regions. The present results indicate that fractal dimension well describes the modulations of brain activity with age. Since fractal dimension has been proposed to be related to the complexity of the signal dynamics, our data demonstrate that the complexity of neuronal electric activity changes across the life span of an individual, with a steady increase during young adulthood and a decrease in the elderly population. PMID:26536036

  15. On semi-classical questions related to signal analysis

    KAUST Repository

    Helffer, Bernard; Laleg-Kirati, Taous-Meriem

    2011-01-01

    . Indeed it provides new spectral quantities that can give relevant information on some signals as it is the case for arterial blood pressure signal. © 2011 - IOS Press and the authors. All rights reserved.

  16. Age-related changes in expression of the neural cell adhesion molecule in skeletal muscle

    DEFF Research Database (Denmark)

    Andersson, A M; Olsen, M; Zhernosekov, D

    1993-01-01

    Neural cell adhesion molecule (NCAM) is expressed by muscle and involved in muscle-neuron and muscle-muscle cell interactions. The expression in muscle is regulated during myogenesis and by the state of innervation. In aged muscle, both neurogenic and myogenic degenerative processes occur. We here...... report quantitative and qualitative changes in NCAM protein and mRNA forms during aging in normal rat skeletal muscle. Determination of the amount of NCAM by e.l.i.s.a. showed that the level decreased from perinatal to adult age, followed by a considerable increase in 24-month-old rat muscle. Thus NCAM...... concentration in aged muscle was sixfold higher than in young adult muscle. In contrast with previous reports, NCAM polypeptides of 200, 145, 125 and 120 kDa were observed by immunoblotting throughout postnatal development and aging, the relative proportions of the individual NCAM polypeptides remaining...

  17. Rotating Wigner molecules and spin-related behaviors in quantum rings

    International Nuclear Information System (INIS)

    Yang Ning; Zhu Jialin; Dai Zhensheng

    2008-01-01

    The trial wavefunctions for few-electron quantum rings are presented to describe the spin-dependent rotating Wigner molecule states. The wavefunctions are constructed from the single-particle orbits which contain two variational parameters to describe the shape and size dependence of electron localization in the ring-like confinement. They can explicitly show the size dependence of single-particle orbital occupation to give an understanding of the spin rules of ground states without magnetic fields. They can also correctly describe the spin and angular momentum transitions in magnetic fields. By examining the von Neumann entropy, it is demonstrated that the wavefunctions can illustrate the entanglement between electrons in quantum rings, including the AB oscillations as well as the spin and size dependence of the entropy. Such trial wavefunctions will be useful in investigating spin-related quantum behaviors of a few electrons in quantum rings

  18. Modulation of signal transduction by tea catechins and related phytochemicals

    International Nuclear Information System (INIS)

    Shimizu, Masahito; Weinstein, I. Bernard

    2005-01-01

    Epidemiologic studies in human populations and experimental studies in rodents provide evidence that green tea and its constituents can inhibit both the development and growth of tumors at a variety of tissue sites. In addition, EGCG, a major biologically active component of green tea, inhibits growth and induces apoptosis in a variety of cancer cell lines. The purpose of this paper is to review evidence that these effects are mediated, at least in part, through inhibition of the activity of specific receptor tyrosine kinases (RTKs) and related downstream pathways of signal transduction. We also review evidence indicating that the antitumor effects of the related polyphenolic phytochemicals resveratrol, genistein, curcumin, and capsaicin are exerted via similar mechanisms. Some of these agents (EGCG, genistein, and curcumin) appear to directly target specific RTKs, and all of these compounds cause inhibition of the activity of the transcription factors AP-1 and NF-κB, thus inhibiting cell proliferation and enhancing apoptosis. Critical areas of future investigation include: (1) identification of the direct molecular target(s) of EGCG and related polyphenolic compounds in cells; (2) the in vivo metabolism and bioavailability of these compounds; (3) the ancillary effects of these compounds on tumor-stromal interactions; (4) the development of synergistic combinations with other antitumor agents to enhance efficacy in cancer prevention and therapy, and also minimize potential toxicities

  19. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    International Nuclear Information System (INIS)

    Kandasamy, Neelamegam; Ashokkumar, Natarajan

    2014-01-01

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

  20. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    Energy Technology Data Exchange (ETDEWEB)

    Kandasamy, Neelamegam; Ashokkumar, Natarajan, E-mail: npashokkumar1@gmail.com

    2014-09-01

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

  1. Biological functions of hCG and hCG-related molecules

    Directory of Open Access Journals (Sweden)

    Cole Laurence A

    2010-08-01

    Full Text Available Abstract Background hCG is a term referring to 4 independent molecules, each produced by separate cells and each having completely separate functions. These are hCG produced by villous syncytiotrophoblast cells, hyperglycosylated hCG produced by cytotrophoblast cells, free beta-subunit made by multiple primary non-trophoblastic malignancies, and pituitary hCG made by the gonadotrope cells of the anterior pituitary. Results and discussion hCG has numerous functions. hCG promotes progesterone production by corpus luteal cells; promotes angiogenesis in uterine vasculature; promoted the fusion of cytotrophoblast cell and differentiation to make syncytiotrophoblast cells; causes the blockage of any immune or macrophage action by mother on foreign invading placental cells; causes uterine growth parallel to fetal growth; suppresses any myometrial contractions during the course of pregnancy; causes growth and differentiation of the umbilical cord; signals the endometrium about forthcoming implantation; acts on receptor in mother's brain causing hyperemesis gravidarum, and seemingly promotes growth of fetal organs during pregnancy. Hyperglycosylated hCG functions to promote growth of cytotrophoblast cells and invasion by these cells, as occurs in implantation of pregnancy, and growth and invasion by choriocarcinoma cells. hCG free beta-subunit is produced by numerous non-trophoblastic malignancies of different primaries. The detection of free beta-subunit in these malignancies is generally considered a sign of poor prognosis. The free beta-subunit blocks apoptosis in cancer cells and promotes the growth and malignancy of the cancer. Pituitary hCG is a sulfated variant of hCG produced at low levels during the menstrual cycle. Pituitary hCG seems to mimic luteinizing hormone actions during the menstrual cycle.

  2. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease.

    Science.gov (United States)

    Mercado, Gabriela; Castillo, Valentina; Soto, Paulina; López, Nélida; Axten, Jeffrey M; Sardi, Sergio P; Hoozemans, Jeroen J M; Hetz, Claudio

    2018-04-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to the progressive decline of motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence suggest that altered proteostasis is a salient feature of PD, highlighting perturbations to the endoplasmic reticulum (ER), the main compartment involved in protein folding and secretion. PERK is a central ER stress sensor that enforces adaptive programs to recover homeostasis through a block of protein translation and the induction of the transcription factor ATF4. In addition, chronic PERK signaling results in apoptosis induction and neuronal dysfunction due to the repression in the translation of synaptic proteins. Here we confirmed the activation of PERK signaling in postmortem brain tissue derived from PD patients and three different rodent models of the disease. Pharmacological targeting of PERK by the oral administration of GSK2606414 demonstrated efficient inhibition of the pathway in the SNpc after experimental ER stress stimulation. GSK2606414 protected nigral-dopaminergic neurons against a PD-inducing neurotoxin, improving motor performance. The neuroprotective effects of PERK inhibition were accompanied by an increase in dopamine levels and the expression of synaptic proteins. However, GSK2606414 treated animals developed secondary effects possibly related to pancreatic toxicity. This study suggests that strategies to attenuate ER stress levels may be effective to reduce neurodegeneration in PD. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures

    Directory of Open Access Journals (Sweden)

    Studzinski Diane

    2009-01-01

    Full Text Available Abstract Background Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS in multiple sclerosis (MS. Methods We have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M. Results In two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE, related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1 seen at 6 hours with microarray. Conclusion Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter

  4. Inhibitory Effect of Curcumol on Jak2-STAT Signal Pathway Molecules of Fibroblast-Like Synoviocytes in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Heng Wang

    2012-01-01

    Full Text Available Hyperplasia of synovial membrane in rheumatoid arthritis (RA is a critical pathological foundation for inducing articular injury. The janus kinase and signal transducer and activator of transcription (Jak-STAT pathway plays a critical role in synovial membrane proliferation induced by platelet-derived growth factor (PDGF. To explore the anti-cell proliferation mechanism of curcumol, a pure monomer extracted from Chinese medical plant zedoary rhizome, the changes of Jak2-STAT1/3 signal pathway-related molecules in synoviocytes were observed in vitro. In this study, the fibroblast-like synoviocytes (FLS in patients with RA were collected and cultured. The following parameters were measured: cell proliferation (WST-1 assay, cell cycles (fluorescence-activated cell sorting, FACS, STAT1 and STAT3 activities (electrophoretic mobility shift assay, EMSA, and the protein expressions of phosphorylated Jak2, STAT1, and STAT3 (Western blot. It was shown that curcumol could inhibit the RA-FLS proliferation and DNA synthesis induced by PDGF-BB in a dose-dependent manner in vitro. The transcription factors activities of STAT1 and STAT3 were obviously elevated after PDGF-BB stimulation (P<0.05. Super-shift experiments identified the STAT1 or STAT3 proteins in the complex. Furthermore, the different concentration curcumol could downregulate the DNA binding activities of STAT1 and STAT3 (P<0.05 and inhibit the phosphorylation of Jak2 while it had no effect on the protein expressions of STAT1 and STAT3. Positive correlations were found between changes of cell proliferation and DNA-binding activities of STAT1 and STAT3, respectively (P<0.01. In conclusion, curcumol might suppress the FLS proliferation and DNA synthesis induced by PDGF-BB through attenuating Jak2 phosphorylation, downregulating STAT1 and STAT3 DNA-binding activities, which could provide theoretical foundation for clinical treatment of RA.

  5. Signaling molecule methylglyoxal ameliorates cadmium injury in wheat (Triticum aestivum L) by a coordinated induction of glutathione pool and glyoxalase system.

    Science.gov (United States)

    Li, Zhong-Guang; Nie, Qian; Yang, Cong-Li; Wang, Yue; Zhou, Zhi-Hao

    2018-03-01

    Methylglyoxal (MG) now is found to be an emerging signaling molecule. It can relieve the toxicity of cadmium (Cd), however its alleviating mechanism still remains unknown. In this study, compared with the Cd-stressed seedlings without MG treatment, MG treatment could stimulate the activities of glutathione reductase (GR) and gamma-glutamylcysteine synthetase (γ-ECS) in Cd-stressed wheat seedlings, which in turn induced an increase of reduced glutathione (GSH). Adversely, the activated enzymes related to GSH biosynthesis and increased GSH were weakened by N-acetyl-L-cysteine (NAC, MG scavenger), 2,4-dihydroxy-benzylamine (DHBA) and 1,3-bischloroethyl-nitrosourea (BCNU, both are specific inhibitors of GR), buthionine sulfoximine (BSO, a specific inhibitors of GSH biosynthesis), and N-ethylmaleimide (NEM, GSH scavenger), respectively. In addition, MG increased the activities of glyoxalase I (Gly I) and glyoxalase II (Gly II) in Cd-treated seedlings, followed by declining an increase in endogenous MG as comparision to Cd-stressed seedlings alone. On the contrary, the increased glyoxalase activity and decreased endogenous MG level were reversed by NAC and specific inhibitors of Gly I (isoascorbate, IAS; squaric acid, SA). Furthermore, MG alleviated an increase in hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) in Cd-treated wheat seedlings. These results indicated that MG could alleviate Cd toxicity and improve the growth of Cd-stressed wheat seedlings by a coordinated induction of glutathione pool and glyoxalase system. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Strategy for signaling molecule detection by using an integrated microfluidic device coupled with mass spectrometry to study cell-to-cell communication.

    Science.gov (United States)

    Mao, Sifeng; Zhang, Jie; Li, Haifang; Lin, Jin-Ming

    2013-01-15

    Cell-to-cell communication is a very important physiological behavior in life entity, and most of human behaviors are related to it. Although cell-to-cell communications are attracting much attention and financial support, rare methods have been successfully developed for in vitro cell-to-cell communication study. In this work, we developed a novel method for cell-to-cell communication study on an integrated microdevice, and signaling molecule and metabolites were online-detected by an electrospray ionization-quadrupole-time-of-flight-mass spectrometer (ESI-Q-TOF-MS) after on-chip solid-phase extraction. Moreover, we presented a "Surface Tension Plug" on a microchip to control cell-to-cell communication. The microdevice consists of three functional sections: cell coculture channel, targets pretreatment, and targets detection sections. To verify the feasibility of cell-to-cell communications on the integrated microdevice, we studied the communication between the 293 and the L-02 cells. Epinephrine and glucose were successfully detected using an ESI-Q-TOF-MS with short analysis time (communication study.

  7. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin-cadmium induced diabetic nephrotoxic rats.

    Science.gov (United States)

    Kandasamy, Neelamegam; Ashokkumar, Natarajan

    2014-09-01

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)-cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ-Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ-Cd induced diabetic nephrotoxic rats. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. The Neural Cell Adhesion Molecule NCAM2/OCAM/RNCAM, a Close Relative to NCAM

    DEFF Research Database (Denmark)

    Kulahin, Nikolaj; Walmod, Peter

    2008-01-01

    molecule (NCAM) is a well characterized, ubiquitously expressed CAM that is highly expressed in the nervous system. In addition to mediating cell adhesion, NCAM participates in a multitude of cellular events, including survival, migration, and differentiation of cells, outgrowth of neurites, and formation......Cell adhesion molecules (CAMs) constitute a large class of plasma membrane-anchored proteins that mediate attachment between neighboring cells and between cells and the surrounding extracellular matrix (ECM). However, CAMs are more than simple mediators of cell adhesion. The neural cell adhesion...... and plasticity of synapses. NCAM shares an overall sequence identity of approximately 44% with the neural cell adhesion molecule 2 (NCAM2), a protein also known as olfactory cell adhesion molecule (OCAM) and Rb-8 neural cell adhesion molecule (RNCAM), and the region-for-region sequence homology between the two...

  9. Sugar signalling and gene expression in relation to carbohydrate ...

    Indian Academy of Sciences (India)

    Sucrose is required for plant growth and development. The sugar status of plant cells is sensed by sensor proteins. The signal generated by signal transduction cascades, which could involve mitogen-activated protein kinases, protein phosphatases, Ca2+ and calmodulins, results in appropriate gene expression. A variety of ...

  10. On semi-classical questions related to signal analysis

    KAUST Repository

    Helffer, Bernard

    2011-12-01

    This study explores the reconstruction of a signal using spectral quantities associated with some self-adjoint realization of an h-dependent Schrödinger operator -h2(d2/dx2)-y(x), h>0, when the parameter h tends to 0. Theoretical results in semi-classical analysis are proved. Some numerical results are also presented. We first consider as a toy model the sech2 function. Then we study a real signal given by arterial blood pressure measurements. This approach seems to be very promising in signal analysis. Indeed it provides new spectral quantities that can give relevant information on some signals as it is the case for arterial blood pressure signal. © 2011 - IOS Press and the authors. All rights reserved.

  11. GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis.

    Science.gov (United States)

    Ooi, Makoto; Nishiumi, Shin; Yoshie, Tomoo; Shiomi, Yuuki; Kohashi, Michitaka; Fukunaga, Ken; Nakamura, Shiro; Matsumoto, Takayuki; Hatano, Naoya; Shinohara, Masakazu; Irino, Yasuhiro; Takenawa, Tadaomi; Azuma, Takeshi; Yoshida, Masaru

    2011-09-01

    The roles that amino acids play in immunity and inflammation are well defined, and the relationship between inflammatory bowel disease (IBD) and certain amino acids has recently attracted attention. In this study, the levels of amino acids and trichloroacetic acid (TCA) cycle-related molecules in the colonic tissues and sera of patients with ulcerative colitis (UC) were profiled by gas chromatography/mass spectrometry (GC/MS), with the aim of evaluating whether the clinical state induced by UC leads to variations in the amino acid profile. Colonic biopsy samples from 22 UC patients were used, as well as serum samples from UC patients (n = 13), Crohn's disease (CD) patients (n = 21), and healthy volunteers (n = 17). In the GC/MS-based profiling of amino acids and TCA cycle-related molecules, lower levels of 16 amino acids and 5 TCA cycle-related molecules were observed in the colonic lesion tissues of the UC patients, and the serum profiles of amino acids and TCA cycle-related molecules of the UC patients were different from those of the CD patients and healthy volunteers. Our study raises the possibility that GC/MS-based profiling of amino acids and TCA cycle-related molecules is a useful early diagnostic tool for UC.

  12. Enhanced Prevalence of Plasmatic Soluble MHC Class I Chain-Related Molecule in Vascular Pregnancy Diseases

    Directory of Open Access Journals (Sweden)

    Jean Baptiste Haumonte

    2014-01-01

    Full Text Available The major histocompatibility complex class I related chain (MIC is a stress-inducible protein modulating the function of immune natural killer (NK cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC may reflect immune disorders associated to vascular pregnancy diseases (VPD. sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32% than in normal term-matched pregnancies (1.6%, P<0.0001, with highest prevalence in intrauterine fetal death (IUDF, 44% and vascular intrauterine growth restriction (IUGR, 39%. sMIC levels were higher in preeclampsia (PE than in IUFD (P<0.01 and vascular IUGR (P<0.05. sMIC detection was associated with bilateral early diastolic uterine notches (P=0.037, thrombocytopenia (P=0.03, and high proteinuria (P=0.03 in PE and with the vascular etiology of IUGR (P=0.0038. Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.

  13. Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects

    Directory of Open Access Journals (Sweden)

    Regina F. Nasyrova

    2015-05-01

    Full Text Available Currently, schizophrenia is considered a multifactorial disease. Over the past 50 years, many investigators have considered the role of toxic free radicals in the etiology of schizophrenia. This is an area of active research which is still evolving. Here, we review the recent data and current concepts on the roles of nitric oxide (NO and related molecules in the pathogenesis of schizophrenia. NO is involved in storage, uptake and release of mediators and neurotransmitters, including glutamate, acetylcholine, noradrenaline, GABA, taurine and glycine. In addition, NO diffuses across cell membranes and activates its own extrasynaptic receptors. Further, NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum and fluids of subjects with schizophrenia. Given the roles of NO in central nervous system development, these changes may result in neurodevelopmental changes associated with schizophrenia. We describe here the recent literature on NOS gene polymorphisms on schizophrenia, which all point to consistent results. We also discuss how NO may be a new target for the therapy of mental disorders. Currently there have been 2 randomized double-blind placebo-controlled trials of L-lysine as an NOS inhibitor in the CNS.

  14. Synthesis of Large Molecules in Cometary Ice Analogs: Physical Properties Related to Self-Assembly Processes

    Science.gov (United States)

    Dworkin, Jason P.; Sandford, Scott A.; Deamer, David W.; Gillette, J. Seb; Zare, Richard N.; Allamandola, Louis J. (Technical Monitor)

    1999-01-01

    The combination of realistic laboratory simulations and infrared observations have revolutionized our understanding of interstellar dust and ice-the main component of comets. Since comets and carbonaceous micrometeorites may have been important sources of volatiles and carbon compounds on the early Earth, their organic composition may be related to the origin of life. Ices on grains in molecular clouds contain a variety of simple molecules. The D/H ratios of the comets Hale-Bopp and Hyakutake are consistent with a primarily interstellar ice mixture. Within the cloud and especially in the presolar nebula through the early solar system, these icy grains would have been photoprocessed by the ultraviolet producing more complex species such as hexamethylenetetramine, polyoxymethylenes, and simple keones. We reported at the 1999 Bioastronomy meeting laboratory simulations studied to identify the types of molecules which could have been generated in pre-cometary ices. Experiments were conducted by forming a realistic interstellar mixed-molecular ice (H2O, CH3OH, NH3 and CO) at approximately 10 K under high vacuum irradiated with UV light from a hydrogen plasma lamp. The gas mixture was typically 100:50:1:1, however when different ratios were used material with similar characteristics was still produced. The residue that remained after warming to room temperature was analyzed by HPLC, and by several mass spectrometric methods. This material contains a rich mixture of complex compounds with mass spectral profiles resembling those found in IDPs and meteorites. Surface tension measurements show that an amphiphilic component is also present. These species do not appear in various controls or in unphotolyzed samples. Residues from the simulations were also dispersed in aqueous media for microscopy. The organic material forms 10-40 gm diameter droplets that fluoresce at 300-450 nm under UV excitation. These droplets have a morphology and internal structure which appear

  15. Apoptosis-related molecules and radiation response in human oral cancers

    International Nuclear Information System (INIS)

    Teni, Tanuja; Mallick, Sanchita; Palve, Vinayak; Yasser, Mohd; Pawar, Sagar; Kannan, Sadhana; Agarwal, Jai Prakash; Kane, Shubhada

    2013-01-01

    The ability of the tumor cells to respond to radiotherapy depends upon their intrinsic radiosensitivity, which may be partly governed by molecules of the intrinsic cell death pathway. To identify the defects in this pathway in oral cancers, transcript expression analysis of the pathway members was done using the Ribonuclease protection assay in oral cell lines and tumors. The intrinsic apoptosis pathway was found to be deregulated in oral cell lines and majority of oral tumors with altered expression of Mcl-l, bclxl, survivin, p53 and p16 mRNA. To identify factors associated with radiosensitivity, differential gene expression profiles of radiation-treated versus untreated oral cell lines of differing radiosensitivities was carried out. To assess the predictive value of above altered molecules in radiotherapy outcome in oral cancer patients, pretreated biopsies from thirty nine oral cancer patients were examined for the expression of the apoptotic markers using immunohistochemistry and their expression was correlated with the clinico pathological parameters. High expression of Mcl-1 (p = 0.05) and PCNA (p = 0.007) was seen to be associated with poor disease free survival. High expression of Bcl-xL was associated with poor response to radiotherapy treatment. PCNA (p=0.04) and Mcl-1 (p=0.05) emerged as independent prognostic markers for predicting disease free survival in oral cancers treated with primary radiotherapy. A predominant overexpression of anti-apoptotic Mcl-1L over pro-apoptotic Mcl-1S isoform was observed in the oral cancer cell lines and oral tumors. An inverse correlation was observed between Mcl-1L expression and apoptosis induction in AW8507 cell line post-radiation treatment supporting its pro-survival role. A rapid and short induction of Mcl-1L versus sustained induction of Mcl-1L was observed in the relatively more radiosensitive FBM versus AW8507 respectively. siRNA treatment in combination with IR demonstrated significant induction of apoptosis

  16. Monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in exudative age-related macular degeneration.

    Science.gov (United States)

    Jonas, Jost B; Tao, Yong; Neumaier, Michael; Findeisen, Peter

    2010-10-01

    To examine intraocular concentrations of monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and vascular endothelial growth factor (VEGF) in eyes with exudative age-related macular degeneration (AMD). The investigation included a study group of 28 patients (28 eyes) with exudative AMD and a control group of 25 patients (25 eyes) with cataract. The concentrations of MCP-1, sICAM-1, sVCAM-1, and VEGF in aqueous humor samples obtained during surgery were measured using a solid-phase chemiluminescence immunoassay. The study group as compared with the control group had higher aqueous concentrations of sICAM-1 (mean [SD], 844 [2073] vs 246 [206] pg/mL, respectively; P < .001), sVCAM-1 (mean [SD], 7978 [7120] vs 2999 [1426] pg/mL, respectively; P < .001), and MCP-1 (mean [SD], 587 [338] vs 435 [221] pg/mL, respectively; P = .07). The concentration of VEGF did not vary significantly between the groups (P = .76). The MCP-1 concentration was significantly associated with macular thickness (r = 0.40; P = .004). It decreased significantly with the type of subfoveal neovascular membrane (classic membrane type, occult membrane, retinal pigment epithelium detachment) (P = .009). The concentrations of sICAM-1, sVCAM-1, and VEGF were not significantly associated with membrane type and macular thickness (P ≥ .18). Concentrations of MCP-1, sICAM-1, and sVCAM-1 are significantly associated with exudative AMD, even in the presence of normal VEGF concentrations. Intraocular MCP-1 concentrations are correlated with the subfoveal neovascular membrane type and the amount of macular edema. One may infer that MCP-1, sICAM-1, and sVCAM-1 could potentially be additional target molecules in therapy for exudative AMD.

  17. Effect of choline on antioxidant defenses and gene expressions of Nrf2 signaling molecule in the spleen and head kidney of juvenile Jian carp (Cyprinus carpio var. Jian).

    Science.gov (United States)

    Wu, Pei; Jiang, Wei-Dan; Liu, Yang; Chen, Gang-Fu; Jiang, Jun; Li, Shu-Hong; Feng, Lin; Zhou, Xiao-Qiu

    2014-06-01

    The present work evaluates the effects of various levels of dietary choline on antioxidant defenses and gene expressions of Nrf2 signaling molecule in spleen and head kidney of juvenile Jian carp (Cyprinus carpio var. Jian). Fish were fed with six different experimental diets containing graded levels of choline at 165 (choline-deficient control), 310, 607, 896, 1167 and 1820 mg kg(-1) diet for 65 days. At the end of the feeding trail, fish were challenged with Aeromonas hydrophila and mortalities were recorded over 17 days. Dietary choline significantly decreased malondialdehyde and protein carbonyl contents in spleen and head kidney. However, anti-superoxide anion and anti-hydroxyl radical activities in spleen and head kidney also decreased. Interestingly, activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) in spleen, GPx activity in head kidney, and glutathione contents in spleen and head kidney were decreased with increase of dietary choline levels up to a certain point, whereas, activities of SOD, GST and GR in head kidney showed no significantly differences among groups. Similarly, expression levels of CuZnSOD, MnSOD, CAT, GPx1a, GPx1b and GR gene in spleen and head kidney were significantly lower in group with choline level of 607 mg kg(-1) diet than those in the choline-deficient group. The relative gene expressions of Nrf2 in head kidney and Keap1a in spleen and head kidney were decreased with increasing of dietary choline up to a certain point. However, the relative gene expression of Nrf2 in spleen were not significantly affected by dietary choline. In conclusion, dietary choline decreased the oxidant damage and regulated the antioxidant system in immune organs of juvenile Jian carp. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: differential regulation of insulin signaling pathways.

    Directory of Open Access Journals (Sweden)

    Jane Palsgaard

    Full Text Available BACKGROUND: Gene expression alterations have previously been associated with type 2 diabetes, however whether these changes are primary causes or secondary effects of type 2 diabetes is not known. As healthy first degree relatives of people with type 2 diabetes have an increased risk of developing type 2 diabetes, they provide a good model in the search for primary causes of the disease. METHODS/PRINCIPAL FINDINGS: We determined gene expression profiles in skeletal muscle biopsies from Caucasian males with type 2 diabetes, healthy first degree relatives, and healthy controls. Gene expression was measured using Affymetrix Human Genome U133 Plus 2.0 Arrays covering the entire human genome. These arrays have not previously been used for this type of study. We show for the first time that genes involved in insulin signaling are significantly upregulated in first degree relatives and significantly downregulated in people with type 2 diabetes. On the individual gene level, 11 genes showed altered expression levels in first degree relatives compared to controls, among others KIF1B and GDF8 (myostatin. LDHB was found to have a decreased expression in both groups compared to controls. CONCLUSIONS/SIGNIFICANCE: We hypothesize that increased expression of insulin signaling molecules in first degree relatives of people with type 2 diabetes, work in concert with increased levels of insulin as a compensatory mechanism, counter-acting otherwise reduced insulin signaling activity, protecting these individuals from severe insulin resistance. This compensation is lost in people with type 2 diabetes where expression of insulin signaling molecules is reduced.

  19. A novel screen-printed mast cell-based electrochemical sensor for detecting spoilage bacterial quorum signaling molecules (N-acyl-homoserine-lactones) in freshwater fish.

    Science.gov (United States)

    Jiang, Donglei; Liu, Yan; Jiang, Hui; Rao, Shengqi; Fang, Wu; Wu, Mangang; Yuan, Limin; Fang, Weiming

    2018-04-15

    A novel screen-printed cell-based electrochemical sensor was developed to assess bacterial quorum signaling molecules, N-acylhomoserine lactones (AHLs). Screen-printed carbon electrode (SPCE), which possesses excellent properties such as low-cost, disposable and energy-efficient, was modified with multi-walled carbon nanotubes (MWNTs) to improve electrochemical signals and enhance the sensitivity. Rat basophilic leukemia (RBL-2H3) mast cells encapsulated in alginate/graphene oxide (NaAgl/GO) hydrogel were immobilized on the MWNTs/SPCE to serve as recognition element. Electrochemical impedance spectroscopy (EIS) was employed to record the cell impedance signal as-influenced by Pseudomonas aeruginosa quorum-sensing molecule, N-3-oxododecanoyl homoserine lactone (3OC 12 -HSL). Experimental results show that 3OC 12 -HSL caused a significant decrease in cell viability in a dose dependent manner. The EIS value decreased with concentrations of 3OC 12 -HSL in the range of 0.1-1μM, and the detection limit for 3OC 12 -HSL was calculated to be 0.094μM. These results were confirmed via cell viability, SEM, TEM analysis. Next, the sensor was successfully applied to monitoring the production of AHLs by spoilage bacteria in three different freshwater fish juice samples which efficiently proved the practicability of this cell based method. Therefore, the proposed cell sensor may serve as an innovative and effective approach to the measurement of quorum signaling molecule and thus provides a new avenue for real-time monitoring the spoilage bacteria in freshwater fish production. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling.

    Science.gov (United States)

    Lee, Min Chul; Okamoto, Masahiro; Liu, Yu Fan; Inoue, Koshiro; Matsui, Takashi; Nogami, Haruo; Soya, Hideaki

    2012-10-15

    Although voluntary running has beneficial effects on hippocampal cognitive functions if done abundantly, it is still uncertain whether resistance running would be the same. For this purpose, voluntary resistance wheel running (RWR) with a load is a suitable model, since it allows increased work levels and resultant muscular adaptation in fast-twitch muscle. Here, we examined whether RWR would have potential effects on hippocampal cognitive functions with enhanced hippocampal brain-derived neurotrophic factor (BDNF), as does wheel running without a load (WR). Ten-week-old male Wistar rats were assigned randomly to sedentary (Sed), WR, and RWR (to a maximum load of 30% of body weight) groups for 4 wk. We found that in RWR, work levels increased with load, but running distance decreased by about half, which elicited muscular adaptation for fast-twitch plantaris muscle without causing any negative stress effects. Both RWR and WR led to improved spatial learning and memory as well as gene expressions of hippocampal BDNF signaling-related molecules. RWR increased hippocampal BDNF, tyrosine-related kinase B (TrkB), and cAMP response element-binding (CREB) protein levels, whereas WR increased only BDNF. With both exercise groups, there were correlations between spatial memory and BDNF protein (r = 0.41), p-CREB protein (r = 0.44), and work levels (r = 0.77). These results suggest that RWR plays a beneficial role in hippocampus-related cognitive functions associated with hippocampal BDNF signaling, even with short distances, and that work levels rather than running distance are more determinant of exercise-induced beneficial effects in wheel running with and without a load.

  1. The yeast three-hybrid system as an experimental platform to identify proteins interacting with small signaling molecules in plant cells: Potential and limitations

    Directory of Open Access Journals (Sweden)

    Stéphanie eCottier

    2011-12-01

    Full Text Available Chemical genetics is a powerful scientific strategy that utilizes small bioactive molecules as experimental tools to unravel biological processes. Bioactive compounds occurring in nature represent an enormous diversity of structures that can be used to dissect functions of biological systems. Once the bioactivity of a natural or synthetic compound has been critically evaluated the challenge remains to identify its molecular target and mode of action, which usually is a time consuming and labor-intensive process. To facilitate this task, we decided to implement the yeast three-hybrid (Y3H technology as a general experimental platform to scan the whole Arabidopsis proteome for targets of small signaling molecules. The Y3H technology is based on the yeast two-hybrid system and allows direct cloning of proteins that interact in vivo with a synthetic hybrid ligand, which comprises the biologically active molecule of interest covalently linked to methotrexate (Mtx. In yeast nucleus the hybrid ligand connects two fusion proteins: the Mtx part binding to dihydrofolate reductase fused to a DNA binding domain (encoded in the yeast strain, and the bioactive molecule part binding to its potential protein target fused to a DNA activating domain (encoded on a cDNA expression vector. During cDNA library screening, the formation of this ternary, transcriptional activator complex leads to reporter gene activation in yeast cells, and thereby allows selection of the putative targets of small bioactive molecules of interest. Here we present the strategy and experimental details for construction and application of a Y3H platform, including chemical synthesis of different hybrid ligands, construction of suitable cDNA libraries, the choice of yeast strains, and appropriate screening conditions. Based on the results obtained and the current literature we discussed the perspectives and limitations of the Y3H approach for identifying targets of small bioactive molecules.

  2. Topology of charge density of flucytosine and related molecules and characteristics of their bond charge distributions.

    Science.gov (United States)

    Murgich, Juan; Franco, Héctor J; San-Blas, Gioconda

    2006-08-24

    The molecular charge distribution of flucytosine (4-amino-5-fluoro-2-pyrimidone), uracil, 5-fluorouracil, and thymine was studied by means of density functional theory calculations (DFT). The resulting distributions were analyzed by means of the atoms in molecules (AIM) theory. Bonds were characterized through vectors formed with the charge density value, its Laplacian, and the bond ellipticity calculated at the bond critical point (BCP). Within each set of C=O, C-H, and N-H bonds, these vectors showed little dispersion. C-C bonds formed three different subsets, one with a significant degree of double bonding, a second corresponding to single bonds with a finite ellipticity produced by hyperconjugation, and a third one formed by a pure single bond. In N-C bonds, a decrease in bond length (an increase in double bond character) was not reflected as an increase in their ellipticity, as in all C-C bonds studied. It was also found that substitution influenced the N-C, C-O, and C-C bond ellipticity much more than density and its Laplacian at the BCP. The Laplacian of charge density pointed to the existence of both bonding and nonbonding maxima in the valence shell charge concentration of N, O, and F, while only bonding ones were found for the C atoms. The nonbonding maxima related to the sites for electrophilic attack and H bonding in O and N, while sites of nucleophilic attack were suggested by the holes in the valence shell of the C atoms of the carbonyl groups.

  3. Age-related changes in the signal value of tears.

    Science.gov (United States)

    Zeifman, Debra M; Brown, Sarah A

    2011-08-12

    Emotional tears may be uniquely human and are an effective signal of distress in adults. The present study explored whether tears signal distress in younger criers and whether the effect of tears on observers is similar in magnitude across the life span. Participants rated photographs of crying infants, young children, and adults, with tears digitally removed or added. The effectiveness of tears in conveying sadness and eliciting sympathy was greatest for images of adults, intermediate for images of children, and least potent for images of infants. These findings suggest that the signal value of tears varies with the age of the crier. The results may shed light on the functional significance of crying at different stages of human development.

  4. Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement

    Science.gov (United States)

    Kim, Kyungsoo; Lim, Sung-Ho; Lee, Jaeseok; Kang, Won-Seok; Moon, Cheil; Choi, Ji-Woong

    2016-01-01

    Electroencephalograms (EEGs) measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI) studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR) is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP) signal that represents a brain’s response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE) schemes based on a joint maximum likelihood (ML) criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°. PMID:27322267

  5. Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement

    Directory of Open Access Journals (Sweden)

    Kyungsoo Kim

    2016-06-01

    Full Text Available Electroencephalograms (EEGs measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP signal that represents a brain’s response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE schemes based on a joint maximum likelihood (ML criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°.

  6. On the electrophilic character of molecules through its relation with electronegativity and chemical hardness.

    Science.gov (United States)

    Islam, Nazmul; Ghosh, Dulal C

    2012-01-01

    Electrophilicity is an intrinsic property of atoms and molecules. It probably originates logistically with the involvement in the physical process of electrostatics of soaked charge in electronic shells and the screened nuclear charge of atoms. Motivated by the existing view of conceptual density functional theory that similar to electronegativity and hardness equalization, there should be a physical process of equalization of electrophilicity during the chemical process of formation of hetero nuclear molecules, we have developed a new theoretical scheme and formula for evaluating the electrophilicity of hetero nuclear molecules. A comparative study with available bench marking reveals that the hypothesis of electrophilicity and equalization, and the present method of evaluating equalized electrophilicity, are scientifically promising.

  7. On the Electrophilic Character of Molecules Through Its Relation with Electronegativity and Chemical Hardness

    Directory of Open Access Journals (Sweden)

    Dulal C. Ghosh

    2012-02-01

    Full Text Available Electrophilicity is an intrinsic property of atoms and molecules. It probably originates logistically with the involvement in the physical process of electrostatics of soaked charge in electronic shells and the screened nuclear charge of atoms. Motivated by the existing view of conceptual density functional theory that similar to electronegativity and hardness equalization, there should be a physical process of equalization of electrophilicity during the chemical process of formation of hetero nuclear molecules, we have developed a new theoretical scheme and formula for evaluating the electrophilicity of hetero nuclear molecules. A comparative study with available bench marking reveals that the hypothesis of electrophilicity and equalization, and the present method of evaluating equalized electrophilicity, are scientifically promising.

  8. Borrowing strength : a likelihood ratio test for related sparse signals

    NARCIS (Netherlands)

    Wit, Ernst C.; Bakewell, David J. G.

    2012-01-01

    Motivation: Cancer biology is a field where the complexity of the phenomena battles against the availability of data. Often only a few observations per signal source, i.e. genes, are available. Such scenarios are becoming increasingly more relevant as modern sensing technologies generally have no

  9. Preface: Special Topic on Single-Molecule Biophysics.

    Science.gov (United States)

    Makarov, Dmitrii E; Schuler, Benjamin

    2018-03-28

    Single-molecule measurements are now almost routinely used to study biological systems and processes. The scope of this special topic emphasizes the physics side of single-molecule observations, with the goal of highlighting new developments in physical techniques as well as conceptual insights that single-molecule measurements bring to biophysics. This issue also comprises recent advances in theoretical physical models of single-molecule phenomena, interpretation of single-molecule signals, and fundamental areas of statistical mechanics that are related to single-molecule observations. A particular goal is to illustrate the increasing synergy between theory, simulation, and experiment in single-molecule biophysics.

  10. The Influence of Lead on Generation of Signalling Molecules and Accumulation of Flavonoids in Pea Seedlings in Response to Pea Aphid Infestation

    Directory of Open Access Journals (Sweden)

    Agnieszka Woźniak

    2017-08-01

    Full Text Available The aim of this study was to investigate the effect of an abiotic factor, i.e., lead at various concentrations (low causing a hormesis effect and causing high toxicity effects, on the generation of signalling molecules in pea (Pisum sativum L. cv. Cysterski seedlings and then during infestation by the pea aphid (Acyrthosiphon pisum Harris. The second objective was to verify whether the presence of lead in pea seedling organs and induction of signalling pathways dependent on the concentration of this metal trigger defense responses to A. pisum. Therefore, the profile of flavonoids and expression levels of genes encoding enzymes of the flavonoid biosynthesis pathway (phenylalanine ammonialyase and chalcone synthase were determined. A significant accumulation of total salicylic acid (TSA and abscisic acid (ABA was recorded in the roots and leaves of pea seedlings growing on lead-supplemented medium and next during infestation by aphids. Increased generation of these phytohormones strongly enhanced the biosynthesis of flavonoids, including a phytoalexin, pisatin. This research provides insights into the cross-talk between the abiotic (lead and biotic factor (aphid infestation on the level of the generation of signalling molecules and their role in the induction of flavonoid biosynthesis.

  11. High expression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 and 8 in primary myelofibrosis

    DEFF Research Database (Denmark)

    Riley, Caroline Hasselbalch; Skov, Vibe; Larsen, Thomas Stauffer

    2011-01-01

    for the egress of CD34+ cells from the bone marrow. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 has been implicated in cell adhesion, cellular invasiveness, angiogenesis, and inflammation, which are all key processes in the pathophysiology of PMF. Accordingly, CEACAMs may play an important...

  12. A relation between the rotational g-factor and the electric dipole moment of a diatomic molecule

    DEFF Research Database (Denmark)

    Sauer, Stephan P. A.

    1998-01-01

    The relation between the rotational g-factor and the electric dipole moment of a diatomic molecule is investigated. An explicit expression for the irreducible nonadiabatic contribution in terms of excited electronic states is derived. The importance of this expression for the analysis of vibration...

  13. Synthetic models related to DNA-intercalating molecules. Interactions between 8-alkoxypsoralen and adenine

    International Nuclear Information System (INIS)

    Decout, J.L.; Lhomme, J.

    1983-01-01

    To investigate the interactions and the photoreactions between furocoumarins and adenine, compounds in which a psoralen molecule is linked by different polymethylene bridges have been synthesised. Ring-ring intramolecular interactions are observed by UV spectroscopy. Thermodynamic parameters of these hydrophobic interactions are determined by the study of the variation of the hypochromic effect with temperature. (author)

  14. Ninth international conference on hole burning, single molecule and related spectroscopies: science and applications (HBSM 2006)

    International Nuclear Information System (INIS)

    2006-01-01

    This conference was organized around 9 sessions: -) single molecule, -) quantum optics, -) hole-burning materials and mechanisms, -) single nano-particle spectroscopy, -) dephasing and spectral diffusion, -) microwave photonics, -) biological systems, -) rare earth doped materials, -) novel laser sources. This document gathers only the slides of the presentations

  15. Ninth international conference on hole burning, single molecule and related spectroscopies: science and applications (HBSM 2006)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-07-01

    This conference was organized around 9 sessions: -) single molecule, -) quantum optics, -) hole-burning materials and mechanisms, -) single nano-particle spectroscopy, -) dephasing and spectral diffusion, -) microwave photonics, -) biological systems, -) rare earth doped materials, -) novel laser sources. This document gathers only the slides of the presentations.

  16. The neural cell adhesion molecule L1 is distinct from the N-CAM related group of surface antigens BSP-2 and D2

    DEFF Research Database (Denmark)

    Faissner, A; Kruse, J; Goridis, C

    1984-01-01

    The neural cell adhesion molecule L1 and the group of N-CAM related molecules, BSP-2 and D2 antigen, are immunochemically distinct molecular species. The two groups of surface molecules are also functionally distinct entities, since inhibition of Ca2+-independent adhesion among early post-natal m...

  17. Inhibitor of PI3K/Akt Signaling Pathway Small Molecule Promotes Motor Neuron Differentiation of Human Endometrial Stem Cells Cultured on Electrospun Biocomposite Polycaprolactone/Collagen Scaffolds.

    Science.gov (United States)

    Ebrahimi-Barough, Somayeh; Hoveizi, Elham; Yazdankhah, Meysam; Ai, Jafar; Khakbiz, Mehrdad; Faghihi, Faezeh; Tajerian, Roksana; Bayat, Neda

    2017-05-01

    Small molecules as useful chemical tools can affect cell differentiation and even change cell fate. It is demonstrated that LY294002, a small molecule inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway, can inhibit proliferation and promote neuronal differentiation of mesenchymal stem cells (MSCs). The purpose of this study was to investigate the differentiation effect of Ly294002 small molecule on the human endometrial stem cells (hEnSCs) into motor neuron-like cells on polycaprolactone (PCL)/collagen scaffolds. hEnSCs were cultured in a neurogenic inductive medium containing 1 μM LY294002 on the surface of PCL/collagen electrospun fibrous scaffolds. Cell attachment and viability of cells on scaffolds were characterized by scanning electron microscope (SEM) and 3-(4,5-dimethylthiazoyl-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay. The expression of neuron-specific markers was assayed by real-time PCR and immunocytochemistry analysis after 15 days post induction. Results showed that attachment and differentiation of hEnSCs into motor neuron-like cells on the scaffolds with Ly294002 small molecule were higher than that of the cells on tissue culture plates as control group. In conclusion, PCL/collagen electrospun scaffolds with Ly294002 have potential for being used in neural tissue engineering because of its bioactive and three-dimensional structure which enhances viability and differentiation of hEnSCs into neurons through inhibition of the PI3K/Akt pathway. Thus, manipulation of this pathway by small molecules can enhance neural differentiation.

  18. A small molecule inhibitor of signal peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity.

    Directory of Open Access Journals (Sweden)

    Iana Parvanova

    Full Text Available The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC(50 of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans.

  19. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD

    DEFF Research Database (Denmark)

    Harada, H; Andersen, Jens S.; Mann, M

    2001-01-01

    Cytokines often deliver simultaneous, yet distinct, cell growth and cell survival signals. The 70-kDa ribosomal protein S6 kinase (p70S6K) is known to regulate cell growth by inducing protein synthesis components. We purified membrane-based p70S6K as a kinase responsible for site-specific phospho...

  20. Hypoxia signaling pathways: modulators of oxygen-related organelles

    Science.gov (United States)

    Schönenberger, Miriam J.; Kovacs, Werner J.

    2015-01-01

    Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health. PMID:26258123

  1. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

    Science.gov (United States)

    Wang, Rui; Wan, Qi; Kozhaya, Lina; Fujii, Hodaka; Unutmaz, Derya

    2008-07-16

    Regulatory T (T(reg)) cells control immune activation and maintain tolerance. How T(regs) mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32), which within T cells is specifically expressed in T(regs) activated through the T cell receptor (TCR). Ectopic expression of GARP in human naïve T (T(N)) cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N) cells induced expression of T(reg) master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg) cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

  2. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

    Directory of Open Access Journals (Sweden)

    Rui Wang

    2008-07-01

    Full Text Available Regulatory T (T(reg cells control immune activation and maintain tolerance. How T(regs mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32, which within T cells is specifically expressed in T(regs activated through the T cell receptor (TCR. Ectopic expression of GARP in human naïve T (T(N cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N cells induced expression of T(reg master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

  3. Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways.

    Science.gov (United States)

    Chamilos, Georgios; Lionakis, Michail S; Kontoyiannis, Dimitrios P

    2018-01-06

    Opportunistic infections caused by Pneumocystis jirovecii, Cryptococcus neoformans, and ubiquitous airborne filamentous fungi have been recently reported in patients with hematological cancers historically considered at low risk for invasive fungal infections (IFIs), after receipt of the Bruton tyrosine kinase inhibitor ibrutinib. The spectrum and severity of IFIs often observed in these patients implies the presence of a complex immunodeficiency that may not be solely attributed to mere inhibition of Bruton tyrosine kinase. In view of the surge in development of small molecule kinase inhibitors for treatment of malignant and autoimmune diseases, it is possible that there would be an emergence of IFIs associated with the effects of these molecules on the immune system. Preclinical assessment of the immunosuppressive effects of kinase inhibitors and human studies aimed at improving patient risk stratification for development of IFIs could lead to prevention, earlier diagnosis, and better outcomes in affected patients. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  4. Benzofuranone derivatives as effective small molecules related to insulin amyloid fibrillation: a structure-function study

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim-Habibi, Azadeh; Navidpour, Latifeh

    2011-01-01

    amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds...... of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds....

  5. Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

    Directory of Open Access Journals (Sweden)

    So-Young Hwang

    2016-06-01

    Full Text Available The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenylsulfonyl]amino}benzoate as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin, promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/β-catenin signaling pathway.

  6. NADPH oxidase and lipid raft-associated redox signaling are required for PCB153-induced upregulation of cell adhesion molecules in human brain endothelial cells

    International Nuclear Information System (INIS)

    Eum, Sung Yong; Andras, Ibolya; Hennig, Bernhard; Toborek, Michal

    2009-01-01

    Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to chronic inflammation and the development of vascular diseases. Because cell adhesion molecules (CAMs) of the cerebrovascular endothelium regulate infiltration of inflammatory cells into the brain, we have explored the molecular mechanisms by which ortho-substituted polychlorinated biphenyls (PCBs), such as PCB153, can upregulate CAMs in brain endothelial cells. Exposure to PCB153 increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as elevated adhesion of leukocytes to brain endothelial cells. These effects were impeded by inhibitors of EGFR, JAKs, or Src activity. In addition, pharmacological inhibition of NADPH oxidase or disruption of lipid rafts by cholesterol depleting agents blocked PCB153-induced phosphorylation of JAK and Src kinases and upregulation of CAMs. In contrast, silencing of caveolin-1 by siRNA interference did not affect upregulation of ICAM-1 and VCAM-1 in brain endothelial cells stimulated by PCB153. Results of the present study indicate that lipid raft-dependent NADPH oxidase/JAK/EGFR signaling mechanisms regulate the expression of CAMs in brain endothelial cells and adhesion of leukocytes to endothelial monolayers. Due to its role in leukocyte infiltration, induction of CAMs may contribute to PCB-induced cerebrovascular disorders and neurotoxic effects in the CNS.

  7. Expression patterns of signaling lymphocytic activation molecule family members in peripheral blood mononuclear cell subsets in patients with systemic lupus erythematosus.

    Science.gov (United States)

    Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Kyttaris, Vasileios C; Tsokos, George C

    2017-01-01

    Genome-wide linkage analysis studies (GWAS) studies in systemic lupus erythematosus (SLE) identified the 1q23 region on human chromosome 1, containing the Signaling Lymphocytic Activation Molecule Family (SLAMF) cluster of genes, as a lupus susceptibility locus. The SLAMF molecules (SLAMF1-7) are immunoregulatory receptors expressed predominantly on hematopoietic cells. Activation of cells of the adaptive immune system is aberrant in SLE and dysregulated expression of certain SLAMF molecules has been reported. We examined the expression of SLAMF1-7 on peripheral blood T cells, B cells, monocytes, and their respective differentiated subsets, in patients with SLE and healthy controls in a systematic manner. SLAMF1 levels were increased on both T cell and B cells and their differentiated subpopulations in patients with SLE. SLAMF2 was increased on SLE CD4+ and CD8+ T cells. The frequency of SLAMF4+ and SLAMF7+ central memory and effector memory CD8+ T cells was reduced in SLE patients. Naïve CD4+ and CD8+ SLE T cells showed a slight increase in SLAMF3 levels. No differences were seen in the expression of SLAMF5 and SLAMF6 among SLE patients and healthy controls. Overall, the expression of various SLAMF receptors is dysregulated in SLE and may contribute to the immunopathogenesis of the disease.

  8. [Estimation of relation between homocysteine concentration and selected lipid parameters and adhesion molecules concentration in children with atherosclerosis risk factors].

    Science.gov (United States)

    Sierakowska-Fijałek, Anna; Baj, Zbigniew; Kaczmarek, Piotr; Stepień, Mariusz; Rysz, Jacek

    2008-10-01

    Atherosclerosis begins in childhood. At present among numerous risk factors of atherosclerosis the role of hiperhomocysteinemia in development of cardiovascular heart disease is taken under consideration. Atherogenic effect of homocystein is related to its cytotoxin action, conducting to endothelial dysfunction and damage. It is correlated with increase of the lipid levels in the blood serum and change of expression of the soluble forms of adhesion molecules. The aim of this study was to estimate relations between the homocystein serum concentration, expression of the selected adhesion molecules and the lipid levels in the blood serum in children with atherosclerosis risk factors. The group consisted of 670 children, 76 of them had atherosclerosis risk factors. In further examination 48 children have taken a part, whose parents were agreed for theirs participation in the program. The comparative group composed of 25 children without the risk factors. We determined total cholesterol (TC), triglycerides (TG), LDL cholesterol fraction (LDL-C), HDL cholesterol fraction (HDL-C), serum homocysteine concentration (Hcy), the expression of the soluble forms of adhesion molecules (sCAM): sP-selectin and sVCAM-1 (vascular cell adhesion molecule-1). Obesity, hypertension and lipid disorders in the shape of higher concentration of TC, LDL-C, TG and lower HDL-C were the most frequent risk factors in the investigated children. No significant differences in serum homocysteine concentration were observed between the investigated groups. However, its concentration was significantly higher in children with two atherosclerosis risk factors. No significant differences in expression of s-VCAM-1 were observed in the investigated groups, concentration of sP-selectin was significantly higher in children with atherosclerosis risk factors (phomocysteine and chosen adhesion molecules in children with atherosclerosis risk factors might potentially constitute the marker of early

  9. Quadra-quantum Dots and Related Patterns of Quantum Dot Molecules:

    Directory of Open Access Journals (Sweden)

    Somsak Panyakeow

    2010-10-01

    Full Text Available Abstract Laterally close-packed quantum dots (QDs called quantum dot molecules (QDMs are grown by modified molecular beam epitaxy (MBE. Quantum dots could be aligned and cross hatched. Quantum rings (QRs created from quantum dot transformation during thin or partial capping are used as templates for the formations of bi-quantum dot molecules (Bi-QDMs and quantum dot rings (QDRs. Preferable quantum dot nanostructure for quantum computation based on quantum dot cellular automata (QCA is laterally close-packed quantum dot molecules having four quantum dots at the corners of square configuration. These four quantum dot sets are called quadra-quantum dots (QQDs. Aligned quadra-quantum dots with two electron confinements work like a wire for digital information transmission by Coulomb repulsion force, which is fast and consumes little power. Combination of quadra-quantum dots in line and their cross-over works as logic gates and memory bits. Molecular Beam Epitaxial growth technique called ‘‘Droplet Epitaxy” has been developed for several quantum nanostructures such as quantum rings and quantum dot rings. Quantum rings are prepared by using 20 ML In-Ga (15:85 droplets deposited on a GaAs substrate at 390°C with a droplet growth rate of 1ML/s. Arsenic flux (7–8×10-6Torr is then exposed for InGaAs crystallization at 200°C for 5 min. During droplet epitaxy at a high droplet thickness and high temperature, out-diffusion from the centre of droplets occurs under anisotropic strain. This leads to quantum ring structures having non-uniform ring stripes and deep square-shaped nanoholes. Using these peculiar quantum rings as templates, four quantum dots situated at the corners of a square shape are regrown. Two of these four quantum dots are aligned either or , which are preferable crystallographic directions of quantum dot alignment in general.

  10. New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia

    International Nuclear Information System (INIS)

    Cojocari, Dan; Vellanki, Ravi N.; Sit, Brandon; Uehling, David; Koritzinsky, Marianne; Wouters, Bradly G.

    2013-01-01

    Background and purpose: The unfolded protein response (UPR) is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three distinct signaling arms. Here we explore the potential of targeting two of these arms with new potent small-molecule inhibitors designed against IRE1α and PERK. Methods: We utilized shRNAs and small-molecule inhibitors of IRE1α (4μ8c) and PERK (GSK-compound 39). XBP1 splicing and DNAJB9 mRNA was measured by qPCR and was used to monitor IRE1α activity. PERK activity was monitored by immunoblotting eIF2α phosphorylation and qPCR of DDIT3 mRNA. Hypoxia tolerance was measured using proliferation and clonogenic cell survival assays of cells exposed to mild or severe hypoxia in the presence of the inhibitors. Results: Using knockdown experiments we show that PERK is essential for survival of KP4 cells while knockdown of IRE1α dramatically decreases the proliferation and survival of HCT116 during hypoxia. Further, we show that in response to both hypoxia and other ER stress-inducing agents both 4μ8c and the PERK inhibitor are selective and potent inhibitors of IRE1α and PERK activation, respectively. However, despite potent inhibition of IRE1α activation, 4μ8c had no effect on cell proliferation or clonogenic survival of cells exposed to hypoxia. This was in contrast to the inactivation of PERK signaling with the PERK inhibitor, which reduced tolerance to hypoxia and other ER stress inducing agents. Conclusions: Our results demonstrate that IRE1α but not its splicing activity is important for hypoxic cell survival. The PERK signaling arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress and should be the focus of future therapeutic efforts

  11. The Pseudomonas aeruginosa quorum sensing signal molecule N-(3-oxododecanoyl) homoserine lactone enhances keratinocyte migration and induces Mmp13 gene expression in vitro

    International Nuclear Information System (INIS)

    Paes, Camila; Nakagami, Gojiro; Minematsu, Takeo; Nagase, Takashi; Huang, Lijuan; Sari, Yunita; Sanada, Hiromi

    2012-01-01

    Highlights: ► An evidence of the positive effect of AHL on epithelialization process is provided. ► AHL enhances keratinocyte’s ability to migrate in an in vitro scratch wound model. ► AHL induces the expression of Mmp13. ► Topical application of AHL represents a possible strategy to treat chronic wounds. -- Abstract: Re-epithelialization is an essential step of wound healing involving three overlapping keratinocyte functions: migration, proliferation and differentiation. While quorum sensing (QS) is a cell density-dependent signaling system that enables bacteria to regulate the expression of certain genes, the QS molecule N-(3-oxododecanoyl) homoserine lactone (AHL) exerts effects also on mammalian cells in a process called inter-kingdom signaling. Recent studies have shown that AHL improves epithelialization in in vivo wound healing models but detailed understanding of the molecular and cellular mechanisms are needed. The present study focused on the AHL as a candidate reagent to improve wound healing through direct modulation of keratinocyte’s activity in the re-epithelialization process. Results indicated that AHL enhances the keratinocyte’s ability to migrate in an in vitro scratch wound healing model probably due to the high Mmp13 gene expression analysis after AHL treatment that was revealed by real-time RT-PCR. Inhibition of activator protein 1 (AP-1) signaling pathway completely prevented the migration of keratinocytes, and also resulted in a diminished Mmp13 gene expression, suggesting that AP-1 might be essential in the AHL-induced migration. Taken together, these results imply that AHL is a promising candidate molecule to improve re-epithelialization through the induction of migration of keratinocytes. Further investigation is needed to clarify the mechanism of action and molecular pathway of AHL on the keratinocyte migration process.

  12. A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling.

    Science.gov (United States)

    Mahmoud, Ayman M; Wilkinson, Fiona L; Jones, Alan M; Wilkinson, James A; Romero, Miguel; Duarte, Juan; Alexander, M Yvonne

    2017-01-01

    Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the bioactive functions of glycosaminoglycans. Therefore, glycomimetics represent a unique source of novel therapies to target aberrant signaling and protein interactions in a wide range of diseases. We investigated the protective effects of four newly synthesized small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and oxidative stress. Four aromatic sugar mimetics were synthesized by the stepwise transformation of 2,5-dihydroxybenzoic acid to derivatives (C1-C4) incorporating sulfate groups to mimic the structure of heparan sulfate. Glycomimetic-treated human umbilical vein endothelial cells (HUVECs) were exposed to palmitic acid to model lipid-induced oxidative stress. Palmitate-induced impairment of NO production was restored by the glycomimetics, through activation of Akt/eNOS signaling. Furthermore, C1-C4 significantly inhibited palmitate-induced reactive oxygen species (ROS) production, lipid peroxidation, and activity and expression of NADPH oxidase. These effects were attributed to activation of the Nrf2/ARE pathway and downstream activation of cellular antioxidant and cytoprotective proteins. In ex vivo vascular reactivity studies, the glycomimetics (C1-C4) also demonstrated a significant improvement in endothelium-dependent relaxation and decreased ROS production and NADPH oxidase activity in isolated mouse thoracic aortic rings exposed to palmitate. The small molecule glycomimetics, C1-C4, protect against lipid-induced endothelial dysfunction through up-regulation of Akt/eNOS and Nrf2/ARE signaling pathways. Thus, carbohydrate-derived therapeutics are a new class of glycomimetic drugs targeting endothelial dysfunction, regarded as the first line of defense against vascular complications in cardiovascular disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. The Pseudomonas aeruginosa quorum sensing signal molecule N-(3-oxododecanoyl) homoserine lactone enhances keratinocyte migration and induces Mmp13 gene expression in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Paes, Camila, E-mail: camilaquinetti@gmail.com [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Nakagami, Gojiro, E-mail: gojiron-tky@umin.ac.jp [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Minematsu, Takeo, E-mail: tminematsu-tky@umin.ac.jp [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Nagase, Takashi, E-mail: tnagase@fb3.so-net.ne.jp [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Huang, Lijuan, E-mail: koureikenhlj@gmail.com [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Sari, Yunita, E-mail: yunita-tky@umin.ac.jp [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Sanada, Hiromi, E-mail: hsanada-tky@umin.ac.jp [University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer An evidence of the positive effect of AHL on epithelialization process is provided. Black-Right-Pointing-Pointer AHL enhances keratinocyte's ability to migrate in an in vitro scratch wound model. Black-Right-Pointing-Pointer AHL induces the expression of Mmp13. Black-Right-Pointing-Pointer Topical application of AHL represents a possible strategy to treat chronic wounds. -- Abstract: Re-epithelialization is an essential step of wound healing involving three overlapping keratinocyte functions: migration, proliferation and differentiation. While quorum sensing (QS) is a cell density-dependent signaling system that enables bacteria to regulate the expression of certain genes, the QS molecule N-(3-oxododecanoyl) homoserine lactone (AHL) exerts effects also on mammalian cells in a process called inter-kingdom signaling. Recent studies have shown that AHL improves epithelialization in in vivo wound healing models but detailed understanding of the molecular and cellular mechanisms are needed. The present study focused on the AHL as a candidate reagent to improve wound healing through direct modulation of keratinocyte's activity in the re-epithelialization process. Results indicated that AHL enhances the keratinocyte's ability to migrate in an in vitro scratch wound healing model probably due to the high Mmp13 gene expression analysis after AHL treatment that was revealed by real-time RT-PCR. Inhibition of activator protein 1 (AP-1) signaling pathway completely prevented the migration of keratinocytes, and also resulted in a diminished Mmp13 gene expression, suggesting that AP-1 might be essential in the AHL-induced migration. Taken together, these results imply that AHL is a promising candidate molecule to improve re-epithelialization through the induction of migration of keratinocytes. Further investigation is needed to clarify the mechanism of action and molecular pathway of AHL on the keratinocyte migration

  14. E3 ligase Hei10: a multifaceted structure-based signaling molecule with roles within and beyond meiosis

    Science.gov (United States)

    De Muyt, Arnaud; Zhang, Liangran; Piolot, Tristan; Kleckner, Nancy; Espagne, Eric; Zickler, Denise

    2014-01-01

    Human enhancer of invasion-10 (Hei10) mediates meiotic recombination and also plays roles in cell proliferation. Here we explore Hei10’s roles throughout the sexual cycle of the fungus Sordaria with respect to localization and effects of null, RING-binding, and putative cyclin-binding (RXL) domain mutations. Hei10 makes three successive types of foci. Early foci form along synaptonemal complex (SC) central regions. At some of these positions, depending on its RING and RXL domains, Hei10 mediates development and turnover of two sequential types of recombination complexes, each demarked by characteristic amplified Hei10 foci. Integration with ultrastructural data for recombination nodules further reveals that recombination complexes differentiate into three types, one of which corresponds to crossover recombination events during or prior to SC formation. Finally, Hei10 positively and negatively modulates SUMO localization along SCs by its RING and RXL domains, respectively. The presented findings suggest that Hei10 integrates signals from the SC, associated recombination complexes, and the cell cycle to mediate both the development and programmed turnover/evolution of recombination complexes via SUMOylation/ubiquitination. Analogous cell cycle-linked assembly/disassembly switching could underlie localization and roles for Hei10 in centrosome/spindle pole body dynamics and associated nuclear trafficking. We suggest that Hei10 is a unique type of structure-based signal transduction protein. PMID:24831702

  15. Dual small-molecule targeting of SMAD signaling stimulates human induced pluripotent stem cells toward neural lineages.

    Directory of Open Access Journals (Sweden)

    Methichit Wattanapanitch

    Full Text Available Incurable neurological disorders such as Parkinson's disease (PD, Huntington's disease (HD, and Alzheimer's disease (AD are very common and can be life-threatening because of their progressive disease symptoms with limited treatment options. To provide an alternative renewable cell source for cell-based transplantation and as study models for neurological diseases, we generated induced pluripotent stem cells (iPSCs from human dermal fibroblasts (HDFs and then differentiated them into neural progenitor cells (NPCs and mature neurons by dual SMAD signaling inhibitors. Reprogramming efficiency was improved by supplementing the histone deacethylase inhibitor, valproic acid (VPA, and inhibitor of p160-Rho associated coiled-coil kinase (ROCK, Y-27632, after retroviral transduction. We obtained a number of iPS colonies that shared similar characteristics with human embryonic stem cells in terms of their morphology, cell surface antigens, pluripotency-associated gene and protein expressions as well as their in vitro and in vivo differentiation potentials. After treatment with Noggin and SB431542, inhibitors of the SMAD signaling pathway, HDF-iPSCs demonstrated rapid and efficient differentiation into neural lineages. Six days after neural induction, neuroepithelial cells (NEPCs were observed in the adherent monolayer culture, which had the ability to differentiate further into NPCs and neurons, as characterized by their morphology and the expression of neuron-specific transcripts and proteins. We propose that our study may be applied to generate neurological disease patient-specific iPSCs allowing better understanding of disease pathogenesis and drug sensitivity assays.

  16. Diethyl hexyl phthalate-induced changes in insulin signaling molecules and the protective role of antioxidant vitamins in gastrocnemius muscle of adult male rat

    International Nuclear Information System (INIS)

    Srinivasan, Chinnapaiyan; Khan, Adam Ismail; Balaji, Venkataraman; Selvaraj, Jayaraman; Balasubramanian, Karundevi

    2011-01-01

    Diethyl hexyl phthalate (DEHP) is an endocrine disruptor, it influences various organ systems in human beings and experimental animals. DEHP reduced the serum testosterone and increased the blood glucose, estradiol, T 3 and T 4 in rats. However, the effect of DEHP on insulin signaling and glucose oxidation in skeletal muscle is not known. Adult male albino rats were divided into four groups: Group I: Control; Groups II and III: DEHP treated (dissolved in olive oil at a dose of 10 and 100 mg/kg body weight, respectively, once daily through gastric intubation for 30 days); and Group IV: DEHP (100 mg/kg body weight) plus vitamins E (50 mg/kg body weight) and C (100 mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubation for 30 days. On completion of treatment, animals were euthanized and perfused (whole body); gastrocnemius muscle was dissected out and subjected to assessment of various parameters. DEHP treatment increased the H 2 O 2 , hydroxyl radical levels and lipid peroxidation which disrupt the membrane integrity and insulin receptor. DEHP impaired the insulin signal transduction, glucose uptake and oxidation through decreased expression of plasma membrane GLUT4, which may partly be responsible for the elevation of fasting blood glucose level. The present study suggests that DEHP exposure affects glucose oxidation in skeletal muscle and is mediated through enhanced lipid peroxidation, impaired insulin signaling and GLUT4 expression in plasma membrane. Antioxidant vitamins (C and E) have a protective role against the adverse effect of DEHP. -- Highlights: ► DEHP treatment significantly decreased serum insulin and testosterone levels. ► Increased ROS and decreased glucose uptake were observed in DEHP treated animals. ► Impaired insulin signaling in gastrocnemius muscle was observed in DEHP treatment. ► Vitamins C and E alter ROS, glucose uptake, oxidation and insulin signaling molecules.

  17. Analysis of global gene expression profile of rice in response to methylglyoxal indicates its possible role as a stress signal molecule

    Directory of Open Access Journals (Sweden)

    Charanpreet eKaur

    2015-09-01

    Full Text Available Methylglyoxal (MG is a toxic metabolite produced primarily as a byproduct of glycolysis. Being a potent glycating agent, it can readily bind macromolecules like DNA, RNA or proteins, modulating their expression and activity. In plants, despite the known inhibitory effects of MG on growth and development, still limited information is available about the molecular mechanisms and response pathways elicited upon elevation in MG levels. To gain insight into the molecular basis of MG response, we have investigated changes in global gene expression profiles in rice upon exposure to exogenous MG using GeneChip microarrays. Initially, growth of rice seedlings was monitored in response to increasing MG concentrations which could retard plant growth in a dose-dependent manner. Upon exposure to 10 mM concentration of MG, a total of 1685 probe sets were up- or down-regulated by more than 1.5-fold in shoot tissues within 16 h. These were classified into ten functional categories. The genes involved in signal transduction such as, protein kinases and transcription factors, were significantly over-represented in the perturbed transcriptome, of which several are known to be involved in abiotic and biotic stress response indicating a cross-talk between MG-responsive and stress-responsive signal transduction pathways. Through in silico studies, we could predict 7-8 bp long conserved motif as a possible MG-responsive element (MGRE in the 1 kb upstream region of genes that were more than ten-fold up- or down-regulated in the analysis. Since several perturbations were found in signaling cascades in response to MG, we hereby suggest that it plays an important role in signal transduction probably acting as a stress signal molecule.

  18. Detecting and identifying small molecules in a nanopore flux capacitor

    International Nuclear Information System (INIS)

    Bearden, Samuel; Zhang, Guigen; McClure, Ethan

    2016-01-01

    A new method of molecular detection in a metallic-semiconductor nanopore was developed and evaluated with experimental and computational methods. Measurements were made of the charging potential of the electrical double layer (EDL) capacitance as charge-carrying small molecules translocated the nanopore. Signals in the charging potential were found to be correlated to the physical properties of analyte molecules. From the measured signals, we were able to distinguish molecules with different valence charge or similar valence charge but different size. The relative magnitude of the signals from different analytes was consistent over a wide range of experimental conditions, suggesting that the detected signals are likely due to single molecules. Computational modeling of the nanopore system indicated that the double layer potential signal may be described in terms of disruption of the EDL structure due to the size and charge of the analyte molecule, in agreement with Huckel and Debye’s analysis of the electrical atmosphere of electrolyte solutions. (paper)

  19. Diversity of Neuropeptide Cell-Cell Signaling Molecules Generated by Proteolytic Processing Revealed by Neuropeptidomics Mass Spectrometry

    Science.gov (United States)

    Hook, Vivian; Lietz, Christopher B.; Podvin, Sonia; Cajka, Tomas; Fiehn, Oliver

    2018-04-01

    Neuropeptides are short peptides in the range of 3-40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications. Global, untargeted neuropeptidomics mass spectrometry is advantageous for defining the structural features of the thousands to tens of thousands of neuropeptides present in biological systems. Defining neuropeptide structures is the basis for defining the proteolytic processing pathways that convert pro-neuropeptides into active peptides. Neuropeptidomics has revealed that processing of pro-neuropeptides occurs at paired basic residues sites, and at non-basic residue sites. Processing results in neuropeptides with known functions and generates novel peptides representing intervening peptide domains flanked by dibasic residue processing sites, identified by neuropeptidomics. While very short peptide products of 2-4 residues are predicted from pro-neuropeptide dibasic processing sites, such peptides have not been readily identified; therefore, it will be logical to utilize metabolomics to identify very short peptides with neuropeptidomics in future studies. Proteolytic processing is accompanied by covalent post-translational modifications (PTMs) of neuropeptides comprising C-terminal amidation, N-terminal pyroglutamate, disulfide bonds, phosphorylation, sulfation, acetylation, glycosylation, and others. Neuropeptidomics can define PTM features of neuropeptides. In summary, neuropeptidomics for untargeted, global analyses of neuropeptides is essential for elucidation of proteases that generate diverse neuropeptides for cell

  20. Diversity of Neuropeptide Cell-Cell Signaling Molecules Generated by Proteolytic Processing Revealed by Neuropeptidomics Mass Spectrometry

    Science.gov (United States)

    Hook, Vivian; Lietz, Christopher B.; Podvin, Sonia; Cajka, Tomas; Fiehn, Oliver

    2018-05-01

    Neuropeptides are short peptides in the range of 3-40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications. Global, untargeted neuropeptidomics mass spectrometry is advantageous for defining the structural features of the thousands to tens of thousands of neuropeptides present in biological systems. Defining neuropeptide structures is the basis for defining the proteolytic processing pathways that convert pro-neuropeptides into active peptides. Neuropeptidomics has revealed that processing of pro-neuropeptides occurs at paired basic residues sites, and at non-basic residue sites. Processing results in neuropeptides with known functions and generates novel peptides representing intervening peptide domains flanked by dibasic residue processing sites, identified by neuropeptidomics. While very short peptide products of 2-4 residues are predicted from pro-neuropeptide dibasic processing sites, such peptides have not been readily identified; therefore, it will be logical to utilize metabolomics to identify very short peptides with neuropeptidomics in future studies. Proteolytic processing is accompanied by covalent post-translational modifications (PTMs) of neuropeptides comprising C-terminal amidation, N-terminal pyroglutamate, disulfide bonds, phosphorylation, sulfation, acetylation, glycosylation, and others. Neuropeptidomics can define PTM features of neuropeptides. In summary, neuropeptidomics for untargeted, global analyses of neuropeptides is essential for elucidation of proteases that generate diverse neuropeptides for cell

  1. Adenosine Triphosphate (ATP Is a Candidate Signaling Molecule in the Mitochondria-to-Nucleus Retrograde Response Pathway

    Directory of Open Access Journals (Sweden)

    Zhengchang Liu

    2013-03-01

    Full Text Available Intracellular communication from the mitochondria to the nucleus is achieved via the retrograde response. In budding yeast, the retrograde response, also known as the RTG pathway, is regulated positively by Rtg1, Rtg2, Rtg3 and Grr1 and negatively by Mks1, Lst8 and two 14-3-3 proteins, Bmh1/2. Activation of retrograde signaling leads to activation of Rtg1/3, two basic helix-loop-helix leucine zipper transcription factors. Rtg1/3 activation requires Rtg2, a cytoplasmic protein with an N-terminal adenosine triphosphate (ATP binding domain belonging to the actin/Hsp70/sugar kinase superfamily. The critical regulatory step of the retrograde response is the interaction between Rtg2 and Mks1. Rtg2 binds to and inactivates Mks1, allowing for activation of Rtg1/3 and the RTG pathway. When the pathway is inactive, Mks1 has dissociated from Rtg2 and bound to Bmh1/2, preventing activation of Rtg1/3. What signals association or disassociation of Mks1 and Rtg2 is unknown. Here, we show that ATP at physiological concentrations dissociates Mks1 from Rtg2 in a highly cooperative fashion. We report that ATP-mediated dissociation of Mks1 from Rtg2 is conserved in two other fungal species, K. lactis and K. waltii. Activation of Rtg1/3 upregulates expression of genes encoding enzymes catalyzing the first three reactions of the Krebs cycle, which is coupled to ATP synthesis through oxidative phosphorylation. Therefore, we propose that the retrograde response is an ATP homeostasis pathway coupling ATP production with ATP-mediated repression of the retrograde response by releasing Mks1 from Rtg2.

  2. Green Production of Indolylquinones, Derivatives of Perezone, and Related Molecules, Promising Antineoplastic Compounds

    Directory of Open Access Journals (Sweden)

    René Gerardo Escobedo-González

    2016-01-01

    Full Text Available A green approach to produce the indolyl derivatives from four natural quinones (perezone, isoperezone, menadione, and plumbagin was performed; in this regard, a comparative study was accomplished among the typical mantle heating and three nonconventional activating modes of reaction (microwave, near-infrared, and high speed ball milling or tribochemical, under solventless conditions and using bentonitic clay as a catalyst. In addition, the tribochemical production of isoperezone from perezone is also commented on. It is also worth noting that the cytotoxicity of the synthesized indolylquinones in human breast cancer cell was tested by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay, with the 3-indolylisoperezone being the most active. The structural attribution of the target molecules was performed by typical spectroscopic procedures; moreover, the experimental and computed 1H and 13C NMR chemical shifts data, with previous acquisition of the corresponding minimum energetic structures, were in good agreement.

  3. Activation of CO{sub 2} and related small molecules by neopentyl-derivatized uranium complexes

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, Anna-Corina

    2015-06-18

    This work reports the newly synthesized neopentyl derivatized tris(aryloxide) U{sup III} complex [(({sup nP,Me}ArO){sub 3}tacn)U{sup III}] (1) and its reactivity with small molecules like nitrous oxide (N{sub 2}O), carbon dioxide (CO{sub 2}), and sulfur dioxide (SO{sub 2}). Additionally, a deeper insight into covalency of U-R bonds with R = O, N and the participation of the f-orbitals to bonding are discussed. For this purpose, a large number of characterization methods were used, such as X-ray diffraction analysis, U{sup V}/vis/NIR, IR vibrational, Raman, X-ray absorption, EPR, and {sup 1}H, {sup 15}N, {sup 13}C and {sup 19}F NMR spectroscopy, cyclic voltammetry, SQUID magnetization measurements and DFT calculations. Moreover, all compounds were checked for purity by elemental analysis.

  4. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor

    Science.gov (United States)

    Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun; Feng, Jian-Quan; Kobayashi, Tatsuya; Merregaert, Joseph; Liu, Chuan-Ju

    2016-01-01

    Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone–related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo. In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis.—Kong, L., Zhao, Y.-P., Tian, Q.-Y., Feng, J.-Q., Kobayashi, T., Merregaert, J., Liu, C.-J. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. PMID:27075243

  5. Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yu-Jen Chen

    Full Text Available Multi-drug resistance (MDR, an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC transporters and activated Sonic hedgehog (Shh signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX, we examined the effect and mechanism of norcantharidin (NCTD, a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S and DOX-resistant (MCF-7R cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.

  6. Control of density-dependent, cell state-specific signal transduction by the cell adhesion molecule CEACAM1, and its influence on cell cycle regulation

    International Nuclear Information System (INIS)

    Scheffrahn, Inka; Singer, Bernhard B.; Sigmundsson, Kristmundur; Lucka, Lothar; Oebrink, Bjoern

    2005-01-01

    Growth factor receptors, extracellular matrix receptors, and cell-cell adhesion molecules co-operate in regulating the activities of intracellular signaling pathways. Here, we demonstrate that the cell adhesion molecule CEACAM1 co-regulates growth-factor-induced DNA synthesis in NBT-II epithelial cells in a cell-density-dependent manner. CEACAM1 exerted its effects by regulating the activity of the Erk 1/2 MAP kinase pathway and the expression levels of the cyclin-dependent kinase inhibitor p27 Kip1 . Interestingly, both inhibitory and stimulatory effects were observed. Confluent cells continuously exposed to fetal calf serum showed little Erk activity and DNA synthesis compared with sparse cells. Under these conditions, anti-CEACAM1 antibodies strongly stimulated Erk activation, decreased p27 expression, and induced DNA synthesis. In serum-starved confluent cells, re-addition of 10% fetal calf serum activated the Erk pathway, decreased p27 expression, and stimulated DNA synthesis to the same levels as in sparse cells. Under these conditions anti-CEACAM1 antibodies de-activated Erk, restored the level of p27, and inhibited DNA synthesis. These data indicate that CEACAM1 mediates contact inhibition of proliferation in cells that are constantly exposed to growth factors, but co-activates growth-factor-induced proliferation in cells that have been starved for growth factors; exposure to extracellular CEACAM1 ligands reverts these responses

  7. AHL signaling molecules with a large acyl chain enhance biofilm formation on sulfur and metal sulfides by the bioleaching bacterium Acidithiobacillus ferrooxidans.

    Science.gov (United States)

    González, Alex; Bellenberg, Sören; Mamani, Sigde; Ruiz, Lina; Echeverría, Alex; Soulère, Laurent; Doutheau, Alain; Demergasso, Cecilia; Sand, Wolfgang; Queneau, Yves; Vera, Mario; Guiliani, Nicolas

    2013-04-01

    Biofilm formation plays a pivotal role in bioleaching activities of bacteria in both industrial and natural environments. Here, by visualizing attached bacterial cells on energetic substrates with different microscopy techniques, we obtained the first direct evidence that it is possible to positively modulate biofilm formation of the extremophilic bacterium Acidithiobacillus ferrooxidans on sulfur and pyrite surfaces by using Quorum Sensing molecules of the N-acylhomoserine lactone type (AHLs). Our results revealed that AHL-signaling molecules with a long acyl chain (12 or 14 carbons) increased the adhesion of A. ferrooxidans cells to these substrates. In addition, Card-Fish experiments demonstrated that C14-AHL improved the adhesion of indigenous A. ferrooxidans cells from a mixed bioleaching community to pyrite. Finally, we demonstrated that this improvement of cell adhesion is correlated with an increased production of extracellular polymeric substances. Our results open up a promising means to develop new strategies for the improvement of bioleaching efficiency and metal recovery, which could also be used to control environmental damage caused by acid mine/rock drainage.

  8. Increased fluidity and oxidation of malarial lipoproteins: relation with severity and induction of endothelial expression of adhesion molecules

    Directory of Open Access Journals (Sweden)

    Looareesuwan Sornchai

    2004-06-01

    Full Text Available Abstract Introduction Oxidative stress has been demonstrated in malaria. The potential oxidative modification of lipoproteins derived from malaria patients was studied. These oxidized lipids may have role in pathogenesis of malaria. Method The plasma lipid profile and existence of oxidized forms of very low density lipoprotein (VLDL, low density lipoprotein (LDL and high density lipoprotein (HDL were investigated in malaria (17 mild and 24 severe patients and 37 control subjects. Thiobarbituric acid reactive substances (TBARs, conjugated dienes, tryptophan fluorescence and fluidity of lipoproteins were determined as markers of oxidation. The biological effect of malarial lipoproteins was assessed by the expression of adhesion molecules on endothelial cells. Results Malarial lipoproteins had decreased cholesterol (except in VLDL and phospholipid. The triglyceride levels were unchanged. The cholesterol/phospholipid ratio of LDL was decreased in malaria, but increased in VLDL and HDL. TBARs and conjugate dienes were increased in malarial lipoproteins, while the tryptophan fluorescence was decreased. The fluidity of lipoproteins was increased in malaria. These indicated the presence of oxidized lipoproteins in malaria by which the degree of oxidation was correlated with severity. Of three lipoproteins from malarial patients, LDL displayed the most pronounced oxidative modification. In addition, oxidized LDL from malaria patients increased endothelial expression of adhesion molecules. Conclusion In malaria, the lipoproteins are oxidatively modified, and the degree of oxidation is related with severity. Oxidized LDL from malarial patients increases the endothelial expression of adhesion molecules. These suggest the role of oxidized lipoproteins, especially LDL, on the pathogenesis of disease.

  9. Auditory Warnings, Signal-Referent Relations, and Natural Indicators: Re-Thinking Theory and Application

    Science.gov (United States)

    Petocz, Agnes; Keller, Peter E.; Stevens, Catherine J.

    2008-01-01

    In auditory warning design the idea of the strength of the association between sound and referent has been pivotal. Research has proceeded via constructing classification systems of signal-referent associations and then testing predictions about ease of learning of different levels of signal-referent relation strength across and within different…

  10. Potential role of proteasome on c-jun related signaling in hypercholesterolemia induced atherosclerosis

    Directory of Open Access Journals (Sweden)

    Erdi Sozen

    2014-01-01

    Full Text Available Atherosclerosis and its complications are major causes of death all over the world. One of the major risks of atherosclerosis is hypercholesterolemia. During atherosclerosis, oxidized low density lipoprotein (oxLDL regulates CD36-mediated activation of c-jun amino terminal kinase-1 (JNK1 and modulates matrix metalloproteinase (MMP induction which stimulates inflammation with an invasion of monocytes. Additionally, inhibition of proteasome leads to an accumulation of c-jun and phosphorylated c-jun and activation of activator protein-1 (AP-1 related increase of MMP expression. We have previously reported a significant increase in cluster of differentiation 36 (CD36 mRNA levels in hypercholesterolemic rabbits and shown that vitamin E treatment prevented the cholesterol induced increase in CD36 mRNA expression. In the present study, our aim is to identify the signaling molecules/transcription factors involved in the progression of atherosclerosis following CD36 activation in an in vivo model of hypercholesterolemic (induced by 2% cholesterol containing diet rabbits. In this direction, proteasomal activities by fluorometry and c-jun, phospo c-jun, JNK1, MMP-9 expressions by quantitative RT-PCR and immunoblotting were tested in aortic tissues. The effects of vitamin E on these changes were also investigated in this model. As a result, c-jun was phosphorylated following decreased proteasomal degradation in hypercholesterolemic group. MMP-9 expression was also increased in cholesterol group rabbits contributing to the development of atherosclerosis. In addition, vitamin E showed its effect by decreasing MMP-9 levels and phosphorylation of c-jun.

  11. Performance Improvement of Power Analysis Attacks on AES with Encryption-Related Signals

    Science.gov (United States)

    Lee, You-Seok; Lee, Young-Jun; Han, Dong-Guk; Kim, Ho-Won; Kim, Hyoung-Nam

    A power analysis attack is a well-known side-channel attack but the efficiency of the attack is frequently degraded by the existence of power components, irrelative to the encryption included in signals used for the attack. To enhance the performance of the power analysis attack, we propose a preprocessing method based on extracting encryption-related parts from the measured power signals. Experimental results show that the attacks with the preprocessed signals detect correct keys with much fewer signals, compared to the conventional power analysis attacks.

  12. Hsp70-Bag3 interactions regulate cancer-related signaling networks.

    Science.gov (United States)

    Colvin, Teresa A; Gabai, Vladimir L; Gong, Jianlin; Calderwood, Stuart K; Li, Hu; Gummuluru, Suryaram; Matchuk, Olga N; Smirnova, Svetlana G; Orlova, Nina V; Zamulaeva, Irina A; Garcia-Marcos, Mikel; Li, Xiaokai; Young, Z T; Rauch, Jennifer N; Gestwicki, Jason E; Takayama, Shinichi; Sherman, Michael Y

    2014-09-01

    Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target. ©2014 American Association for Cancer Research.

  13. A comprehensive glossary of autophagy-related molecules and processes (2nd edition)

    DEFF Research Database (Denmark)

    Klionsky, Daniel J; Baehrecke, Eric H; Brumell, John H

    2011-01-01

    for readers--even those who work in the field--to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief...

  14. The node-weighted Steiner tree approach to identify elements of cancer-related signaling pathways.

    Science.gov (United States)

    Sun, Yahui; Ma, Chenkai; Halgamuge, Saman

    2017-12-28

    Cancer constitutes a momentous health burden in our society. Critical information on cancer may be hidden in its signaling pathways. However, even though a large amount of money has been spent on cancer research, some critical information on cancer-related signaling pathways still remains elusive. Hence, new works towards a complete understanding of cancer-related signaling pathways will greatly benefit the prevention, diagnosis, and treatment of cancer. We propose the node-weighted Steiner tree approach to identify important elements of cancer-related signaling pathways at the level of proteins. This new approach has advantages over previous approaches since it is fast in processing large protein-protein interaction networks. We apply this new approach to identify important elements of two well-known cancer-related signaling pathways: PI3K/Akt and MAPK. First, we generate a node-weighted protein-protein interaction network using protein and signaling pathway data. Second, we modify and use two preprocessing techniques and a state-of-the-art Steiner tree algorithm to identify a subnetwork in the generated network. Third, we propose two new metrics to select important elements from this subnetwork. On a commonly used personal computer, this new approach takes less than 2 s to identify the important elements of PI3K/Akt and MAPK signaling pathways in a large node-weighted protein-protein interaction network with 16,843 vertices and 1,736,922 edges. We further analyze and demonstrate the significance of these identified elements to cancer signal transduction by exploring previously reported experimental evidences. Our node-weighted Steiner tree approach is shown to be both fast and effective to identify important elements of cancer-related signaling pathways. Furthermore, it may provide new perspectives into the identification of signaling pathways for other human diseases.

  15. Effect of the signaling lymphocytic activation molecule (SLAM in the modulation of T cells in immune response to Leishmania braziliensis in vitro

    Directory of Open Access Journals (Sweden)

    Zirlane Castelo Branco Coêlho

    2017-02-01

    Full Text Available Introduction: Signaling lymphocyte activation molecule (SLAM is a self-ligand receptor on the surface of activated T- and B-lymphocytes, macrophages, and DC. Studies have shown PBMC from healthy individuals exposed to Leishmania differ in IFN-γ production. Objective: We investigated the role of SLAM signaling pathway in PMBC from high (HP and low (LP IFN-γ producers exposed to L. braziliensis in vitro. Methods: PBMC from 43 healthy individuals were cultured with or without antigen, α-SLAM, rIL-12 and rIFN-γ. The cytokines production was evaluated by ELISA, and SLAM expression by flow cytometry. Results: L. braziliensis associated with rIFN-γ or rIL-12 reduced early SLAM but did not modify this response later in HP. α-SLAM did not alter CD3+SLAM+ expression, and not affected IFN-γ and IL-13 production, in both groups, but increased significantly IL-10 in HP. Leishmania associated with α-SLAM and rIL-12 increased IFN-γ in LP, as well as IL-13 in HP. LP group presented low IFN-γ and IL-13 production, and low SLAM expression. Conclusion: Collectively, these findings suggest that when PBMC from healthy individuals are sensitized with L. braziliensis in vitro, SLAM acts in modulating Th1 response in HP individuals and induces a condition of immunosuppression in LP individuals.

  16. Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules

    DEFF Research Database (Denmark)

    Joosten, I; Wauben, M H; Holewijn, M C

    1994-01-01

    New strategies applied in the treatment of experimental autoimmune disease models involve blocking or modulation of MHC-peptide-TCR interactions either at the level of peptide-MHC interaction or, alternatively, at the level of T cell recognition. In order to identify useful competitor peptides one...... characteristics of the Lewis rat MHC class II RT1.B1 molecule. We have now developed a biochemical binding assay which enables competition studies in which the relative MHC binding affinity of a set of non-labelled peptides can be assessed while employing detection of biotinylated marker peptides...

  17. Attractor Structures of Signaling Networks: Consequences of Different Conformational Barcode Dynamics and Their Relations to Network-Based Drug Design.

    Science.gov (United States)

    Szalay, Kristóf Z; Nussinov, Ruth; Csermely, Peter

    2014-06-01

    Conformational barcodes tag functional sites of proteins and are decoded by interacting molecules transmitting the incoming signal. Conformational barcodes are modified by all co-occurring allosteric events induced by post-translational modifications, pathogen, drug binding, etc. We argue that fuzziness (plasticity) of conformational barcodes may be increased by disordered protein structures, by integrative plasticity of multi-phosphorylation events, by increased intracellular water content (decreased molecular crowding) and by increased action of molecular chaperones. This leads to increased plasticity of signaling and cellular networks. Increased plasticity is both substantiated by and inducing an increased noise level. Using the versatile network dynamics tool, Turbine (www.turbine.linkgroup.hu), here we show that the 10 % noise level expected in cellular systems shifts a cancer-related signaling network of human cells from its proliferative attractors to its largest, apoptotic attractor representing their health-preserving response in the carcinogen containing and tumor suppressor deficient environment modeled in our study. Thus, fuzzy conformational barcodes may not only make the cellular system more plastic, and therefore more adaptable, but may also stabilize the complex system allowing better access to its largest attractor. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Mechanisms and mediators of hypertension induced by erythropoietin and related molecules.

    Science.gov (United States)

    Agarwal, Rajiv

    2017-12-08

    Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce

  19. Improvement of the closed cranial window model in rats by intracarotid infusion of signalling molecules implicated in migraine

    DEFF Research Database (Denmark)

    Gupta, S; Bhatt, D K; Boni, L J

    2010-01-01

    required, respectively, compared with i.v. infusion to induce the same dilation in dural artery. Dilating intracarotid (i.c.) doses caused no or a minimal fall in BP, whereas equi-responsive i.v. doses caused a marked BP reduction. The CGRP blocking potential of olcegepant was amplified by > 20 times on i......-related peptide (CGRP) and pituitary adenylate cyclase polypeptide (PACAP)-38. High i.v. doses are required to study their craniovascular pharmacology. Unfortunately, this leads to a drop in blood pressure (BP) that subsequently causes blood vessels to dilate by autoregulation. Hence it is difficult to decipher.......c. infusion. Pial artery responses to CGRP did not change with i.c. infusion, demonstrating that dilations after i.v. CGRP are mediated by autoregulation rather than through specific receptors. We applied CGRP topically, which induced concentration-dependent dural vasodilation, but no effect on pial artery...

  20. Diethyl hexyl phthalate-induced changes in insulin signaling molecules and the protective role of antioxidant vitamins in gastrocnemius muscle of adult male rat

    Energy Technology Data Exchange (ETDEWEB)

    Srinivasan, Chinnapaiyan; Khan, Adam Ismail; Balaji, Venkataraman; Selvaraj, Jayaraman; Balasubramanian, Karundevi, E-mail: kbala82@rediffmail.com

    2011-12-15

    -Right-Pointing-Pointer Vitamins C and E alter ROS, glucose uptake, oxidation and insulin signaling molecules.

  1. Oxidative stress parameters induced by exposure to either cadmium or 17β-estradiol on Mytilus galloprovincialis hemocytes. The role of signaling molecules

    International Nuclear Information System (INIS)

    Koutsogiannaki, Sophia; Franzellitti, Silvia; Fabbri, Elena; Kaloyianni, Martha

    2014-01-01

    Highlights: •Oxidative parameters in Mytilus galloprovincialis hemocytes were measured. •Comparison between cadmium and 17β-estradiol cytotoxicity is discussed. •NHE, PKC, PI3-K, NADPH oxidase, NO synthase, JNK involvement was observed. •Protective role of cAMP is suggested. •Signaling molecules studied could constitute novel biomarkers. -- Abstract: The aim of the present study was to determine and compare the possible effects of exposure to an estrogen, 17β-estradiol and to a metal, cadmium on oxidative parameters of Mytilus galloprovincialis hemocytes and to elucidate the signaling pathways that probably mediate the studied effects exerted by these two chemicals. In addition, it was of interest to investigate if the studied parameters could constitute biomarkers for aquatic pollution monitoring. Our results suggest that micromolar concentrations of either cadmium or 17β-estradiol affected the redox status of mussels by modulating oxidative parameters and antioxidant enzymes gene expression in mussel M. galloprovincialis hemocytes. In particular, our results showed that treatment of hemocytes with either 5 μM of cadmium chloride or with 25 nM of 17β-estradiol for 30 min caused significant increased ROS production; this led to oxidative damage exemplified by significant increased DNA damage, protein carbonylation and lipid peroxidation, as well as increased mRNA levels of the antioxidant enzymes catalase (CAT), superoxide dismoutase (SOD) and glutathione S-transferase (GST). Furthermore, our results suggest that either cadmium or 17β-estradiol signal is mediated either through one of the already known pathways initiated by photatidyl-inositol 3-kinase (PI3 K) and reaching Na + /H + exchanger (NHE) probably through protein kinase C (PKC) or a kinase-mediated signaling pathway that involves in most of the cases NHE, PKC, Ca 2+ -dependent PKC isoforms, PI3-K, NADPH oxidase, nitric oxide (NO) synthase, c-Jun N-terminal kinase (JNK) and cyclic adenosine

  2. Oxidative stress parameters induced by exposure to either cadmium or 17β-estradiol on Mytilus galloprovincialis hemocytes. The role of signaling molecules

    Energy Technology Data Exchange (ETDEWEB)

    Koutsogiannaki, Sophia [Laboratory of Animal Physiology, Zoology Department, School of Biology, Faculty of Science, Aristotle University of Thessaloniki, 54124 Thessaloniki (Greece); Franzellitti, Silvia [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); Fabbri, Elena [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); University of Bologna, Department of Biological, Geological, and Environmental Sciences, via Selmi 3, 40100 Bologna (Italy); Kaloyianni, Martha, E-mail: kaloyian@bio.auth.gr [Laboratory of Animal Physiology, Zoology Department, School of Biology, Faculty of Science, Aristotle University of Thessaloniki, 54124 Thessaloniki (Greece)

    2014-01-15

    Highlights: •Oxidative parameters in Mytilus galloprovincialis hemocytes were measured. •Comparison between cadmium and 17β-estradiol cytotoxicity is discussed. •NHE, PKC, PI3-K, NADPH oxidase, NO synthase, JNK involvement was observed. •Protective role of cAMP is suggested. •Signaling molecules studied could constitute novel biomarkers. -- Abstract: The aim of the present study was to determine and compare the possible effects of exposure to an estrogen, 17β-estradiol and to a metal, cadmium on oxidative parameters of Mytilus galloprovincialis hemocytes and to elucidate the signaling pathways that probably mediate the studied effects exerted by these two chemicals. In addition, it was of interest to investigate if the studied parameters could constitute biomarkers for aquatic pollution monitoring. Our results suggest that micromolar concentrations of either cadmium or 17β-estradiol affected the redox status of mussels by modulating oxidative parameters and antioxidant enzymes gene expression in mussel M. galloprovincialis hemocytes. In particular, our results showed that treatment of hemocytes with either 5 μM of cadmium chloride or with 25 nM of 17β-estradiol for 30 min caused significant increased ROS production; this led to oxidative damage exemplified by significant increased DNA damage, protein carbonylation and lipid peroxidation, as well as increased mRNA levels of the antioxidant enzymes catalase (CAT), superoxide dismoutase (SOD) and glutathione S-transferase (GST). Furthermore, our results suggest that either cadmium or 17β-estradiol signal is mediated either through one of the already known pathways initiated by photatidyl-inositol 3-kinase (PI3 K) and reaching Na{sup +}/H{sup +} exchanger (NHE) probably through protein kinase C (PKC) or a kinase-mediated signaling pathway that involves in most of the cases NHE, PKC, Ca{sup 2+}-dependent PKC isoforms, PI3-K, NADPH oxidase, nitric oxide (NO) synthase, c-Jun N-terminal kinase (JNK) and

  3. Identification of Carboxylate, Phosphate, and Phenoxide Functionalities in Deprotonated Molecules Related to Drug Metabolites via Ion-Molecule Reactions with water and Diethylhydroxyborane

    Science.gov (United States)

    Zhu, Hanyu; Ma, Xin; Kong, John Y.; Zhang, Minli; Kenttämaa, Hilkka I.

    2017-10-01

    Tandem mass spectrometry based on ion-molecule reactions has emerged as a powerful tool for structural elucidation of ionized analytes. However, most currently used reagents were designed to react with protonated analytes, making them suboptimal for acidic analytes that are preferentially detected in negative ion mode. In this work we demonstrate that the phenoxide, carboxylate, and phosphate functionalities can be identified in deprotonated molecules by use of a combination of two reagents, diethylmethoxyborane (DEMB) and water. A novel reagent introduction setup that allowed DEMB and water to be separately introduced into the ion trap region of the mass spectrometer was developed to facilitate fundamental studies of this reaction. A new reagent, diethylhydroxyborane (DEHB), was generated inside the ion trap by hydrolysis of DEMB on introduction of water. Most carboxylates and phenoxides formed a DEHB adduct, followed by addition of one water molecule and subsequent ethane elimination (DEHB adduct +H2O - CH3CH3) as the major product ion. Phenoxides with a hydroxy group adjacent to the deprotonation site and phosphates formed a DEHB adduct, followed by ethane elimination (DEHB adduct - CH3CH3). Deprotonated molecules with strong intramolecular hydrogen bonds or without the aforementioned functionalities, including sulfates, were unreactive toward DEHB/H2O. Reaction mechanisms were explored via isotope labeling experiments and quantum chemical calculations. The mass spectrometry method allowed the differentiation of phenoxide-, carboxylate-, phosphate-, and sulfate-containing analytes. Finally, it was successfully coupled with high-performance liquid chromatography for the analysis of a mixture containing hymecromone, a biliary spasm drug, and its three possible metabolites. [Figure not available: see fulltext.

  4. Characteristics of Helicopter-Generated and Volcano-Related Seismic Tremor Signals

    Science.gov (United States)

    Eibl, Eva P. S.; Lokmer, Ivan; Bean, Christopher J.; Akerlie, Eggert; Vogfjörd, Kristin S.

    2017-04-01

    In volcanic environments it is crucial to distinguish between man-made seismic signals and signals created by the volcano. We compare volcanic, seismic signals with helicopter generated, seismic signals recorded in the last 2.5 years in Iceland. In both cases a long-lasting, emergent seismic signal, that can be referred to as seismic tremor, was generated. In the case of a helicopter, the rotating blades generate pressure pulses that travel through the air and excite Rayleigh waves at up to 40 km distance depending on wind speed, wind direction and topographic features. The longest helicopter related seismic signal we recorded was at the order of 40 minutes long. The tremor usually has a fundamental frequency of more than 10 Hz and overtones at integers of the fundamental frequency. Changes in distance lead to either increases or decreases of the frequency due to the Doppler Effect and are strongest for small source-receiver distances. The volcanic tremor signal was recorded during the Bardarbunga eruption at Holuhraun in 2014/15. For volcano-related seismic signals it is usually more difficult to determine the source process that generated the tremor. The pre-eruptive tremor persists for 2 weeks, while the co-eruptive tremor lasted for 6 months. We observed no frequency changes, most energy between 1 and 2 Hz and no or very little energy above 5 Hz. We compare the different characteristics of helicopter-related and volcano-related seismic signals and discuss how they can be distinguished. In addition we discuss how we can determine if a frequency change is related to a moving source or change in repeat time or a change in the geometry of the resonating body.

  5. The role of learning-related dopamine signals in addiction vulnerability.

    Science.gov (United States)

    Huys, Quentin J M; Tobler, Philippe N; Hasler, Gregor; Flagel, Shelly B

    2014-01-01

    Dopaminergic signals play a mathematically precise role in reward-related learning, and variations in dopaminergic signaling have been implicated in vulnerability to addiction. Here, we provide a detailed overview of the relationship between theoretical, mathematical, and experimental accounts of phasic dopamine signaling, with implications for the role of learning-related dopamine signaling in addiction and related disorders. We describe the theoretical and behavioral characteristics of model-free learning based on errors in the prediction of reward, including step-by-step explanations of the underlying equations. We then use recent insights from an animal model that highlights individual variation in learning during a Pavlovian conditioning paradigm to describe overlapping aspects of incentive salience attribution and model-free learning. We argue that this provides a computationally coherent account of some features of addiction. © 2014 Elsevier B.V. All rights reserved.

  6. Carbonyl Stress and Microinflammation-Related Molecules as Potential Biomarkers in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Tohru Ohnuma

    2018-03-01

    Full Text Available This literature review primarily aims to summarize our research, comprising both cross-sectional and longitudinal studies, and discuss the possibility of using microinflammation-related biomarkers as peripheral biomarkers in the diagnosis and monitoring of patients with schizophrenia. To date, several studies have been conducted on peripheral biomarkers to recognize the potential markers for the diagnosis of schizophrenia and to determine the state and effects of therapy in patients with schizophrenia. Research has established a correlation between carbonyl stress, an environmental factor, and the pathophysiology of neuropsychiatric diseases, including schizophrenia. In addition, studies on biomarkers related to these stresses have achieved results that are either replicable or exhibit consistent increases or decreases in patients with schizophrenia. For instance, pentosidine, an advanced glycation end product (AGE, is considerably elevated in patients with schizophrenia; however, low levels of vitamin B6 [a detoxifier of reactive carbonyl compounds (RCOs] have also been reported in some patients with schizophrenia. Another study on peripheral markers of carbonyl stress in patients with schizophrenia revealed a correlation of higher levels of glyceraldehyde-derived AGEs with higher neurotoxicity and lower levels of soluble receptors capable of diminishing the effects of AGEs. Furthermore, studies on evoked microinflammation-related biomarkers (e.g., soluble tumor necrosis factor receptor 1 have reported relatively consistent results, suggesting the involvement of microinflammation in the pathophysiology of schizophrenia. We believe that our cross-sectional and longitudinal studies as well as various previous inflammation marker studies that could be interpreted from several perspectives, such as mild localized encephalitis and microvascular disturbance, highlighted the importance of early intervention as prevention and distinguished the possible

  7. The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis.

    Science.gov (United States)

    Zhong, Ming-Chao; Veillette, André

    2013-11-01

    Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types.

  8. Utilization of dimethyl fumarate and related molecules for treatment of multiple sclerosis, cancer, and other diseases

    Directory of Open Access Journals (Sweden)

    Azzam Maghazachi

    2016-07-01

    Full Text Available Several drugs have been approved for treatment of multiple sclerosis. Dimethyl fumarate (DMF is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF, a related compound has not been examined in greater details although it has the potential as a therapeutic drug for multiple sclerosis and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species. However, other mechanisms have also been described which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage, osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article we will touch on some of these diseases with an emphasis on the effects of DMF and MMF on various immune cells.

  9. Effects of chronic REM sleep restriction on D1 receptor and related signal pathways in rat prefrontal cortex.

    Science.gov (United States)

    Han, Yan; Wen, Xiaosa; Rong, Fei; Chen, Xinmin; Ouyang, Ruying; Wu, Shuai; Nian, Hua; Ma, Wenling

    2015-01-01

    The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R' signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (P CSR rats (P CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function.

  10. Altered expression of signalling lymphocyte activation molecule receptors in T-cells from lupus nephritis patients-a potential biomarker of disease activity.

    Science.gov (United States)

    Stratigou, Victoria; Doyle, Anne F; Carlucci, Francesco; Stephens, Lauren; Foschi, Valentina; Castelli, Marco; McKenna, Nicola; Cook, H Terence; Lightstone, Liz; Cairns, Thomas D; Pickering, Matthew C; Botto, Marina

    2017-07-01

    The aim was to investigate whether the signalling lymphocyte activation molecule (SLAM) signalling pathways contribute to LN and whether SLAM receptors could be valuable biomarkers of disease activity. Peripheral blood mononuclear cells from 30National Research Ethics Service SLE patients with biopsy-proven LN were analysed by flow cytometry. Clinical measures of disease activity were assessed. The expression of the SLAM family receptors on T-cell subpopulations [CD4, CD8 and double negative (DN) T cells] was measured and compared between lupus patients with active renal disease and those in remission. The frequency of CD8 T cells expressing SLAMF3, SLAMF5 and SLAMF7 was significantly lower in LN patients who were in remission. In contrast, these subsets were similar in patients with active renal disease and in healthy individuals. Patients with active nephritis had an increased percentage of circulating monocytes, consistent with a potential role played by these cells in glomerular inflammation. Changes in the frequency of DN T cells positive for SLAMF2, SLAMF4 and SLAMF7 were observed in lupus patients irrespective of the disease activity. We detected alterations in the cellular expression of the SLAM family receptors, but these changes were less obvious and did not reveal any specific pattern. The percentage of DN T cells expressing SLAMF6 could predict the clinical response to B-cell depletion in patients with LN. Our study demonstrates altered expression of the SLAM family receptors in SLE T lymphocytes. This is consistent with the importance of the SLAM-associated pathways in lupus pathogenesis. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.

  11. Glucose: an Energy Currency and Structural Precursor in Articular Cartilage and Bone with Emerging Roles as an Extracellular Signalling Molecule and Metabolic Regulator

    Directory of Open Access Journals (Sweden)

    Ali eMobasheri

    2012-12-01

    Full Text Available In the musculoskeletal system glucose serves as an essential source of energy for the development, growth and maintenance of bone and articular cartilage. It is particularly needed for skeletal morphogenesis during embryonic growth and foetal development. Glucose is vital for osteogenesis and chondrogenesis, and is used as a precursor for the synthesis of glycosaminoglycans, glycoproteins and glycolipids. Glucose sensors are present in tissues and organs that carry out bulk glucose fluxes (i.e. intestine, kidney and liver. The beta cells of the pancreatic islets of Langerhans respond to changes in glucose concentration by varying the rate of insulin synthesis and secretion. Neuronal cells in the hypothalamus are also capable of sensing extracellular glucose. Glucosensing neurons use glucose as a signalling molecule to alter their action potential frequency in response to variations in ambient glucose levels. Skeletal muscle and adipose tissue can respond to changes in circulating glucose but much less is known about glucosensing in bone and cartilage. Recent research suggests that bone cells can influence (and be influenced by systemic glucose metabolism. This focused review article discusses what we know about glucose transport and metabolism in bone and cartilage and highlights recent studies that have linked glucose metabolism, insulin signalling and osteocalcin activity in bone and cartilage. These new findings in bone cells raise important questions about nutrient sensing, uptake, storage and processing mechanisms and how they might contribute to overall energy homeostasis in health and disease. The role of glucose in modulating anabolic and catabolic gene expression in normal and osteoarthritic chondrocytes is also discussed. In summary, cartilage and bone cells are sensitive to extracellular glucose and adjust their gene expression and metabolism in response to varying extracellular glucose concentrations.

  12. Deuterium-labelled N-acyl-l-homoserine lactones (AHLs) - inter-kingdom signalling molecules - synthesis, structural studies, and interactions with model lipid membranes

    Energy Technology Data Exchange (ETDEWEB)

    Jakubczyk, Dorota [Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe (Germany); Institute of Functional Interfaces, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen (Germany); Barth, Christoph; Anastassacos, Frances; Koelsch, Patrick; Schepers, Ute [Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen (Germany); Kubas, Adam; Fink, Karin [Institute of Nanotechnology, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen (Germany); Brenner-Weiss, Gerald [Institute of Functional Interfaces, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen (Germany); Braese, Stefan [Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe (Germany)

    2012-04-15

    N-Acyl-l-homoserine lactones (AHLs) are synthesized by Gram-negative bacteria. These quorum-sensing molecules play an important role in the context of bacterial infection and biofilm formation. They also allow communication between microorganisms and eukaryotic cells (inter-kingdom signalling). However, very little is known about the entire mechanism of those interactions. Precise structural studies are required to analyse the different AHL isomers as only one form is biologically most active. Theoretical studies combined with experimental infrared and Raman spectroscopic data are therefore undertaken to characterise the obtained compounds. To mimic interactions between AHL and cell membranes, we studied the insertion of AHL in supported lipid bilayers, using vibrational sum-frequency-generation spectroscopy. Deuterium-labelled AHLs were thus synthesized. Starting from readily available deuterated fatty acids, a two-step procedure towards deuterated N-acyl-l-homoserine lactones with varying chain lengths is described. This included the acylation of Meldrum's acid followed by amidation. Additionally, the detailed analytical evaluation of the products is presented herein. (orig.)

  13. Deuterium-labelled N-acyl-l-homoserine lactones (AHLs) - inter-kingdom signalling molecules - synthesis, structural studies, and interactions with model lipid membranes

    International Nuclear Information System (INIS)

    Jakubczyk, Dorota; Barth, Christoph; Anastassacos, Frances; Koelsch, Patrick; Schepers, Ute; Kubas, Adam; Fink, Karin; Brenner-Weiss, Gerald; Braese, Stefan

    2012-01-01

    N-Acyl-l-homoserine lactones (AHLs) are synthesized by Gram-negative bacteria. These quorum-sensing molecules play an important role in the context of bacterial infection and biofilm formation. They also allow communication between microorganisms and eukaryotic cells (inter-kingdom signalling). However, very little is known about the entire mechanism of those interactions. Precise structural studies are required to analyse the different AHL isomers as only one form is biologically most active. Theoretical studies combined with experimental infrared and Raman spectroscopic data are therefore undertaken to characterise the obtained compounds. To mimic interactions between AHL and cell membranes, we studied the insertion of AHL in supported lipid bilayers, using vibrational sum-frequency-generation spectroscopy. Deuterium-labelled AHLs were thus synthesized. Starting from readily available deuterated fatty acids, a two-step procedure towards deuterated N-acyl-l-homoserine lactones with varying chain lengths is described. This included the acylation of Meldrum's acid followed by amidation. Additionally, the detailed analytical evaluation of the products is presented herein. (orig.)

  14. The possible role of bacterial signal molecules N-acyl homoserine lactones in the formation of diatom-biofilm (Cylindrotheca sp.)

    International Nuclear Information System (INIS)

    Yang, Cuiyun; Fang, Shengtao; Chen, Dehui; Wang, Jianhua; Liu, Fanghua; Xia, Chuanhai

    2016-01-01

    Bacterial quorum sensing signal molecules N-acyl homoserine lactones (AHLs) (C10-HSL, 3-OXO-C10-HSL and 3-OH-C10-HSL) as possible chemical cues were employed to investigate the role in the formation of fouling diatom-biofilm (Cylindrotheca sp.). Results showed that AHLs promoted Chlorophyll a (Chl.a) and extracellular polymeric substance (EPS) contents in the diatom-biofilm. In the presence of AHLs-inhibitor 3, 4-Dibromo-2(5)H-furanone, which was used to avoid the possible interference of AHLs from bacteria, AHLs also increased the Chl.a and EPS contents. Scanning electron microscope and confocal laser scanning microscope analysis further demonstrated that AHLs promoted the formation of the diatom-biofilm. Non-invasive micro-test technique showed that AHLs promoted Ca 2+ efflux in Cylindrotheca sp., which implied that Ca 2+ might be correlated with AHLs-induced positive effect on the formation of diatom-biofilm. This study provides direct evidences that AHLs play an important role in developing the diatom-biofilm and AHLs-inhibitors might be promising active agents in marine antifouling. - Highlights: •AHLs effectively increase Chl.a and EPS contents in diatom-biofilm. •SEM and CLSM further demonstrate that AHLs promote the formation of diatom-biofilm. •AHLs trigger algal cellular Ca 2+ efflux. •AHLs-inhibitors might be promising active agents in marine antifouling.

  15. Ascorbic Acid-Induced Cardiac Differentiation of Murine Pluripotent Stem Cells: Transcriptional Profiling and Effect of a Small Molecule Synergist of Wnt/β-Catenin Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Dina Ivanyuk

    2015-05-01

    Full Text Available Background: Reproducible and efficient differentiation of pluripotent stem cells (PSCs to cardiomyocytes (CMs is essential for their use in regenerative medicine, drug testing and disease modeling. The aim of this study was to evaluate the effect of some previously reported cardiogenic substances on cardiac differentiation of mouse PSCs. Methods: Differentiation was performed by embryoid body (EB-based method using three different murine PSC lines. The differentiation efficiency was monitored by RT-qPCR, immunocytochemistry and flow cytometry, and the effect mechanistically evaluated by transcriptome analysis of treated EBs. Results: Among the five tested compounds (ascorbic acid, dorsomorphin, cyclic adenosine 3',5'-monophosphate, cardiogenol C, cyclosporin A only ascorbic acid (AA exerted a strong and reproducible cardiogenic effect in CGR8 cells which was less consistent in other two PSC lines. AA induced only minor changes in transcriptome of CGR8 cells after administration during the initial two days of differentiation. Cardiospecific genes and transcripts involved in angiogenesis, erythropoiesis and hematopoiesis were up-regulated on day 5 but not on days 2 or 3 of differentiation. The cardiac differentiation efficiency was improved when QS11, a small-molecule synergist of Wnt/β-catenin signaling pathway, was added to cultures after AA-treatment. Conclusion: This study demonstrates that only minor transcriptional changes are sufficient for enhancement of cardiogenesis of murine PSCs by AA and that AA and QS11 exhibit synergistic effects and enhance the efficiency of CM differentiation of murine PSCs.

  16. Intracellular Redox Compartmentation and ROS-Related Communication in Regulation and Signaling.

    Science.gov (United States)

    Noctor, Graham; Foyer, Christine H

    2016-07-01

    Recent years have witnessed enormous progress in understanding redox signaling related to reactive oxygen species (ROS) in plants. The consensus view is that such signaling is intrinsic to many developmental processes and responses to the environment. ROS-related redox signaling is tightly wedded to compartmentation. Because membranes function as barriers, highly redox-active powerhouses such as chloroplasts, peroxisomes, and mitochondria may elicit specific signaling responses. However, transporter functions allow membranes also to act as bridges between compartments, and so regulated capacity to transmit redox changes across membranes influences the outcome of triggers produced at different locations. As well as ROS and other oxidizing species, antioxidants are key players that determine the extent of ROS accumulation at different sites and that may themselves act as signal transmitters. Like ROS, antioxidants can be transported across membranes. In addition, the intracellular distribution of antioxidative enzymes may be modulated to regulate or facilitate redox signaling appropriate to the conditions. Finally, there is substantial plasticity in organellar shape, with extensions such as stromules, peroxules, and matrixules playing potentially crucial roles in organelle-organelle communication. We provide an overview of the advances in subcellular compartmentation, identifying the gaps in our knowledge and discussing future developments in the area. © 2016 American Society of Plant Biologists. All Rights Reserved.

  17. A theoretical and experimental study on the molecular and electronic structures of artemisinin and related drug molecules

    International Nuclear Information System (INIS)

    Galasso, V.; Kovac, B.; Modelli, A.

    2007-01-01

    The equilibrium structures of artemisinin and a selection of its derivatives (potent antimalarial drugs) have been studied with the density functional theory ansatz B3LYP. Of the five rings of the artemisinin framework, it is only the pyranose ring B that exhibits a marked conformational flexibility, especially on addition of a pendant side chain at C-10. For the derivatives, the β isomer with the axial substituent group is found to be energetically more stable than the α isomer with the equatorial group. The assignment of the vibrational fundamentals has been supported by calculations on related model molecules and a normal coordinate analysis. This allows for a reliable characterization of the normal modes, mainly involving the peroxide linkage, in the claimed fingerprint region of 1,2,4-trioxanes. The electronic structures have also been studied by measuring and calculating significant features of the NMR, photoelectron and electron transmission spectra. In particular, a representative set of NMR chemical shifts and nuclear spin-spin coupling constants, obtained with DFT formalisms, compares favourably with experiment and fits expectation in terms of stereoelectronic effects of the vicinal oxygen lone pairs. Based on ab initio outer valence Green's function calculations, a consistent interpretation of the uppermost bands in the photoelectron spectra of artemisinin and derivatives has been advanced. The top ionization energies reflect a complex interaction of the various oxygen lone pair orbitals. Electron transmission spectroscopy is applied for the first time to compounds containing the peroxide bond and elucidates the empty level electronic structure of artemisinin and derivatives in the 0-6 eV energy range, with the support of MO calculations and comparison with the spectra of reference molecules. Electron attachment to the lowest-lying empty σ* MO, mainly localized on the O-O bridge, occurs at an energy (1.7 eV) exceptionally low for compounds not

  18. RAFTK, a novel member of the focal adhesion kinase family, is phosphorylated and associates with signaling molecules upon activation of mature T lymphocytes.

    Science.gov (United States)

    Ganju, R K; Hatch, W C; Avraham, H; Ona, M A; Druker, B; Avraham, S; Groopman, J E

    1997-03-17

    The related adhesion focal tyrosine kinase (RAFTK), a recently discovered member of the focal adhesion kinase family, has previously been reported to participate in signal transduction in neuronal cells, megakaryocytes, and B lymphocytes. We have found that RAFTK is constitutively expressed in human T cells and is rapidly phosphorylated upon the activation of the T cell receptor (TCR). This activation also results in an increase in the autophosphorylation and kinase activity of RAFTK. After its stimulation, there was an increase in the association of the src cytoplasmic tyrosine kinase Fyn and the adapter protein Grb2. This association was mediated through the SH2 domains of Fyn and Grb2. RAFTK also co-immunoprecipitates with the SH2 domain of Lck and with the cytoskeletal protein paxillin through its COOH-terminal proline-rich domain. The tyrosine phosphorylation of RAFTK after T cell receptor-mediated stimulation was reduced by the pretreatment of cells with cytochalasin D, suggesting the role of the cytoskeleton in this process. These observations indicate that RAFTK participates in T cell receptor signaling and may act to link signals from the cell surface to the cytoskeleton and thereby affect the host immune response.

  19. Subretinal Fluid Levels of Signal-Transduction Proteins and Apoptosis Molecules in Macula-Off Retinal Detachment Undergoing Scleral Buckle Surgery.

    Science.gov (United States)

    Carpineto, Paolo; Aharrh-Gnama, Agbeanda; Ciciarelli, Vincenzo; Borrelli, Enrico; Petti, Francesco; Aloia, Raffaella; Lamolinara, Alessia; Di Nicola, Marta; Mastropasqua, Leonardo

    2016-12-01

    To evaluate signal transduction and early apoptosis protein levels in subretinal fluid collected during scleral buckling surgery for macula-off rhegmatogenous retinal detachment (RRD). Our aim was to assess both their relation with RRD features and their influence on the posttreatment outcome. Thirty-three eyes of 33 RRD patients scheduled for scleral buckle surgery were enrolled in the study. Undiluted subretinal fluid samples were collected during surgery and analyzed via magnetic bead-based immunoassay. All patients underwent a complete ophthalmologic evaluation at baseline and at each follow-up visit (months 1, 3, and 6). Moreover, both at baseline and at the postsurgery month 6 visit, the patients were tested by means of spectral-domain optical coherence tomography (SD-OCT) in order to evaluate the average ganglion cell-inner plexiform complex thickness, as well as the photoreceptor inner segment/outer segment junction status. Patients' clinical features (retinal detachment size, detachment duration, and occurrence of proliferative vitreoretinopathy) were associated with several early apoptotic factors (caspase-8, caspase-9, and B-cell lymphoma 2 [Bcl-2]-associated death promoter [BAD]). Furthermore, both early apoptosis factors (caspase-8, Bcl-2, and p53) and signal-transduction proteins (ERK 1/2) were found to influence the postsurgery month 3 OCT characteristics. Signal-transduction proteins and early apoptosis proteins are associated with different clinical features and postsurgery outcomes.

  20. Gamma-butyrolactone and furan signaling systems in Streptomyces.

    Science.gov (United States)

    Sidda, John D; Corre, Christophe

    2012-01-01

    Streptomyces bacteria produce different classes of diffusible signaling molecules that trigger secondary metabolite production and/or morphological development within the cell population. The biosynthesis of gamma-butyrolactones (GBLs) and 2-alkyl-4-hydroxymethylfuran-3-carboxylic acids (AHFCAs) signaling molecules is related and involves an essential AfsA-like butenolide synthase. This chapter first describes the catalytic role of AfsA-like enzyme then provides details about methods for the discovery and characterization of potentially novel signaling molecules. In section 4, one approach for establishing the biological role of these signaling molecules is presented. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Effects of heat stress on serum insulin, adipokines, AMP-activated protein kinase, and heat shock signal molecules in dairy cows.

    Science.gov (United States)

    Min, Li; Cheng, Jian-bo; Shi, Bao-lu; Yang, Hong-jian; Zheng, Nan; Wang, Jia-qi

    2015-06-01

    Heat stress affects feed intake, milk production, and endocrine status in dairy cows. The temperature-humidity index (THI) is employed as an index to evaluate the degree of heat stress in dairy cows. However, it is difficult to ascertain whether THI is the most appropriate measurement of heat stress in dairy cows. This experiment was conducted to investigate the effects of heat stress on serum insulin, adipokines (leptin and adiponectin), AMP-activated protein kinase (AMPK), and heat shock signal molecules (heat shock transcription factor (HSF) and heat shock proteins (HSP)) in dairy cows and to research biomarkers to be used for better understanding the meaning of THI as a bioclimatic index. To achieve these objectives, two experiments were performed. The first experiment: eighteen lactating Holstein dairy cows were used. The treatments were: heat stress (HS, THI average=81.7, n=9) and cooling (CL, THI average=53.4, n=9). Samples of HS were obtained on August 16, 2013, and samples of CL were collected on April 7, 2014 in natural conditions. The second experiment: HS treatment cows (n=9) from the first experiment were fed for 8 weeks from August 16, 2013 to October 12, 2013. Samples for moderate heat stress, mild heat stress, and no heat stress were obtained, respectively, according to the physical alterations of the THI. Results showed that heat stress significantly increased the serum adiponectin, AMPK, HSF, HSP27, HSP70, and HSP90 (Pdairy cows. When heat stress treatment lasted 8 weeks, a higher expression of HSF and HSP70 was observed under moderate heat stress. Serum HSF and HSP70 are sensitive and accurate in heat stress and they could be potential indicators of animal response to heat stress. We recommend serum HSF and HSP70 as meaningful biomarkers to supplement the THI and evaluate moderate heat stress in dairy cows in the future.

  2. Effects of heat stress on serum insulin, adipokines, AMP-activated protein kinase, and heat shock signal molecules in dairy cows*

    Science.gov (United States)

    Min, Li; Cheng, Jian-bo; Shi, Bao-lu; Yang, Hong-jian; Zheng, Nan; Wang, Jia-qi

    2015-01-01

    Heat stress affects feed intake, milk production, and endocrine status in dairy cows. The temperature-humidity index (THI) is employed as an index to evaluate the degree of heat stress in dairy cows. However, it is difficult to ascertain whether THI is the most appropriate measurement of heat stress in dairy cows. This experiment was conducted to investigate the effects of heat stress on serum insulin, adipokines (leptin and adiponectin), AMP-activated protein kinase (AMPK), and heat shock signal molecules (heat shock transcription factor (HSF) and heat shock proteins (HSP)) in dairy cows and to research biomarkers to be used for better understanding the meaning of THI as a bioclimatic index. To achieve these objectives, two experiments were performed. The first experiment: eighteen lactating Holstein dairy cows were used. The treatments were: heat stress (HS, THI average=81.7, n=9) and cooling (CL, THI average=53.4, n=9). Samples of HS were obtained on August 16, 2013, and samples of CL were collected on April 7, 2014 in natural conditions. The second experiment: HS treatment cows (n=9) from the first experiment were fed for 8 weeks from August 16, 2013 to October 12, 2013. Samples for moderate heat stress, mild heat stress, and no heat stress were obtained, respectively, according to the physical alterations of the THI. Results showed that heat stress significantly increased the serum adiponectin, AMPK, HSF, HSP27, HSP70, and HSP90 (Pheat-stressed dairy cows. When heat stress treatment lasted 8 weeks, a higher expression of HSF and HSP70 was observed under moderate heat stress. Serum HSF and HSP70 are sensitive and accurate in heat stress and they could be potential indicators of animal response to heat stress. We recommend serum HSF and HSP70 as meaningful biomarkers to supplement the THI and evaluate moderate heat stress in dairy cows in the future. PMID:26055916

  3. Planck intermediate results: III. the relation between galaxy cluster mass and Sunyaev-Zeldovich signal

    DEFF Research Database (Denmark)

    Bartlett, J.G.; Bucher, M.; Cardoso, J.-F.

    2013-01-01

    We examine the relation between the galaxy cluster mass M and Sunyaev-Zeldovich (SZ) effect signal DA2 Y500 for a sample of 19 objects for which weak lensing (WL) mass measurements obtained from Subaru Telescope data are available in the literature. Hydrostatic X-ray masses are derived from XMM-N...

  4. Right Hemisphere Sensitivity to Novel Metaphoric Relations: Application of the Signal Detection Theory

    Science.gov (United States)

    Mashal, N.; Faust, M.

    2008-01-01

    The present study used the signal detection theory to test the hypothesis that the right hemisphere (RH) is more sensitive than the left hemisphere (LH) to the distant semantic relations in novel metaphoric expressions. In two divided visual field experiments, sensitivity (d') and criterion ([beta]) were calculated for responses to different types…

  5. Relation between stability and resilience determines the performance of early warning signals under different environmental drivers.

    Science.gov (United States)

    Dai, Lei; Korolev, Kirill S; Gore, Jeff

    2015-08-11

    Shifting patterns of temporal fluctuations have been found to signal critical transitions in a variety of systems, from ecological communities to human physiology. However, failure of these early warning signals in some systems calls for a better understanding of their limitations. In particular, little is known about the generality of early warning signals in different deteriorating environments. In this study, we characterized how multiple environmental drivers influence the dynamics of laboratory yeast populations, which was previously shown to display alternative stable states [Dai et al., Science, 2012]. We observed that both the coefficient of variation and autocorrelation increased before population collapse in two slowly deteriorating environments, one with a rising death rate and the other one with decreasing nutrient availability. We compared the performance of early warning signals across multiple environments as "indicators for loss of resilience." We find that the varying performance is determined by how a system responds to changes in a specific driver, which can be captured by a relation between stability (recovery rate) and resilience (size of the basin of attraction). Furthermore, we demonstrate that the positive correlation between stability and resilience, as the essential assumption of indicators based on critical slowing down, can break down in this system when multiple environmental drivers are changed simultaneously. Our results suggest that the stability-resilience relation needs to be better understood for the application of early warning signals in different scenarios.

  6. A size exclusion-reversed phase two dimensional-liquid chromatography methodology for stability and small molecule related species in antibody drug conjugates.

    Science.gov (United States)

    Li, Yi; Gu, Christine; Gruenhagen, Jason; Zhang, Kelly; Yehl, Peter; Chetwyn, Nik P; Medley, Colin D

    2015-05-08

    Antibody drug conjugates (ADCs) are complex therapeutic agents combining the specific targeting properties of antibodies and highly potent cytotoxic small molecule drugs to selectively eliminate tumor cells while limiting the toxicity to normal healthy tissues. One unique critical quality attribute of ADCs is the content of unconjugated small molecule drug present from either incomplete conjugation or degradation of the ADC. In this work, size exclusion chromatography (SEC) was coupled with reversed-phase (RP) HPLC in an online 2-dimensional chromatography format for identification and quantitation of unconjugated small molecule drugs and related small molecule impurities in ADC samples directly without sample preparation. The SEC method in the 1st dimension not only separated the small molecule impurities from the intact ADC, but also provided information about the size variants (monomer, dimer, aggregates, etc.) of the ADC. The small molecule peak from the SEC was trapped and sent to a RP-HPLC in the 2nd dimension to further separate and quantify the different small molecule impurities present in the ADC sample. This SEC-RP 2D-LC method demonstrated excellent precision (%RSDmolecule degradation products and aggregation of the conjugate were observed in the stability samples and the degradation pathways of the ADC were investigated. This 2D-LC method offers a powerful tool for ADC characterization and provides valuable information for conjugation and formulation development. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Relative orientation of collagen molecules within a fibril: a homology model for homo sapiens type I collagen.

    Science.gov (United States)

    Collier, Thomas A; Nash, Anthony; Birch, Helen L; de Leeuw, Nora H

    2018-02-15

    Type I collagen is an essential extracellular protein that plays an important structural role in tissues that require high tensile strength. However, owing to the molecule's size, to date no experimental structural data are available for the Homo sapiens species. Therefore, there is a real need to develop a reliable homology model and a method to study the packing of the collagen molecules within the fibril. Through the use of the homology model and implementation of a novel simulation technique, we have ascertained the orientations of the collagen molecules within a fibril, which is currently below the resolution limit of experimental techniques. The longitudinal orientation of collagen molecules within a fibril has a significant effect on the mechanical and biological properties of the fibril, owing to the different amino acid side chains available at the interface between the molecules.

  8. Modulation, resolution and signal processing in radar, sonar and related systems

    CERN Document Server

    Benjamin, R; Costrell, L

    1966-01-01

    Electronics and Instrumentation, Volume 35: Modulation, Resolution and Signal Processing in Radar, Sonar and Related Systems presents the practical limitations and potentialities of advanced modulation systems. This book discusses the concepts and techniques in the radar context, but they are equally essential to sonar and to a wide range of signaling and data-processing applications, including seismology, radio astronomy, and band-spread communications.Organized into 15 chapters, this volume begins with an overview of the principal developments sought in pulse radar. This text then provides a

  9. Cancer-related marketing centrality motifs acting as pivot units in the human signaling network and mediating cross-talk between biological pathways.

    Science.gov (United States)

    Li, Wan; Chen, Lina; Li, Xia; Jia, Xu; Feng, Chenchen; Zhang, Liangcai; He, Weiming; Lv, Junjie; He, Yuehan; Li, Weiguo; Qu, Xiaoli; Zhou, Yanyan; Shi, Yuchen

    2013-12-01

    Network motifs in central positions are considered to not only have more in-coming and out-going connections but are also localized in an area where more paths reach the networks. These central motifs have been extensively investigated to determine their consistent functions or associations with specific function categories. However, their functional potentials in the maintenance of cross-talk between different functional communities are unclear. In this paper, we constructed an integrated human signaling network from the Pathway Interaction Database. We identified 39 essential cancer-related motifs in central roles, which we called cancer-related marketing centrality motifs, using combined centrality indices on the system level. Our results demonstrated that these cancer-related marketing centrality motifs were pivotal units in the signaling network, and could mediate cross-talk between 61 biological pathways (25 could be mediated by one motif on average), most of which were cancer-related pathways. Further analysis showed that molecules of most marketing centrality motifs were in the same or adjacent subcellular localizations, such as the motif containing PI3K, PDK1 and AKT1 in the plasma membrane, to mediate signal transduction between 32 cancer-related pathways. Finally, we analyzed the pivotal roles of cancer genes in these marketing centrality motifs in the pathogenesis of cancers, and found that non-cancer genes were potential cancer-related genes.

  10. Expression of the Grb2-related protein of the lymphoid system in B cell subsets enhances B cell antigen receptor signaling through mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Yankee, Thomas M; Solow, Sasha A; Draves, Kevin D; Clark, Edward A

    2003-01-01

    Adapter proteins play a critical role in regulating signals triggered by Ag receptor cross-linking. These small molecules link receptor proximal events with downstream signaling pathways. In this study, we explore the expression and function of the Grb2-related protein of the lymphoid system (GrpL)/Grb2-related adaptor downstream of Shc adapter protein in human B cells. GrpL is expressed in naive B cells and is down-regulated following B cell Ag receptor ligation. By contrast, germinal center and memory B cells express little or no GrpL. Using human B cell lines, we detected constitutive interactions between GrpL and B cell linker protein, Src homology (SH)2 domain-containing leukocyte protein of 76 kDa, hemopoietic progenitor kinase 1, and c-Cbl. The N-terminal SH3 domain of GrpL binds c-Cbl while the C-terminal SH3 domain binds B cell linker protein and SH2 domain-containing leukocyte protein of 76 kDa. Exogenous expression of GrpL in a GrpL-negative B cell line leads to enhanced Ag receptor-induced extracellular signal-related kinase and p38 mitogen-activated protein kinase phosphorylation. Thus, GrpL expression in human B cell subsets appears to regulate Ag receptor-mediated signaling events.

  11. Molecule nanoweaver

    Science.gov (United States)

    Gerald, II; Rex, E [Brookfield, IL; Klingler, Robert J [Glenview, IL; Rathke, Jerome W [Homer Glen, IL; Diaz, Rocio [Chicago, IL; Vukovic, Lela [Westchester, IL

    2009-03-10

    A method, apparatus, and system for constructing uniform macroscopic films with tailored geometric assemblies of molecules on the nanometer scale. The method, apparatus, and system include providing starting molecules of selected character, applying one or more force fields to the molecules to cause them to order and condense with NMR spectra and images being used to monitor progress in creating the desired geometrical assembly and functionality of molecules that comprise the films.

  12. ON THE RELATIVE ABUNDANCE OF LiH AND LiH+ MOLECULES IN THE EARLY UNIVERSE: NEW RESULTS FROM QUANTUM REACTIONS

    International Nuclear Information System (INIS)

    Bovino, Stefano; Tacconi, Mario; Gianturco, Franco A.; Galli, Daniele; Palla, Francesco

    2011-01-01

    The relative efficiencies of the chemical pathways that can lead to the destruction of LiH and LiH + molecules, conjectured to be present in the primordial gas and to control molecular cooling processes in the gravitational collapse of the post-recombination era, are revisited by using accurate quantum calculations for the several reactions involved. The new rates are employed to survey the behavior of the relative abundance of these molecules at redshifts of interest for early universe conditions. We find significant differences with respect to previous calculations, the present ones yielding LiH abundances higher than LiH + at all redshifts.

  13. Cellular Signal Mechanisms of Reward-Related Plasticity in the Hippocampus

    Directory of Open Access Journals (Sweden)

    Masako Isokawa

    2012-01-01

    Full Text Available The hippocampus has the extraordinary capacity to process and store information. Consequently, there is an intense interest in the mechanisms that underline learning and memory. Synaptic plasticity has been hypothesized to be the neuronal substrate for learning. Ca2+ and Ca2+-activated kinases control cellular processes of most forms of hippocampal synapse plasticity. In this paper, I aim to integrate our current understanding of Ca2+-mediated synaptic plasticity and metaplasticity in motivational and reward-related learning in the hippocampus. I will introduce two representative neuromodulators that are widely studied in reward-related learning (e.g., ghrelin and endocannabinoids and show how they might contribute to hippocampal neuron activities and Ca2+-mediated signaling processes in synaptic plasticity. Additionally, I will discuss functional significance of these two systems and their signaling pathways for its relevance to maladaptive reward learning leading to addiction.

  14. Differential effects of exposure to maternal obesity or maternal weight loss during the periconceptional period in the sheep on insulin signalling molecules in skeletal muscle of the offspring at 4 months of age.

    Directory of Open Access Journals (Sweden)

    Lisa M Nicholas

    Full Text Available Exposure to maternal obesity before and/or throughout pregnancy may increase the risk of obesity and insulin resistance in the offspring in childhood and adult life, therefore, resulting in its transmission into subsequent generations. We have previously shown that exposure to maternal obesity around the time of conception alone resulted in increased adiposity in female lambs. Changes in the abundance of insulin signalling molecules in skeletal muscle and adipose tissue precede the development of insulin resistance and type 2 diabetes. It is not clear, however, whether exposure to maternal obesity results in insulin resistance in her offspring as a consequence of the impact of increased adiposity on skeletal muscle or as a consequence of the programming of specific changes in the abundance of insulin signalling molecules in this tissue. We have used an embryo transfer model in the sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for one week after conception on the expression and abundance of insulin signalling molecules in muscle in the offspring. We found that exposure to maternal obesity resulted in lower muscle GLUT-4 and Ser 9 phospho-GSK3α and higher muscle GSK3α abundance in lambs when compared to lambs conceived in normally nourished ewes. Exposure to maternal weight loss in normal or obese mothers, however, resulted in lower muscle IRS1, PI3K, p110β, aPKCζ, Thr 642 phospho-AS160 and GLUT-4 abundance in the offspring. In conclusion, maternal obesity or weight loss around conception have each programmed specific changes on subsets of molecules in the insulin signalling, glucose transport and glycogen synthesis pathways in offspring. There is a need for a stronger evidence base to ensure that weight loss regimes in obese women seeking to become pregnant minimize the metabolic costs for the next generation.

  15. Cantharidin Induced Oral Squamous Cell Carcinoma Cell Apoptosis via the JNK-Regulated Mitochondria and Endoplasmic Reticulum Stress-Related Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Chin-Chuan Su

    Full Text Available Oral cancer is a subtype of head and neck cancer which represents 2.65% of all human malignancies. Most of oral cancer is histopathologically diagnosed as oral squamous cell carcinoma (OSCC. OSCC is characterized by a high degree of local invasion and a high rate of metastasis to the cervical lymph nodes. How to prevention and treatment of OSCC is important and imperative. Here, we investigated the therapeutic effect and molecular mechanism of cantharidin, an active compound isolated from blister beetles, on OSCC in vitro. Results showed that cantharidin significantly decreased cell viability in human tongue squamous carcinoma-derived SAS, CAL-27, and SCC-4 cell lines. The further mechanistic studies were carried out in SAS cells. Cantharidin also significantly increased apoptosis-related signals, including caspase-9, caspase-7 and caspase-3 proteins. Besides, cantharidin decreased mitochondrial transmembrane potential (MMP and induced cytochrome c and apoptosis inducing factor (AIF release. Cantharidin also increased Bax, Bid, and Bak protein expressions and decreased Bcl-2 protein expression. Cantharidin could also increase the endoplasmic reticulum (ER stress signals, including the expressions of phosphorylated eIF-2α and CHOP, but not Grp78 and Grp94. Furthermore, cantharidin reduced pro-caspase-12 protein expression. In signals of mitogen-activated protein kinases, cantharidin increased the phosphorylation of JNK, but not ERK and p38. Transfection of shRNA-JNK to OSCC cells effectively reversed the cantharidin-induced cell apoptotic signals, including the mitochondrial and ER stress-related signaling molecules. Taken together, these findings suggest that cantharidin induces apoptosis in OSCC cells via the JNK-regulated mitochondria and ER stress-related signaling pathways.

  16. Numerical modelling of the pump-to-signal relative intensity noise ...

    Indian Academy of Sciences (India)

    An accurate numerical model to investigate the pump-to-signal relative intensity noise (RIN) transfer in two-pump fibre optical parametric amplifiers (2-P FOPAs) for low modulation frequencies is presented. Compared to other models in the field, this model takes into account the fibre loss, pump depletion as well as the gain ...

  17. Alleviation of Drought Stress by Hydrogen Sulfide Is Partially Related to the Abscisic Acid Signaling Pathway in Wheat.

    Science.gov (United States)

    Ma, Dongyun; Ding, Huina; Wang, Chenyang; Qin, Haixia; Han, Qiaoxia; Hou, Junfeng; Lu, Hongfang; Xie, Yingxin; Guo, Tiancai

    2016-01-01

    Little information is available describing the effects of exogenous H2S on the ABA pathway in the acquisition of drought tolerance in wheat. In this study, we investigated the physiological parameters, the transcription levels of several genes involved in the abscisic acid (ABA) metabolism pathway, and the ABA and H2S contents in wheat leaves and roots under drought stress in response to exogenous NaHS treatment. The results showed that pretreatment with NaHS significantly increased plant height and the leaf relative water content of seedlings under drought stress. Compared with drought stress treatment alone, H2S application increased antioxidant enzyme activities and reduced MDA and H2O2 contents in both leaves and roots. NaHS pretreatment increased the expression levels of ABA biosynthesis and ABA reactivation genes in leaves; whereas the expression levels of ABA biosynthesis and ABA catabolism genes were up-regulated in roots. These results indicated that ABA participates in drought tolerance induced by exogenous H2S, and that the responses in leaves and roots are different. The transcription levels of genes encoding ABA receptors were up-regulated in response to NaHS pretreatment under drought conditions in both leaves and roots. Correspondingly, the H2S contents in leaves and roots were increased by NaHS pretreatment, while the ABA contents of leaves and roots decreased. This implied that there is complex crosstalk between these two signal molecules, and that the alleviation of drought stress by H2S, at least in part, involves the ABA signaling pathway.

  18. Influence of vitamin D on cell cycle, apoptosis, and some apoptosis related molecules in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Nafise Tabasi

    2015-11-01

    Full Text Available Objective(s:Genetic and environmental factors are involved in the pathogenesis of systemic lupus erythematosus (SLE. Autoreactive lymphocytes are cleared through apoptosis and any disturbance in the apoptosis or clearance of apoptotic cells may disturb tolerance and lead to autoimmunity. Vitamin D has anti-proliferative effects and controls cell cycle progression. In this study we investigated the effects of vitamin D on cell cycle and apoptosis induction in lupus patients. Materials and Methods:Isolated peripheral blood mononuclear cells (PBMCs from 25 SLE patients were cultured in the presence of 50 nM of 1,25(OH2D3; then one part of the cells were stained with FITC labeled Annexin V and PI and were analyzed for apoptosis determination. For gene expression assessment of FasL, Bcl-2 and Bax, RNA was extracted from one another part of the cells, cDNA was synthesized and gene expression analysis was performed using Real time PCR. An additional part of the cells were treated with PI and the cell cycle was analyzed using flowcytometer. Results: The mean number of early apoptotic cells in vitamin D treated cells decreased significantly (18.48±7.9% compared to untreated cells (22.02±9.4% (P=0.008. Cell cycle analysis showed a significant increase in G1 phase in vitamin D treated cells (67.33±5.2% compared to non treated ones (60.77±5.7% (P =0.02. Vitamin D up-regulated the expression levels of Bcl-2 by (18.87 fold increase, and down-regulated expression of Bax (23% and FasL (25%. Conclusion:Vitamin D has regulatory effects on cell cycle progression, apoptosis and apoptosis related molecules in lupus patients.

  19. Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.

    Science.gov (United States)

    Meyers, Emily A; Gobeske, Kevin T; Bond, Allison M; Jarrett, Jennifer C; Peng, Chian-Yu; Kessler, John A

    2016-02-01

    Aging is associated with decreased neurogenesis in the hippocampus and diminished hippocampus-dependent cognitive functions. Expression of bone morphogenetic protein 4 (BMP4) increases with age by more than 10-fold in the mouse dentate gyrus while levels of the BMP inhibitor, noggin, decrease. This results in a profound 30-fold increase in phosphorylated-SMAD1/5/8, the effector of canonical BMP signaling. Just as observed in mice, a profound increase in expression of BMP4 is observed in the dentate gyrus of humans with no known cognitive abnormalities. Inhibition of BMP signaling either by overexpression of noggin or transgenic manipulation not only increases neurogenesis in aging mice, but remarkably, is associated with a rescue of cognitive deficits to levels comparable to young mice. Additive benefits are observed when combining inhibition of BMP signaling and environmental enrichment. These findings indicate that increased BMP signaling contributes significantly to impairments in neurogenesis and to cognitive decline associated with aging, and identify this pathway as a potential druggable target for reversing age-related changes in cognition. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Prenatal physical activity and diet composition affect the expression of nutrient transporters and mTOR signaling molecules in the human placenta.

    Science.gov (United States)

    Brett, K E; Ferraro, Z M; Holcik, M; Adamo, K B

    2015-02-01

    Adequate nutrient delivery to the fetus is essential for optimal growth. Differences in prenatal physical activity level and diet quality influence maternal energy balance and these factors may alter placental nutrient transport. We investigated the associations between meeting physical activity guidelines and the quality of maternal diet on the expression of genes involved in fatty acid, amino acid and glucose transport, and mammalian target of rapamycin (mTOR) and insulin signaling in the placenta from 16 term pregnancies. Physical activity was directly measured with accelerometry, diet composition was assessed with 24 h dietary recalls, and gene expression was measured with custom polymerase chain reaction (PCR) arrays. Women who met physical activity guidelines had lower gene expression of fatty acid transport protein 4 (FATP4), insulin-like growth factor 1 (IGF1), and the beta non-catalytic subunit of AMP-activated protein kinase (AMPK), and a higher expression of SNAT2. There was a strong positive correlation observed between total sugar intake and glucose transporter 1 (GLUT1) (r = 0.897, p = 0.000, n = 12), and inverse correlations between total sugar and mTOR and IGF1 expression. Percentage of total calories from protein was inversely related to insulin-like growth factor 1 receptor (IGF1R) (r = -0.605, p = 0.028, n = 13). Variations in maternal physical activity and diet composition altered the expression of genes involved in fatty acid, amino acid and glucose transport and mTOR signaling. Future research on placental nutrient transport should include direct measures of maternal PA and dietary habits to help eliminate confounding factors. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Molecules in stars

    International Nuclear Information System (INIS)

    Tsuji, T.

    1986-01-01

    Recently, research related to molecules in stars has rapidly expanded because of progress in related fields. For this reason, it is almost impossible to cover all the topics related to molecules in stars. Thus, here the authors focus their attention on molecules in the atmospheres of cool stars and do not cover in any detail topics related to circumstellar molecules originating from expanding envelopes located far from the stellar surface. However, the authors do discuss molecules in quasi-static circumstellar envelopes (a recently discovered new component of circumstellar envelopes) located near the stellar surface, since molecular lines originating from such envelopes show little velocity shift relative to photospheric lines, and hence they directly affect the interpretation and analysis of stellar spectra

  2. Estrogen signalling in the pathogenesis of age-related macular degeneration.

    Science.gov (United States)

    Kaarniranta, Kai; Machalińska, Anna; Veréb, Zoltán; Salminen, Antero; Petrovski, Goran; Kauppinen, Anu

    2015-02-01

    Age-related macular degeneration (AMD) is a multifactorial eye disease that is associated with aging, family history, smoking, obesity, cataract surgery, arteriosclerosis, hypertension, hypercholesterolemia and unhealthy diet. Gender has commonly been classified as a weak or inconsistent risk factor for AMD. This disease is characterized by degeneration of retinal pigment epithelial (RPE) cells, Bruch's membrane, and choriocapillaris, which secondarily lead to damage and death of photoreceptor cells and central visual loss. Pathogenesis of AMD involves constant oxidative stress, chronic inflammation, and increased accumulation of lipofuscin and drusen. Estrogen has both anti-oxidative and anti-inflammatory capacity and it regulates signaling pathways that are involved in the pathogenesis of AMD. In this review, we discuss potential cellular signaling targets of estrogen in retinal cells and AMD pathology.

  3. 10Be and relative paleointensity signals across the last geomagnetic reversal

    Science.gov (United States)

    Savranskaia, T.; Valet, J. P.; Bassinot, F. C.; Meynadier, L.; Simon, Q.; Bourles, D. L.; Thouveny, N.; Thevarasan, A.; Villedieu, A.; Choy, S.; Gacem, L.

    2017-12-01

    Two techniques can be used to determine the evolution of the geomagnetic field intensity in the past. The first one relies on records of relative paleointensity (RPI) in sediments. Although they remain relatively sparse detailed records of 10Be production (expressed in terms of 10Be/9Be) provide an alternative approach. However integration of 10Be within the sediment is not better understood than the magnetization process, and therefore paleofield studies should greatly benefit from the integration of both datasets. In order to achieve this goal, it is crucial to compare and analyze the signals over a common time period. We selected five sedimentary cores from the Indian, Pacific and Atlantic Oceans and focused on the last reversal which is characterized by the largest intensity changes. Since 10Be is homogenized in the atmosphere, the same amount of 10Be should be recorded everywhere. We found different amounts of 10Be at each site during the last reversal which appear roughly correlated with accumulation rate. In contrast the 10Be amplitude is similar at all locations while higher amplitude signals are expected for low deposition rates. Taking advantage of the distribution of tektites layers, the beryllium signals have been deconvolved, but this procedure did not strikingly change the results. Despite atmospheric mixing we wonder whether 10Be production was slightly different at each location in presence of a multipolar transitional field. The comparison between the 10Be and RPI signals reveals large similarities but also puzzling differences. In particular, the relationship between the two signals is not the same during periods of stable polarity as during the transitional interval. A precursor with low intensity is present in several RPI records but not clearly marked on the beryllium records. We also addressed the question of a possible offset between the two signals that would be indicative of a delayed magnetization acquisition. After correlating and

  4. Age-Related Cognitive Impairments in Mice with a Conditional Ablation of the Neural Cell Adhesion Molecule

    Science.gov (United States)

    Bisaz, Reto; Boadas-Vaello, Pere; Genoux, David; Sandi, Carmen

    2013-01-01

    Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However,…

  5. HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients

    DEFF Research Database (Denmark)

    Melsted, Wenna Nascimento; Johansen, Lasse Lindholm; Lock-Andersen, Jørgen

    2017-01-01

    HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM...

  6. Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study

    NARCIS (Netherlands)

    A.E. Hak (Liesbeth); H.A.P. Pols (Huib); C.D. Stehouwer (Coen); J. Meijer (John); A.J. Kiliaan (Amanda); M.M.B. Breteler (Monique); J.C.M. Witteman (Jacqueline); A. Hofman (Albert)

    2001-01-01

    textabstractInsulin resistance, which is highly prevalent in the elderly, is suggested to be accompanied by an increased acute phase response. Until now, it is unclear whether cellular adhesion molecules are involved in the clustering of insulin resistance. In the present study, we

  7. Potential for luxS related signalling in marine bacteria and production of autoinducer-2 in the genus Shewanella

    Directory of Open Access Journals (Sweden)

    Wagner-Döbler Irene

    2008-01-01

    Full Text Available Abstract Background The autoinducer-2 (AI-2 group of signalling molecules are produced by both Gram positive and Gram negative bacteria as the by-product of a metabolic transformation carried out by the LuxS enzyme. They are the only non species-specific quorum sensing compounds presently known in bacteria. The luxS gene coding for the AI-2 synthase enzyme was found in many important pathogens. Here, we surveyed its occurrence in a collection of 165 marine isolates belonging to abundant marine phyla using conserved degenerated PCR primers and sequencing of selected positive bands to determine if the presence of the luxS gene is phylogenetically conserved or dependent on the habitat. Results The luxS gene was not present in any of the Alphaproteobacteria (n = 71 and Bacteroidetes strains (n = 29 tested; by contrast, these bacteria harboured the sahH gene, coding for an alternative enzyme for the detoxification of S-adenosylhomocysteine (SAH in the activated methyl cycle. Within the Gammaproteobacteria (n = 76, luxS was found in all Shewanella, Vibrio and Alteromonas isolates and some Pseudoalteromonas and Halomonas species, while sahH was detected in Psychrobacter strains. A number of Gammaproteobacteria (n = 27 appeared to have neither the luxS nor the sahH gene. We then studied the production of AI-2 in the genus Shewanella using the Vibrio harveyi bioassay. All ten species of Shewanella tested produced a pronounced peak of AI-2 towards the end of the exponential growth phase in several media investigated. The maximum of AI-2 activity was different in each Shewanella species, ranging from 4% to 46% of the positive control. Conclusion The data are consistent with those of fully sequenced bacterial genomes and show that the potential for luxS related signalling is dependent on phylogenetic affiliation rather than ecological niche and is largest in certain groups of Gammaproteobacteria in the marine environment. This is the first report on AI-2

  8. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 4. Molecule Matters – van der Waals Molecules - History and Some Perspectives on Intermolecular Forces. E Arunan. Feature Article Volume 14 Issue 4 April 2009 pp 346-356 ...

  9. Pachymic acid promotes induction of autophagy related to IGF-1 signaling pathway in WI-38 cells.

    Science.gov (United States)

    Lee, Su-Gyeong; Kim, Moon-Moo

    2017-12-01

    The insulin-like growth factor 1 (IGF-1) signaling pathway has spotlighted as a mechanism to elucidate aging associated with autophagy in recent years. Therefore, we have tried to screen an effective compound capable of inducing autophagy to delay aging process. The aim of this study is to investigate whether pachymic acid, a main compound in Poria cocos, induces autophagy in the aged cells. The aging of young cells was induced by treatment with IGF-1 at 50 ng/ml three times every two days. The effect of pachymic acid on cell viability was evaluated in human lung fibroblasts, WI-38 cells, using MTT assay. The induction of autophagy was detected using autophagy detection kit. The expression of proteins related to autophagy and IGF-1 signaling pathway was examined by western blot analysis and immunofluorescence assay. In this study, pachymic acid showed cytotoxic effect in a dose dependent manner and remarkably induced autophagy at the same time. Moreover, pachymic acid increased the expression of proteins related to autophagy such as LC3-II and Beclin1 and decreased the levels of mTor phosphorylation and p70S6K in the aged cells. In particular, pachymic acid increased the expression of p-PI3K, p-FoxO and Catalase. In addition, pachymic acid remarkably increased the expression of IGFBP-3. Above results suggest that pachymic acid could induce autophagy related to IGF-1 signaling pathway in the aged cells. Copyright © 2017 Elsevier GmbH. All rights reserved.

  10. Evaluating signal-to-noise ratios, loudness, and related measures as indicators of airborne sound insulation.

    Science.gov (United States)

    Park, H K; Bradley, J S

    2009-09-01

    Subjective ratings of the audibility, annoyance, and loudness of music and speech sounds transmitted through 20 different simulated walls were used to identify better single number ratings of airborne sound insulation. The first part of this research considered standard measures such as the sound transmission class the weighted sound reduction index (R(w)) and variations of these measures [H. K. Park and J. S. Bradley, J. Acoust. Soc. Am. 126, 208-219 (2009)]. This paper considers a number of other measures including signal-to-noise ratios related to the intelligibility of speech and measures related to the loudness of sounds. An exploration of the importance of the included frequencies showed that the optimum ranges of included frequencies were different for speech and music sounds. Measures related to speech intelligibility were useful indicators of responses to speech sounds but were not as successful for music sounds. A-weighted level differences, signal-to-noise ratios and an A-weighted sound transmission loss measure were good predictors of responses when the included frequencies were optimized for each type of sound. The addition of new spectrum adaptation terms to R(w) values were found to be the most practical approach for achieving more accurate predictions of subjective ratings of transmitted speech and music sounds.

  11. Quantifying uncertainties of climate signals related to the 11-year solar cycle

    Science.gov (United States)

    Kruschke, T.; Kunze, M.; Matthes, K. B.; Langematz, U.; Wahl, S.

    2017-12-01

    Although state-of-the-art reconstructions based on proxies and (semi-)empirical models converge in terms of total solar irradiance, they still significantly differ in terms of spectral solar irradiance (SSI) with respect to the mean spectral distribution of energy input and temporal variability. This study aims at quantifying uncertainties for the Earth's climate related to the 11-year solar cycle by forcing two chemistry-climate models (CCMs) - CESM1(WACCM) and EMAC - with five different SSI reconstructions (NRLSSI1, NRLSSI2, SATIRE-T, SATIRE-S, CMIP6-SSI) and the reference spectrum RSSV1-ATLAS3, derived from observations. We conduct a unique set of timeslice experiments. External forcings and boundary conditions are fixed and identical for all experiments, except for the solar forcing. The set of analyzed simulations consists of one solar minimum simulation, employing RSSV1-ATLAS3 and five solar maximum experiments. The latter are a result of adding the amplitude of solar cycle 22 according to the five reconstructions to RSSV1-ATLAS3. Our results show that the climate response to the 11y solar cycle is generally robust across CCMs and SSI forcings. However, analyzing the variance of the solar maximum ensemble by means of ANOVA-statistics reveals additional information on the uncertainties of the mean climate signals. The annual mean response agrees very well between the two CCMs for most parts of the lower and middle atmosphere. Only the upper mesosphere is subject to significant differences related to the choice of the model. However, the different SSI forcings lead to significant differences in ozone concentrations, shortwave heating rates, and temperature throughout large parts of the mesosphere and upper stratosphere. Regarding the seasonal evolution of the climate signals, our findings for short wave heating rates, and temperature are similar to the annual means with respect to the relative importance of the choice of the model or the SSI forcing for the

  12. Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation

    DEFF Research Database (Denmark)

    Biskup, Edyta; Naym, David Gram; Gniadecki, Robert

    2016-01-01

    inhibited by small molecule antagonists VE-821, VE-822 or Chir-124, or by small interfering RNAs (siRNAs). Cell cycle and viability were assessed by flow cytometry. RESULTS: Small molecule inhibitors of ATR and Chk1 potently sensitized all cell lines to PUVA and, importantly, also to UVA, which by itself...... did not cause apoptotic response. VE-821/2 blocked ATR pathway activation and released the cells from the G2/M block caused by UVA and PUVA, but did not affect apoptosis caused by other chemotherapeutics (etoposide, gemcitabine, doxorubicine) or by hydrogen peroxide. Knockdown of ATR and Chk1 with si......RNA also blocked the ATR pathway and released the cells from G2/M block but did not sensitize the cells to UVA as observed with the small molecule inhibitors. The latter suggested that the synergism between VE-821/2 or Chir-124 and UVA was not solely caused by specific blocking of ATR kinase but also ATR...

  13. Functional morphology of the bovid astragalus in relation to habitat: controlling phylogenetic signal in ecomorphology.

    Science.gov (United States)

    Barr, W Andrew

    2014-11-01

    Bovid astragali are one of the most commonly preserved bones in the fossil record. Accordingly, astragali are an important target for studies seeking to predict the habitat preferences of fossil bovids based on bony anatomy. However, previous work has not tested functional hypotheses linking astragalar morphology with habitat while controlling for body size and phylogenetic signal. This article presents a functional framework relating the morphology of the bovid astragalus to habitat-specific locomotor ecology and tests four hypotheses emanating from this framework. Highly cursorial bovids living in structurally open habitats are hypothesized to differ from their less cursorial closed-habitat dwelling relatives in having (1) relatively short astragali to maintain rotational speed throughout the camming motion of the rotating astragalus, (2) a greater range of angular excursion at the hock, (3) relatively larger joint surface areas, and (4) a more pronounced "spline-and-groove" morphology promoting lateral joint stability. A diverse sample of 181 astragali from 50 extant species was scanned using a Next Engine laser scanner. Species were assigned to one of four habitat categories based on the published ecological literature. A series of 11 linear measurements and three joint surface areas were measured on each astragalus. A geometric mean body size proxy was used to size-correct the measurement data. Phylogenetic generalized least squares (PGLS) was used to test for differences between habitat categories while controlling for body size differences and phylogenetic signal. Statistically significant PGLS results support Hypotheses 1 and 2 (which are not mutually exclusive) as well as Hypothesis 3. No support was found for Hypothesis 4. These findings confirm that the morphology of the bovid astragalus is related to habitat-specific locomotor ecology, and that this relationship is statistically significant after controlling for body size and phylogeny. Thus, this study

  14. Hippocampal leptin signaling reduces food intake and modulates food-related memory processing.

    Science.gov (United States)

    Kanoski, Scott E; Hayes, Matthew R; Greenwald, Holly S; Fortin, Samantha M; Gianessi, Carol A; Gilbert, Jennifer R; Grill, Harvey J

    2011-08-01

    The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 μg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 μg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.

  15. Netrin-1 - DCC Signaling Systems and Age-Related Macular Degeneration.

    Directory of Open Access Journals (Sweden)

    John Paul SanGiovanni

    Full Text Available We conducted a nested candidate gene study and pathway-based enrichment analysis on data from a multi-national 77,000-person project on the molecular genetics of age-related macular degeneration (AMD to identify AMD-associated DNA-sequence variants in genes encoding constituents of a netrin-1 (NTN1-based signaling pathway that converges on DNA-binding transcription complexes through a 3'-5'-cyclic adenosine monophosphate-calcineurin (cAMP-CN-dependent axis. AMD-associated single nucleotide polymorphisms (SNPs existed in 9 linkage disequilibrium-independent genomic regions; these included loci overlapping NTN1 (rs9899630, P ≤ 9.48 x 10(-5, DCC (Deleted in Colorectal Cancer--the gene encoding a primary NTN1 receptor (rs8097127, P ≤ 3.03 x 10(-5, and 6 other netrin-related genes. Analysis of the NTN1-DCC pathway with exact methods demonstrated robust enrichment with AMD-associated SNPs (corrected P-value = 0.038, supporting the idea that processes driven by NTN1-DCC signaling systems operate in advanced AMD. The NTN1-DCC pathway contains targets of FDA-approved drugs and may offer promise for guiding applied clinical research on preventive and therapeutic interventions for AMD.

  16. The Recording and Quantification of Event-Related Potentials: II. Signal Processing and Analysis

    Directory of Open Access Journals (Sweden)

    Paniz Tavakoli

    2015-06-01

    Full Text Available Event-related potentials are an informative method for measuring the extent of information processing in the brain. The voltage deflections in an ERP waveform reflect the processing of sensory information as well as higher-level processing that involves selective attention, memory, semantic comprehension, and other types of cognitive activity. ERPs provide a non-invasive method of studying, with exceptional temporal resolution, cognitive processes in the human brain. ERPs are extracted from scalp-recorded electroencephalography by a series of signal processing steps. The present tutorial will highlight several of the analysis techniques required to obtain event-related potentials. Some methodological issues that may be encountered will also be discussed.

  17. Copper-induced tight junction mRNA expression changes, apoptosis and antioxidant responses via NF-κB, TOR and Nrf2 signaling molecules in the gills of fish: Preventive role of arginine

    International Nuclear Information System (INIS)

    Wang, Biao; Feng, Lin; Jiang, Wei-Dan; Wu, Pei; Kuang, Sheng-Yao; Jiang, Jun; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Liu, Yang

    2015-01-01

    Highlights: • Cu exposure induced oxidative stress via disruption of antioxidant system. • Cu exposure disrupted TJ mRNA expression through regulation of cytokines in fish. • Cu induced gill apoptosis partly via intrinsic pathway but not extrinsic pathway. • Cu exposure can regulate Nrf2, NF-κB and TOR signaling molecules in fish. • Arginine can effectively prevent Cu-induced fish gill damage. - Abstract: This study explored the possible preventive effects of dietary arginine on copper (Cu)-induced tight junction mRNA expression changes, apoptosis and antioxidant responses in the gills of young grass carp (Ctenopharyngodon idella). The results indicated that exposure to 0.7 mg/L (11.01 μmol/L) Cu for 96 h induced the production of reactive oxygen species (ROS), thereby increasing protein oxidation, lipid peroxidation and DNA damage in the gills of fish. However, these oxidative effects were prevented by arginine supplementation. Arginine also prevented the toxic effects of Cu on the activities of copper/zinc superoxide dismutase (SOD1), glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and the glutathione (GSH) content (P < 0.05). However, Cu induced an adaptive increase in the activity of catalase (CAT), and arginine supplementation further increased CAT activity (P < 0.05). Moreover, Cu induced increases in the relative mRNA expressions of SOD1, CAT, GPx, GST, caspase-3, caspase-9, NF-E2-related factor 2 (Nrf2), Kelch-like-ECH-associated protein 1a (Keap1a), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-8 (IL-8), transforming growth factor-β (TGF-β) and nuclear transcription factor-κB p65 (NF-κB p65) in the gills of grass carp (P < 0.05). In contrast, the relative mRNA expression levels of occludin, zonula occludens-1 (ZO-1), claudin b, claudin 3, claudin 12, target of rapamycin (TOR) and inhibitor factor κBα (IκBα) in the gills were decreased by Cu (P < 0.05). However, pre

  18. Copper-induced tight junction mRNA expression changes, apoptosis and antioxidant responses via NF-κB, TOR and Nrf2 signaling molecules in the gills of fish: Preventive role of arginine

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Biao [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Feng, Lin; Jiang, Wei-Dan [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Wu, Pei [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Kuang, Sheng-Yao [Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, 610066, Sichuan (China); Jiang, Jun [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Tang, Ling; Tang, Wu-Neng [Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, 610066, Sichuan (China); Zhang, Yong-An [Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072 (China); Liu, Yang, E-mail: kyckgk@hotmail.com [Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu 611130, Sichuan (China); and others

    2015-01-15

    Highlights: • Cu exposure induced oxidative stress via disruption of antioxidant system. • Cu exposure disrupted TJ mRNA expression through regulation of cytokines in fish. • Cu induced gill apoptosis partly via intrinsic pathway but not extrinsic pathway. • Cu exposure can regulate Nrf2, NF-κB and TOR signaling molecules in fish. • Arginine can effectively prevent Cu-induced fish gill damage. - Abstract: This study explored the possible preventive effects of dietary arginine on copper (Cu)-induced tight junction mRNA expression changes, apoptosis and antioxidant responses in the gills of young grass carp (Ctenopharyngodon idella). The results indicated that exposure to 0.7 mg/L (11.01 μmol/L) Cu for 96 h induced the production of reactive oxygen species (ROS), thereby increasing protein oxidation, lipid peroxidation and DNA damage in the gills of fish. However, these oxidative effects were prevented by arginine supplementation. Arginine also prevented the toxic effects of Cu on the activities of copper/zinc superoxide dismutase (SOD1), glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and the glutathione (GSH) content (P < 0.05). However, Cu induced an adaptive increase in the activity of catalase (CAT), and arginine supplementation further increased CAT activity (P < 0.05). Moreover, Cu induced increases in the relative mRNA expressions of SOD1, CAT, GPx, GST, caspase-3, caspase-9, NF-E2-related factor 2 (Nrf2), Kelch-like-ECH-associated protein 1a (Keap1a), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-8 (IL-8), transforming growth factor-β (TGF-β) and nuclear transcription factor-κB p65 (NF-κB p65) in the gills of grass carp (P < 0.05). In contrast, the relative mRNA expression levels of occludin, zonula occludens-1 (ZO-1), claudin b, claudin 3, claudin 12, target of rapamycin (TOR) and inhibitor factor κBα (IκBα) in the gills were decreased by Cu (P < 0.05). However, pre

  19. Atkins' molecules

    CERN Document Server

    Atkins, Peters

    2003-01-01

    Originally published in 2003, this is the second edition of a title that was called 'the most beautiful chemistry book ever written'. In it, we see the molecules responsible for the experiences of our everyday life - including fabrics, drugs, plastics, explosives, detergents, fragrances, tastes, and sex. With engaging prose Peter Atkins gives a non-technical account of an incredible range of aspects of the world around us, showing unexpected connections, and giving an insight into how this amazing world can be understood in terms of the atoms and molecules from which it is built. The second edition includes dozens of extra molecules, graphical presentation, and an even more accessible and enthralling account of the molecules themselves.

  20. Interstellar Molecules

    Science.gov (United States)

    Solomon, Philip M.

    1973-01-01

    Radioastronomy reveals that clouds between the stars, once believed to consist of simple atoms, contain molecules as complex as seven atoms and may be the most massive objects in our Galaxy. (Author/DF)

  1. Quadra-Quantum Dots and Related Patterns of Quantum Dot Molecules: Basic Nanostructures for Quantum Dot Cellular Automata Application

    Directory of Open Access Journals (Sweden)

    Somsak Panyakeow

    2010-10-01

    Full Text Available Laterally close-packed quantum dots (QDs called quantum dot molecules (QDMs are grown by modified molecular beam epitaxy (MBE. Quantum dots could be aligned and cross hatched. Quantum rings (QRs created from quantum dot transformation during thin or partial capping are used as templates for the formations of bi-quantum dot molecules (Bi-QDMs and quantum dot rings (QDRs. Preferable quantum dot nanostructure for quantum computation based on quantum dot cellular automata (QCA is laterally close-packed quantum dot molecules having four quantum dots at the corners of square configuration. These four quantum dot sets are called quadra-quantum dots (QQDs. Aligned quadra-quantum dots with two electron confinements work like a wire for digital information transmission by Coulomb repulsion force, which is fast and consumes little power. Combination of quadra-quantum dots in line and their cross-over works as logic gates and memory bits. Molecular Beam Epitaxial growth technique called 'Droplet Epitaxy' has been developed for several quantum nanostructures such as quantum rings and quantum dot rings. Quantum rings are prepared by using 20 ML In-Ga (15:85 droplets deposited on a GaAs substrate at 390'C with a droplet growth rate of 1ML/s. Arsenic flux (7'8'10-6Torr is then exposed for InGaAs crystallization at 200'C for 5 min. During droplet epitaxy at a high droplet thickness and high temperature, out-diffusion from the centre of droplets occurs under anisotropic strain. This leads to quantum ring structures having non-uniform ring stripes and deep square-shaped nanoholes. Using these peculiar quantum rings as templates, four quantum dots situated at the corners of a square shape are regrown. Two of these four quantum dots are aligned either or, which are preferable crystallographic directions of quantum dot alignment in general.

  2. Multiple interactions between maternally-activated signalling pathways control Xenopus nodal-related genes.

    Science.gov (United States)

    Rex, Maria; Hilton, Emma; Old, Robert

    2002-03-01

    We have investigated the induction of the six Xenopus nodal-related genes, Xnr1-Xnr6, by maternal determinants. The beta-catenin pathway was modelled by stimulation using Xwnt8, activin-like signalling was modelled by activin, and VegT action was studied by overexpression in animal cap explants. Combinations of factors were examined, and previously unrecognised interactions were revealed in animal caps and whole embryos. For the induction of Xnr5 and Xnr6 in whole embryos, using a beta-catenin antisense morpholino oligonucleotide or a dominant negative XTcf3, we have demonstrated an absolute permissive requirement for the beta-catenin/Tcf pathway, in addition to the requirement for VegT action. In animal caps Xnr5 and Xnr6 are induced in response to VegT overexpression, and this induction is dependent upon the concomitant activation of the beta-catenin pathway that VegT initiates in animal caps. For the induction of Xnr3, VegT interacts negatively so as to inhibit the induction otherwise observed with wnt-signalling alone. The negative effect of VegT is not the result of a general inhibition of wnt-signalling, and does not result from an inhibition of wnt-induced siamois expression. A 294 bp proximal promoter fragment of the Xnr3 gene is sufficient to mediate the negative effect of VegT. Further experiments, employing cycloheximide to examine the dependence of Xnr gene expression upon proteins translated after the mid-blastula stage, demonstrated that Xnrs 4, 5 and 6 are 'primary' Xnr genes whose expression in the late blastula is solely dependent upon factors present before the mid-blastula stage.

  3. Relative contributions of norspermidine synthesis and signaling pathways to the regulation of Vibrio cholerae biofilm formation.

    Directory of Open Access Journals (Sweden)

    Caitlin K Wotanis

    Full Text Available The polyamine norspermidine is one of the major polyamines synthesized by Vibrionales and has also been found in various aquatic organisms. Norspermidine is among the environmental signals that positively regulate Vibrio cholerae biofilm formation. The NspS/MbaA signaling complex detects extracellular norspermidine and mediates the response to this polyamine. Norspermidine binding to the NspS periplasmic binding protein is thought to inhibit the phosphodiesterase activity of MbaA, increasing levels of the biofilm-promoting second messenger cyclic diguanylate monophosphate, thus enhancing biofilm formation. V. cholerae can also synthesize norspermidine using the enzyme NspC as well as import it from the environment. Deletion of the nspC gene was shown to reduce accumulation of bacteria in biofilms, leading to the conclusion that intracellular norspermidine is also a positive regulator of biofilm formation. Because V. cholerae uses norspermidine to synthesize the siderophore vibriobactin it is possible that intracellular norspermidine is required to obtain sufficient amounts of iron, which is also necessary for robust biofilm formation. The objective of this study was to assess the relative contributions of intracellular and extracellular norspermidine to the regulation of biofilm formation in V. cholerae. We show the biofilm defect of norspermidine synthesis mutants does not result from an inability to produce vibriobactin as vibriobactin synthesis mutants do not have diminished biofilm forming abilities. Furthermore, our work shows that extracellular, but not intracellular norspermidine, is mainly responsible for promoting biofilm formation. We establish that the NspS/MbaA signaling complex is the dominant mediator of biofilm formation in response to extracellular norspermidine, rather than norspermidine synthesized by NspC or imported into the cell.

  4. Comparison of GFL–GFRα complexes: further evidence relating GFL bend angle to RET signalling

    International Nuclear Information System (INIS)

    Parkash, Vimal; Goldman, Adrian

    2009-01-01

    The second crystal structure of the GDNF-GFRα1 complex provides further evidence that GFL signalling through RET is determined by the bend angle in the GFL. Glial cell line-derived neurotrophic factor (GDNF) activates the receptor tyrosine kinase RET by binding to the GDNF-family receptor α1 (GFRα1) and forming the GDNF 2 –GFRα1 2 –RET 2 heterohexamer complex. A previous crystal structure of the GDNF 2 –GFRα1 2 complex suggested that differences in signalling in GDNF-family ligand (GFL) complexes might arise from differences in the bend angle between the two monomers in the GFL homodimer. Here, a 2.35 Å resolution structure of the GDNF 2 –GFRα1 2 complex crystallized with new cell dimensions is reported. The structure was refined to a final R factor of 22.5% (R free = 28%). The structures of both biological tetrameric complexes in the asymmetric unit are very similar to 2v5e and different from the artemin–GFRα3 structure, even though there is a small change in the structure of the GDNF. By comparison of all known GDNF and artemin structures, it is concluded that GDNF is more bent and more flexible than artemin and that this may be related to RET signalling. Comparisons also suggest that the differences between artemin and GDNF arise from the increased curvature of the artemin ‘fingers’, which both increases the buried surface area in the monomer–monomer interface and changes the intermonomer bend angle. From sequence comparison, it is suggested that neuturin (the second GFL) adopts an artemin-like conformation, while persephin has a different conformation to the other three

  5. The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling

    Directory of Open Access Journals (Sweden)

    Dianaly T. Au

    2017-01-01

    Full Text Available The metabolic syndrome is an escalating worldwide public health concern. Defined by a combination of physiological, metabolic, and biochemical factors, the metabolic syndrome is used as a clinical guideline to identify individuals with a higher risk for type 2 diabetes and cardiovascular disease. Although risk factors for type 2 diabetes and cardiovascular disease have been known for decades, the molecular mechanisms involved in the pathophysiology of these diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1 is a large endocytic and signaling receptor that is widely expressed in several tissues. As a member of the LDL receptor family, LRP1 is involved in the clearance of chylomicron remnants from the circulation and has been demonstrated to be atheroprotective. Recently, studies have shown that LRP1 is involved in insulin receptor trafficking and regulation and glucose metabolism. This review summarizes the role of tissue-specific LRP1 in insulin signaling and its potential role as a link between lipoprotein and glucose metabolism in diabetes.

  6. Relating climate change signals and physiographic catchment properties to clustered hydrological response types

    Directory of Open Access Journals (Sweden)

    N. Köplin

    2012-07-01

    Full Text Available We propose an approach to reduce a comprehensive set of 186 mesoscale catchments in Switzerland to fewer response types to climate change and to name sensitive regions as well as catchment characteristics that govern hydrological change. We classified the hydrological responses of our study catchments through an agglomerative-hierarchical cluster analysis, and we related the dominant explanatory variables, i.e. the determining catchment properties and climate change signals, to the catchments' hydrological responses by means of redundancy analysis. All clusters except for one exhibit clearly decreasing summer runoff and increasing winter runoff. This seasonal shift was observed for the near future period (2025–2046 but is particularly obvious in the far future period (2074–2095. Within a certain elevation range (between 1000 and 2500 m a.s.l., the hydrological change is basically a function of elevation, because the latter governs the dominant hydro-climatological processes associated with temperature, e.g. the ratio of liquid to solid precipitation and snow melt processes. For catchments below the stated range, hydrological change is mainly a function of precipitation change, which is not as pronounced as the temperature signal is. Future impact studies in Switzerland can be conducted on a reduced sample of catchments representing the sensitive regions or covering a range of altitudes.

  7. Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Falzon, Miriam, E-mail: mfalzon@utmb.edu; Bhatia, Vandanajay [Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 (United States)

    2015-06-18

    Chronic pancreatitis (CP), a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes that predispose to CP. The different environmental and genetic factors produce the same clinical phenotype; once CP develops, disease course is the same regardless of etiology. Critical questions still need to be answered to understand what modifies predisposition to develop CP in persons exposed to risk factors. We postulate that risk factors modulate endogenous pathways, with parathyroid hormone-related protein (PTHrP) signaling being one such pathway. In support, PTHrP levels are elevated in mice treated with alcohol, and in mouse models of cerulein- and pancreatic duct ligation-induced CP. Disrupting the Pthrp gene in acinar cells exerts protective effects (decreased edema, histological damage, amylase and cytokine release, and fibrosis) in these CP models. PTHrP levels are elevated in human CP. Currently, CP care lacks specific pharmacological interventions. Targeting PTHrP signaling may present a novel therapeutic strategy that inhibits pancreatic inflammation and fibrosis, especially since the risk of developing pancreatic cancer is strongly associated with duration of chronic inflammation.

  8. Impaired Insulin/IGF Signaling in Experimental Alcohol-Related Myopathy

    Directory of Open Access Journals (Sweden)

    Elizabeth Silbermann

    2012-08-01

    Full Text Available Alcohol-related myopathy (Alc-M is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8 or 35.5% (N = 13 ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.

  9. Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Miriam Falzon

    2015-06-01

    Full Text Available Chronic pancreatitis (CP, a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes that predispose to CP. The different environmental and genetic factors produce the same clinical phenotype; once CP develops, disease course is the same regardless of etiology. Critical questions still need to be answered to understand what modifies predisposition to develop CP in persons exposed to risk factors. We postulate that risk factors modulate endogenous pathways, with parathyroid hormone-related protein (PTHrP signaling being one such pathway. In support, PTHrP levels are elevated in mice treated with alcohol, and in mouse models of cerulein- and pancreatic duct ligation-induced CP. Disrupting the Pthrp gene in acinar cells exerts protective effects (decreased edema, histological damage, amylase and cytokine release, and fibrosis in these CP models. PTHrP levels are elevated in human CP. Currently, CP care lacks specific pharmacological interventions. Targeting PTHrP signaling may present a novel therapeutic strategy that inhibits pancreatic inflammation and fibrosis, especially since the risk of developing pancreatic cancer is strongly associated with duration of chronic inflammation.

  10. Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis

    International Nuclear Information System (INIS)

    Falzon, Miriam; Bhatia, Vandanajay

    2015-01-01

    Chronic pancreatitis (CP), a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes that predispose to CP. The different environmental and genetic factors produce the same clinical phenotype; once CP develops, disease course is the same regardless of etiology. Critical questions still need to be answered to understand what modifies predisposition to develop CP in persons exposed to risk factors. We postulate that risk factors modulate endogenous pathways, with parathyroid hormone-related protein (PTHrP) signaling being one such pathway. In support, PTHrP levels are elevated in mice treated with alcohol, and in mouse models of cerulein- and pancreatic duct ligation-induced CP. Disrupting the Pthrp gene in acinar cells exerts protective effects (decreased edema, histological damage, amylase and cytokine release, and fibrosis) in these CP models. PTHrP levels are elevated in human CP. Currently, CP care lacks specific pharmacological interventions. Targeting PTHrP signaling may present a novel therapeutic strategy that inhibits pancreatic inflammation and fibrosis, especially since the risk of developing pancreatic cancer is strongly associated with duration of chronic inflammation

  11. Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease

    Directory of Open Access Journals (Sweden)

    Natalie Sampson

    2012-01-01

    Full Text Available Myofibroblast activation plays a central role during normal wound healing. Whereas insufficient myofibroblast activation impairs wound healing, excessive myofibroblast activation promotes fibrosis in diverse tissues (including benign prostatic hyperplasia, BPH leading to organ dysfunction and also promotes a stromal response that supports tumor progression. The incidence of impaired wound healing, tissue fibrosis, BPH, and certain cancers strongly increases with age. This paper summarizes findings from in vitro fibroblast-to-myofibroblast differentiation systems that serve as cellular models to study fibrogenesis of diverse tissues. Supported by substantial in vivo data, a large body of evidence indicates that myofibroblast differentiation induced by the profibrotic cytokine transforming growth factor beta is driven by a prooxidant shift in redox homeostasis due to elevated production of NADPH oxidase 4 (NOX4-derived hydrogen peroxide and supported by concomitant decreases in nitric oxide/cGMP signaling and reactive oxygen species (ROS scavenging enzymes. Fibroblast-to-myofibroblast differentiation can be inhibited and reversed by restoring redox homeostasis using antioxidants or NOX4 inactivation as well as enhancing nitric oxide/cGMP signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases. Current evidence indicates the therapeutic potential of targeting the prooxidant shift in redox homeostasis for the treatment of age-related diseases associated with myofibroblast dysregulation.

  12. The globus pallidus sends reward-related signals to the lateral habenula.

    Science.gov (United States)

    Hong, Simon; Hikosaka, Okihide

    2008-11-26

    As a major output station of the basal ganglia, the globus pallidus internal segment (GPi) projects to the thalamus and brainstem nuclei thereby controlling motor behavior. A less well known fact is that the GPi also projects to the lateral habenula (LHb) which is often associated with the limbic system. Using the monkey performing a saccade task with positionally biased reward outcomes, we found that antidromically identified LHb-projecting neurons were distributed mainly in the dorsal and ventral borders of the GPi and that their activity was strongly modulated by expected reward outcomes. A majority of them were excited by the no-reward-predicting target and inhibited by the reward-predicting target. These reward-dependent modulations were similar to those in LHb neurons but started earlier than those in LHb neurons. These results suggest that GPi may initiate reward-related signals through its effects on the LHb, which then influences the dopaminergic and serotonergic systems.

  13. Application of Chemical Genomics to Plant-Bacteria Communication: A High-Throughput System to Identify Novel Molecules Modulating the Induction of Bacterial Virulence Genes by Plant Signals.

    Science.gov (United States)

    Vandelle, Elodie; Puttilli, Maria Rita; Chini, Andrea; Devescovi, Giulia; Venturi, Vittorio; Polverari, Annalisa

    2017-01-01

    The life cycle of bacterial phytopathogens consists of a benign epiphytic phase, during which the bacteria grow in the soil or on the plant surface, and a virulent endophytic phase involving the penetration of host defenses and the colonization of plant tissues. Innovative strategies are urgently required to integrate copper treatments that control the epiphytic phase with complementary tools that control the virulent endophytic phase, thus reducing the quantity of chemicals applied to economically and ecologically acceptable levels. Such strategies include targeted treatments that weaken bacterial pathogens, particularly those inhibiting early infection steps rather than tackling established infections. This chapter describes a reporter gene-based chemical genomic high-throughput screen for the induction of bacterial virulence by plant molecules. Specifically, we describe a chemical genomic screening method to identify agonist and antagonist molecules for the induction of targeted bacterial virulence genes by plant extracts, focusing on the experimental controls required to avoid false positives and thus ensuring the results are reliable and reproducible.

  14. Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder.

    Science.gov (United States)

    Turan, Serap

    2017-12-30

    Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsα protein activity in peripheral erythrocyte membranes in vitro. However, PHP classification fails to differentiate all patients with different clinical and molecular findings for PHP subtypes and classification become more complicated with more recent molecular characterization and new forms having been identified. So far, new classifications have been established by the EuroPHP network to cover all disorders of the PTH receptor and its signaling pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for a group of these disorders and which can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsα mutations (PHP-Ia, PHP-Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described. With these new classifications, the aim is to clarify the borders of each different subtype of disease and make the classification

  15. Increased working memory related fMRI signal in children following Tick Borne Encephalitis.

    Science.gov (United States)

    Henrik, Ullman; Åsa, Fowler; Ronny, Wickström

    2016-01-01

    Tick Borne Encephalitis (TBE) is a viral infection in the central nervous system endemic in Europe and Asia. While pediatric infection may carry a lower risk for serious neurological sequelae compared to adults, a large proportion of children experience long term cognitive problems, most markedly decreased working memory capacity. We explored whether task related functional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) could reveal a biological correlate of status-post TBE in children. We examined 11 serologically verified pediatric TBE patients with central nervous system involvement with 55 healthy controls with working memory tests and MRI. The TBE patients showed a prominent deficit in working memory capacity and an increased task related functional MRI signal in working memory related cortical areas during a spatial working memory task performed without sedation. No diffusion differences could be found with DTI, in line with the reported paucity of anatomical abnormalities. This study is the first to demonstrate functional MRI abnormalities in TBE patients that bears similarity to other patient groups with diffuse neuronal damage. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  16. Relative signal intensity changes of frontal and occipital white matters on T 2 weighted axial MR image : correlation with age

    International Nuclear Information System (INIS)

    Kim, You Me; Kim, Seung Cheol

    1998-01-01

    The purpose of this study is to assess relative signal intensity changes in frontal and occipital white matter with age, as seen on T 2 weighted axial MR images. Thirty eight normal adults (20-29 years old) and 114 children (0-11 years old) were investigated. All had nonspecific neurologic symptoms and their MR images, obtained using a 1.5 T system (Signa, GE Medical Systems, Milwaukee, U.S.A.), appeared to be normal. The signal intensities of frontal and occipital white matter were evaluated on T2 weighted axial images at the level of the foramen of Monro. When the signal intensity of white matter was higher than that of gray matter, grade 0 was assigned; when the opposite situation pertained, this was graded I - III. Grade I indicated that the signal intensity of occipital white matter was lower than that of frontal white matter; grade II, that the signal intensity of white matter of both lobes was similar. When the signal intensity of frontal white matter was lower than that of occipital age, and by one year after 2 years of age, and then determined grade according to age, age distribution according to grade, and the ages at which signal intensities were similar to those of adults. On T2-weighted MR images, the signal intensity of frontal white matter ultimately shows a lower signal intensity than that of occipital white matter. (author). 11 refs., 6 figs

  17. Motor-related signals in the auditory system for listening and learning.

    Science.gov (United States)

    Schneider, David M; Mooney, Richard

    2015-08-01

    In the auditory system, corollary discharge signals are theorized to facilitate normal hearing and the learning of acoustic behaviors, including speech and music. Despite clear evidence of corollary discharge signals in the auditory cortex and their presumed importance for hearing and auditory-guided motor learning, the circuitry and function of corollary discharge signals in the auditory cortex are not well described. In this review, we focus on recent developments in the mouse and songbird that provide insights into the circuitry that transmits corollary discharge signals to the auditory system and the function of these signals in the context of hearing and vocal learning. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway.

    Directory of Open Access Journals (Sweden)

    Ruslan Hlushchuk

    Full Text Available Angiogenesis is a highly coordinated, extremely complex process orchestrated by multiple signaling molecules and blood flow conditions. While sprouting mode of angiogenesis is very well investigated, the molecular mechanisms underlying intussusception, the second mode of angiogenesis, remain largely unclear. In the current study two molecules involved in vascular growth and differentiation, namely endoglin (ENG/CD105 and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII were examined to unravel their specific roles in angiogenesis. Down- respectively up-regulation of both molecules tightly correlates with intussusceptive microvascular growth. Upon ENG inhibition in chicken embryo model, formation of irregular capillary meshwork accompanied by increased expression of COUP-TFII could be observed. This dynamic expression pattern of ENG and COUP-TFII during vascular development and remodeling correlated with formation of pillars and progression of intussusceptive angiogenesis. Similar findings could be observed in mammalian model of acute rat Thy1.1 glomerulonephritis, which was induced by intravenous injection of anti-Thy1 antibody and has shown upregulation of COUP-TFII in initial phase of intussusception, while ENG expression was not disturbed compared to the controls but decreased over the time of pillar formation. In this study, we have shown that ENG inhibition and at the same time up-regulation of COUP-TFII expression promotes intussusceptive angiogenesis.

  19. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 16; Issue 12. Molecule Matters - Dinitrogen. A G Samuelson J Jabadurai. Volume 16 Issue 12 ... Author Affiliations. A G Samuelson1 J Jabadurai1. Department of Inroganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India.

  20. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 9. Molecule Matters - A Chromium Compound with a Quintuple Bond. K C Kumara Swamy. Feature Article Volume 11 Issue 9 September 2006 pp 72-75. Fulltext. Click here to view fulltext PDF. Permanent link:

  1. The Protective Effects of Curcumin on Obesity-Related Glomerulopathy Are Associated with Inhibition of Wnt/β-Catenin Signaling Activation in Podocytes

    Directory of Open Access Journals (Sweden)

    Bao-li Liu

    2015-01-01

    Full Text Available The present study investigated the effects of curcumin, one of the most important active ingredients of turmeric, on podocyte injury in vitro and obesity-related glomerulopathy (ORG in vivo. Cellular experiments in vitro showed that curcumin significantly antagonized leptin-induced downregulation of the mRNA and protein expression of podocyte-associated molecules including nephrin, podocin, podoplanin, and podocalyxin. Animal experiments in vivo showed that curcumin significantly reduced the body weight, Lee’s index, abdominal fat index, urinary protein excretion, and average glomerular diameter and significantly upregulated the mRNA and protein expressions of the above podocyte-associated molecules in ORG mice. Furthermore, the experiments in vitro and in vivo both displayed that curcumin could downregulate the mRNA and protein expressions of Wnt1, Wnt2b, Wnt6, and β-catenin and upregulate the phosphorylation level of β-catenin protein in podocytes and renal tissue. In conclusion, curcumin is able to alleviate the harmful reaction of leptin on podocytes and reduce the severity of ORG. The above protective effects are associated with the inhibition of Wnt/β-catenin signaling activation in podocytes.

  2. Salinity-induced inhibition of growth in the aquatic pteridophyte Azolla microphylla primarily involves inhibition of photosynthetic components and signaling molecules as revealed by proteome analysis.

    Science.gov (United States)

    Thagela, Preeti; Yadav, Ravindra Kumar; Mishra, Vagish; Dahuja, Anil; Ahmad, Altaf; Singh, Pawan Kumar; Tiwari, Budhi Sagar; Abraham, Gerard

    2017-01-01

    Salinity stress causes adverse physiological and biochemical changes in the growth and productivity of a plant. Azolla, a symbiotic pteridophyte and potent candidate for biofertilizer due to its nitrogen fixation ability, shows reduced growth and nitrogen fixation during saline stress. To better understand regulatory components involved in salinity-induced physiological changes, in the present study, Azolla microphylla plants were exposed to NaCl (6.74 and 8.61 ds/m) and growth, photochemical reactions of photosynthesis, ion accumulation, and changes in cellular proteome were studied. Maximum dry weight was accumulated in control and untreated plant while a substantial decrease in dry weight was observed in the plants exposed to salinity. Exposure of the organism to different concentrations of salt in hydroponic conditions resulted in differential level of Na + and K + ion accumulation. Comparative analysis of salinity-induced proteome changes in A. microphylla revealed 58 salt responsive proteins which were differentially expressed during the salt exposure. Moreover, 42 % spots among differentially expressed proteins were involved in different signaling events. The identified proteins are involved in photosynthesis, energy metabolism, amino acid biosynthesis, protein synthesis, and defense. Downregulation of these key metabolic proteins appears to inhibit the growth of A. microphylla in response to salinity. Altogether, the study revealed that in Azolla, increased salinity primarily affected signaling and photosynthesis that in turn leads to reduced biomass.

  3. Differential Regulation of cGMP Signaling in Human Melanoma Cells at Altered Gravity: Simulated Microgravity Down-Regulates Cancer-Related Gene Expression and Motility

    Science.gov (United States)

    Ivanova, Krassimira; Eiermann, Peter; Tsiockas, Wasiliki; Hemmersbach, Ruth; Gerzer, Rupert

    2018-03-01

    Altered gravity is known to affect cellular function by changes in gene expression and cellular signaling. The intracellular signaling molecule cyclic guanosine-3',5'-monophosphate (cGMP), a product of guanylyl cyclases (GC), e.g., the nitric oxide (NO)-sensitive soluble GC (sGC) or natriuretic peptide-activated GC (GC-A/GC-B), is involved in melanocyte response to environmental stress. NO-sGC-cGMP signaling is operational in human melanocytes and non-metastatic melanoma cells, whereas up-regulated expression of GC-A/GC-B and inducible NO synthase (iNOS) are found in metastatic melanoma cells, the deadliest skin cancer. Here, we investigated the effects of altered gravity on the mRNA expression of NOS isoforms, sGC, GC-A/GC-B and multidrug resistance-associated proteins 4/5 (MRP4/MRP5) as selective cGMP exporters in human melanoma cells with different metastatic potential and pigmentation. A specific centrifuge (DLR, Cologne Germany) was used to generate hypergravity (5 g for 24 h) and a fast-rotating 2-D clinostat (60 rpm) to simulate microgravity values ≤ 0.012 g for 24 h. The results demonstrate that hypergravity up-regulates the endothelial NOS-sGC-MRP4/MRP5 pathway in non-metastatic melanoma cells, but down-regulates it in simulated microgravity when compared to 1 g. Additionally, the suppression of sGC expression and activity has been suggested to correlate inversely to tumor aggressiveness. Finally, hypergravity is ineffective in highly metastatic melanoma cells, whereas simulated microgravity down-regulates predominantly the expression of the cancer-related genes iNOS and GC-A/GC-B (shown additionally on protein levels) as well as motility in comparison to 1 g. The results suggest that future studies in real microgravity can benefit from considering GC-cGMP signaling as possible factor for melanocyte transformation.

  4. Conformation-related exciton localization and charge-pair formation in polythiophenes: ensemble and single-molecule study.

    Science.gov (United States)

    Sugimoto, Toshikazu; Habuchi, Satoshi; Ogino, Kenji; Vacha, Martin

    2009-09-10

    We study conformation-dependent photophysical properties of polythiophene (PT) by molecular dynamics simulations and by ensemble and single-molecule optical experiments. We use a graft copolymer consisting of a polythiophene backbone and long polystyrene branches and compare its properties with those obtained on the same polythiophene derivative without the side chains. Coarse-grain molecular dynamics simulations show that in a poor solvent, the PT without the side chains (PT-R) forms a globulelike conformation in which distances between any two conjugated segments on the chain are within the Forster radius for efficient energy transfer. In the PT with the polystyrene branches (PT-PS), the polymer main PT chain retains an extended coillike conformation, even in a poor solvent, and the calculated distances between conjugated segments favor energy transfer only between a few neighboring chromophores. The theoretical predictions are confirmed by measurements of fluorescence anisotropy and fluorescence blinking of the polymers' single chains. High anisotropy ratios and two-state blinking in PT-R are due to localization of the exciton on a single conjugated segment. These signatures of exciton localization are absent in single chains of PT-PS. Electric-field-induced quenching measured as a function of concentration of PT dispersed in an inert matrix showed that in well-isolated chains of PT-PS, the exciton dissociation is an intrachain process and that aggregation of the PT-R chains causes an increase in quenching due to the onset of interchain interactions. Measurements of the field-induced quenching on single chains indicate that in PT-R, the exciton dissociation is a slower process that takes place only after the exciton is localized on one conjugated segment.

  5. Small Molecules Targeting Ataxia Telangiectasia and Rad3-Related (ATR) Kinase: An Emerging way to Enhance Existing Cancer Therapy

    Czech Academy of Sciences Publication Activity Database

    Andrs, M.; Korábečný, J.; Nepovimova, E.; Jun, D.; Hodný, Zdeněk; Kuca, K.

    2016-01-01

    Roč. 16, č. 3 (2016), s. 200-208 ISSN 1568-0096 Institutional support: RVO:68378050 Keywords : Ataxia telangiectasia and Rad3-related kinase (ATR) * cancer * chemosensitization * DNA damage response * phosphatidylinositol 3-kinase-related protein kinases (PIKK) * radiosensitization * synthetic lethality Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.992, year: 2016

  6. Expressional Changes of Water Transport-related Molecules in the Efferent Ductules and Initial Segment of Mouse Treated with Bisphenol A-Containing Drinking Water for Two Generations.

    Science.gov (United States)

    Han, Su-Yong; Lee, Ki-Ho

    2013-09-01

    Bisphenol A (BPA) is an estrogenic endocrine disrupter. However, depending on a way of treatment, the harmful effects of BPA have not been confirmed. Also, trans-generational effects of BPA on male reproduction are still controversial. Because the reabsorption of testicular fluid in the efferent ductules (ED) and initial segment (IS) is important for sperm maturation, the present study was designed to determine trans-generational effect of BPA administrated orally on expression of water transport-related molecules in the mouse ED and IS. Ethanol-dissolved BPA was diluted in water to be 100 ng (low), 10 μg (medium), and 1 mg/Ml water (high). BPA-containing water was provided for two generations. Expression of ion transporters and water channels in the ED and IS were measured by relative real-time PCR analysis. In the ED, BPA treatment caused expressional increases of carbonic anhydrase II, cystic fibrosis transmembrane regulator, Na(+)/K(+) ATPase α1 subunit, and aquaporin (AQP) 1. No change of Na(+)/H(+) exchange (NHE) 3 expression was detected. BPA treatment at medium dose resulted in an increase of AQP9 expression. In the IS, the highest expressional levels of all molecules tested were observed in medium-dose BPA treatment. Generally, high-dose BPA treatment resulted in a decrease or no change of gene expression. Fluctuation of NHE3 gene expression by BPA treatment at different concentrations was detected. These findings suggest that trans-generational exposure to BPA, even at low dose, could affect gene expression of water-transport related molecules. However, such effects of BPA would be differentially occurred in the ED and IS.

  7. [Effect of Biejiajian Pills on Wnt signal pathway molecules β-catenin and GSK-3β and the target genes CD44v6 and VEGF in hepatocellular carcinoma cells].

    Science.gov (United States)

    Sun, Haitao; He, Songqi; Wen, Bin; Jia, Wenyan; Fan, Eryan; Zheng, Yan

    2014-10-01

    To investigate the effect of Biejiajian Pills on the expressions of the signal molecules and target genes of Wnt signal pathway in HepG2 cells and explore the mechanisms by which Biejiajian pills suppress the invasiveness of hepatocellular carcinoma. HepG2 cells were cultured for 48 h in the presence of serum collected from rats fed with Biejiajian Pills. The expressions of β-catenin, GSK-3β and P-GSK-3β in the cultured cells were assessed by Western blotting and the expressions of CD44v6 and VEGF were detected using immunohistochemistry. HepG2 cells cultured with the serum of rats fed with Biejiajian Pills showed lowered expressions of β-catenin protein both in the cytoplasm and the nuclei with also inhibition of phosphorylation of GSK-3β and reduced expression of CD44v6 and VEGF. Biejiajian Pills can significantly reduce the expression of β-catenin by decreasing the phosphorylation of GSK-3β and blocking the Wnt/β-catenin signaling pathway to cause down-regulation of the target genes CD44v6 and VEGF, which may be one of the molecular mechanisms by which Biejiajian Pills suppress the proliferation and invasiveness of hepatocellular carcinoma.

  8. Dynamics of Activated Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Mullin, Amy S. [Univ. of Maryland, College Park, MD (United States)

    2016-11-16

    Experimental studies have been performed to investigate the collisional energy transfer processes of gas-phase molecules that contain large amounts of internal energy. Such molecules are prototypes for molecules under high temperature conditions relevant in combustion and information about their energy transfer mechanisms is needed for a detailed understanding and modeling of the chemistry. We use high resolution transient IR absorption spectroscopy to measure the full, nascent product distributions for collisions of small bath molecules that relax highly vibrationally excited pyrazine molecules with E=38000 cm-1 of vibrational energy. To perform these studies, we developed new instrumentation based on modern IR light sources to expand our experimental capabilities to investigate new molecules as collision partners. This final report describes our research in four areas: the characterization of a new transient absorption spectrometer and the results of state-resolved collision studies of pyrazine(E) with HCl, methane and ammonia. Through this research we have gained fundamental new insights into the microscopic details of relatively large complex molecules at high energy as they undergo quenching collisions and redistribute their energy.

  9. The NOD-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer: a case-control study and gene expression analyses.

    Directory of Open Access Journals (Sweden)

    Natalia Castaño-Rodríguez

    Full Text Available BACKGROUND: Currently, it is well established that cancer arises in chronically inflamed tissue. A number of NOD-like receptors (NLRs form inflammasomes, intracellular multiprotein complexes critical for generating mature pro-inflammatory cytokines (IL-1β and IL-18. As chronic inflammation of the gastric mucosa is a consequence of Helicobacter pylori infection, we investigated the role of genetic polymorphisms and expression of genes involved in the NLR signalling pathway in H. pylori infection and related gastric cancer (GC. MATERIALS AND METHODS: Fifty-one genetic polymorphisms were genotyped in 310 ethnic Chinese (87 non-cardia GC cases and 223 controls with functional dyspepsia. In addition, gene expression of 84 molecules involved in the NLR signalling pathway was assessed in THP-1 cells challenged with two H. pylori strains, GC026 (GC and 26695 (gastritis. RESULTS: CARD8-rs11672725, NLRP3-rs10754558, NLRP3-rs4612666, NLRP12-rs199475867 and NLRX1-rs10790286 showed significant associations with GC. On multivariate analysis, CARD8-rs11672725 remained a risk factor (OR: 4.80, 95% CI: 1.39-16.58. Further, NLRP12-rs2866112 increased the risk of H. pylori infection (OR: 2.13, 95% CI: 1.22-3.71. Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (CARD8, NLRP3, CASP1 and NLRP12 polymorphisms. In gene expression analyses, five genes encoding NLRs were significantly regulated in H. pylori-challenged cells (NLRC4, NLRC5, NLRP9, NLRP12 and NLRX1. Interestingly, persistent up-regulation of NFKB1 with simultaneous down-regulation of NLRP12 and NLRX1 was observed in H. pylori GC026-challenged cells. Further, NF-κB target genes encoding pro-inflammatory cytokines, chemokines and molecules involved in carcinogenesis were markedly up-regulated in H. pylori GC026-challenged cells. CONCLUSIONS: Novel associations between polymorphisms in the NLR signalling pathway (CARD8

  10. Trehalose 6-phosphate signal is closely related to sorbitol in apple (Malus domestica Borkh. cv. Gala)

    Science.gov (United States)

    Zhang, Wen; Lunn, John E.; Feil, Regina; Wang, Yufei; Zhao, Jingjing; Tao, Hongxia; Zhao, Zhengyang

    2017-01-01

    ABSTRACT Trehalose-6-phosphate (Tre6P) is a precursor of trehalose, which is widespread in nature and greatly influences plant growth and development. Tre6P acts as a signal of carbon availability in many plants, but little is known about the function of Tre6P in rosaceous plants, which have specific sorbitol biosynthesis and transportation pathways. In the present study, Tre6P levels and Sorbitol:Tre6P ratios were analyzed in apple (Malus domestica, Borkh. cv. Gala). Tre6P levels were positively correlated with sorbitol content but negatively correlated with sucrose, glucose, and fructose content in developing fruit. However, under sorbitol-limited conditions, Tre6P levels were positively correlated with both sorbitol and sucrose. In the presence of different exogenous sugar supply, Tre6P levels increased corresponding with sorbitol, but this was not the case with sucrose. In addition, Tre6P content and sorbitol:Tre6P ratios were more highly correlated with ADP-glucose levels under sorbitol-limited conditions and fruit development stages, respectively. These results suggest that Tre6P is more closely related to sorbitol than other soluble sugars and has an important role in influencing carbon metabolism in apple. PMID:28069587

  11. Does signaling of estrogen-related receptors affect structure and function of bank vole Leydig cells?

    Science.gov (United States)

    Pawlicki, P; Milon, A; Zarzycka, M; Galas, J; Tworzydlo, W; Kaminska, A; Pardyak, L; Lesniak, K; Pacwa, A; Bilinska, B; Gorowska-Wojtowicz, E; Kotula-Balak, M

    2017-06-01

    To get a deeper insight into the function of estrogen-related receptors (ERRs) and dissect underlying mechanism in Leydig cells, ERRs (type α, β and γ) were blocked or activated in testes of adult bank voles (Myodes glareolus) which show seasonal changes in the intratesticular sex hormones level. Both actively reproducing animals (long day conditions; LD) and those with regression of the reproductive system (short day conditions; SD) received intraperitoneal injections of selective ERRα antagonist 3-[4-(2,4-Bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acrylamide (XCT 790) or selective ERRβ/ERRγ agonist N-(4-(Diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) (50 μ/kg bw; six doses every other day). Markedly more, XCT 790 (P endogenous estrogen level in treated males. Notably, immunolocalization of ERRs and above proteins, exclusively in Leydig cells, indicated their involvement in Leydig cell function control based on interactions with endogenous estrogen level and/or estrogen signaling via ERRs. Treatment with XCT 790 or DY131 significantly decreased (P endogenous estrogen status in the testis. Further understanding of mechanism(s) by which individual types of ERRs can control Leydig cell function is relevant for predicting and preventing steroidogenic and spermatogenic disorders.

  12. Trehalose 6-phosphate signal is closely related to sorbitol in apple (Malus domestica Borkh. cv. Gala

    Directory of Open Access Journals (Sweden)

    Wen Zhang

    2017-02-01

    Full Text Available Trehalose-6-phosphate (Tre6P is a precursor of trehalose, which is widespread in nature and greatly influences plant growth and development. Tre6P acts as a signal of carbon availability in many plants, but little is known about the function of Tre6P in rosaceous plants, which have specific sorbitol biosynthesis and transportation pathways. In the present study, Tre6P levels and Sorbitol:Tre6P ratios were analyzed in apple (Malus domestica, Borkh. cv. Gala. Tre6P levels were positively correlated with sorbitol content but negatively correlated with sucrose, glucose, and fructose content in developing fruit. However, under sorbitol-limited conditions, Tre6P levels were positively correlated with both sorbitol and sucrose. In the presence of different exogenous sugar supply, Tre6P levels increased corresponding with sorbitol, but this was not the case with sucrose. In addition, Tre6P content and sorbitol:Tre6P ratios were more highly correlated with ADP-glucose levels under sorbitol-limited conditions and fruit development stages, respectively. These results suggest that Tre6P is more closely related to sorbitol than other soluble sugars and has an important role in influencing carbon metabolism in apple.

  13. Is the number of microembolic signals related to neurologic outcome in coronary bypass surgery?

    Directory of Open Access Journals (Sweden)

    Malheiros Suzana M. F.

    2001-01-01

    Full Text Available Coronary artery bypass surgery (CABG without cardiopulmonary bypass (CPB may potentially reduce the number of microembolic signals (MES associated with aortic manipulation or generated by the pump circuit, resulting in a better neurologic outcome after surgery. Our aim was to compare the frequency of MES and neurologic complications in CABG with and without CPB. Twenty patients eligible to routine CABG without CPB were randomized to surgery with CPB and without CPB and continuously monitored by transcranial Doppler. Neurologic examination was performed in all patients before and after surgery. The two groups were similar with respect to demographics, risk factors, grade of aortic atheromatous disease and number of grafts. The frequency of MES in the nonCPB group was considerably lower than in CPB patients, however, we did not observe any change in the neurologic examination during the early postoperative period. Neurologic complications after CABG may be related to the size and composition of MES rather than to their absolute numbers. A large prospective multicentric randomized trial may help to elucidate this complex issue.

  14. Relaxin-3 receptor (RXFP3 signalling mediates stress-related alcohol preference in mice.

    Directory of Open Access Journals (Sweden)

    Andrew W Walker

    Full Text Available Stressful life events are causally linked with alcohol use disorders (AUDs, providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3 prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT and Rxfp3 knockout (KO (C57/B6JRXFP3TM1/DGen littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.

  15. Effects of Synthetic Neural Adhesion Molecule Mimetic Peptides and Related Proteins on the Cardiomyogenic Differentiation of Mouse Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    Ruodan Xu

    2015-04-01

    Full Text Available Background/Aims: Pluripotent stem cells differentiating into cardiomyocyte-like cells in an appropriate cellular environment have attracted significant attention, given the potential use of such cells for regenerative medicine. However, the precise mechanisms of lineage specification of pluripotent stem cells are still largely to be explored. Identifying the role of various small synthetic peptides involved in cardiomyogenesis may provide new insights into pathways promoting cardiomyogenesis. Methods: In the present study, using a transgenic murine embryonic stem (ES cell lineage expressing enhanced green fluorescent protein (EGFP under the control of α-myosin heavy chain (α-MHC promoter (pαMHC-EGFP, we investigated the cardiomyogenic effects of 7 synthetic peptides (Betrofin3, FGLs, FGLL, hNgf_C2, EnkaminE, Plannexin and C3 on cardiac differentiation. The expression of several cardiac-specific markers was determined by RT-PCR whereas the structural and functional properties of derived cardiomyocytes were examined by immunofluorescence and electrophysiology, respectively. Results: The results revealed that Betrofin3, an agonist of brain derived neurotrophic factor (BDNF peptide exerted the most striking pro-cardiomyogenic effect on ES cells. We found that BDNF receptor, TrkB expression was up-regulated during differentiation. Treatment of differentiating cells with Betrofin3 between days 3 and 5 enhanced the expression of cardiac-specific markers and improved cardiomyocyte differentiation and functionality as revealed by genes regulation, flow cytometry and patch clamp analysis. Thus Betrofin3 may exert its cardiomyogenic effects on ES cells via TrkB receptor. Conclusion: Taken together, the results suggest that Betrofin3 modulates BDNF signaling with positive cardiomyogenic effect in stage and dose-dependent manner providing an effective strategy to increase ES cell-based generation of cardiomyocytes and offer a novel therapeutic approach to

  16. Insulin/IGF signaling-related gene expression in the brain of a sporadic Alzheimer's disease monkey model induced by intracerebroventricular injection of streptozotocin.

    Science.gov (United States)

    Lee, Youngjeon; Kim, Young-Hyun; Park, Sang-Je; Huh, Jae-Won; Kim, Sang-Hyun; Kim, Sun-Uk; Kim, Ji-Su; Jeong, Kang-Jin; Lee, Kyoung-Min; Hong, Yonggeun; Lee, Sang-Rae; Chang, Kyu-Tae

    2014-01-01

    We reported previously that the intracerebroventricular streptozotocin (icv-STZ)-treated cynomolgus monkey showed regionally specific glucose hypometabolism in FDG-PET imaging, similar to that observed in the early stages of sporadic Alzheimer's disease (sAD). However, further pathological analyses of this model at the molecular level are needed to validate it as a feasible model for sAD. Two cynomolgus monkeys were injected with 2 mg/kg STZ into the cerebellomedullary cistern at day 1, 7 and 14. Two control monkeys were given normal saline. At 5 months after injection, the expression levels of genes encoding 9 upstream molecules in insulin/insulin-like growth factor (IGF) signaling and markers for 4 cell-type populations in the frontal cortex, hippocampus, posterior cingulate, precuneus, and occipital cortex of control and icv-STZ treated cynomolgus monkeys were examined. Real-time quantitative PCR analyses demonstrated that the overall mRNA expression of insulin/IGF signaling-related genes was mainly impaired in the anterior part of the cerebrum, frontal cortex, and hippocampus, similar to the early stage of sAD. The changes were accompanied by the loss of oligodendrocytes and neurons. The posterior part of the cerebrum did not show degenerative alterations. The present study provides important fundamental information on the icv-STZ monkey model for sAD. These results may help guide future studies using this model for the investigation of pathological mechanisms and the development of drugs for sAD.

  17. Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected

    DEFF Research Database (Denmark)

    Storgaard, H; Song, X M; Jensen, C B

    2001-01-01

    To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects...... phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. However...... resistance in skeletal muscle from relatives of patients with type 2 diabetes....

  18. Liquid-Diet with Alcohol Alters Maternal, Fetal and Placental Weights and the Expression of Molecules Involved in Integrin Signaling in the Fetal Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Ujjwal K. Rout

    2010-11-01

    Full Text Available Maternal alcohol consumption during pregnancy causes wide range of behavioral and structural deficits in children, commonly known as Fetal Alcohol Syndrome (FAS. Children with FAS may suffer behavioral deficits in the absence of obvious malformations. In rodents, the exposure to alcohol during gestation changes brain structures and weights of offspring. The mechanism of FAS is not completely understood. In the present study, an established rat (Long-Evans model of FAS was used. The litter size and the weights of mothers, fetuses and placentas were examined on gestation days 18 or 20. On gestation day 18, the effects of chronic alcohol on the expression levels of integrin receptor subunits, phospholipase-Cγ and N-cadherin were examined in the fetal cerebral cortices. Presence of alcohol in the liquid-diet reduced the consumption and decreased weights of mothers and fetuses but increased the placental weights. Expression levels of β1 and α3 integrin subunits and phospholipase-Cγ2 were significantly altered in the fetal cerebral cortices of mothers on alcohol containing diet. Results show that alcohol consumption during pregnancy even with protein, mineral and vitamin enriched diet may affect maternal and fetal health, and alter integrin receptor signaling pathways in the fetal cerebral cortex disturbing the development of fetal brains.

  19. The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Obesity and Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Krithika Srikanthan

    2016-09-01

    Full Text Available Na/K-ATPase has been extensively studied for its ion pumping function, but, in the past several decades, has been identified as a scaffolding and signaling protein. Initially it was found that cardiotonic steroids (CTS mediate signal transduction through the Na/K-ATPase and result in the generation of reactive oxygen species (ROS, which are also capable of initiating the signal cascade. However, in recent years, this Na/K-ATPase/ROS amplification loop has demonstrated significance in oxidative stress related disease states, including obesity, atherosclerosis, heart failure, uremic cardiomyopathy, and hypertension. The discovery of this novel oxidative stress signaling pathway, holds significant therapeutic potential for the aforementioned conditions and others that are rooted in ROS.

  20. Interleukin-2 induces beta2-integrin-dependent signal transduction involving the focal adhesion kinase-related protein B (fakB)

    DEFF Research Database (Denmark)

    Brockdorff, J; Kanner, S B; Nielsen, M

    1998-01-01

    beta2 integrin molecules are involved in a multitude of cellular events, including adhesion, migration, and cellular activation. Here, we studied the influence of beta2 integrins on interleukin-2 (IL-2)-mediated signal transduction in human CD4(+) T cell lines obtained from healthy donors...

  1. Modulation of ASIC channels in rat cerebellar purkinje neurons by ischaemia-related signals

    Science.gov (United States)

    Allen, Nicola J; Attwell, David

    2002-01-01

    Acid-sensing ion channels (ASICs), activated by a decrease of extracellular pH, are found in neurons throughout the nervous system. They have an amino acid sequence similar to that of ion channels activated by membrane stretch, and have been implicated in touch sensation. Here we characterize the pH-dependent activation of ASICs in cerebellar Purkinje cells and investigate how they are modulated by factors released in ischaemia. Lowering the external pH from 7.4 activated an inward current at −66 mV, carried largely by Na+ ions, which was half-maximal for a step to pH 6.4 and was blocked by amiloride and gadolinium. The H+-gated current desensitized within a few seconds, but approximately 30% of cells showed a sustained inward current (11% of the peak current) in response to the maintained presence of pH 6 solution. The peak H+-evoked current was potentiated by membrane stretch (which occurs in ischaemia when [K+]o rises) and by arachidonic acid (which is released when [Ca2+]i rises in ischaemia). Arachidonic acid increased to 77% the fraction of cells showing a sustained current evoked by acid pH. The ASIC currents were also potentiated by lactate (which is released when metabolism becomes anaerobic in ischaemia) and by FMRFamide (which may mimic the action of related mammalian RFamide transmitters). These data reinforce suggestions of a mechanosensory aspect to ASIC channel function, and show that the activation of ASICs reflects the integration of multiple signals which are present during ischaemia. PMID:12205186

  2. In hypertrophic cardiomyopathy reduction of relative resting myocardial blood flow is related to late enhancement, T2-signal and LV wall thickness.

    Directory of Open Access Journals (Sweden)

    Katja Hueper

    Full Text Available To quantify resting myocardial blood flow (MBF in the left ventricular (LV wall of HCM patients and to determine the relationship to important parameters of disease: LV wall thickness, late gadolinium enhancement (LGE, T2-signal abnormalities (dark and bright signal, LV outflow tract obstruction and age.Seventy patients with proven HCM underwent cardiac MRI. Absolute and relative resting MBF were calculated from cardiac perfusion MRI by using the Fermi function model. The relationship between relative MBF and LV wall thickness, T2-signal abnormalities (T2 dark and T2 bright signal, LGE, age and LV outflow gradient as determined by echocardiography was determined using simple and multiple linear regression analysis. Categories of reduced and elevated perfusion in relation to non- or mildly affected reference segments were defined, and T2-signal characteristics and extent as well as pattern of LGE were examined. Statistical testing included linear and logistic regression analysis, unpaired t-test, odds ratios, and Fisher's exact test.804 segments in 70 patients were included in the analysis. In a simple linear regression model LV wall thickness (p<0.001, extent of LGE (p<0.001, presence of edema, defined as focal T2 bright signal (p<0.001, T2 dark signal (p<0.001 and age (p = 0.032 correlated inversely with relative resting MBF. The LV outflow gradient did not show any effect on resting perfusion (p = 0.901. Multiple linear regression analysis revealed that LGE (p<0.001, edema (p = 0.026 and T2 dark signal (p = 0.019 were independent predictors of relative resting MBF. Segments with reduced resting perfusion demonstrated different LGE patterns compared to segments with elevated resting perfusion.In HCM resting MBF is significantly reduced depending on LV wall thickness, extent of LGE, focal T2 signal abnormalities and age. Furthermore, different patterns of perfusion in HCM patients have been defined, which may represent different stages of

  3. Klotho-related Molecules Upregulated by Smoking Habit in Apparently Healthy Men: A Cross-sectional Study.

    Science.gov (United States)

    Nakanishi, Kaori; Nishida, Makoto; Harada, Masaya; Ohama, Tohru; Kawada, Noritaka; Murakami, Masaaki; Moriyama, Toshiki; Yamauchi-Takihara, Keiko

    2015-09-18

    While aging is unavoidable, the aging mechanism is still unclear because of its complexity. Smoking causes premature death and is considered as an environmental aging accelerator. In the present study, we focused on the influence of smoking to the serum concentration of anti-aging protein α-klotho (αKl) and the β-klotho-associated protein fibroblast growth factor (FGF)-21 in men. Subjects consisted of apparently healthy men over 40 years of age who underwent health examination. Physical and biochemical parameters, including the levels of several cytokines and growth factors, were obtained from the subjects. Among middle-aged men (46.1 ± 5.1 years), serum levels of FGF-21, soluble αKl (sαKl), and inflammation-related cytokine interleukin (IL)-6 were significantly higher in smokers than in never-smokers. Serum levels of FGF-21 increased and correlated with alanine transaminase, γ guanosine-5'-triphosphate, and total cholesterol only in smokers, suggesting FGF-21 as a metabolic disorder-related factor in smokers. In aged men (60.3 ± 1.7 years), although the serum levels of sαKl in never-smokers were low, smokers showed highly increased serum levels of sαKl. Serum levels of sαKl was correlated with IL-6 in middle-aged never-smokers, suggesting sαKl regulates IL-6. However, this correlation was disrupted in smokers and aged men.

  4. Study on AI-2 signaling molecules activity and the effect of matrine on AI-2 in Staphylococcus epidermidis LuxS/AI-2 quorum sensing%产膜表皮葡萄球菌LuxS/AI-2型密度感应系统AI-2的活性及苦参碱对其的影响

    Institute of Scientific and Technical Information of China (English)

    李雪; 何芳; 卢金霞; 管翠萍; 周学章

    2017-01-01

    [Objective] This study investigated the activity of AI-2 signaling molecules in Staphylococcus epidermidis planktonic bacteria and biofilm bacteria and the effect of matrine.[Method] The growth curve of Staphylococcus epidermidis planktonic bacteria and biofilm bacteria was drawn and AI-2 concentration was measured using the V.harveyi bioluminescence assay.The transcription level of luxS gene was analyzed using real-time PCR.The AI-2 signaling molecules of Staphylococcus epidermidis ATCC35984 were treated with matrine and the changes of AI-2 signaling molecules activity were determined.[Result] In Staphylococcus epidermidis planktonic bacteria growth process,AI-2 signaling molecule activity and the relative expression quantity of luxS gene reached the maximum in the logarithmic phase before decreasing gradually.Their change curves were similar with planktonic growth curve.However,in the growth process of Staphylococcus epidermidis biofilm bacteria,the activity trend was similar with the biofilm growth.The relative expression quantity of luxS gene had an opposite trend to biofilm growth.Matrine had inhibitory effect on AI-2 signaling molecule activity in planktonic and biofilm bacteria,and the inhibitory effect was stronger to planktonic bacteria.[Conclusion] AI-2 signaling molecule activity and relative expression quantity of luxS gene highly correlated with the growth of Staphylococcus epidermidis and its biofilm formation.Matrine significantly reduced the AI-2 signaling molecule activity of Staphylococcus epidermidis.%[目的]研究产膜表皮葡萄球菌生物被膜菌和液相浮游菌LuxS/AI-2型密度感应系统中AI-2信号分子的活性及苦参碱对其的影响.[方法]绘制产膜表皮葡萄球菌ATCC35984液相浮游菌及生物被膜菌的生长曲线;利用哈维氏弧菌BB170(Vibrio harveyi BB170)作为报告菌株检测表皮葡萄球菌AI-2信号分子的活性;用荧光定量PCR法检测luxS基因的转录水平;用苦参碱

  5. Analysis of the presence of cell proliferation-related molecules in the Tgf-β3 null mutant mouse palate reveals misexpression of EGF and Msx-1.

    Science.gov (United States)

    del Río, A; Barrio, M C; Murillo, J; Maldonado, E; López-Gordillo, Y; Martínez-Sanz, E; Martínez, M L; Martínez-Álvarez, C

    2011-01-01

    The Tgf-β(3) null mutant mouse palate presents several cellular anomalies that lead to the appearance of cleft palate. One of them concerns the cell proliferation of both the palatal medial edge epithelium and mesenchyme. In this work, our aim was to determine whether there was any variation in the presence/distribution of several cell proliferation-related molecules that could be responsible for the cell proliferation defects observed in these palates. Our results showed no difference in the presence of EGF-R, PDGF-A, TGF-β(2), Bmp-2, and Bmp-4, and differences were minimal for FGF-10 and Shh. However, the expression of EGF and Msx-1 changed substantially. The shift of the EGF protein expression was the one that most correlated with that of cell proliferation. This molecule is regulated by TGF-β(3), and experiments blocking its activity in culture suggest that EGF misexpression in the Tgf-β(3) null mutant mouse palate plays a role in the cell proliferation defect observed. Copyright © 2010 S. Karger AG, Basel.

  6. Factors related to the magnitude of T2* MR signal changes during functional imaging

    Energy Technology Data Exchange (ETDEWEB)

    Krings, T. [Department of Neuroradiology, University Hospital of the Technical University Aachen (Germany); Department of Neurosurgery, University Hospital of the Technical University Aachen (Germany); Interdisciplinary Centre for Clinical Research - Central Nervous System, University Hospital of the Technical University Aachen, Pauwelsstrasse 30, 52057 Aachen (Germany); Reinges, M.H.T.; Gilsbach, J.M. [Department of Neurosurgery, University Hospital of the Technical University Aachen (Germany); Willmes, K.; Nuerk, H.C. [Section of Neuropsychology, Department of Neurology, University Hospital of the Technical University Aachen (Germany); Meister, I.G. [Department of Neurology, University Hospital of the Technical University Aachen (Germany); Thron, A. [Department of Neuroradiology, University Hospital of the Technical University Aachen (Germany)

    2002-06-01

    Our aim was to determine whether age, sex, the degree of weakness, anticonvulsants, the histology of the underlying lesion(s), the presence of oedema or the distance of the lesion from the motor region have an impact on the blood oxygenation level-dependent (BOLD) signal strength and therefore on the validity of functional MRI (fMRI). We studied 98 patients with masses near the central region imaged for surgical planning at 1.5 tesla, employing a BOLD sequence during a motor task. We calculated percentage signal change in the primary motor cortex between rest and activation and carried out multiple linear regression to examine the impact of the above factors on signal strength. Using a stepwise analysis strategy, the distance of the lesion from the motor region had the strongest influence (r=0.653, P<0.001). The factor with largest uncorrelated additional impact on signal change was the presence of oedema. Both predictors together formed a highly significant multiple r=0.739 (P<0.001). No other predictive factor was identified (all P>0.20). Disturbances of cerebral blood flow and metabolism induced by the tumour were presumed to be the causes of a decrease in signal in the adjacent cortex. (orig.)

  7. [Effects of Biejiajian Pills on Wnt signal pathway signal molecules β-catenin/TCF4 complex activities and downstream proteins cyclin D1 and MMP-2 in hepatocellular carcinoma cells].

    Science.gov (United States)

    Wen, Bin; Sun, Haitao; He, Songqi; Cheng, Yang; Jia, Wenyan; Fan, Eryan; Pang, Jie

    2014-12-01

    To study the effect of Biejiajian Pills on Wnt signal pathway and the mechanisms underlying its action to suppress the invasiveness of hepatocellular carcinoma. HepG2 cells cultured in the serum of rats fed with Biejiajian Pills for 48 h were examined for β-catenin expression using immunofluorescence, β-catenin/TCF4 complex activity with luciferase, and expressions of the downstream proteins cyclin D1 and MMP-2 using qRT-PCR. Biejiajian Pills-treated sera significantly reduced the expressions of cytoplasmic and nuclear β-catenin protein, cyclin D1 and MMP-2 proteins and lowered the activities of β-catenin/TCF4 complex. Biejiajian Pills may serve as a potential anti-tumor agent, whose effect might be mediated by inhibiting the Wnt/β-catenin pathway.

  8. Cellular signalling properties in microcircuits

    DEFF Research Database (Denmark)

    Toledo-Rodriguez, Maria; El Manira, Abdeljabbar; Wallén, Peter

    2005-01-01

    Molecules and cells are the signalling elements in microcircuits. Recent studies have uncovered bewildering diversity in postsynaptic signalling properties in all areas of the vertebrate nervous system. Major effort is now being invested in establishing the specialized signalling properties...

  9. Relative importance of driving force and electrostatic interactions in the reduction of multihaem cytochromes by small molecules.

    Science.gov (United States)

    Quintas, Pedro O; Cepeda, Andreia P; Borges, Nuno; Catarino, Teresa; Turner, David L

    2013-06-01

    Multihaem cytochromes are essential to the energetics of organisms capable of bioremediation and energy production. The haems in several of these cytochromes have been discriminated thermodynamically and their individual rates of reduction by small electron donors were characterized. The kinetic characterization of individual haems used the Marcus theory of electron transfer and assumed that the rates of reduction of each haem by sodium dithionite depend only on the driving force, while electrostatic interactions were neglected. To determine the relative importance of these factors in controlling the rates, we studied the effect of ionic strength on the redox potential and the rate of reduction by dithionite of native Methylophilus methylotrophus cytochrome c″ and three mutants at different pH values. We found that the main factor determining the rate is the driving force and that Marcus theory describes this satisfactorily. This validates the method of the simultaneous fitting of kinetic and thermodynamic data in multihaem cytochromes and opens the way for further investigation into the mechanisms of these proteins. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. The application of Signalling Theory to health-related trust problems: The example of herbal clinics in Ghana and Tanzania.

    Science.gov (United States)

    Hampshire, Kate; Hamill, Heather; Mariwah, Simon; Mwanga, Joseph; Amoako-Sakyi, Daniel

    2017-09-01

    In contexts where healthcare regulation is weak and levels of uncertainty high, how do patients decide whom and what to trust? In this paper, we explore the potential for using Signalling Theory (ST, a form of Behavioural Game Theory) to investigate health-related trust problems under conditions of uncertainty, using the empirical example of 'herbal clinics' in Ghana and Tanzania. Qualitative, ethnographic fieldwork was conducted over an eight-month period (2015-2016) in eight herbal clinics in Ghana and ten in Tanzania, including semi-structured interviews with herbalists (N = 18) and patients (N = 68), plus detailed ethnographic observations and twenty additional key informant interviews. The data were used to explore four ST-derived predictions, relating to herbalists' strategic communication ('signalling') of their trustworthiness to patients, and patients' interpretation of those signals. Signalling Theory is shown to provide a useful analytical framework, allowing us to go beyond the primary trust problem addressed by other researchers - cataloguing observable indicators of trustworthiness - and providing tools for tackling the trickier secondary trust problem, where the trustworthiness of those indicators must be ascertained. Signalling Theory also enables a basis for comparative work between different empirical contexts that share the underlying condition of uncertainty. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Preliminary code development for seismic signal analysis related to test ban treaty questions

    International Nuclear Information System (INIS)

    Brolley, J.E.

    1977-01-01

    Forensic seismology, from a present day viewpoint, appears to be divided into several areas. Overwhelmingly important, in view of current Complete Test Ban (CTB) discussions, is the seismological study of waves generated in the earth by underground nuclear explosions. Over the last two decades intensive effort has been devoted to developing improved observational apparatus and to the interpretation of the data produced by this equipment. It is clearly desirable to extract the maximum amount of information from seismic signals. It is, therefore, necessary to quantitatively compare various modes of analysis to establish which mode or combination of modes provides the most useful information. Preliminary code development for application of some modern developments in signal processing to seismic signals is described. Applications of noncircular functions are considered and compared with circular function results. The second portion of the discussion concerns maximum entropy analysis. Lastly, the multivariate aspects of the general problem are considered

  12. [The role of Smads and related transcription factors in the signal transduction of bone morphogenetic protein inducing bone formation].

    Science.gov (United States)

    Xu, Xiao-liang; Dai, Ke-rong; Tang, Ting-ting

    2003-09-01

    To clarify the mechanisms of the signal transduction of bone morphogenetic proteins (BMPs) inducing bone formation and to provide theoretical basis for basic and applying research of BMPs. We looked up the literature of the role of Smads and related transcription factors in the signal transduction of BMPs inducing bone formation. The signal transduction processes of BMPs included: 1. BMPs combined with type II and type I receptors; 2. the type I receptor phosphorylated Smads; and 3. Smads entered the cell nucleus, interacted with transcription factors and influenced the transcription of related proteins. Smads could be divided into receptor-regulated Smads (R-Smads: Smad1, Smad2, Smad3, Smad5, Smad8 and Smad9), common-mediator Smad (co-Smad: Smad4), and inhibitory Smads (I-Smads: Smad6 and Smad7). Smad1, Smad5, Smad8, and probable Smad9 were involved in the signal transduction of BMPs. Multiple kinases, such as focal adhesion kinase (FAK), Ras-extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and Akt serine/threonine kinase were related to Smads signal transduction. Smad1 and Smad5 related with transcription factors included core binding factor A1 (CBFA1), smad-interacting protein 1 (SIP1), ornithine decarboxylase antizyme (OAZ), activating protein-1 (AP-1), xenopus ventralizing homeobox protein-2 (Xvent-2), sandostatin (Ski), antiproliferative proteins (Tob), and homeodomain-containing transcriptian factor-8 (Hoxc-8), et al. CBFA1 could interact with Smad1, Smad2, Smad3, and Smad5, so it was involved in TGF-beta and BMP-2 signal transduction, and played an important role in the bone formation. Cleidocranial dysplasia (CCD) was thought to be caused by heterozygous mutations in CBFA1. The CBFA1 knockout mice showed no osteogenesis and had maturational disturbance of chondrocytes. Smads and related transcription factors, especially Smad1, Smad5, Smad8 and CBFA1, play an important role in the signal transduction of BMPs inducing bone

  13. A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid.

    Science.gov (United States)

    Zhou, Ru; Horai, Reiko; Mattapallil, Mary J; Caspi, Rachel R

    2011-10-15

    The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-γ production, and generation of regulatory T cells (Tregs) by aqueous humor (AH) and identified TGF-β as a critical factor. However, T cell subsets including Foxp3(+) Treg and Th17 were unknown at that time, as was the role of retinoic acid (RA) in Treg induction. Consequently, the effect of the ocular microenvironment on T cell lineage commitment and function, and the role of RA in this process, had not been explored. We now use gene-manipulated mice and highly purified T cell populations to demonstrate that AH suppresses lineage commitment and acquisition of Th1 and Th17 effector function of naive T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted its massive conversion to Foxp3(+) Tregs that expressed CD25, GITR, CTLA-4, and CD103 and were functionally suppressive. TGF-β and RA were both needed and synergized for Treg conversion by AH, with TGF-β-enhancing T cell expression of RA receptor α. Newly converted Foxp3(+) Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-aza-2'-deoxycytidine. In contrast, T cells already committed to effector function were resistant to the suppressive and Treg-inducing effects of AH. We conclude that RA in the eye plays a dual role: in vision and in immune privilege. Nevertheless, primed effector T cells are relatively insensitive to AH, helping to explain their ability to induce uveitis despite an inhibitory ocular microenvironment.

  14. Arrestin-related proteins mediate pH signaling in fungi

    OpenAIRE

    Herranz, Silvia; Rodríguez, José M.; Bussink, Henk-Jan; Sánchez-Ferrero, Juan C.; Arst, Herbert N.; Peñalva, Miguel A.; Vincent, Olivier

    2005-01-01

    Metazoan arrestins bind to seven-transmembrane (7TM) receptors to regulate function. Aspergillus nidulans PalF, a protein involved in the fungal ambient pH signaling pathway, contains arrestin N-terminal and C-terminal domains and binds strongly to two different regions within the C-terminal cytoplasmic tail of the 7TM, putative pH sensor PalH. Upon exposure to alkaline ambient pH, PalF is phosphorylated and, like mammalian β-arrestins, ubiquitinated in a signal-dependent and 7TM protein-depe...

  15. Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure.

    Science.gov (United States)

    Alam, Shahabuddin; Javor, Sacha; Degardin, Melissa; Ajami, Dariush; Rebek, Mitra; Kissner, Teri L; Waag, David M; Rebek, Julius; Saikh, Kamal U

    2015-08-01

    Both Gram-positive and Gram-negative pathogens or pathogen-derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88-mediated pro-inflammatory cellular immunity for host defense. However, dysregulated MyD88-mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB-loop structure of MyD88 was capable of inhibiting pro-inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non-polar cyclohexane linker which strongly inhibited the production of pro-inflammatory cytokines in human primary cells to SEB (IC50 1-50 μm) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC50 10-200 μm). Consistent with cytokine inhibition, in a ligand-induced cell-based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS-induced MyD88-mediated NF-kB-dependent expression of reporter activity (IC50 10-30 μm). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro-inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin-induced inflated pro-inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic. © 2014 John Wiley & Sons A/S.

  16. Molecule Matters van der Waals Molecules

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 12. Molecule Matters van der Waals Molecules - Noble Gas Clusters are London Molecules! E Arunan. Feature Article Volume 14 Issue 12 December 2009 pp 1210-1222 ...

  17. Small molecules CK-666 and CK-869 inhibit actin-related protein 2/3 complex by blocking an activating conformational change.

    Science.gov (United States)

    Hetrick, Byron; Han, Min Suk; Helgeson, Luke A; Nolen, Brad J

    2013-05-23

    Actin-related protein 2/3 (Arp2/3) complex is a seven-subunit assembly that nucleates branched actin filaments. Small molecule inhibitors CK-666 and CK-869 bind to Arp2/3 complex and inhibit nucleation, but their modes of action are unknown. Here, we use biochemical and structural methods to determine the mechanism of each inhibitor. Our data indicate that CK-666 stabilizes the inactive state of the complex, blocking movement of the Arp2 and Arp3 subunits into the activated filament-like (short pitch) conformation, while CK-869 binds to a serendipitous pocket on Arp3 and allosterically destabilizes the short pitch Arp3-Arp2 interface. These results provide key insights into the relationship between conformation and activity in Arp2/3 complex and will be critical for interpreting the influence of the inhibitors on actin filament networks in vivo. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Two intestinal specific nuclear factors binding to the lactase-phlorizin hydrolase and sucrase-isomaltase promoters are functionally related oligomeric molecules

    DEFF Research Database (Denmark)

    Troelsen, J T; Mitchelmore, C; Sjöström, H

    1994-01-01

    Lactase-phlorizin hydrolase (LPH) and sucrase-isomaltase (SI) are enterocyte-specific gene products. The identification of regulatory cis-elements in the promoter of these two genes has enabled us to carry out comparative studies of the corresponding intestinal-specific nuclear factors (NF-LPH1...... and SIF1-BP). Electrophoretic mobility shift assays demonstrated that the two nuclear factors compete for binding on the same cis-elements. The molecular size of the DNA binding polypeptide is estimated to be approximately 50 kDa for both factors. In the native form the factors are found as 250 k......Da oligomeric complexes. Based on these results NF-LPH1 and SIF1-BP are suggested to be either identical or closely related molecules....

  19. Factors related to the magnitude of T2* MR signal changes during functional imaging

    International Nuclear Information System (INIS)

    Krings, T.; Reinges, M.H.T.; Gilsbach, J.M.; Willmes, K.; Nuerk, H.C.; Meister, I.G.; Thron, A.

    2002-01-01

    Our aim was to determine whether age, sex, the degree of weakness, anticonvulsants, the histology of the underlying lesion(s), the presence of oedema or the distance of the lesion from the motor region have an impact on the blood oxygenation level-dependent (BOLD) signal strength and therefore on the validity of functional MRI (fMRI). We studied 98 patients with masses near the central region imaged for surgical planning at 1.5 tesla, employing a BOLD sequence during a motor task. We calculated percentage signal change in the primary motor cortex between rest and activation and carried out multiple linear regression to examine the impact of the above factors on signal strength. Using a stepwise analysis strategy, the distance of the lesion from the motor region had the strongest influence (r=0.653, P 0.20). Disturbances of cerebral blood flow and metabolism induced by the tumour were presumed to be the causes of a decrease in signal in the adjacent cortex. (orig.)

  20. Locating proteins in the cell using TargetP, SignalP and related tools

    DEFF Research Database (Denmark)

    Emanuelsson, O.; Brunak, Søren; von Heijne, G.

    2007-01-01

    of methods to predict subcellular localization based on these sorting signals and other sequence properties. We then outline how to use a number of internet-accessible tools to arrive at a reliable subcellular localization prediction for eukaryotic and prokaryotic proteins. In particular, we provide detailed...

  1. Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling

    Energy Technology Data Exchange (ETDEWEB)

    Marschall, Zofia von [Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, DHHS, Bethesda, MD (United States); Fisher, Larry W., E-mail: lfisher@dir.nidcr.nih.gov [Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, DHHS, Bethesda, MD (United States)

    2010-09-24

    Research highlights: {yields} sFRP2 enhances the Wnt3a-induced {beta}-catenin stabilization and its nuclear translocation. {yields} sFRP2 enhances LRP6 phosphorylation and Wnt3a/{beta}-catenin transcriptional reporter activity. {yields} Dickkopf-1 (DKK1) fully antagonizes both Wnt3a/sFRP2-induced LRP6 phosphorylation and transcriptional activity. {yields} sFRP2 enhances expression of genes known to be regulated by Wnt3a signaling. -- Abstract: Secreted Frizzled-related proteins (sFRP) are involved in embryonic development as well as pathological conditions including bone and myocardial disorders and cancer. Because of their sequence homology with the Wnt-binding domain of Frizzled, they have generally been considered antagonists of canonical Wnt signaling. However, additional activities of various sFRPs including both synergism and mimicry of Wnt signaling as well as functions other than modulation of Wnt signaling have been reported. Using human embryonic kidney cells (HEK293A), we found that sFRP2 enhanced Wnt3a-dependent phosphorylation of LRP6 as well as both cytosolic {beta}-catenin levels and its nuclear translocation. While addition of recombinant sFRP2 had no activity by itself, Top/Fop luciferase reporter assays showed a dose-dependent increase of Wnt3a-mediated transcriptional activity. sFRP2 enhancement of Wnt3a signaling was abolished by treatment with the Wnt antagonist, Dickkopf-1 (DKK1). Wnt-signaling pathway qPCR arrays showed that sFRP2 enhanced the Wnt3a-mediated transcriptional up-regulation of several genes regulated by Wnt3a including its antagonists, DKK1, and Naked cuticle-1 homolog (NKD1). These results support sFRP2's role as an enhancer of Wnt/{beta}-catenin signaling, a result with biological impact for both normal development and diverse pathologies such as tumorigenesis.

  2. Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling

    International Nuclear Information System (INIS)

    Marschall, Zofia von; Fisher, Larry W.

    2010-01-01

    Research highlights: → sFRP2 enhances the Wnt3a-induced β-catenin stabilization and its nuclear translocation. → sFRP2 enhances LRP6 phosphorylation and Wnt3a/β-catenin transcriptional reporter activity. → Dickkopf-1 (DKK1) fully antagonizes both Wnt3a/sFRP2-induced LRP6 phosphorylation and transcriptional activity. → sFRP2 enhances expression of genes known to be regulated by Wnt3a signaling. -- Abstract: Secreted Frizzled-related proteins (sFRP) are involved in embryonic development as well as pathological conditions including bone and myocardial disorders and cancer. Because of their sequence homology with the Wnt-binding domain of Frizzled, they have generally been considered antagonists of canonical Wnt signaling. However, additional activities of various sFRPs including both synergism and mimicry of Wnt signaling as well as functions other than modulation of Wnt signaling have been reported. Using human embryonic kidney cells (HEK293A), we found that sFRP2 enhanced Wnt3a-dependent phosphorylation of LRP6 as well as both cytosolic β-catenin levels and its nuclear translocation. While addition of recombinant sFRP2 had no activity by itself, Top/Fop luciferase reporter assays showed a dose-dependent increase of Wnt3a-mediated transcriptional activity. sFRP2 enhancement of Wnt3a signaling was abolished by treatment with the Wnt antagonist, Dickkopf-1 (DKK1). Wnt-signaling pathway qPCR arrays showed that sFRP2 enhanced the Wnt3a-mediated transcriptional up-regulation of several genes regulated by Wnt3a including its antagonists, DKK1, and Naked cuticle-1 homolog (NKD1). These results support sFRP2's role as an enhancer of Wnt/β-catenin signaling, a result with biological impact for both normal development and diverse pathologies such as tumorigenesis.

  3. Age-related changes in expression and signaling of TAM receptor inflammatory regulators in monocytes.

    Science.gov (United States)

    Wang, Xiaomei; Malawista, Anna; Qian, Feng; Ramsey, Christine; Allore, Heather G; Montgomery, Ruth R

    2018-02-09

    The multifactorial immune deterioration in aging--termed "inflamm-aging"--is comprised of a state of low-grade, chronic inflammation and complex dysregulation of responses to immune stimulation. The TAM family (Tyro 3, Axl, and Mer) of receptor tyrosine kinases are negative regulators of Toll like receptor-mediated immune responses that broadly inhibit cytokine receptor cascades to inhibit inflammation. Here we demonstrate elevated expression of TAM receptors in monocytes of older adults, and an age-dependent difference in signaling mediator AKT resulting in dysregulated responses to signaling though Mer. Our results may be especially significant in tissue, where levels of Mer are highest, and may present avenues for modulation of chronic tissue inflammation noted in aging.

  4. On the tear proteome of the house mouse (Mus musculus musculus in relation to chemical signalling

    Directory of Open Access Journals (Sweden)

    Romana Stopkova

    2017-07-01

    Full Text Available Mammalian tears are produced by lacrimal glands to protect eyes and may function in chemical communication and immunity. Recent studies on the house mouse chemical signalling revealed that major urinary proteins (MUPs are not individually unique in Mus musculus musculus. This fact stimulated us to look for other sexually dimorphic proteins that may—in combination with MUPs—contribute to a pool of chemical signals in tears. MUPs and other lipocalins including odorant binding proteins (OBPs have the capacity to selectively transport volatile organic compounds (VOCs in their eight-stranded beta barrel, thus we have generated the tear proteome of the house mouse to detect a wider pool of proteins that may be involved in chemical signalling. We have detected significant male-biased (7.8% and female-biased (7% proteins in tears. Those proteins that showed the most elevated sexual dimorphisms were highly expressed and belong to MUP, OBP, ESP (i.e., exocrine gland-secreted peptides, and SCGB/ABP (i.e., secretoglobin families. Thus, tears may have the potential to elicit sex-specific signals in combination by different proteins. Some tear lipocalins are not sexually dimorphic—with MUP20/darcin and OBP6 being good examples—and because all proteins may flow with tears through nasolacrimal ducts to nasal and oral cavities we suggest that their roles are wider than originally thought. Also, we have also detected several sexually dimorphic bactericidal proteins, thus further supporting an idea that males and females may have adopted alternative strategies in controlling microbiota thus yielding different VOC profiles.

  5. Two MYB-related transcription factors play opposite roles in sugar signaling in Arabidopsis.

    Science.gov (United States)

    Chen, Yi-Shih; Chao, Yi-Chi; Tseng, Tzu-Wei; Huang, Chun-Kai; Lo, Pei-Ching; Lu, Chung-An

    2017-02-01

    Sugar regulation of gene expression has profound effects at all stages of the plant life cycle. Although regulation at the transcriptional level is one of the most prominent mechanisms by which gene expression is regulated, only a few transcription factors have been identified and demonstrated to be involved in the regulation of sugar-regulated gene expression. OsMYBS1, an R1/2-type MYB transcription factor, has been demonstrated to be involved in sugar- and hormone-regulated α-amylase gene expression in rice. Arabidopsis contains two OsMYBS1 homologs. In the present study, we investigate MYBS1 and MYBS2 in sugar signaling in Arabidopsis. Our results indicate that MYBS1 and MYBS2 play opposite roles in regulating glucose and ABA signaling in Arabidopsis during seed germination and early seedling development. MYB proteins have been classified into four subfamilies: R2R3-MYB, R1/2-MYB, 3R-MYB, and 4R-MYB. An R1/2-type MYB transcription factor, OsMYBS1, has been demonstrated to be involved in sugar- and hormone-regulated α-amylase genes expression in rice. In this study, two genes homologous to OsMYBS1, MYBS1 and MYBS2, were investigated in Arabidopsis. Subcellular localization analysis showed that MYBS1 and MYBS2 were localized in the nucleus. Rice embryo transient expression assays indicated that both MYBS1 and MYBS2 could recognize the sugar response element, TA-box, in the promoter and induced promoter activity. mybs1 mutant exhibited hypersensitivity to glucose, whereas mybs2 seedlings were hyposensitive to it. MYBS1 and MYBS2 are involved in the control of glucose-responsive gene expression, as the mybs1 mutant displayed increased expression of a hexokinase gene (HXK1), chlorophyll a/b-binding protein gene (CAB1), ADP-glucose pyrophosphorylase gene (APL3), and chalcone synthase gene (CHS), whereas the mybs2 mutant exhibited decreased expression of these genes. mybs1 also showed an enhanced response to abscisic acid (ABA) in the seed germination and seedling

  6. Basal ganglia impairments in autism spectrum disorder are related to abnormal signal gating to prefrontal cortex.

    Science.gov (United States)

    Prat, Chantel S; Stocco, Andrea; Neuhaus, Emily; Kleinhans, Natalia M

    2016-10-01

    Research on the biological basis of autism spectrum disorder has yielded a list of brain abnormalities that are arguably as diverse as the set of behavioral symptoms that characterize the disorder. Among these are patterns of abnormal cortical connectivity and abnormal basal ganglia development. In attempts to integrate the existing literature, the current paper tests the hypothesis that impairments in the basal ganglia's function to flexibly select and route task-relevant neural signals to the prefrontal cortex underpins patterns of abnormal synchronization between the prefrontal cortex and other cortical processing centers observed in individuals with autism spectrum disorder (ASD). We tested this hypothesis using a Dynamic Causal Modeling analysis of neuroimaging data collected from 16 individuals with ASD (mean age=25.3 years; 6 female) and 17 age- and IQ-matched neurotypical controls (mean age=25.6, 6 female), who performed a Go/No-Go test of executive functioning. Consistent with the hypothesis tested, a random-effects Bayesian model selection procedure determined that a model of network connectivity in which basal ganglia activation modulated connectivity between the prefrontal cortex and other key cortical processing centers best fit the data of both neurotypicals and individuals with ASD. Follow-up analyses suggested that the largest group differences were observed for modulation of connectivity between prefrontal cortex and the sensory input region in the occipital lobe [t(31)=2.03, p=0.025]. Specifically, basal ganglia activation was associated with a small decrease in synchronization between the occipital region and prefrontal cortical regions in controls; however, in individuals with ASD, basal ganglia activation resulted in increased synchronization between the occipital region and the prefrontal cortex. We propose that this increased synchronization may reflect a failure in basal ganglia signal gating mechanisms, resulting in a non-selective copying

  7. Zinc signaling in the hippocampus and its relation to pathogenesis of depression.

    Science.gov (United States)

    Takeda, Atsushi

    2012-06-01

    Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons, a subclass of glutamatergic neurons. Zn(2+) serves as a signal factor in both the extracellular and intracellular compartments. Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of hippocampal function, i.e., cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation

  8. ABI1 and PP2CA Phosphatases Are Negative Regulators of Snf1-Related Protein Kinase1 Signaling in Arabidopsis

    OpenAIRE

    Rodrigues, A.; Adamo, M.; Crozet, P.; Margalha, L.; Confraria, A.; Martinho, C.; Elias, A.; Rabissi, A.; Lumbreras, V.; Gonzalez-Guzman, M.; Antoni, R.; Rodriguez, P. L.; Baena-Gonzalez, E.

    2013-01-01

    Plant survival under environmental stress requires the integration of multiple signaling pathways into a coordinated response, but the molecular mechanisms underlying this integration are poorly understood. Stress-derived energy deprivation activates the Snf1-related protein kinases1 (SnRK1s), triggering a vast transcriptional and metabolic reprogramming that restores homeostasis and promotes tolerance to adverse conditions. Here, we show that two clade A type 2C protein phosphatases (PP2Cs),...

  9. Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes.

    Science.gov (United States)

    Daskalakis, Nikolaos P; Cohen, Hagit; Cai, Guiqing; Buxbaum, Joseph D; Yehuda, Rachel

    2014-09-16

    Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology and treatment of posttraumatic stress disorder (PTSD). In this study, 7 d after predator-scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., "PTSD-like") and resilient (i.e., minimally affected) phenotypes on the basis of their performance on a variety of behavioral measures. Genome-wide expression profiling in blood and two limbic brain regions (amygdala and hippocampus), followed by quantitative PCR validation, was performed in these two groups of animals, as well as in an unexposed control group. Differentially expressed genes were identified in blood and brain associated with PSS-exposure and with distinct behavioral profiles postexposure. There was a small but significant between-tissue overlap (4-21%) for the genes associated with exposure-related individual differences, indicating convergent gene expression in both sexes. To uncover convergent signaling pathways across tissue and sex, upstream activated/deactivated transcription factors were first predicted for each tissue and then the respective pathways were identified. Glucocorticoid receptor (GR) signaling was the only convergent pathway associated with individual differences when using the most stringent statistical threshold. Corticosterone treatment 1 h after PSS-exposure prevented anxiety and hyperarousal 7 d later in both sexes, confirming the GR involvement in the PSS behavioral response. In conclusion, genes and pathways associated with extreme differences in the traumatic stress behavioral response can be distinguished from those associated with trauma exposure. Blood-based biomarkers can predict aspects of brain signaling. GR signaling is a convergent signaling pathway, associated with trauma-related individual differences in both sexes.

  10. Expression and clinical value of the soluble major histocompatibility complex class I-related chain A molecule in the serum of patients with renal tumors.

    Science.gov (United States)

    Zhao, Y-K; Jia, C-M; Yuan, G-J; Liu, W; Qiu, Y; Zhu, Q-G

    2015-06-29

    We investigated the expression and clinical value of the soluble major histocompatibility complex class I-related chain A (sMICA) molecule in the serum of patients with renal tumors. Sixty patients diagnosed with renal tumors were enrolled in the experimental group, whereas 20 healthy volunteers served as the control group. The sMICA levels were measured via enzyme-linked immunosorbent assay, and the results were analyzed in combination with data from pathol-ogy examination. The experimental group had a statistically significant higher sMICA level (P < 0.05) than the control group. The sMICA level was higher in patients with malignant tumors than in those with be-nign tumors. We also observed a positive relationship among different tumor-node-metastasis (TNM) pathological stages with more advanced diseases exhibiting higher sMICA levels. As a tumor-associated antigen, MICA has a close relationship with renal tumorigenesis and immune es-cape. Our results indicated that sMICA levels were related to tumor pathol-ogy, TNM stage, and metastasis. Therefore, sMICA might be a potential marker for tumor characteristics, prognosis, and recurrence prediction.

  11. Safety surrogate histograms (SSH): A novel real-time safety assessment of dilemma zone related conflicts at signalized intersections.

    Science.gov (United States)

    Ghanipoor Machiani, Sahar; Abbas, Montasir

    2016-11-01

    Drivers' indecisiveness in dilemma zones (DZ) could result in crash-prone situations at signalized intersections. DZ is to the area ahead of an intersection in which drivers encounter a dilemma regarding whether to stop or proceed through the intersection when the signal turns yellow. An improper decision to stop by the leading driver, combined with the following driver deciding to go, can result in a rear-end collision, unless the following driver recognizes a collision is imminent and adjusts his or her behavior at or shortly after the onset of yellow. Considering the significance of DZ-related crashes, a comprehensive safety measure is needed to characterize the level of safety at signalized intersections. In this study, a novel safety surrogate measure was developed utilizing real-time radar field data. This new measure, called safety surrogate histogram (SSH), captures the degree and frequency of DZ-related conflicts at each intersection approach. SSH includes detailed information regarding the possibility of crashes, because it is calculated based on the vehicles conflicts. An example illustrating the application of the new methodology at two study sites in Virginia is presented and discussed, and a comparison is provided between SSH and other DZ-related safety surrogate measures mentioned in the literature. The results of the study reveal the efficacy of the SSH as complementary to existing surrogate measures. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling.

    Science.gov (United States)

    Correa, Ricardo G; Krajewska, Maryla; Ware, Carl F; Gerlic, Motti; Reed, John C

    2014-03-30

    Prostate cancer (PCa) is among the leading causes of cancer-related death in men. Androgen receptor (AR) signaling plays a seminal role in prostate development and homeostasis, and dysregulation of this pathway is intimately linked to prostate cancer pathogenesis and progression. Here, we identify the cytosolic NLR-related protein NWD1 as a novel modulator of AR signaling. We determined that expression of NWD1 becomes elevated during prostate cancer progression, based on analysis of primary tumor specimens. Experiments with cultured cells showed that NWD1 expression is up-regulated by the sex-determining region Y (SRY) family proteins. Gene silencing procedures, in conjunction with transcriptional profiling, showed that NWD1 is required for expression of PDEF (prostate-derived Ets factor), which is known to bind and co-regulate AR. Of note, NWD1 modulates AR protein levels. Depleting NWD1 in PCa cell lines reduces AR levels and suppresses activity of androgen-driven reporter genes. NWD1 knockdown potently suppressed growth of androgen-dependent LNCaP prostate cancer cells, thus showing its functional importance in an AR-dependent tumor cell model. Proteomic analysis suggested that NWD1 associates with various molecular chaperones commonly related to AR complexes. Altogether, these data suggest a role for tumor-associated over-expression of NWD1 in dysregulation of AR signaling in PCa.

  13. Assessment of a wearable force- and electromyography device and comparison of the related signals for myocontrol

    Directory of Open Access Journals (Sweden)

    Mathilde Connan

    2016-11-01

    Full Text Available In the frame of assistive robotics, multi-finger prosthetic hand/wrists have recently appeared,offering an increasing level of dexterity; however, in practice their control is limited to a few handgrips and still unreliable, with the effect that pattern recognition has not yet appeared in the clinicalenvironment. According to the scientific community, one of the keys to improve the situation ismulti-modal sensing, i.e., using diverse sensor modalities to interpret the subject’s intent andimprove the reliability and safety of the control system in daily life activities. In this work, wefirst describe and test a novel wireless, wearable force- and electromyography device; throughan experiment conducted on ten intact subjects, we then compare the obtained signals bothqualitatively and quantitatively, highlighting their advantages and disadvantages. Our resultsindicate that force-myography yields signals which are more stable across time during whenevera pattern is held, than those obtained by electromyography. We speculate that fusion of the twomodalities might be advantageous to improve the reliability of myocontrol in the near future.

  14. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.

    Directory of Open Access Journals (Sweden)

    Dane Parker

    2014-02-01

    Full Text Available The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar⁻/⁻ mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia.

  15. Analysis of network motifs in cellular regulation: Structural similarities, input-output relations and signal integration.

    Science.gov (United States)

    Straube, Ronny

    2017-12-01

    Much of the complexity of regulatory networks derives from the necessity to integrate multiple signals and to avoid malfunction due to cross-talk or harmful perturbations. Hence, one may expect that the input-output behavior of larger networks is not necessarily more complex than that of smaller network motifs which suggests that both can, under certain conditions, be described by similar equations. In this review, we illustrate this approach by discussing the similarities that exist in the steady state descriptions of a simple bimolecular reaction, covalent modification cycles and bacterial two-component systems. Interestingly, in all three systems fundamental input-output characteristics such as thresholds, ultrasensitivity or concentration robustness are described by structurally similar equations. Depending on the system the meaning of the parameters can differ ranging from protein concentrations and affinity constants to complex parameter combinations which allows for a quantitative understanding of signal integration in these systems. We argue that this approach may also be extended to larger regulatory networks. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer.

    Science.gov (United States)

    Philip, Philip A; Lutz, Manfred P

    2015-10-01

    Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

  17. Spatial attention related SEP amplitude modulations covary with BOLD signal in S1--a simultaneous EEG--fMRI study.

    Science.gov (United States)

    Schubert, Ruth; Ritter, Petra; Wüstenberg, Torsten; Preuschhof, Claudia; Curio, Gabriel; Sommer, Werner; Villringer, Arno

    2008-11-01

    Recent studies investigating the influence of spatial-selective attention on primary somatosensory processing have produced inconsistent results. The aim of this study was to explore the influence of tactile spatial-selective attention on spatiotemporal aspects of evoked neuronal activity in the primary somatosensory cortex (S1). We employed simultaneous electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) in 14 right-handed subjects during bilateral index finger Braille stimulation to investigate the relationship between attentional effects on somatosensory evoked potential (SEP) components and the blood oxygenation level-dependent (BOLD) signal. The 1st reliable EEG response following left tactile stimulation (P50) was significantly enhanced by spatial-selective attention, which has not been reported before. FMRI analysis revealed increased activity in contralateral S1. Remarkably, the effect of attention on the P50 component as well as long-latency SEP components starting at 190 ms for left stimuli correlated with attentional effects on the BOLD signal in contralateral S1. The implications are 2-fold: First, the correlation between early and long-latency SEP components and the BOLD effect suggest that spatial-selective attention enhances processing in S1 at 2 time points: During an early passage of the signal and during a later passage, probably via re-entrant feedback from higher cortical areas. Second, attentional modulations of the fast electrophysiological signals and the slow hemodynamic response are linearly related in S1.

  18. Climate-related environmental variation in a visual signalling device: the male and female dewlap in Anolis sagrei lizards.

    Science.gov (United States)

    Driessens, T; Baeckens, S; Balzarolo, M; Vanhooydonck, B; Huyghe, K; Van Damme, R

    2017-10-01

    Animals communicate using a variety of signals that differ dramatically among and within species. The astonishing dewlap diversity in anoles has attracted considerable attention in this respect. Yet, the evolutionary processes behind it remain elusive and have mostly been explored for males only. Here, we considered Anolis sagrei males and females to study signal divergence among populations. First, we assessed the degree of variation in dewlap design (size, pattern and colour) and displays by comparing 17 populations distributed across the Caribbean. Second, we assessed whether the observed dewlap diversity is associated with variation in climate-related environmental conditions. Results showed that populations differed in all dewlap characteristics, with the exception of display rate in females. We further found that males and females occurring in 'xeric' environments had a higher proportion of solid dewlaps with higher UV reflectance. In addition, lizards inhabiting 'mesic' environments had primarily marginal dewlaps showing high reflectance in red. For dewlap display, a correlation with environment was only observed in males. Our study provides evidence for a strong relationship between signal design and prevailing environmental conditions, which may result from differential selection on signal efficacy. Moreover, our study highlights the importance of including females when studying dewlaps in an evolutionary context. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  19. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis

    Directory of Open Access Journals (Sweden)

    Tahtouh Muriel

    2012-02-01

    Full Text Available Abstract Background In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR, which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Methods Recombinant HmC1q (rHmC1q was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. Results rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. Conclusions A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal

  20. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis.

    Science.gov (United States)

    Tahtouh, Muriel; Garçon-Bocquet, Annelise; Croq, Françoise; Vizioli, Jacopo; Sautière, Pierre-Eric; Van Camp, Christelle; Salzet, Michel; Nagnan-le Meillour, Patricia; Pestel, Joël; Lefebvre, Christophe

    2012-02-22

    In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech.

  1. Temporal protein expression pattern in intracellular signalling ...

    Indian Academy of Sciences (India)

    2015-09-28

    Sep 28, 2015 ... targets for the treatment of various T-cells, immune-related diseases. We hope ... signifies the alternative routes of signal propagation. The molecules kept in ...... growth factor, mitogens for vascular cells and fibroblasts: dif- ferential ..... tumor necrosis factor contributes to CD8(+) T cell survival in the transition ...

  2. Methamphetamine exposure triggers apoptosis and autophagy in neuronal cells by activating the C/EBPβ-related signaling pathway.

    Science.gov (United States)

    Xu, Xiang; Huang, Enping; Luo, Baoying; Cai, Dunpeng; Zhao, Xu; Luo, Qin; Jin, Yili; Chen, Ling; Wang, Qi; Liu, Chao; Lin, Zhoumeng; Xie, Wei-Bing; Wang, Huijun

    2018-06-25

    Methamphetamine (Meth) is a widely abused psychoactive drug that primarily damages the nervous system, notably causing dopaminergic neuronal apoptosis. CCAAT-enhancer binding protein (C/EBPβ) is a transcription factor and an important regulator of cell apoptosis and autophagy. Insulin-like growth factor binding protein (IGFBP5) is a proapoptotic factor that mediates Meth-induced neuronal apoptosis, and Trib3 (tribbles pseudokinase 3) is an endoplasmic reticulum (ER) stress-inducible gene involved in autophagic cell death through the mammalian target of rapamycin (mTOR) signaling pathway. To test the hypothesis that C/EBPβ is involved in Meth-induced IGFBP5-mediated neuronal apoptosis and Trib3-mediated neuronal autophagy, we measured the protein expression of C/EBPβ after Meth exposure and evaluated the effects of silencing C/EBPβ, IGFBP5, or Trib3 on Meth-induced apoptosis and autophagy in neuronal cells and in the rat striatum after intrastriatal Meth injection. We found that, at relatively high doses, Meth exposure increased C/EBPβ protein expression, which was accompanied by increased neuronal apoptosis and autophagy; triggered the IGFBP5-mediated, p53-up-regulated modulator of apoptosis (PUMA)-related mitochondrial apoptotic signaling pathway; and stimulated the Trib3-mediated ER stress signaling pathway through the Akt-mTOR signaling axis. We also found that autophagy is an early response to Meth-induced stress upstream of apoptosis and plays a detrimental role in Meth-induced neuronal cell death. These results suggest that Meth exposure induces C/EBPβ expression, which plays an essential role in the neuronal apoptosis and autophagy induced by relatively high doses of Meth; however, relatively low concentrations of Meth did not change the expression of C/EBPβ in vitro. Further studies are needed to elucidate the role of C/EBPβ in low-dose Meth-induced neurotoxicity.-Xu, X., Huang, E., Luo, B., Cai, D., Zhao, X., Luo, Q., Jin, Y., Chen, L., Wang, Q

  3. Postnatal changes in electromyographic signals during piglet growth, and in relation to muscle fibre types

    DEFF Research Database (Denmark)

    Andersen, Ninette Kieme; Ravn, L.S.; Guy, J.H.

    2008-01-01

    This study uses non-invasive evoked surface electromyography (SEMG) to investigate postnatal muscle development in pigs, and to assess any correlation between recorded signal parameters and muscle fibre types in two different skeletal muscles. Four litters (n=43) of Large White x Landrace pigs were...... used. Evoked SEMG mesurements were taken on days 2, 5, 14, 26, 60 and 151 post partum from m. Longissimus dorsi (LD) and on days 14, 26, 60 and 151 post partum from m. Biceps femoris (BF). A third of each litter was slaughtered at days 27, 61 and 153 post partum. Biopsy samples for LD and BF were taken...... to categorize day 5 post partum, whilst for BF significant increases occurred from days 14 to 26 post partum. Fibre type development in both muscles showed a significant decrease in type IIA fibre number (Ptype IIB fibre number (P

  4. Albumin Overload and PINK1/Parkin Signaling-Related Mitophagy in Renal Tubular Epithelial Cells.

    Science.gov (United States)

    Tan, Jin; Xie, Qi; Song, Shuling; Miao, Yuyang; Zhang, Qiang

    2018-03-01

    BACKGROUND Albumin, as a major urinary protein component, is a risk factor for chronic kidney disease progression. Mitochondrial dysfunction is one of the main causes of albumin-induced proximal tubule cells injury. Mitophagy is considered as a pivotal protective mechanism for the elimination of dysfunctional mitochondria. The objective of this research was to determine whether albumin overload-induced mitochondrial dysfunction can activate PINK1/Parkin-mediated mitophagy in renal tubular epithelial cells (TECs). MATERIAL AND METHODS Immunofluorescence assay and Western blot assay were used to detect the effects of albumin overload on autophagy marker protein LC3. Transmission electron microscopy and Western blot assay were used to investigate the role of albumin in mitochondrial injury. Western blot assay and co-localization of acidic lysosomes and mitochondria assay were employed to detect the activation of mitophagy induced by albumin. Finally, we explored the role of PINK1/Parkin signaling in albumin-induced mitophagy by inhibiting mitophagy by knockdown of PARK2 (Parkin) level. RESULTS Immunofluorescence and Western blot results showed that the expression level of LC3-II increased, and the maximum increase point was observed after 8 h of albumin treatment. Transmission electron microscopy results demonstrated that albumin overload-induced mitochondrial injury and quantity of autophagosomes increased. Additionally, expression of PINK1 and cytosolic cytochrome C increased and mitochondria cytochrome C decreased in the albumin group. The co-localization of acidic lysosomes and mitochondria demonstrated that the number of albumin overload-induced mitophagy-positive dots increased. The transient transfection of PARK2 siRNA result showed knockdown of the expression level of PARK2 can inhibit mitophagy induced by albumin. CONCLUSIONS In conclusion, our study suggests that mitochondrial dysfunction activates the PINK1/Parkin signaling and mitophagy in renal tubular

  5. Calcium signaling in closely related protozoan groups (Alveolata): non-parasitic ciliates (Paramecium, Tetrahymena) vs. parasitic Apicomplexa (Plasmodium, Toxoplasma).

    Science.gov (United States)

    Plattner, H; Sehring, I M; Mohamed, I K; Miranda, K; De Souza, W; Billington, R; Genazzani, A; Ladenburger, E-M

    2012-05-01

    The importance of Ca2+-signaling for many subcellular processes is well established in higher eukaryotes, whereas information about protozoa is restricted. Recent genome analyses have stimulated such work also with Alveolates, such as ciliates (Paramecium, Tetrahymena) and their pathogenic close relatives, the Apicomplexa (Plasmodium, Toxoplasma). Here we compare Ca2+ signaling in the two closely related groups. Acidic Ca2+ stores have been characterized in detail in Apicomplexa, but hardly in ciliates. Two-pore channels engaged in Ca2+-release from acidic stores in higher eukaryotes have not been stingently characterized in either group. Both groups are endowed with plasma membrane- and endoplasmic reticulum-type Ca2+-ATPases (PMCA, SERCA), respectively. Only recently was it possible to identify in Paramecium a number of homologs of ryanodine and inositol 1,3,4-trisphosphate receptors (RyR, IP3R) and to localize them to widely different organelles participating in vesicle trafficking. For Apicomplexa, physiological experiments suggest the presence of related channels although their identity remains elusive. In Paramecium, IP3Rs are constitutively active in the contractile vacuole complex; RyR-related channels in alveolar sacs are activated during exocytosis stimulation, whereas in the parasites the homologous structure (inner membrane complex) may no longer function as a Ca2+ store. Scrutinized comparison of the two closely related protozoan phyla may stimulate further work and elucidate adaptation to parasitic life. See also "Conclusions" section. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected

    DEFF Research Database (Denmark)

    Storgaard, H; Song, X M; Jensen, C B

    2001-01-01

    before and during a euglycemic-hyperinsulinemic clamp. IGT relatives were insulin-resistant in oxidative and nonoxidative pathways for glucose metabolism. In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide......To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects...... 3-kinase (PI 3-kinase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P

  7. Superexcited states of molecules

    International Nuclear Information System (INIS)

    Nakamura, Hiroki; Takagi, Hidekazu.

    1990-01-01

    The report addresses the nature and major features of molecule's superexcited states, focusing on their involvement in dynamic processes. It also outlines the quantum defect theory which allows various processes involving these states to be treated in a unified way. The Rydberg state has close relation with an ionized state with a positive energy. The quantum defect theory interprets such relation. Specifically, the report first describes the quantum defect theory focusing on its basic principle. The multi-channel quantum defect theory is then outlined centering on how to describe a Rydberg-type superexcited state. Description of a dissociative double-electron excited state is also discussed. The quantum defect theory is based on the fact that the physics of the motion of a Rydberg electron vary with the region in the electron's coordinate space. Finally, various molecular processes that involve a superexcited state are addressed focusing on autoionization, photoionization, dissociative recombination and bonding ionization of diatomic molecules. (N.K.)

  8. Clinical and experimental studies regarding the expression and diagnostic value of carcinoembryonic antigen-related cell adhesion molecule 1 in non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Zhou, Mu-qing; Du, Yan; Liu, Yi-wen; Wang, Ying-zhi; He, Yi-qing; Yang, Cui-xia; Wang, Wen-juan; Gao, Feng

    2013-01-01

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in non-small-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC. The expression of the serum CEACAM1 was determined by enzyme-linked immunosorbent assay. The protein expression and the location of CEACAM1 in tumours were observed by immunohistochemical staining. The CEACAM1 mRNA levels in tumour and normal adjacent tissues were measured using quantitative real-time PCR, and the expression patterns and the rate of CEACAM1-S and CEACAM1-L were analysed by reverse transcription-PCR. Serum CEACAM1 levels were significantly higher in NSCLC patients compared with that from normal healthy controls (P <0.0001). 17 patients (81%) among 21 showed high expression of CEACAM1 by immunohistochemical staining. Although no significant differences were found between tumour and normal tissues on mRNA expression levels of CEACAM1 (P >0.05), the CEACAM1-S and the CEACAM1-S/L (S: L) ratios were significantly higher in tumour than normal tissues (P <0.05). Our data indicated that the serum levels of CEACAM1 could discriminate lung cancer patients from health donors and that CEACAM1 might be a useful marker in early diagnosis of NSCLC. Moreover, our results showed that the expression patterns of CEACAM1 isoforms could be changed during oncogenesis, even when total CEACAM1 in tumour tissues did not show significant changes. Our study suggested that the expression ratios of CEACAM1-S/CEACAM1-L might be a better diagnostic indicator in NSCLC than the quantitative

  9. Signals of speciation within Arabidopsis thaliana in comparison with its relatives

    NARCIS (Netherlands)

    Alcazar, R.; Pecinka, A.; Aarts, M.G.M.; Fransz, P.F.; Koornneef, M.

    2012-01-01

    The species within the now well-defined Arabidopsis genus provide biological materials suitable to investigate speciation and the development of reproductive isolation barriers between related species. Even within the model species A. thaliana, genetic differentiation between populations due to

  10. N,N-dimethyl hexadecylamine and related amines regulate root morphogenesis via jasmonic acid signaling in Arabidopsis thaliana.

    Science.gov (United States)

    Raya-González, Javier; Velázquez-Becerra, Crisanto; Barrera-Ortiz, Salvador; López-Bucio, José; Valencia-Cantero, Eduardo

    2017-05-01

    Plant growth-promoting rhizobacteria are natural inhabitants of roots, colonize diverse monocot and dicot species, and affect several functional traits such as root architecture, adaptation to adverse environments, and protect plants from pathogens. N,N-dimethyl-hexadecylamine (C16-DMA) is a rhizobacterial amino lipid that modulates the postembryonic development of several plants, likely as part of volatile blends. In this work, we evaluated the bioactivity of C16-DMA and other related N,N-dimethyl-amines with varied length and found that inhibition of primary root growth was related to the length of the acyl chain. C16-DMA inhibited primary root growth affecting cell division and elongation, while promoting lateral root formation and root hair growth and density in Arabidopsis thaliana (Arabidopsis) wild-type (WT) seedlings. Interestingly, C16-DMA induced the expression of the jasmonic acid (JA)-responsive gene marker pLOX2:uidA, while JA-related mutants jar1, coi1-1, and myc2 affected on JA biosynthesis and perception, respectively, are compromised in C16-DMA responses. Comparison of auxin-regulated gene expression, root architectural changes in WT, and auxin-related mutants aux1-7, tir1/afb2/afb3, and arf7-1/arf19-1 to C16-DMA shows that the C16-DMA effects occur independently of auxin signaling. Together, these results reveal a novel class of aminolipids modulating root organogenesis via crosstalk with the JA signaling pathway.

  11. Equine grass sickness in Scotland: a case-control study of signalment- and meteorology-related risk factors.

    Science.gov (United States)

    Wylie, C E; Shaw, D J; Fordyce, F M; Lilly, A; McGorum, B C

    2014-01-01

    Equine grass sickness (EGS) remains a frequently fatal disease of equids in Britain. Since previous investigations of signalment- and meteorology-related risk factors for EGS have yielded some conflicting data, further investigation is warranted. To identify signalment- and meteorology-related risk factors for EGS in Scotland. Retrospective time-matched case-control study. This study was undertaken using data for 455 EGS cases and 910 time-matched controls that were referred to the Royal (Dick) School of Veterinary Studies, and average UK Meteorological Office weather station meteorological values from the month of admission of the animal, from the 3, 6 and 12 months prior to admission, and for the entire 1990-2006 period. Signalment-related risk factors associated with an increased risk of EGS were native Scottish pure breeds compared with crossbreeds (odds ratio [OR] = 3.56, 95% confidence interval [CI] 2.43-5.43) and animals living on premises located further north within the study region (OR = 1.08, 95% CI 1.06-1.10). There was a decreased risk of EGS in animals aged 11-20 years compared with animals 2-10 years (OR = 0.32, 95% CI 0.22-0.45), non-native Scottish pure breeds compared with crossbreeds (OR = 0.71, 95% CI 0.54-0.94), and stallions compared with mares (OR = 0.43, 95% CI 0.22-0.86). Meteorology-related risk factors associated with an increased risk of EGS were (if Ordnance Survey northing is excluded) more sun hours (OR>1.43) and more frost days (OR>1.13), while there was a decreased risk of EGS with higher average maximum temperature (ORmeteorological risk factors may assist studies on the aetiology of EGS. © 2013 EVJ Ltd.

  12. Signal recognition particle assembly in relation to the function of amplified nucleoli of Xenopus oocytes.

    Science.gov (United States)

    Sommerville, John; Brumwell, Craig L; Politz, Joan C Ritland; Pederson, Thoru

    2005-03-15

    The signal recognition particle (SRP) is a ribonucleoprotein machine that controls the translation and intracellular sorting of membrane and secreted proteins. The SRP contains a core RNA subunit with which six proteins are assembled. Recent work in both yeast and mammalian cells has identified the nucleolus as a possible initial site of SRP assembly. In the present study, SRP RNA and protein components were identified in the extrachromosomal, amplified nucleoli of Xenopus laevis oocytes. Fluorescent SRP RNA microinjected into the oocyte nucleus became specifically localized in the nucleoli, and endogenous SRP RNA was also detected in oocyte nucleoli by RNA in situ hybridization. An initial step in the assembly of SRP involves the binding of the SRP19 protein to SRP RNA. When green fluorescent protein (GFP)-tagged SRP19 protein was injected into the oocyte cytoplasm it was imported into the nucleus and became concentrated in the amplified nucleoli. After visiting the amplified nucleoli, GFP-tagged SRP19 protein was detected in the cytoplasm in a ribonucleoprotein complex, having a sedimentation coefficient characteristic of the SRP. These results suggest that the amplified nucleoli of Xenopus oocytes produce maternal stores not only of ribosomes, the classical product of nucleoli, but also of SRP, presumably as a global developmental strategy for stockpiling translational machinery for early embryogenesis.

  13. Real-time measurement of relative sensor position changes using ultrasonic signal evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Yastrebova, O.; Bulavinov, A.; Kroening, M. [Fraunhofer Institute Nondestructive Testing IZFP, Saarbruecken (Germany)

    2008-07-01

    Ultrasonic testing is considered to be one of the most commonly applied nondestructive testing techniques for flaw detection and material characterization. Traditional Nondestructive Testing (NDT) provides detection of material discontinuities that may cause failure within the designed lifetime of a part or component. In addition, Quantitative Nondestructive Testing (QNDT) provides means to obtain required information about type, size and location of deficiencies to the integrity of the inspected structure and further use under specific, given load conditions. The ''Acoustic Mouse'' technique has been developed as a tool for manual ultrasonic inspection to provide test results that can be evaluated quantitatively. The ultrasonic data are processed by real-time variation methods to extract position information from backscattered acoustic noise and geometric scatter signals in the inspection volume. The position and positional changes of the ''Acoustic Mouse'' sensor (transducer) are determined by the sequential analysis of ultrasonic data (highresolution sector-scans), which are acquired and reconstructed using the Sampling Phased Array technique. The results of first experiments conducted with linear scanning and intentional lift-offs demonstrate sufficient accuracy in position measurements. (orig.)

  14. PKA/AMPK signaling in relation to adiponectin's antiproliferative effect on multiple myeloma cells.

    Science.gov (United States)

    Medina, E A; Oberheu, K; Polusani, S R; Ortega, V; Velagaleti, G V N; Oyajobi, B O

    2014-10-01

    Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin's ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.

  15. Deep learning for single-molecule science

    Science.gov (United States)

    Albrecht, Tim; Slabaugh, Gregory; Alonso, Eduardo; Al-Arif, SM Masudur R.

    2017-10-01

    Exploring and making predictions based on single-molecule data can be challenging, not only due to the sheer size of the datasets, but also because a priori knowledge about the signal characteristics is typically limited and poor signal-to-noise ratio. For example, hypothesis-driven data exploration, informed by an expectation of the signal characteristics, can lead to interpretation bias or loss of information. Equally, even when the different data categories are known, e.g., the four bases in DNA sequencing, it is often difficult to know how to make best use of the available information content. The latest developments in machine learning (ML), so-called deep learning (DL) offer interesting, new avenues to address such challenges. In some applications, such as speech and image recognition, DL has been able to outperform conventional ML strategies and even human performance. However, to date DL has not been applied much in single-molecule science, presumably in part because relatively little is known about the ‘internal workings’ of such DL tools within single-molecule science as a field. In this Tutorial, we make an attempt to illustrate in a step-by-step guide how one of those, a convolutional neural network (CNN), may be used for base calling in DNA sequencing applications. We compare it with a SVM as a more conventional ML method, and discuss some of the strengths and weaknesses of the approach. In particular, a ‘deep’ neural network has many features of a ‘black box’, which has important implications on how we look at and interpret data.

  16. Reactive oxygen species, essential molecules, during plant-pathogen interactions.

    Science.gov (United States)

    Camejo, Daymi; Guzmán-Cedeño, Ángel; Moreno, Alexander

    2016-06-01

    Reactive oxygen species (ROS) are continually generated as a consequence of the normal metabolism in aerobic organisms. Accumulation and release of ROS into cell take place in response to a wide variety of adverse environmental conditions including salt, temperature, cold stresses and pathogen attack, among others. In plants, peroxidases class III, NADPH oxidase (NOX) locates in cell wall and plasma membrane, respectively, may be mainly enzymatic systems involving ROS generation. It is well documented that ROS play a dual role into cells, acting as important signal transduction molecules and as toxic molecules with strong oxidant power, however some aspects related to its function during plant-pathogen interactions remain unclear. This review focuses on the principal enzymatic systems involving ROS generation addressing the role of ROS as signal molecules during plant-pathogen interactions. We described how the chloroplasts, mitochondria and peroxisomes perceive the external stimuli as pathogen invasion, and trigger resistance response using ROS as signal molecule. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Fluorescent Biosensors Based on Single-Molecule Counting.

    Science.gov (United States)

    Ma, Fei; Li, Ying; Tang, Bo; Zhang, Chun-Yang

    2016-09-20

    fluorescence signals by specific in vitro/in vivo fluorescent labeling, and consequently, the fluorescent molecules indicate the presence of target molecules. The resultant fluorescence signals may be simply counted by either microfluidic device-integrated confocal microscopy or total internal reflection fluorescence-based single-molecule imaging. We have developed a series of single-molecule counting-based biosensors which can be classified as separation-free and separation-assisted assays. As a proof-of-concept, we demonstrate the applications of single-molecule counting-based biosensors for sensitive detection of various target biomolecules such as DNAs, miRNAs, proteins, enzymes, and intact cells, which may function as the disease-related biomarkers. Moreover, we give a summary of future directions to expand the usability of single-molecule counting-based biosensors including (1) the development of more user-friendly and automated instruments, (2) the discovery of new fluorescent labels and labeling strategies, and (3) the introduction of new concepts for the design of novel biosensors. Due to their high sensitivity, good selectivity, rapidity, and simplicity, we believe that the single-molecule counting-based fluorescent biosensors will indubitably find wide applications in biological research, clinical diagnostics, and drug discovery.

  18. Striatal Activity and Reward Relativity: Neural Signals Encoding Dynamic Outcome Valuation.

    Science.gov (United States)

    Webber, Emily S; Mankin, David E; Cromwell, Howard C

    2016-01-01

    The striatum is a key brain region involved in reward processing. Striatal activity has been linked to encoding reward magnitude and integrating diverse reward outcome information. Recent work has supported the involvement of striatum in the valuation of outcomes. The present work extends this idea by examining striatal activity during dynamic shifts in value that include different levels and directions of magnitude disparity. A novel task was used to produce diverse relative reward effects on a chain of instrumental action. Rats ( Rattus norvegicus ) were trained to respond to cues associated with specific outcomes varying by food pellet magnitude. Animals were exposed to single-outcome sessions followed by mixed-outcome sessions, and neural activity was compared among identical outcome trials from the different behavioral contexts. Results recording striatal activity show that neural responses to different task elements reflect incentive contrast as well as other relative effects that involve generalization between outcomes or possible influences of outcome variety. The activity that was most prevalent was linked to food consumption and post-food consumption periods. Relative encoding was sensitive to magnitude disparity. A within-session analysis showed strong contrast effects that were dependent upon the outcome received in the immediately preceding trial. Significantly higher numbers of responses were found in ventral striatum linked to relative outcome effects. Our results support the idea that relative value can incorporate diverse relationships, including comparisons from specific individual outcomes to general behavioral contexts. The striatum contains these diverse relative processes, possibly enabling both a higher information yield concerning value shifts and a greater behavioral flexibility.

  19. Molecule Matters van der Waals Molecules

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 15; Issue 7. Molecule Matters van der Waals Molecules - Rg•••HF Complexes are Debye Molecules! E Arunan. Feature Article Volume 15 Issue 7 July 2010 pp 667-674. Fulltext. Click here to view fulltext PDF. Permanent link:

  20. Recurrence of task set-related MEG signal patterns during auditory working memory.

    Science.gov (United States)

    Peters, Benjamin; Bledowski, Christoph; Rieder, Maria; Kaiser, Jochen

    2016-06-01

    Processing of auditory spatial and non-spatial information in working memory has been shown to rely on separate cortical systems. While previous studies have demonstrated differences in spatial versus non-spatial processing from the encoding of to-be-remembered stimuli onwards, here we investigated whether such differences would be detectable already prior to presentation of the sample stimulus. We analyzed broad-band magnetoencephalography data from 15 healthy adults during an auditory working memory paradigm starting with a visual cue indicating the task-relevant stimulus feature for a given trial (lateralization or pitch) and a subsequent 1.5-s pre-encoding phase. This was followed by a sample sound (0.2s), the delay phase (0.8s) and a test stimulus (0.2s) after which participants made a match/non-match decision. Linear discriminant functions were trained to decode task-specific signal patterns throughout the task, and temporal generalization was used to assess whether the neural codes discriminating between the tasks during the pre-encoding phase would recur during later task periods. The spatial versus non-spatial tasks could indeed be discriminated after the onset of the cue onwards, and decoders trained during the pre-encoding phase successfully discriminated the tasks during both sample stimulus encoding and during the delay phase. This demonstrates that task-specific neural codes are established already before the memorandum is presented and that the same patterns are reestablished during stimulus encoding and maintenance. This article is part of a Special Issue entitled SI: Auditory working memory. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Signals of speciation: Volatile organic compounds resolve closely related sagebrush taxa, suggesting their importance in evolution

    Science.gov (United States)

    Deidre M. Jaeger; Justin B. Runyon; Bryce A. Richardson

    2016-01-01

    Volatile organic compounds (VOCs) play important roles in the environmental adaptation and fitness of plants. Comparison of the qualitative and quantitative differences in VOCs among closely related taxa and assessing the effects of environment on their emissions are important steps to deducing VOC function and evolutionary importance.

  2. Comparative Transcriptomic and Proteomic Analyses Reveal a FluG-Mediated Signaling Pathway Relating to Asexual Sporulation of Antrodia camphorata.

    Science.gov (United States)

    Li, Hua-Xiang; Lu, Zhen-Ming; Zhu, Qing; Gong, Jin-Song; Geng, Yan; Shi, Jin-Song; Xu, Zheng-Hong; Ma, Yan-He

    2017-09-01

    Medicinal mushroom Antrodia camphorata sporulate large numbers of arthroconidia in submerged fermentation, which is rarely reported in basidiomycetous fungi. Nevertheless, the molecular mechanisms underlying this asexual sporulation (conidiation) remain unclear. Here, we used comparative transcriptomic and proteomic approaches to elucidate possible signaling pathway relating to the asexual sporulation of A. camphorata. First, 104 differentially expressed proteins and 2586 differential cDNA sequences during the culture process of A. camphorata were identified by 2DE and RNA-seq, respectively. By applying bioinformatics analysis, a total of 67 genes which might play roles in the sporulation were obtained, and 18 of these genes, including fluG, sfgA, SfaD, flbA, flbB, flbC, flbD, nsdD, brlA, abaA, wetA, ganB, fadA, PkaA, veA, velB, vosA, and stuA might be involved in a potential FluG-mediated signaling pathway. Furthermore, the mRNA expression levels of the 18 genes in the proposed FluG-mediated signaling pathway were analyzed by quantitative real-time PCR. In summary, our study helps elucidate the molecular mechanisms underlying the asexual sporulation of A. camphorata, and provides also useful transcripts and proteome for further bioinformatics study of this valuable medicinal mushroom. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Development of an Immunoperoxidase Monolayer Assay for the Detection of Antibodies against Peste des Petits Ruminants Virus Based on BHK-21 Cell Line Stably Expressing the Goat Signaling Lymphocyte Activation Molecule.

    Directory of Open Access Journals (Sweden)

    Jialin Zhang

    Full Text Available From 2013 to 2015, peste des petits ruminants (PPR broke out in more than half of the provinces of China; thus, the application and development of diagnostic methods are very important for the control of PPR. Here, an immunoperoxidase monolayer assay (IPMA was developed to detect antibodies against PPR. However, during IPMA development, we found that Vero cells were not the appropriate choice because staining results were not easily observed. Therefore, we first established a baby hamster kidney-goat signaling lymphocyte activation molecule (BHK-SLAM cell line that could stably express goat SLAM for at least 20 generations. Compared with Vero cells, the PPR-mediated cytopathic effect occurred earlier in BHK-SLAM cells, and large syncytia appeared after virus infection. Based on this cell line and recombinant PPR virus expressing the green fluorescent protein (GFP (rPPRV-GFP, an IPMA for PPR diagnosis was developed. One hundred and ninety-eight PPR serum samples from goats or sheep were tested by the IPMA and virus neutralization test (VNT. Compared with the VNT, the sensitivity and specificity of the IPMA were 91% and 100%, respectively, and the coincidence rate of the two methods was 95.5%. The IPMA assay could be completed in 4 h, compared with more than 6 d for the VNT using rPPRV-GFP, and it is easily performed, as the staining results can be observed under a microscope. Additionally, unlike the VNT, the IPMA does not require antigen purification, which will reduce its cost. In conclusion, the established IPMA will be an alternative method that replaces the VNT for detecting antibodies against PPRV in the field.

  4. Sphingosine signaling and atherogenesis

    DEFF Research Database (Denmark)

    Xu, Cang-bao; Hansen-Schwartz, Jacob; Edvinsson, Lars

    2004-01-01

    Sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger to regulate cell proliferation and survival, and extracellularly, as a ligand for a group of G protein-coupled receptors (GPCRs) named the endothelial differentiation gene (EDG) family. Five...... closely related GPCRs of EDG family (EDG1, EDG3, EDG5, EDG6, and EDG8) have recently been identified as high-affinity S1P receptors. These receptors are coupled via Gi, Gq, G12/13, and Rho. The signaling pathways are linked to vascular cell migration, proliferation, apoptosis, intracellular Ca2......+ mobilization, and expression of adhesion molecules. The formation of an atherosclerotic lesion occurs through activation of cellular events that include monocyte adhesion to the endothelium and vascular smooth muscle cell (VSMC) migration and proliferation. Thus, S1P signaling may play an important role...

  5. Signal transduction-related responses to phytohormones and environmental challenges in sugarcane

    Directory of Open Access Journals (Sweden)

    Hemerly Adriana S

    2007-03-01

    Full Text Available Abstract Background Sugarcane is an increasingly economically and environmentally important C4 grass, used for the production of sugar and bioethanol, a low-carbon emission fuel. Sugarcane originated from crosses of Saccharum species and is noted for its unique capacity to accumulate high amounts of sucrose in its stems. Environmental stresses limit enormously sugarcane productivity worldwide. To investigate transcriptome changes in response to environmental inputs that alter yield we used cDNA microarrays to profile expression of 1,545 genes in plants submitted to drought, phosphate starvation, herbivory and N2-fixing endophytic bacteria. We also investigated the response to phytohormones (abscisic acid and methyl jasmonate. The arrayed elements correspond mostly to genes involved in signal transduction, hormone biosynthesis, transcription factors, novel genes and genes corresponding to unknown proteins. Results Adopting an outliers searching method 179 genes with strikingly different expression levels were identified as differentially expressed in at least one of the treatments analysed. Self Organizing Maps were used to cluster the expression profiles of 695 genes that showed a highly correlated expression pattern among replicates. The expression data for 22 genes was evaluated for 36 experimental data points by quantitative RT-PCR indicating a validation rate of 80.5% using three biological experimental replicates. The SUCAST Database was created that provides public access to the data described in this work, linked to tissue expression profiling and the SUCAST gene category and sequence analysis. The SUCAST database also includes a categorization of the sugarcane kinome based on a phylogenetic grouping that included 182 undefined kinases. Conclusion An extensive study on the sugarcane transcriptome was performed. Sugarcane genes responsive to phytohormones and to challenges sugarcane commonly deals with in the field were identified

  6. Brain Signals of Face Processing as Revealed by Event-Related Potentials

    Directory of Open Access Journals (Sweden)

    Ela I. Olivares

    2015-01-01

    Full Text Available We analyze the functional significance of different event-related potentials (ERPs as electrophysiological indices of face perception and face recognition, according to cognitive and neurofunctional models of face processing. Initially, the processing of faces seems to be supported by early extrastriate occipital cortices and revealed by modulations of the occipital P1. This early response is thought to reflect the detection of certain primary structural aspects indicating the presence grosso modo of a face within the visual field. The posterior-temporal N170 is more sensitive to the detection of faces as complex-structured stimuli and, therefore, to the presence of its distinctive organizational characteristics prior to within-category identification. In turn, the relatively late and probably more rostrally generated N250r and N400-like responses might respectively indicate processes of access and retrieval of face-related information, which is stored in long-term memory (LTM. New methods of analysis of electrophysiological and neuroanatomical data, namely, dynamic causal modeling, single-trial and time-frequency analyses, are highly recommended to advance in the knowledge of those brain mechanisms concerning face processing.

  7. Differential Expression of Osteo-Modulatory Molecules in Periodontal Ligament Stem Cells in Response to Modified Titanium Surfaces

    Directory of Open Access Journals (Sweden)

    So Yeon Kim

    2014-01-01

    Full Text Available This study assessed differential gene expression of signaling molecules involved in osteogenic differentiation of periodontal ligament stem cells (PDLSCs subjected to different titanium (Ti surface types. PDLSCs were cultured on tissue culture polystyrene (TCPS, and four types of Ti discs (PT, SLA, hydrophilic PT (pmodPT, and hydrophilic SLA (modSLA with no osteoinductive factor and then osteogenic activity, including alkaline phosphatase (ALP activity, mRNA expression of runt-related gene 2, osterix, FOSB, FRA1, and protein levels of osteopontin and collagen type IA, were examined. The highest osteogenic activity appeared in PDLSCs cultured on SLA, compared with the TCPS and other Ti surfaces. The role of surface properties in affecting signaling molecules to modulate PDLSC behavior was determined by examining the regulation of Wnt pathways. mRNA expression of the canonical Wnt signaling molecules, Wnt3a and β-catenin, was higher on SLA and modSLA than on smooth surfaces, but gene expression of the calcium-dependent Wnt signaling molecules Wnt5a, calmodulin, and NFATc1 was increased significantly on PT and pmodPT. Moreover, integrin α2/β1, sonic hedgehog, and Notch signaling molecules were affected differently by each surface modification. In conclusion, surface roughness and hydrophilicity can affect differential Wnt pathways and signaling molecules, targeting the osteogenic differentiation of PDLSCs.

  8. Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling

    Science.gov (United States)

    O’Neill, Casey E.; Newsom, Ryan J.; Stafford, Jacob; Scott, Talia; Archuleta, Solana; Levis, Sophia C.; Spencer, Robert L.; Campeau, Serge; Bachtell, Ryan K.

    2016-01-01

    Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.3 g/L) for 28 consecutive days from postnatal day 28 (P28) to P55. Age-matched control rats consumed water. Behavioral testing for anxiety-related behavior began in adulthood (P62) 7 days after removal of caffeine. Adolescent caffeine consumption enhanced anxiety-related behavior in an open field, social interaction test, and elevated plus maze. Similar caffeine consumption in adult rats did not alter anxiety-related behavior after caffeine removal. Characterization of neuroendocrine measures was next assessed to determine whether the changes in anxiety were associated with modifications in the HPA axis. Blood plasma levels of corticosterone (CORT) were assessed throughout the caffeine consumption procedure in adolescent rats. Adolescent caffeine consumption elevated plasma CORT 24 h after initiation of caffeine consumption that normalized over the course of the 28-day consumption procedure. CORT levels were also elevated 24 h after caffeine removal and remained elevated for 7 days. Despite elevated basal CORT in adult rats that consumed caffeine during adolescence, the adrenocorticotropic hormone (ACTH) and CORT response to placement on an elevated pedestal (a mild stressor) was significantly blunted. Lastly, we assessed changes in basal and stress-induced c-fos and corticotropin-releasing factor (Crf) mRNA expression in brain tissue collected at 7 days withdrawal from adolescent caffeine. Adolescent caffeine consumption increased basal c-fos mRNA in the paraventricular nucleus of the hypothalamus. Adolescent caffeine consumption had no other effects on the basal or stress-induced c-fos mRNA changes. Caffeine consumption during adolescence

  9. Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling.

    Science.gov (United States)

    O'Neill, Casey E; Newsom, Ryan J; Stafford, Jacob; Scott, Talia; Archuleta, Solana; Levis, Sophia C; Spencer, Robert L; Campeau, Serge; Bachtell, Ryan K

    2016-05-01

    Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.3g/L) for 28 consecutive days from postnatal day 28 (P28) to P55. Age-matched control rats consumed water. Behavioral testing for anxiety-related behavior began in adulthood (P62) 7 days after removal of caffeine. Adolescent caffeine consumption enhanced anxiety-related behavior in an open field, social interaction test, and elevated plus maze. Similar caffeine consumption in adult rats did not alter anxiety-related behavior after caffeine removal. Characterization of neuroendocrine measures was next assessed to determine whether the changes in anxiety were associated with modifications in the HPA axis. Blood plasma levels of corticosterone (CORT) were assessed throughout the caffeine consumption procedure in adolescent rats. Adolescent caffeine consumption elevated plasma CORT 24h after initiation of caffeine consumption that normalized over the course of the 28-day consumption procedure. CORT levels were also elevated 24h after caffeine removal and remained elevated for 7 days. Despite elevated basal CORT in adult rats that consumed caffeine during adolescence, the adrenocorticotropic hormone (ACTH) and CORT response to placement on an elevated pedestal (a mild stressor) was significantly blunted. Lastly, we assessed changes in basal and stress-induced c-fos and corticotropin-releasing factor (Crf) mRNA expression in brain tissue collected at 7 days withdrawal from adolescent caffeine. Adolescent caffeine consumption increased basal c-fos mRNA in the paraventricular nucleus of the hypothalamus. Adolescent caffeine consumption had no other effects on the basal or stress-induced c-fos mRNA changes. Caffeine consumption during adolescence increased

  10. Light-induced energetic decoupling as a mechanism for phycobilisome-related energy dissipation in red algae: a single molecule study.

    Directory of Open Access Journals (Sweden)

    Lu-Ning Liu

    Full Text Available BACKGROUND: Photosynthetic organisms have developed multiple protective mechanisms to prevent photodamage in vivo under high-light conditions. Cyanobacteria and red algae use phycobilisomes (PBsomes as their major light-harvesting antennae complexes. The orange carotenoid protein in some cyanobacteria has been demonstrated to play roles in the photoprotective mechanism. The PBsome-itself-related energy dissipation mechanism is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, single-molecule spectroscopy is applied for the first time on the PBsomes of red alga Porphyridium cruentum, to detect the fluorescence emissions of phycoerythrins (PE and PBsome core complex simultaneously, and the real-time detection could greatly characterize the fluorescence dynamics of individual PBsomes in response to intense light. CONCLUSIONS/SIGNIFICANCE: Our data revealed that strong green-light can induce the fluorescence decrease of PBsome, as well as the fluorescence increase of PE at the first stage of photobleaching. It strongly indicated an energetic decoupling occurring between PE and its neighbor. The fluorescence of PE was subsequently observed to be decreased, showing that PE was photobleached when energy transfer in the PBsomes was disrupted. In contrast, the energetic decoupling was not observed in either the PBsomes fixed with glutaraldehyde, or the mutant PBsomes lacking B-PE and remaining b-PE. It was concluded that the energetic decoupling of the PBsomes occurs at the specific association between B-PE and b-PE within the PBsome rod. Assuming that the same process occurs also at the much lower physiological light intensities, such a decoupling process is proposed to be a strategy corresponding to PBsomes to prevent photodamage of the photosynthetic reaction centers. Finally, a novel photoprotective role of gamma-subunit-containing PE in red algae was discussed.

  11. Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb® sorbent porous polymer beads.

    Directory of Open Access Journals (Sweden)

    Maryann C Gruda

    Full Text Available Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In sepsis and septic shock, pathogen-associated molecular pattern molecules (PAMPS, such as bacterial exotoxins, cause direct cellular damage and/or trigger an immune response in the host often leading to excessive cytokine production, a maladaptive systemic inflammatory response syndrome response (SIRS, and tissue damage that releases DAMPs, such as activated complement and HMGB-1, into the bloodstream causing further organ injury. Cytokine reduction using extracorporeal blood filtration has been correlated with improvement in survival and clinical outcomes in experimental studies and clinical reports, but the ability of this technology to reduce a broader range of inflammatory mediators has not been well-described. This study quantifies the size-selective adsorption of a wide range of sepsis-related inflammatory bacterial and fungal PAMPs, DAMPs and cytokines, in a single compartment, in vitro whole blood recirculation system.Purified proteins were added to whole blood at clinically relevant concentrations and recirculated through a device filled with CytoSorb® hemoadsorbent polymer beads (CytoSorbents Corporation, USA or control (no bead device in vitro. Except for the TNF-α trimer, hemoadsorption through porous polymer bead devices reduced the levels of a broad spectrum of cytokines, DAMPS, PAMPS and mycotoxins by more than 50 percent.This study demonstrates that CytoSorb® hemoadsorbent polymer beads efficiently remove a broad spectrum of toxic PAMPS and DAMPS from blood providing an additional means of reducing the uncontrolled inflammatory cascade that contributes to a maladaptive SIRS response, organ dysfunction and death in patients with a broad range of life-threatening inflammatory conditions such as sepsis, toxic shock syndrome, necrotizing fasciitis, and other severe inflammatory conditions.

  12. Lipid accumulation, oxidative stress and immune-related molecules affected by tributyltin exposure in muscle tissues of rare minnow (Gobiocypris rarus).

    Science.gov (United States)

    Zhang, Jiliang; Zhang, Chunnuan; Ma, Dongdong; Liu, Min; Huang, Shuntao

    2017-12-01

    Tributyltin (TBT) is reported to induce adipogenesis in fish, which might affect nutritional qualities and health status. Muscle tissues account for the majority of body mass, and have been described as a major site of fat deposition and an immunologically active organ. Therefore, the present study aims to evaluate whether chronic exposures of TBT, at environmental concentrations of 1, 10 and 100 ng/L, affects lipid accumulation, oxidative stress and immune status in muscle tissues of rare minnow (Gobiocypris rarus). After 60 d of exposure, TBT increased contents of total lipid, total cholesterol, triglyceride and fatty acids in muscle tissues. Interestingly, TBT exposure disrupted fatty acid composition and increased contents of unsaturated fatty acids (such as eicosapentaenoic acid and docosahexaenoic acid) in muscle tissues, which might be a response to preserve membrane functions from TBT exposure. Meanwhile, the concentrations of hepatic fatty acid desaturase 2 (Δ6-desaturase) and stearoyl-CoA desaturase (Δ9-desaturase) were increased after TBT exposure, which might contribute the increase of unsaturated fatty acids. Furthermore, TBT increased muscle lipid peroxidation products, antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase), and the expression of immune-related molecules (tumor necrosis factor alpha, interleukin 1 beta and nuclear factor kappa B) in muscle tissues. The disruption of TBT on the lipid accumulation, oxidative stress and immune-toxic effects in muscle tissues of fish might reduce nutritional qualities, and affect growth and health status, which might pose a constant and serious threat to fish and result in economic loss in aquaculture. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Geochemical variation of groundwater in the Abruzzi region: earthquakes related signals?

    Science.gov (United States)

    Cardellini, C.; Chiodini, G.; Caliro, S.; Frondini, F.; Avino, R.; Minopoli, C.; Morgantini, N.

    2009-12-01

    detail, during a campaign performed ten years ago, constituting a pre-crisis reference case. The new data includes the determination of the main dissolved ions, the dissolved gases (CO2, CH4, N2, Ar, He) and the stable isotopes of the water (H, O), CO2 (13C) and He (3He/4He). All the springs collected in 2009 show a systematic increase in the content of the deeply derived CO2 dissolved in the aquifers, respect to the 1997. The origin of this regional variation is still under investigation. A monthly sampling of the main spring has been programmed in order to differentiate the variation derived by seasonal processes from eventual signals linked to seismic processes. The first results will be presented and discussed.

  14. Are MRI high-signal changes of alar and transverse ligaments in acute whiplash injury related to outcome?

    Directory of Open Access Journals (Sweden)

    Eide Geir E

    2010-11-01

    Full Text Available Abstract Background Upper neck ligament high-signal changes on magnetic resonance imaging (MRI have been found in patients with whiplash-associated disorders (WAD but also in non-injured controls. The clinical relevance of such changes is controversial. Their prognostic role has never been evaluated. The purpose of this study was to examine if alar and transverse ligament high-signal changes on MRI immediately following the car accident are related to outcome after 12 months for patients with acute WAD grades 1-2. Methods Within 13 days after a car accident, 114 consecutive acute WAD1-2 patients without prior neck injury or prior neck problems underwent upper neck high-resolution proton-weighted MRI. High-signal changes of the alar and transverse ligaments were graded 0-3. A questionnaire including the impact of event scale for measuring posttraumatic stress response and questions on patients' expectations of recovery provided clinical data at injury. At 12 months follow-up, 111 (97.4% patients completed the Neck Disability Index (NDI and an 11-point numeric rating scale (NRS-11 on last week neck pain intensity. Factors potentially related to these outcomes were assessed using multiple logistic regression analyses. Results Among the 111 responders (median age 29.8 years; 63 women, 38 (34.2% had grades 2-3 alar ligament changes and 25 (22.5% had grades 2-3 transverse ligament changes at injury. At 12 months follow-up, 49 (44.1% reported disability (NDI > 8 and 23 (20.7% neck pain (NRS-11 > 4. Grades 2-3 ligament changes in the acute phase were not related to disability or neck pain at 12 months. More severe posttraumatic stress response increased the odds for disability (odds ratio 1.46 per 10 points on the impact of event scale, p = 0.007 and so did low expectations of recovery (odds ratio 4.66, p = 0.005. Conclusions High-signal changes of the alar and transverse ligaments close after injury did not affect outcome for acute WAD1-2 patients

  15. Altered expression of the TCR signaling related genes CD3 and FcεRIγ in patients with aplastic anemia

    Directory of Open Access Journals (Sweden)

    Li Bo

    2012-03-01

    Full Text Available Abstract Background Aplastic anemia (AA is characterized by pancytopenia and bone marrow hypoplasia, which results from immune-mediated hematopoiesis suppression. Understanding the pathophysiology of the immune system, particularly T cells immunity, has led to improved AA treatment over the past decades. However, primary and secondary failure after immunosuppressive therapy is frequent. Thus, knowledge of the immune mechanisms leading to AA is crucial to fundamentally understand the disease. Findings To elucidate the T cell receptor (TCR signal transduction features in AA, the expression levels of CD3γ, δ, ε and ζ chain and FcεRIγ genes, which are involved in TCR signal transduction, and the negative correlation of the expression levels between the CD3ζ and FcεRIγ genes in T cells from peripheral blood mononuclear cells (PBMCs were analyzed. Real-time RT-PCR using the SYBR Green method was used to detect the expression level of these genes in PBMCs from 18 patients with AA and 14 healthy individuals. The β2microglobulin gene (β2M was used as an endogenous reference. The expression levels of the CD3γ, CD3δ, CD3ε and CD3ζ genes in patients with AA were significantly increased compared to a healthy control group, whereas the FcεRIγ gene expression level was significantly decreased in patients with AA in comparison with the healthy control group. Moreover, the negative correlation of the expression levels between the CD3ζ and FcεRIγ genes was lost. Conclusions To our knowledge, this is the first report of the CD3γ, CD3δ, CD3ε, CD3ζ and FcεRIγ gene expression in patients with AA. The abnormally expressed TCR signaling related genes may relate to T cells dysfunction in AA.

  16. Expression of osteoprotegerin, RNAK and RANKL genes in femoral head avascular necrosis and related signaling pathway.

    Science.gov (United States)

    Miao, Qingtang; Hao, Sibin; Li, Hongmei; Sun, Fang; Wang, Xueling

    2015-01-01

    Femoral head avascular necrosis (AVN) causes the damage of hip joint and related dysfunctions, thus consisting of a clinical challenge. Osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) all regulate the formation of bones via gene transcriptional regulation for the balance between osteoblasts and osteoclasts. This study thus investigated the expressional profiles of OPG, RANK and RANKL genes in AVN patients, and explored related molecular mediating pathways. Real-time qPCR was used to measure the gene expression of OPG, RANK and RANKL genes in AVN femoral head tissue samples from 42 patients, along with normal tissues. Western blotting analysis was performed to quantify protein levels of OPG and RANKL. There was a trend but not statistically significant elevation of mRNA levels of OPG in femoral head AVN tissues compared to normal tissues (P>0.05). The expression of RNAK and RNAKL, however, was significantly elevated in necrotic tissues (P<0.05). No significant difference in protein levels of OPG or RANKL between groups. The expression of OPG, RANK and RANKL genes exert a crucial role in the progression of AVN, suggesting their roles in mediating bone homeostasis and potential effects on bone destruction.

  17. Correction to: Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus.

    Science.gov (United States)

    Zagaar, Munder A; Dao, An T; Alhaider, Ibrahim A; Alkadhi, Karim A

    2018-01-01

    The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.

  18. Emerging Signaling Pathway in Arcuate Feeding-Related Neurons: Role of the Acbd7

    Directory of Open Access Journals (Sweden)

    Damien Lanfray

    2017-06-01

    Full Text Available The understanding of the mechanisms whereby energy balance is regulated is essential to the unraveling of the pathophysiology of obesity. In the last three decades, focus was put on the metabolic role played by the hypothalamic neurons expressing proopiomelanocortin (POMC and cocaine and amphetamine regulated transcript (CART and the neurons co-localizing agouti-related peptide (AgRP, neuropeptide Y (NPY, and gamma-aminobutyric acid (GABA. These neurons are part of the leptin-melanocortin pathway, whose role is key in energy balance regulation. More recently, the metabolic involvement of further hypothalamic uncharacterized neuron populations has been suggested. In this review, we discuss the potential homeostatic implication of hypothalamic GABAergic neurons that produce Acyl-Coa-binding domain containing protein 7 (ACBD7, precursor of the nonadecaneuropeptide (NDN, which has recently been characterized as a potent anorexigenic neuropeptide capable of relaying the leptin anorectic/thermogenic effect via the melanocortin system.

  19. ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders.

    Science.gov (United States)

    Torres, Mauricio; Matamala, José Manuel; Duran-Aniotz, Claudia; Cornejo, Victor Hugo; Foley, Andrew; Hetz, Claudio

    2015-09-02

    Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Age-related differences in signaling efficiency of human lens cells underpin differential wound healing response rates following cataract surgery.

    Science.gov (United States)

    Dawes, Lucy Jean; Duncan, George; Wormstone, Ian Michael

    2013-01-14

    Cataract surgery is blighted by posterior capsule opacification (PCO), which is more severe and frequent in the young than the elderly (>60 years). Our aim was to understand the biological basis for these age-related differences in PCO/wound healing rates. Human capsular bags were prepared by cataract surgery on donor lenses (young [60 years] groups) and maintained in serum-free Eagle's minimum essential medium. Cell growth was determined using the MTS assay. Fibroblast growth factor (FGF) and hepatocyte growth factor (HGF) levels were determined using ELISA. Protein synthesis rates were elucidated by 35S-methionine incorporation. U0126, SB203580, and SP600125 were used to disrupt ERK-, p38-, and JNK-mediated signaling, respectively. Level of total and phospho-ERK, -c-jun, -P38, and -JNK plus cytokines were detected using a BIOPLEX array system. Following a 2-day culture period, significant decreases in IL-1β and IL-6, and increases in IL-10, IL-12, IL-13, and VEGF in the >60 years group were observed compared with their younger counterparts. Capsular bags (cells and capsule) from aged donors contained greater than or equal levels of HGF and FGF than younger counterparts and had greater rates of protein synthesis. Inhibition of ERK, p38, and JNK signaling significantly suppressed cell coverage on the posterior capsule. pERK, p-c-jun, p-p38, and pJNK were consistently lower in aged cell populations; total signaling protein expression was unaffected by age. Serum stimulation increased pERK, p-c-jun, and pJNK levels in cells of all ages; p-p38 was significantly increased in the >60 years group only. Ligand availability to cells is not a limiting factor as we age, but the ability to convert this resource into signaling activity is. We therefore propose that overall signaling efficiency is reduced as a function of age, which consequently limits wound-healing response rates after injury.

  1. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  2. Expression of transforming growth factor beta 1-related signaling proteins in irradiated vessels

    Energy Technology Data Exchange (ETDEWEB)

    Preidl, Raimund H.M.; Moebius, Patrick; Weber, Manuel; Neukam, Friedrich W.; Schlegel, Andreas; Wehrhan, Falk [University of Erlangen- Nuernberg, Department of Oral and Maxillofacial Surgery, Erlangen (Germany); University of Erlangen- Nuernberg, Erlangen (Germany); Amann, Kerstin [University of Erlangen- Nuernberg, Erlangen (Germany)

    2014-12-09

    Microvascular free tissue transfer is a standard method in head and neck reconstructive surgery. However, previous radiotherapy of the operative region is associated with an increased incidence in postoperative flap-related complications and complete flap loss. As transforming growth factor beta (TGF-β) 1 and galectin-3 are well known markers in the context of fibrosis and lectin-like oxidized low-density lipoprotein 1 (LOX-1) supports vascular atherosclerosis, the aim of this study was to evaluate the expression of TGF-β1 and related markers as well as LOX-1 in irradiated vessels. To evaluate the expression of galectin-3, Smad 2/3, TGF-β1, and LOX-1, 20 irradiated and 20 nonirradiated arterial vessels were used for immunohistochemical staining. We semiquantitatively assessed the ratio of stained cells/total number of cells (labeling index). Expression of galectin-3, Smad 2/3, and TGF-β1 was significantly increased in previously irradiated vessels compared with nonirradiated controls. Furthermore, LOX-1 was expressed significantly higher in irradiated compared with nonirradiated vessels. Fibrosis-related proteins like galectin-3, Smad 2/3, and TGF-β1 are upregulated after radiotherapy and support histopathological changes leading to vasculopathy of the irradiated vessels. Furthermore, postoperative complications in irradiated patients can be explained by increased endothelial dysfunction caused by LOX-1 in previously irradiated patients. Consequently, not only TGF-β1 but also galectin-3inhibitors may decrease complications after microsurgical tissue transfer. (orig.) [German] Der freie mikrovaskulaere Gewebetransfer gilt heute als fester Standard in der rekonstruktiven Kopf-Hals-Chirurgie. Es zeigte sich jedoch, dass im Falle einer stattgehabten Bestrahlung im Operationsgebiet mit einer erhoehten Rate an transplantatbezogenen Komplikationen gerechnet werden muss. Sowohl TGF-β1 als auch Galektin-3 sind bekannte Mediatoren in Bezug auf die Fibroseentstehung

  3. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Eunhui Seo

    2015-04-01

    Full Text Available The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old were maintained on a regular diet (CON or a regular diet supplemented with 0.05% ginseng berry extract (GBD for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016 and insulin resistance scores (HOMA-IR (p = 0.012, suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007. Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS-1 (p = 0.047, and protein kinase B (AKT (p = 0.037, were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1 (p = 0.036 and peroxisome proliferator-activated receptor gamma (PPARγ (p = 0.032, which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice.

  4. Signal intensity in T2' magnetic resonance imaging is related to brain glioma grade

    International Nuclear Information System (INIS)

    Saitta, Laura; Castellan, Lucio; Heese, Oliver; Westphal, Manfred; Foerster, Ann-Freya; Siemonsen, Susanne; Fiehler, Jens; Goebell, Einar; Matschke, Jakob

    2011-01-01

    T2' values reflect the presence of deoxyhaemoglobin related to high local oxygen extraction. We assessed the feasibility of T2' imaging to display regions with high metabolic activity in brain gliomas. MRI was performed in 25 patients (12 female; median age 46 years; range 2-69) with brain gliomas with additional T2 and T2* sequences. T2' maps were derived from T2 and T2*. Dynamic susceptibility weighted contrast (DSC) perfusion was performed in 12/25 patients. Images were visually assessed by two readers and five ROIs were evaluated for each patient. Pearson correlation, Mann-Whitney and Kruskal-Wallis tests were applied for statistical analysis. Three patients were not further evaluated because of artefacts. Mean values of high-grade (III-IV) gliomas showed significantly lower T2' values than low-grade (II) gliomas (p < 0.001). An inverse relationship was observed between rCBV and sqr (T2') (r = -0.463, p < 0.001). No correlation was observed between T2' and rCBV for grade II tumours (r = 0.038; p = 0.875). High-grade tumours revealed lower T2' values, presumably because of higher oxygen consumption in proliferating tissue. Our results indicate that T2' imaging can be used as an alternative to DSC perfusion in the detection of subtle deviations in tumour metabolism. (orig.)

  5. Age-related signal intensity changes in the corpus callosum: assessment with three orthogonal FLAIR images

    Energy Technology Data Exchange (ETDEWEB)

    Yamamoto, Akira; Miki, Yukio; Kanagaki, Mitsunori; Takahashi, Takahiro; Fushimi, Yasutaka; Haque, Tabassum Laz; Togashi, Kaori [Kyoto University, Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto (Japan); Tomimoto, Hidekazu [Kyoto University, Department of Neurology, Graduate School of Medicine, Kyoto (Japan); Konishi, Junya [Kobe University, Department of Radiology, Graduate School of Medicine, Kobe, Hyogo (Japan)

    2005-11-01

    The presence of age-related hyperintensities of the corpus callosum has not been thoroughly evaluated. Fifty-two patients of 50 years of age or older (mean, 71 years; range, 50-87 years) were included in this study. Fluid-attenuated inversion recovery images were obtained in three orthogonal planes. Periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) were graded according to Fazekas' rating scale. Correlations between the presence of hyperintensities in the corpus callosum and age, and the grade of PVH and DWMH were statistically analyzed. PVH was categorized as grade 0 (n=4), grade 1 (n=28), grade 2 (n=10), or grade 3 (n=10). DWMH was categorized as grade 0 (n=4), grade 1 (n=25), grade 2 (n=8), or grade 3 (n=15). Hyperintensity was considered present in the corpus callosum in 31 of the 52 patients (60%). In these 31 patients, PVH was categorized as grade 1 (n=16), grade 2 (n=7), or grade 3 (n=8), while DWMH was categorized as grade 0 (n=1), grade 1 (n=10), grade 2 (n=7), or grade 3 (n=13). The presence of callosal hyperintensities was significantly correlated with age (p=0.001), and with PVH (p=0.04) and DWMH grades (p=0.004). Hyperintensities may be present in the corpus callosum with aging, and are correlated with PVH and DWMH. (orig.)

  6. Age-related signal intensity changes in the corpus callosum: assessment with three orthogonal FLAIR images

    International Nuclear Information System (INIS)

    Yamamoto, Akira; Miki, Yukio; Kanagaki, Mitsunori; Takahashi, Takahiro; Fushimi, Yasutaka; Haque, Tabassum Laz; Togashi, Kaori; Tomimoto, Hidekazu; Konishi, Junya

    2005-01-01

    The presence of age-related hyperintensities of the corpus callosum has not been thoroughly evaluated. Fifty-two patients of 50 years of age or older (mean, 71 years; range, 50-87 years) were included in this study. Fluid-attenuated inversion recovery images were obtained in three orthogonal planes. Periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) were graded according to Fazekas' rating scale. Correlations between the presence of hyperintensities in the corpus callosum and age, and the grade of PVH and DWMH were statistically analyzed. PVH was categorized as grade 0 (n=4), grade 1 (n=28), grade 2 (n=10), or grade 3 (n=10). DWMH was categorized as grade 0 (n=4), grade 1 (n=25), grade 2 (n=8), or grade 3 (n=15). Hyperintensity was considered present in the corpus callosum in 31 of the 52 patients (60%). In these 31 patients, PVH was categorized as grade 1 (n=16), grade 2 (n=7), or grade 3 (n=8), while DWMH was categorized as grade 0 (n=1), grade 1 (n=10), grade 2 (n=7), or grade 3 (n=13). The presence of callosal hyperintensities was significantly correlated with age (p=0.001), and with PVH (p=0.04) and DWMH grades (p=0.004). Hyperintensities may be present in the corpus callosum with aging, and are correlated with PVH and DWMH. (orig.)

  7. Ras signaling in aging and metabolic regulation.

    Science.gov (United States)

    Slack, Cathy

    2017-12-07

    Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline.

  8. Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, and exaggerates protein synthesis.

    Science.gov (United States)

    Soltani, Asma; Lebrun, Solène; Carpentier, Gilles; Zunino, Giulia; Chantepie, Sandrine; Maïza, Auriane; Bozzi, Yuri; Desnos, Claire; Darchen, François; Stettler, Olivier

    2017-01-01

    Engrailed 1 (En1) and 2 (En2) code for closely related homeoproteins acting as transcription factors and as signaling molecules that contribute to midbrain and hindbrain patterning, to development and maintenance of monoaminergic pathways, and to retinotectal wiring. En2 has been suggested to be an autism susceptibility gene and individuals with autism display an overexpression of this homeogene but the mechanisms remain unclear. We addressed in the present study the effect of exogenously added En2 on the morphology of hippocampal cells that normally express only low levels of Engrailed proteins. By means of RT-qPCR, we confirmed that En1 and En2 were expressed at low levels in hippocampus and hippocampal neurons, and observed a pronounced decrease in En2 expression at birth and during the first postnatal week, a period characterized by intense synaptogenesis. To address a putative effect of Engrailed in dendritogenesis or synaptogenesis, we added recombinant En1 or En2 proteins to hippocampal cell cultures. Both En1 and En2 treatment increased the complexity of the dendritic tree of glutamatergic neurons, but only En2 increased that of GABAergic cells. En1 increased the density of dendritic spines both in vitro and in vivo. En2 had similar but less pronounced effect on spine density. The number of mature synapses remained unchanged upon En1 treatment but was reduced by En2 treatment, as well as the area of post-synaptic densities. Finally, both En1 and En2 elevated mTORC1 activity and protein synthesis in hippocampal cells, suggesting that some effects of Engrailed proteins may require mRNA translation. Our results indicate that Engrailed proteins can play, even at low concentrations, an active role in the morphogenesis of hippocampal cells. Further, they emphasize the over-regulation of GABA cell morphology and the vulnerability of excitatory synapses in a pathological context of En2 overexpression.

  9. Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, and exaggerates protein synthesis.

    Directory of Open Access Journals (Sweden)

    Asma Soltani

    Full Text Available Engrailed 1 (En1 and 2 (En2 code for closely related homeoproteins acting as transcription factors and as signaling molecules that contribute to midbrain and hindbrain patterning, to development and maintenance of monoaminergic pathways, and to retinotectal wiring. En2 has been suggested to be an autism susceptibility gene and individuals with autism display an overexpression of this homeogene but the mechanisms remain unclear. We addressed in the present study the effect of exogenously added En2 on the morphology of hippocampal cells that normally express only low levels of Engrailed proteins. By means of RT-qPCR, we confirmed that En1 and En2 were expressed at low levels in hippocampus and hippocampal neurons, and observed a pronounced decrease in En2 expression at birth and during the first postnatal week, a period characterized by intense synaptogenesis. To address a putative effect of Engrailed in dendritogenesis or synaptogenesis, we added recombinant En1 or En2 proteins to hippocampal cell cultures. Both En1 and En2 treatment increased the complexity of the dendritic tree of glutamatergic neurons, but only En2 increased that of GABAergic cells. En1 increased the density of dendritic spines both in vitro and in vivo. En2 had similar but less pronounced effect on spine density. The number of mature synapses remained unchanged upon En1 treatment but was reduced by En2 treatment, as well as the area of post-synaptic densities. Finally, both En1 and En2 elevated mTORC1 activity and protein synthesis in hippocampal cells, suggesting that some effects of Engrailed proteins may require mRNA translation. Our results indicate that Engrailed proteins can play, even at low concentrations, an active role in the morphogenesis of hippocampal cells. Further, they emphasize the over-regulation of GABA cell morphology and the vulnerability of excitatory synapses in a pathological context of En2 overexpression.

  10. Interstellar molecules and masers

    International Nuclear Information System (INIS)

    Nguyen-Q-Rieu; Guibert, J.

    1978-01-01

    The study of dense and dark clouds, in which hydrogen is mostly in molecular form, became possible since the discovery of interstellar molecules, emitting in the centimeter and millimeter wavelengths. The molecular lines are generally not in local thermal equilibrium (LTE). Their intensity can often be explained by invoking a population inversion mechanism. Maser emission lines due to OH, H 2 O and SiO molecules are among the most intense molecular lines. The H 2 CO molecule, detected in absorption in front of the cold cosmic background radiation of 2.7 K, illustrates the inverse phenomenon, the antimaser absorption. For a radio transition of frequency v, the inversion rate Δn (relative population difference between the upper and lower level) as well as the maser gain can be determined from the radio observations. In the case of the OH lines in the 2 PIsub(3/2), J=3/2 state, the inversion rates approximately 1 to 2% derived from the observations, are comparable with those obtained in the laboratory. The determination of the excitation mechanisms of the masers, through the statistical equilibrium and radiative transfer equations, implies the knowledge of collisional and radiative transition probabilities. A pumping model, which can satisfactorily explain the radio observations of some interstellar OH clouds, will be discussed [fr

  11. Interactions of electrons with biologically important molecules

    International Nuclear Information System (INIS)

    Pisklova, K.; Papp, P.; Stano, M.

    2012-01-01

    For the study of interactions of low-energy electrons with the molecules in the gas phase, the authors used electron-molecule cross-beam apparatus. The experiment is carried out in high vacuum, where molecules of the tested compound are inducted through a capillary. For purposes of this experiment the sample was electrically heated to 180 Deg C., giving a bundle of GlyGly molecules into the gas phase. The resulting signals can be evaluated in two different modes: mass spectrum - at continuous electron energy (e.g. 100 eV) they obtained the signal of intensity of the ions according to their mass to charge ratio; ionization and resonance spectra - for selected ion mass when the authors received the signal of intensity of the ions, depending on the energy of interacting electron.

  12. Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

    Directory of Open Access Journals (Sweden)

    Ana ePalomino

    2014-03-01

    Full Text Available Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression (CB1 receptors and enzymes that produce (DAGLα/β and NAPE-PLD and degrade (MAGL and FAAH eCB were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system (glutamate synthesizing enzymes LGA and KGA, mGluR3/5 metabotropic receptors, and NR1/2A/2B/2C-NMDA and GluR1/2/3/4-AMPA ionotropic receptor subunits and the gene expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-AG production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that

  13. Soluble intercellular adhesion molecule 1 and flow-mediated dilatation are related to the estimated risk of coronary heart disease independently from each other

    NARCIS (Netherlands)

    Witte, D.R.; Broekmans, W.M.R.; Kardinaal, A.F.M.; Klöpping-Ketelaars, I.A.A.; Poppel, G. van; Bots, M.L.; Kluft, C.; Princen, J.M.G.

    2003-01-01

    Background: Flow mediated dilatation (FMD) of the brachial artery and soluble intercellular adhesion molecule 1 (sICAM-1) are measures of distinct functions of the endothelium, reflecting nitric oxide (NO)-mediated and pro-inflammatory status, respectively. The comparative value of the two measures

  14. Different binding motifs of the celiac disease-associated HLA molecules DQ2.5, DQ2.2, and DQ7.5 revealed by relative quantitative proteomics of endogenous peptide repertoires

    DEFF Research Database (Denmark)

    Bergseng, Elin; Dørum, Siri; Arntzen, Magnus Ø.

    2014-01-01

    Celiac disease is caused by intolerance to cereal gluten proteins, and HLA-DQ molecules are involved in the disease pathogenesis by presentation of gluten peptides to CD4+ T cells. The α- or β-chain sharing HLA molecules DQ2.5, DQ2.2, and DQ7.5 display different risks for the disease...... established binding motifs. The binding motif of DQ2.2 was strikingly different from that of DQ2.5 with position P3 being a major anchor having a preference for threonine and serine. This is notable as three recently identified epitopes of gluten recognized by T cells of DQ2.2 celiac patients harbor serine...... at position P3. This study demonstrates that relative quantitative comparison of endogenous peptides sampled from our protein metabolism by HLA molecules provides clues to understand HLA association with disease....

  15. The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling.

    Science.gov (United States)

    Wang, Gang; Chen, Ling; Pan, Xiaoyu; Chen, Jiechun; Wang, Liqun; Wang, Weijie; Cheng, Ruochuan; Wu, Fan; Feng, Xiaoqing; Yu, Yingcong; Zhang, Han-Ting; O'Donnell, James M; Xu, Ying

    2016-04-05

    Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.

  16. Tacrolimus increases Nox4 expression in human renal fibroblasts and induces fibrosis-related genes by aberrant TGF-beta receptor signalling.

    Directory of Open Access Journals (Sweden)

    Georg Kern

    Full Text Available Chronic nephrotoxicity of immunosuppressives is one of the main limiting factors in the long-term outcome of kidney transplants, leading to tissue fibrosis and ultimate organ failure. The cytokine TGF-β is considered a key factor in this process. In the human renal fibroblast cell line TK-173, the macrolide calcineurin inhibitor tacrolimus (FK-506 induced TGF-β-like effects, manifested by increased expression of NAD(PH-oxidase 4 (Nox4, transgelin, tropomyosin 1, and procollagen α1(V mRNA after three days. The macrolide mTOR inhibitor rapamycin had similar effects, while cyclosporine A did not induce fibrose-related genes. Concentration dependence curves were sigmoid, where mRNA expression was induced already at low nanomolar levels of tacrolimus, and reached saturation at 100-300 nM. The effects were independent of extracellular TGF-β as confirmed by the use of neutralizing antibodies, and thus most likely caused by aberrant TGF-β receptor signaling, where binding of tacrolimus to the regulatory FKBP12 protein results in a "leaky" TGF-β receptor. The myofibroblast marker α-smooth muscle actin was neither induced by tacrolimus nor by TGF-β1, indicating an incomplete activation of TK-173 fibroblasts under culture conditions. Tacrolimus- and TGF-β1-induced Nox4 protein upregulation was confirmed by Western blotting, and was accompanied by a rise in intracellular H2O2 concentration. Si-RNA mediated knock-down of Nox4 expression prevented up-regulation of procollagen α1(V mRNA in tacrolimus-treated cells, but induced procollagen α1(V expression in control cells. Nox4 knock-down had no significant effect on the other genes tested. TGF-β is a key molecule in fibrosis, and the constant activation of aberrant receptor signaling by tacrolimus might contribute to the long-term development of interstitial kidney fibrosis in immunosuppressed patients. Nox4 levels possibly play a regulatory role in these processes.

  17. Plant natriuretic peptides are apoplastic and paracrine stress response molecules

    KAUST Repository

    Wang, Yuhua; Gehring, Christoph A; Irving, Helen R.

    2011-01-01

    plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions. © 2011 The Author.

  18. Alteration of cancer pain-related signals by radiation: Proteomic analysis in an animal model with cancer bone invasion

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jinsil; An, Jung Hee; Kim, Jiyoung; Kim, Un Jung; Lee, Bae Whan

    2005-01-01

    Purpose: Although radiotherapy is highly effective in relieving bone pain due to cancer invasion, its mechanism remains unclear. The aim of this study was to explore this mechanism in an animal model system. Methods and Materials: A hind paw model of cancer pain was developed by transplanting a murine hepatocarcinoma, HCa-1, into the periosteal membrane of the foot dorsum of C3H/HeJ mice. Bone invasion from HCa-1 was histopathologically confirmed from sequential tumor sampling. For three experimental groups, a control (N), tumor without radiation (T), and tumor with radiation (TR), the development and level of pain were objectively examined in mice with a growing tumor by assessing pain-associated behavior. The differential expression of pain-related signals in the spinal cord was analyzed by proteomic analysis using high-resolution two-dimensional gel electrophoresis (2-DE) and mass spectrometry, and those of proteins by Western blotting. The pain-mediating neurotransmitters in the spinal cord were also examined by immunohistochemical staining for calcitonin gene-related peptide (CGRP) and substance P. Results: In the histopathologic examinations, bone invasion from HCa-1 was seen from Day 7 and was evident at Day 14 after transplantation, and measurable pain-associated behaviors were developed from Day 7. After 25 Gy of radiation to the tumors, the objective level of pain in the TR group decreased, with higher thresholds to mechanical and thermal stimulation than in the T group. From the 2-DE of spinal cord, 107 spots were identified; 12 proteins were changed more than fivefold because of tumor formation but then reversed after radiation in the tumor-bearing mice. The proteins involved included secretagogin, syntenin, P2X purinoreceptor 6 (P2X6), and Ca 2+ /Calmodulin-dependent protein kinase 1 (CaM kinase 1), the functions of which have been known to be involved in the Ca 2+ -signaling cascade, ATP-mediated fast synaptic transmission, or control of vesicular

  19. Alteration of cancer pain-related signals by radiation: Proteomic analysis in an animal model with cancer bone invasion

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hee Chul [Department of Radiation Oncology, Hallym University, Chuncheon (Korea, Republic of); Seong, Jinsil [Department of Radiation Oncology, Brain Korea 21 Project for Medicine, Yonsei University, Seoul (Korea, Republic of); An, Jung Hee [Department of Radiation Oncology, Brain Korea 21 Project for Medicine, Yonsei University, Seoul (Korea, Republic of); Kim, Jiyoung [Department of Radiation Oncology, Brain Korea 21 Project for Medicine, Yonsei University, Seoul (Korea, Republic of); Kim, Un Jung [Yonsei Medical Research Center, Brain Korea 21 Project for Medicine, Yonsei University, Seoul (Korea, Republic of); Lee, Bae Whan [Yonsei Medical Research Center, Brain Korea 21 Project for Medicine, Yonsei University, Seoul (Korea, Republic of)

    2005-04-01

    Purpose: Although radiotherapy is highly effective in relieving bone pain due to cancer invasion, its mechanism remains unclear. The aim of this study was to explore this mechanism in an animal model system. Methods and Materials: A hind paw model of cancer pain was developed by transplanting a murine hepatocarcinoma, HCa-1, into the periosteal membrane of the foot dorsum of C3H/HeJ mice. Bone invasion from HCa-1 was histopathologically confirmed from sequential tumor sampling. For three experimental groups, a control (N), tumor without radiation (T), and tumor with radiation (TR), the development and level of pain were objectively examined in mice with a growing tumor by assessing pain-associated behavior. The differential expression of pain-related signals in the spinal cord was analyzed by proteomic analysis using high-resolution two-dimensional gel electrophoresis (2-DE) and mass spectrometry, and those of proteins by Western blotting. The pain-mediating neurotransmitters in the spinal cord were also examined by immunohistochemical staining for calcitonin gene-related peptide (CGRP) and substance P. Results: In the histopathologic examinations, bone invasion from HCa-1 was seen from Day 7 and was evident at Day 14 after transplantation, and measurable pain-associated behaviors were developed from Day 7. After 25 Gy of radiation to the tumors, the objective level of pain in the TR group decreased, with higher thresholds to mechanical and thermal stimulation than in the T group. From the 2-DE of spinal cord, 107 spots were identified; 12 proteins were changed more than fivefold because of tumor formation but then reversed after radiation in the tumor-bearing mice. The proteins involved included secretagogin, syntenin, P2X purinoreceptor 6 (P2X6), and Ca{sup 2+}/Calmodulin-dependent protein kinase 1 (CaM kinase 1), the functions of which have been known to be involved in the Ca{sup 2+}-signaling cascade, ATP-mediated fast synaptic transmission, or control of

  20. Age-related Resistance and the Defense Signaling Pathway of Ph-3 Gene Against Phytophthora infestans in Tomatoes

    Directory of Open Access Journals (Sweden)

    Sayed Rashad Ali Shah

    2015-09-01

    Full Text Available Resistance (R genes against plant pathogens often have age-related resistance (ARR effects. However, the mechanism involved in this phenomenon remains unknown. In this paper, Solanum lycopersicum ‘CLN2037B’ and S. pimpinellifolium ‘L3708’ harboring the Ph-3 gene, as well as S. habrochaites ‘LA2099’, ‘LA1777’ and ‘LA1033’ harboring quantitative trait loci (QTLs, were tested to investigate age-related resistance against late blight (LB; caused by Phytophthora infestans in the three-leaf stage of the plants. The results demonstrated that the QTL-related LB resistance showed the same age-related resistance as the Ph-3-mediated resistance at the six- and nine-leaf stages compared with the three-leaf stage. This indicated that there is a common defense mechanism in tomatoes against P. infestans via ARR. In addition, we combined ethylene (ET, salicylic acid (SA and jasmonic acid (JA mutants with virus-induced gene silencing (VIGS to study the Ph-3-dependent resistance signaling pathway. The results showed that ethylene and salicylic acid, but not jasmonic acid, are involved in the LB resistance mediated by the Ph-3 gene.

  1. Final Report on LDRD project 130784 : functional brain imaging by tunable multi-spectral Event-Related Optical Signal (EROS).

    Energy Technology Data Exchange (ETDEWEB)

    Speed, Ann Elizabeth; Spahn, Olga Blum; Hsu, Alan Yuan-Chun

    2009-09-01

    Functional brain imaging is of great interest for understanding correlations between specific cognitive processes and underlying neural activity. This understanding can provide the foundation for developing enhanced human-machine interfaces, decision aides, and enhanced cognition at the physiological level. The functional near infrared spectroscopy (fNIRS) based event-related optical signal (EROS) technique can provide direct, high-fidelity measures of temporal and spatial characteristics of neural networks underlying cognitive behavior. However, current EROS systems are hampered by poor signal-to-noise-ratio (SNR) and depth of measure, limiting areas of the brain and associated cognitive processes that can be investigated. We propose to investigate a flexible, tunable, multi-spectral fNIRS EROS system which will provide up to 10x greater SNR as well as improved spatial and temporal resolution through significant improvements in electronics, optoelectronics and optics, as well as contribute to the physiological foundation of higher-order cognitive processes and provide the technical foundation for miniaturized portable neuroimaging systems.

  2. A decade of decoding reward-related fMRI signals and where we go from here.

    Science.gov (United States)

    Kahnt, Thorsten

    2017-06-04

    Information about potential rewards in the environment is essential for guiding adaptive behavior, and understanding neural reward processes may provide insights into neuropsychiatric dysfunctions. Over the past 10 years, multivoxel pattern analysis (MVPA) techniques have been used to study brain areas encoding information about expected and experienced outcomes. These studies have identified reward signals throughout the brain, including the striatum, medial prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, and parietal cortex. This review article discusses some of the assumptions and models that are used to interpret results from these studies, and how they relate to findings from animal electrophysiology. The article reviews and summarizes some of the key findings from MVPA studies on reward. In particular, it first focuses on studies that, in addition to mapping out the brain areas that process rewards, have provided novel insights into the coding mechanisms of value and reward. Then, it discusses examples of how multivariate imaging approaches are being used more recently to decode features of expected rewards that go beyond value, such as the identity of an expected outcome or the action required to obtain it. The study of such complex and multifaceted reward representations highlights the key advantage of using representational methods, which are uniquely able to reveal these signals and may narrow the gap between animal and human research. Applied in a clinical context, MVPA may advance our understanding of neuropsychiatric disorders and the development of novel treatment strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. LDL receptor-related protein 1 regulates the abundance of diverse cell-signaling proteins in the plasma membrane proteome.

    Science.gov (United States)

    Gaultier, Alban; Simon, Gabriel; Niessen, Sherry; Dix, Melissa; Takimoto, Shinako; Cravatt, Benjamin F; Gonias, Steven L

    2010-12-03

    LDL receptor-related protein 1 (LRP1) is an endocytic receptor, reported to regulate the abundance of other receptors in the plasma membrane, including uPAR and tissue factor. The goal of this study was to identify novel plasma membrane proteins, involved in cell-signaling, that are regulated by LRP1. Membrane protein ectodomains were prepared from RAW 264.7 cells in which LRP1 was silenced and control cells using protease K. Peptides were identified by LC-MS/MS. By analysis of spectral counts, 31 transmembrane and secreted proteins were regulated in abundance at least 2-fold when LRP1 was silenced. Validation studies confirmed that semaphorin4D (Sema4D), plexin domain-containing protein-1 (Plxdc1), and neuropilin-1 were more abundant in the membranes of LRP1 gene-silenced cells. Regulation of Plxdc1 by LRP1 was confirmed in CHO cells, as a second model system. Plxdc1 coimmunoprecipitated with LRP1 from extracts of RAW 264.7 cells and mouse liver. Although Sema4D did not coimmunoprecipitate with LRP1, the cell-surface level of Sema4D was increased by RAP, which binds to LRP1 and inhibits binding of other ligands. These studies identify Plxdc1, Sema4D, and neuropilin-1 as novel LRP1-regulated cell-signaling proteins. Overall, LRP1 emerges as a generalized regulator of the plasma membrane proteome.

  4. Activating Nrf-2