Expressing genes do not forget their LINEs: transposable elements and gene expression

PubMed Central

Kines, Kristine J.; Belancio, Victoria P.

2012-01-01

1. ABSTRACT Historically the accumulated mass of mammalian transposable elements (TEs), particularly those located within gene boundaries, was viewed as a genetic burden potentially detrimental to the genomic landscape. This notion has been strengthened by the discovery that transposable sequences can alter the architecture of the transcriptome, not only through insertion, but also long after the integration process is completed. Insertions previously considered harmless are now known to impact the expression of host genes via modification of the transcript quality or quantity, transcriptional interference, or by the control of pathways that affect the mRNA life-cycle. Conversely, several examples of the evolutionary advantageous impact of TEs on the host gene structure that diversified the cellular transcriptome are reported. TE-induced changes in gene expression can be tissue-or disease-specific, raising the possibility that the impact of TE sequences may vary during development, among normal cell types, and between normal and disease-affected tissues. The understanding of the rules and abundance of TE-interference with gene expression is in its infancy, and its contribution to human disease and/or evolution remains largely unexplored. PMID:22201807

High glucose inhibits the aspirin-induced activation of the nitric oxide/cGMP/cGMP-dependent protein kinase pathway and does not affect the aspirin-induced inhibition of thromboxane synthesis in human platelets.

PubMed

Russo, Isabella; Viretto, Michela; Barale, Cristina; Mattiello, Luigi; Doronzo, Gabriella; Pagliarino, Andrea; Cavalot, Franco; Trovati, Mariella; Anfossi, Giovanni

2012-11-01

Since hyperglycemia is involved in the "aspirin resistance" occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin-induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5-25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1-300 μmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA-induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA-induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action.

Myeloperoxidase Oxidized LDL Interferes with Endothelial Cell Motility through miR-22 and Heme Oxygenase 1 Induction: Possible Involvement in Reendothelialization of Vascular Injuries

PubMed Central

Daher, Jalil; Martin, Maud; Rousseau, Alexandre; Nuyens, Vincent; Fayyad-Kazan, Hussein; Van Antwerpen, Pierre; Courbebaisse, Guy; Martiat, Philippe; Badran, Bassam; Dequiedt, Frank

2014-01-01

Cardiovascular disease linked to atherosclerosis is the leading cause of death worldwide. Atherosclerosis is mainly linked to dysfunction in vascular endothelial cells and subendothelial accumulation of oxidized forms of LDL. In the present study, we investigated the role of myeloperoxidase oxidized LDL (Mox-LDL) in endothelial cell dysfunction. We studied the effect of proinflammatory Mox-LDL treatment on endothelial cell motility, a parameter essential for normal vascular processes such as angiogenesis and blood vessel repair. This is particularly important in the context of an atheroma plaque, where vascular wall integrity is affected and interference with its repair could contribute to progression of the disease. We investigated in vitro the effect of Mox-LDL on endothelial cells angiogenic properties and we also studied the signalling pathways that could be affected by analysing Mox-LDL effect on the expression of angiogenesis-related genes. We report that Mox-LDL inhibits endothelial cell motility and tubulogenesis through an increase in miR-22 and heme oxygenase 1 expression. Our in vitro data indicate that Mox-LDL interferes with parameters associated with angiogenesis. They suggest that high LDL levels in patients would impair their endothelial cell capacity to cope with a damaged endothelium contributing negatively to the progression of the atheroma plaque. PMID:25530680

Predicting Pharmacodynamic Drug-Drug Interactions through Signaling Propagation Interference on Protein-Protein Interaction Networks.

PubMed

Park, Kyunghyun; Kim, Docyong; Ha, Suhyun; Lee, Doheon

2015-01-01

As pharmacodynamic drug-drug interactions (PD DDIs) could lead to severe adverse effects in patients, it is important to identify potential PD DDIs in drug development. The signaling starting from drug targets is propagated through protein-protein interaction (PPI) networks. PD DDIs could occur by close interference on the same targets or within the same pathways as well as distant interference through cross-talking pathways. However, most of the previous approaches have considered only close interference by measuring distances between drug targets or comparing target neighbors. We have applied a random walk with restart algorithm to simulate signaling propagation from drug targets in order to capture the possibility of their distant interference. Cross validation with DrugBank and Kyoto Encyclopedia of Genes and Genomes DRUG shows that the proposed method outperforms the previous methods significantly. We also provide a web service with which PD DDIs for drug pairs can be analyzed at http://biosoft.kaist.ac.kr/targetrw.

Molecular requirements for RNA-induced silencing complex assembly in the Drosophila RNA interference pathway.

PubMed

Pham, John W; Sontheimer, Erik J

2005-11-25

Complexes in the Drosophila RNA-induced silencing complex (RISC) assembly pathway can be resolved using native gel electrophoresis, revealing an initiator called R1, an intermediate called R2, and an effector called R3 (now referred to as holo-RISC). Here we show that R1 forms when the Dicer-2/R2D2 heterodimer binds short interfering RNA (siRNA) duplexes. The heterodimer alone can initiate RISC assembly, indicating that other factors are dispensable for initiation. During assembly, R2 requires Argonaute 2 to convert into holo-RISC. This requirement is reminiscent of the RISC-loading complex, which also requires Argonaute 2 for assembly into RISC. We have compared R2 to the RISC-loading complex and show that the two complexes are similar in their sensitivities to ATP and to chemical modifications on siRNA duplexes, indicating that they are likely to be identical. We have examined the requirements for RISC formation and show that the siRNA 5'-termini are repeatedly monitored during RISC assembly, first by the Dcr-2/R2D2 heterodimer and again after R2 formation, before siRNA unwinding. The 2'-position of the 5'-terminal nucleotide also affects RISC assembly, because an siRNA strand bearing a 2'-deoxyribose at this position can inhibit the cognate strand from entering holo-RISC; in contrast, the 2'-deoxyribose-modified strand has enhanced activity in the RNA interference pathway.

Endocrine-disrupting chemicals in aquatic environment: what are the risks for fish gametes?

PubMed

Carnevali, Oliana; Santangeli, Stefania; Forner-Piquer, Isabel; Basili, Danilo; Maradonna, Francesca

2018-06-11

Over the past 25 years, extensive research in vertebrate species has identified several genomic pathways altered by exposures to anthropogenic chemicals with hormone-like activity mediated by their interaction with nuclear receptors. In addition, many pollutants have been shown to interfere with non-genomic (non-classical) pathways, but this mechanism of endocrine disruption is still poorly understood. Recently, the number of publications describing the effects of Endocrine disrupting chemicals (EDCs) on fish reproduction, focusing on the deregulation of the hypothalamus-pituitary-gonadal axis as well as on gamete quality, significantly increased. Depending on their ability to mimic endogenous hormones, the may differently affect male or female reproductive physiology. Inhibition of gametogenesis, development of intersex gonads, alteration of the gonadosomatic index, and decreased fertility rate have been largely documented. In males, alterations of sperm density, motility, and fertility have been observed in several wild species. Similar detrimental effects were described in females, including negative outcomes on oocyte growth and maturation plus the occurrence of apoptotic/autophagic processes. These pathways may affect gamete viability considered as one of the major indicators of reproductive endocrine disruption. Pollutants act also at DNA level producing DNA mutations and changes in epigenetic pathways inducing specific mechanisms of toxicity and/or aberrant cellular responses that may affect subsequent generation(s) through the germline. In conclusion, this review summarizes the effects caused by EDC exposure on fish reproduction, focusing on gametogenesis, giving a general overview of the different aspects dealing with this issue, from morphological alteration, deregulation of steroidogenesis, hormonal synthesis, and occurrence of epigenetic process.

Increased actin polymerization and stabilization interferes with neuronal function and survival in the AMPKγ mutant Loechrig.

PubMed

Cook, Mandy; Bolkan, Bonnie J; Kretzschmar, Doris

2014-01-01

loechrig (loe) mutant flies are characterized by progressive neuronal degeneration, behavioral deficits, and early death. The mutation is due to a P-element insertion in the gene for the γ-subunit of the trimeric AMP-activated protein kinase (AMPK) complex, whereby the insertion affects only one of several alternative transcripts encoding a unique neuronal isoform. AMPK is a cellular energy sensor that regulates a plethora of signaling pathways, including cholesterol and isoprenoid synthesis via its downstream target hydroxy-methylglutaryl (HMG)-CoA reductase. We recently showed that loe interferes with isoprenoid synthesis and increases the prenylation and thereby activation of RhoA. During development, RhoA plays an important role in neuronal outgrowth by activating a signaling cascade that regulates actin dynamics. Here we show that the effect of loe/AMPKγ on RhoA prenylation leads to a hyperactivation of this signaling pathway, causing increased phosphorylation of the actin depolymerizating factor cofilin and accumulation of filamentous actin. Furthermore, our results show that the resulting cytoskeletal changes in loe interfere with neuronal growth and disrupt axonal integrity. Surprisingly, these phenotypes were enhanced by expressing the Slingshot (SSH) phosphatase, which during development promotes actin depolymerization by dephosphorylating cofilin. However, our studies suggest that in the adult SSH promotes actin polymerization, supporting in vitro studies using human SSH1 that suggested that SSH can also stabilize and bundle filamentous actin. Together with the observed increase in SSH levels in the loe mutant, our experiments suggest that in mature neurons SSH may function as a stabilization factor for filamentous actin instead of promoting actin depolymerization.

Effects of dabigatran on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. Results from a prospective, randomised, double-blind, placebo-controlled study.

PubMed

Franchi, Francesco; Rollini, Fabiana; Cho, Jung Rae; King, Rhodri; Phoenix, Fladia; Bhatti, Mona; DeGroat, Christopher; Tello-Montoliu, Antonio; Zenni, Martin M; Guzman, Luis A; Bass, Theodore A; Ajjan, Ramzi A; Angiolillo, Dominick J

2016-03-01

There is growing interest in understanding the effects of adding an oral anticoagulant in patients on dual antiplatelet therapy (DAPT). Vitamin K antagonists (VKAs) and clopidogrel represent the most broadly utilised oral anticoagulant and P2Y12 receptor inhibitor, respectively. However, VKAs can interfere with clopidogrel metabolism via the cytochrome P450 (CYP) system which in turn may result in an increase in platelet reactivity. Dabigatran is a direct acting (anti-II) oral anticoagulant which does not interfere with CYP and has favourable safety and efficacy profiles compared with VKAs. The pharmacodynamic (PD) effects on platelet reactivity and clot kinetic of adjunctive dabigatran therapy in patients on DAPT are poorly explored. In this prospective, randomised, double-blind, placebo-controlled PD study, patients (n=30) on maintenance DAPT with aspirin and clopidogrel were randomised to either dabigatran 150 mg bid or placebo for seven days. PD testing was performed before and after treatment using four different assays exploring multiple pathways of platelet aggregation and fibrin clot kinetics: light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA), kaolin-activated thromboelastography (TEG) and turbidimetric assays. There were no differences in multiple measures of platelet reactivity investigating purinergic and non-purinergic signaling pathways assessed by LTA, MEA and TEG platelet mapping. Dabigatran significantly increased parameters related to thrombin activity and thrombus generation, and delayed fibrin clot formation, without affecting clot structure or fibrinolysis. In conclusion, in patients on DAPT with aspirin and clopidogrel, adjunctive dabigatran therapy is not associated with modulation of profiles of platelet reactivity as determined by several assays assessing multiple platelet signalling pathways. However, dabigatran significantly interferes with parameters related to thrombin activity and delays fibrin clot formation.

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways.

PubMed

Stellzig, J; Chariot, A; Shostak, K; Ismail Göktuna, S; Renner, F; Acker, T; Pagenstecher, A; Schmitz, M L

2013-11-11

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.

Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases.

PubMed

Jager, Martine J; Dogrusöz, Mehmet; Woodman, Scott E

2017-01-01

Uveal melanoma is an intraocular malignancy that, depending on its size and genetic make-up, may lead to metastases in up to 50% of cases. Currently, no therapy has been proven to improve survival. However, new therapies exploiting immune responses against metastases are being developed. The primary tumor is well characterized: tumors at high risk of developing metastases often contain macrophages and lymphocytes. However, these lymphocytes are often regulatory T cells that may suppress immune response. Currently, immune checkpoint inhibitors have shown marked efficacy in multiple cancers (eg, cutaneous melanoma) but do not yet improve survival in uveal melanoma patients. More knowledge needs to be acquired regarding the function of T cells in uveal melanoma. Other therapeutic options are related to the biochemical pathways. Targeting the RAF-MEK-ERK pathway with small molecule MEK inhibitors abrogates the growth of UM cells harboring GNAQ/GNA11 Q209 mutations, suggesting that these aberrant G-protein oncogenes mediate, at least in part, their effect through this hallmark proliferation pathway. Other pathways are also implicated, such as those involving c-Jun and YAP. Further studies may show how interference in the different pathways may affect survival. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways

PubMed Central

Stellzig, J; Chariot, A; Shostak, K; Ismail Göktuna, S; Renner, F; Acker, T; Pagenstecher, A; Schmitz, M L

2013-01-01

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity. PMID:24217713

RNA interference of argininosuccinate synthetase restores sensitivity to recombinant arginine deiminase (rADI) in resistant cancer cells

PubMed Central

2011-01-01

Background Sensitivity of cancer cells to recombinant arginine deiminase (rADI) depends on expression of argininosuccinate synthetase (AS), a rate-limiting enzyme in synthesis of arginine from citrulline. To understand the efficiency of RNA interfering of AS in sensitizing the resistant cancer cells to rADI, the down regulation of AS transiently and permanently were performed in vitro, respectively. Methods We studied the use of down-regulation of this enzyme by RNA interference in three human cancer cell lines (A375, HeLa, and MCF-7) as a way to restore sensitivity to rADI in resistant cells. The expression of AS at levels of mRNA and protein was determined to understand the effect of RNA interference. Cell viability, cell cycle, and possible mechanism of the restore sensitivity of AS RNA interference in rADI treated cancer cells were evaluated. Results AS DNA was present in all cancer cell lines studied, however, the expression of this enzyme at the mRNA and protein level was different. In two rADI-resistant cell lines, one with endogenous AS expression (MCF-7 cells) and one with induced AS expression (HeLa cells), AS small interference RNA (siRNA) inhibited 37-46% of the expression of AS in MCF-7 cells. ASsiRNA did not affect cell viability in MCF-7 which may be due to the certain amount of residual AS protein. In contrast, ASsiRNA down-regulated almost all AS expression in HeLa cells and caused cell death after rADI treatment. Permanently down-regulated AS expression by short hairpin RNA (shRNA) made MCF-7 cells become sensitive to rADI via the inhibition of 4E-BP1-regulated mTOR signaling pathway. Conclusions Our results demonstrate that rADI-resistance can be altered via AS RNA interference. Although transient enzyme down-regulation (siRNA) did not affect cell viability in MCF-7 cells, permanent down-regulation (shRNA) overcame the problem of rADI-resistance due to the more efficiency in AS silencing. PMID:21453546

Carrier-envelope phase control over pathway interference in strong-field dissociation of H2+.

PubMed

Kling, Nora G; Betsch, K J; Zohrabi, M; Zeng, S; Anis, F; Ablikim, U; Jochim, Bethany; Wang, Z; Kübel, M; Kling, M F; Carnes, K D; Esry, B D; Ben-Itzhak, I

2013-10-18

The dissociation of an H2+ molecular-ion beam by linearly polarized, carrier-envelope-phase-tagged 5 fs pulses at 4×10(14) W/cm2 with a central wavelength of 730 nm was studied using a coincidence 3D momentum imaging technique. Carrier-envelope-phase-dependent asymmetries in the emission direction of H+ fragments relative to the laser polarization were observed. These asymmetries are caused by interference of odd and even photon number pathways, where net zero-photon and one-photon interference predominantly contributes at H+ + H kinetic energy releases of 0.2-0.45 eV, and net two-photon and one-photon interference contributes at 1.65-1.9 eV. These measurements of the benchmark H2+ molecule offer the distinct advantage that they can be quantitatively compared with ab initio theory to confirm our understanding of strong-field coherent control via the carrier-envelope phase.

Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects.

PubMed

Jurgeit, Andreas; McDowell, Robert; Moese, Stefan; Meldrum, Eric; Schwendener, Reto; Greber, Urs F

2012-01-01

Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H(+)-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.

Supersonic Wave Interference Affecting Stability

NASA Technical Reports Server (NTRS)

Love, Eugene S.

1958-01-01

Some of the significant interference fields that may affect stability of aircraft at supersonic speeds are briefly summarized. Illustrations and calculations are presented to indicate the importance of interference fields created by wings, bodies, wing-body combinations, jets, and nacelles.

Distracted and down: neural mechanisms of affective interference in subclinical depression

PubMed Central

Andrews-Hanna, Jessica R.; Spielberg, Jeffrey M.; Warren, Stacie L.; Sutton, Bradley P.; Miller, Gregory A.; Heller, Wendy; Banich, Marie T.

2015-01-01

Previous studies have shown that depressed individuals have difficulty directing attention away from negative distractors, a phenomenon known as affective interference. However, findings are mixed regarding the neural mechanisms and network dynamics of affective interference. The present study addressed these issues by comparing neural activation during emotion-word and color-word Stroop tasks in participants with varying levels of (primarily subclinical) depression. Depressive symptoms predicted increased activation to negative distractors in areas of dorsal anterior cingulate cortex (dACC) and posterior cingulate cortex (PCC), regions implicated in cognitive control and internally directed attention, respectively. Increased dACC activity was also observed in the group-average response to incongruent distractors, suggesting that dACC activity during affective interference is related to overtaxed cognitive control. In contrast, regions of PCC were deactivated across the group in response to incongruent distractors, suggesting that PCC activity during affective interference represents task-independent processing. A psychophysiological interaction emerged in which higher depression predicted more positively correlated activity between dACC and PCC during affective interference, i.e. greater connectivity between cognitive control and internal-attention systems. These findings suggest that, when individuals high in depression are confronted by negative material, increased attention to internal thoughts and difficulty shifting resources to the external world interfere with goal-directed behavior. PMID:25062838

Small RNA binding is a common strategy to suppress RNA silencing by several viral suppressors

PubMed Central

Lakatos, Lóránt; Csorba, Tibor; Pantaleo, Vitantonio; Chapman, Elisabeth J; Carrington, James C; Liu, Yu-Ping; Dolja, Valerian V; Calvino, Lourdes Fernández; López-Moya, Juan José; Burgyán, József

2006-01-01

RNA silencing is an evolutionarily conserved system that functions as an antiviral mechanism in higher plants and insects. To counteract RNA silencing, viruses express silencing suppressors that interfere with both siRNA- and microRNA-guided silencing pathways. We used comparative in vitro and in vivo approaches to analyse the molecular mechanism of suppression by three well-studied silencing suppressors. We found that silencing suppressors p19, p21 and HC-Pro each inhibit the intermediate step of RNA silencing via binding to siRNAs, although the molecular features required for duplex siRNA binding differ among the three proteins. None of the suppressors affected the activity of preassembled RISC complexes. In contrast, each suppressor uniformly inhibited the siRNA-initiated RISC assembly pathway by preventing RNA silencing initiator complex formation. PMID:16724105

The Fat-Dachsous signaling pathway regulates growth of horns in Trypoxylus dichotomus, but does not affect horn allometry.

PubMed

Hust, James; Lavine, Mark D; Worthington, Amy M; Zinna, Robert; Gotoh, Hiroki; Niimi, T; Lavine, Laura

Males of the Asian rhinoceros beetle, Trypoxylus dichotomus, possess exaggerated head and thoracic horns that scale dramatically out of proportion to body size. While studies of insulin signaling suggest that this pathway regulates nutrition-dependent growth including exaggerated horns, what regulates disproportionate growth has yet to be identified. The Fat signaling pathway is a potential candidate for regulating disproportionate growth of sexually-selected traits, a hypothesis we advanced in a previous paper (Gotoh et al., 2015). To investigate the role of Fat signaling in the growth and scaling of the sexually dimorphic, condition-dependent traits of the in the Asian rhinoceros beetle T. dichotomus, we used RNA interference to knock down expression of fat and its co-receptor dachsous. Knockdown of fat, and to a lesser degree dachsous, caused shortening and widening of appendages, including the head and thoracic horns. However, scaling of horns to body size was not affected. Our results show that Fat signaling regulates horn growth in T. dichotomus as it does in appendage growth in other insects. However, we provide evidence that Fat signaling does not mediate the disproportionate, positive allometric growth of horns in T. dichotomus. Copyright © 2018 Elsevier Ltd. All rights reserved.

Rostro-caudal and dorso-ventral gradients in medial and lateral prefrontal cortex during cognitive control of affective and cognitive interference.

PubMed

Rahm, Christoffer; Liberg, Benny; Wiberg-Kristoffersen, Maria; Aspelin, Peter; Msghina, Mussie

2013-04-01

Characterizing the anatomical substrates of major brain functions such as cognition and emotion is of utmost importance to the ongoing efforts of understanding the nature of psychiatric ailments and their potential treatment. The aim of our study was to investigate how the brain handles affective and cognitive interferences on cognitive processes. Functional magnetic resonance imaging investigation was performed on healthy individuals, comparing the brain oxygenation level dependent activation patterns during affective and cognitive counting Stroop tasks. The affective Stroop task activated rostral parts of medial prefrontal cortex (PFC) and rostral and ventral parts of lateral PFC, while cognitive Stroop activated caudal parts of medial PFC and caudal and dorsal parts of lateral PFC. Our findings suggest that the brain may handle affective and cognitive interference on cognitive processes differentially, with affective interference preferentially activating rostral and ventral PFC networks and cognitive interference activating caudal and dorsal PFC networks. © 2013 The Authors. Scandinavian Journal of Psychology © 2013 The Scandinavian Psychological Associations.

Knockdown of RNA interference pathway genes impacts the fitness of western corn rootworm.

PubMed

Davis-Vogel, Courtney; Ortiz, Angel; Procyk, Lisa; Robeson, Jonathan; Kassa, Adane; Wang, Yiwei; Huang, Emily; Walker, Carl; Sethi, Amit; Nelson, Mark E; Sashital, Dipali G

2018-05-18

Western corn rootworm (Diabrotica virgifera virgifera) is a serious agricultural pest known for its high adaptability to various management strategies, giving rise to a continual need for new control options. Transgenic maize expressing insecticidal RNAs represents a novel mode of action for rootworm management that is dependent on the RNA interference (RNAi) pathways of the insect for efficacy. Preliminary evidence suggests that western corn rootworm could develop broad resistance to all insecticidal RNAs through changes in RNAi pathway genes; however, the likelihood of field-evolved resistance occurring through this mechanism remains unclear. In the current study, eight key genes involved in facilitating interference in the microRNA and small interfering RNA pathways were targeted for knockdown in order to evaluate impact on fitness of western corn rootworm. These genes include drosha, dicer-1, dicer-2, pasha, loquacious, r2d2, argonaute 1, and argonaute 2. Depletion of targeted transcripts in rootworm larvae led to changes in microRNA expression, decreased ability to pupate, reduced adult beetle emergence, and diminished reproductive capacity. The observed effects do not support evolution of resistance through changes in expression of these eight genes due to reduced insect fitness.

Distracted and down: neural mechanisms of affective interference in subclinical depression.

PubMed

Kaiser, Roselinde H; Andrews-Hanna, Jessica R; Spielberg, Jeffrey M; Warren, Stacie L; Sutton, Bradley P; Miller, Gregory A; Heller, Wendy; Banich, Marie T

2015-05-01

Previous studies have shown that depressed individuals have difficulty directing attention away from negative distractors, a phenomenon known as affective interference. However, findings are mixed regarding the neural mechanisms and network dynamics of affective interference. The present study addressed these issues by comparing neural activation during emotion-word and color-word Stroop tasks in participants with varying levels of (primarily subclinical) depression. Depressive symptoms predicted increased activation to negative distractors in areas of dorsal anterior cingulate cortex (dACC) and posterior cingulate cortex (PCC), regions implicated in cognitive control and internally directed attention, respectively. Increased dACC activity was also observed in the group-average response to incongruent distractors, suggesting that dACC activity during affective interference is related to overtaxed cognitive control. In contrast, regions of PCC were deactivated across the group in response to incongruent distractors, suggesting that PCC activity during affective interference represents task-independent processing. A psychophysiological interaction emerged in which higher depression predicted more positively correlated activity between dACC and PCC during affective interference, i.e. greater connectivity between cognitive control and internal-attention systems. These findings suggest that, when individuals high in depression are confronted by negative material, increased attention to internal thoughts and difficulty shifting resources to the external world interfere with goal-directed behavior. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Role of RNA interference in plant improvement

NASA Astrophysics Data System (ADS)

Jagtap, Umesh Balkrishna; Gurav, Ranjit Gajanan; Bapat, Vishwas Anant

2011-06-01

Research to alter crops for their better performance involving modern technology is underway in numerous plants, and achievements in transgenic plants are impacting crop improvements in unparalleled ways. Striking progress has been made using genetic engineering technology over the past two decades in manipulating genes from diverse and exotic sources, and inserting them into crop plants for inducing desirable characteristics. RNA interference (RNAi) has recently been identified as a natural mechanism for regulation of gene expression in all higher organisms from plants to humans and promises greater accuracy and precision to plant improvement. The expression of any gene can be down-regulated in a highly explicit manner exclusive of affecting the expression of any other gene by using RNAi technologies. Additional research in this field has been focused on a number of other areas including microRNAs, hairpin RNA, and promoter methylation. Manipulating new RNAi pathways, which generate small RNA molecules to amend gene expression in crops, can produce new quality traits and having better potentiality of protection against abiotic and biotic stresses. Nutritional improvement, change in morphology, or enhanced secondary metabolite synthesis are some of the other advantages of RNAi technology. In addition to its roles in regulating gene expression, RNAi is also used as a natural defense mechanism against molecular parasites such as jumping genes and viral genetic elements that affect genome stability. Even though much advancement has been made on the field of RNAi over the preceding few years, the full prospective of RNAi for crop improvement remains to be fully realized. The intricacy of RNAi pathway, the molecular machineries, and how it relates to plant development are still to be explained.

Utilization of Mytilus digestive gland cells for the in vitro screening of potential metabolic disruptors in aquatic invertebrates.

PubMed

Balbi, Teresa; Ciacci, Caterina; Grasselli, Elena; Smerilli, Arianna; Voci, Adriana; Canesi, Laura

2017-01-01

In vertebrate systems, many endocrine disruptors (EDs) can also interfere with energy and lipid metabolism, thus acting as metabolic disruptors. At the cellular level, these effects are mainly mediated by interactions with nuclear receptors/transcription factors, leading to the modulation of genes involved in lipid homeostasis, as well as by rapid, receptor-independent pathways. Several potential metabolic disruptors are found in aquatic environments. In fish, different EDs have been shown to affect hepatic lipid homeostasis both in vivo and in vitro. However, little information is available in aquatic invertebrates due to our poor knowledge of the regulatory pathways of lipid metabolism. In this work, primary cell cultures from the digestive gland of the bivalve Mytilus galloprovincialis were utilized to investigate the effects of model EDs (bisphenol A (BPA) and perfluorooctane sulphonate (PFOS)) on lipid homeostasis. Both compounds (at 24 and 3h of exposure) increased intracellular lipid and tryglyceride-TAG content, with strongest effects of PFOS at 10 -7 M. Acyl-CoA oxidase activity was unaffected, whereas some changes in the activity of glycolytic, antioxidant/biotransformation enzymes were observed; however, no clear relationship was found with lipid accumulation. Evaluation of mitochondrial membrane potential Δψm and determination of extracellular TAG content indicate that PFOS interferes with mitochondrial function and lipid secretion, whereas BPA mainly affects lipid secretion. Experiments with specific inhibitors showed that activation of PI-3 kinase and extracellularly regulated mitogen-activated protein kinase (ERK MAPK) plays a key role in mediating lipid accumulation. Mussel digestive gland cells represent a simple in vitro model for screening the metabolic effects of EDs in marine invertebrates. Copyright © 2016 Elsevier Inc. All rights reserved.

Metabolic effects of p,p'-DDE on Atlantic salmon hepatocytes.

PubMed

Olsvik, Pål A; Søfteland, Liv

2018-04-01

Decades after being banned in many countries, DDT and its metabolites are still considered major environmental hazards. The p,p'-DDE isomer, the DDT metabolite found in highest concentration in aquaculture feeds, is an endocrine disruptor with demonstrated ability to induce epigenetic effects. This study aimed at examining the impact of p,p'-DDE on Atlantic salmon. Primary hepatocytes were exposed to four concentrations of p,p'-DDE (0.1, 1, 10, 100 μm) for 48 hours, and endpoints included cytotoxicity, global DNA methylation, targeted transcription and metabolomics profiling (100 μm). p,p'-DDE was moderately cytotoxic at 100 μm. No impact was seen on global DNA methylation. Vtg1 and esr1 transcription, markers of endocrine disruption, was most strongly induced at 10 μm p,p'-DDE, while ar showed strongest response at 100 μm. Metabolomics profiling showed that p,p'-DDE at 100 μm most strongly affected carbohydrate metabolism, primary bile acid metabolism, leucine, isoleucine and valine metabolism, diacylglycerol and sphingolipid metabolism. Observed changes in lipid levels suggest that p,p'-DDE interferes with phospholipid membrane biosynthesis. Elevation of bile acid levels in p,p'-DDE-exposed hepatocytes indicates upregulation of synthesis of bile acids after cytochrome P450 activation. Pathway analysis showed that the superpathway of methionine degradation was the most significantly affected pathway by p,p'-DDE exposure, while endocrine system disorder topped the diseases and disorder ranking. In conclusion, this work predicts an endocrine response to p,p'-DDE exposure, and demonstrates how this legacy pesticide might interfere with mechanisms linked to DNA methylation in Atlantic salmon hepatocytes. Copyright © 2017 John Wiley & Sons, Ltd.

Enrichment with Wood Blocks Does Not Affect Toxicity Assessment in an Exploratory Toxicology Model Using Sprague–Dawley Rats

PubMed Central

Ditewig, Amy C; Bratcher, Natalie A; Davila, Donna R; Dayton, Brian D; Ebert, Paige; Lesuisse, Philippe; Liguori, Michael J; Wetter, Jill M; Yang, Hyuna; Buck, Wayne R

2014-01-01

Environmental enrichment in rodents may improve animal well-being but can affect neurologic development, immune system function, and aging. We tested the hypothesis that wood block enrichment affects the interpretation of traditional and transcriptomic endpoints in an exploratory toxicology testing model using a well-characterized reference compound, cyclophosphamide. ANOVA was performed to distinguish effects of wood block enrichment separate from effects of 40 mg/kg cyclophosphamide treatment. Biologically relevant and statistically significant effects of wood block enrichment occurred only for body weight gain. ANOVA demonstrated the expected effects of cyclophosphamide on food consumption, spleen weight, and hematology. According to transcriptomic endpoints, cyclophosphamide induced fewer changes in gene expression in liver than in spleen. Splenic transcriptomic pathways affected by cyclophosphamide included: iron hemostasis; vascular tissue angiotensin system; hepatic stellate cell activation and fibrosis; complement activation; TGFβ-induced hypertrophy and fibrosis; monocytes, macrophages, and atherosclerosis; and platelet activation. Changes in these pathways due to cyclophosphamide treatment were consistent with bone marrow toxicity regardless of enrichment. In a second study, neither enrichment nor type of cage flooring altered body weight or food consumption over a 28-d period after the first week. In conclusion, wood block enrichment did not interfere with a typical exploratory toxicology study; the effects of ingested wood on drug level kinetics may require further consideration. PMID:24827566

[Wnt/β-catenin pathway involved in the regulation of rat mesangial cell proliferation by adipose-derived mesenchymal stem cells].

PubMed

Li, Zhi; Zhang, Mengying; Li, Xueqin; Lu, Jinming; Xu, Liang

2016-11-01

Objective To investigate the effect of adipose-derived mesenchymal stem cells (ADSCs) on glomerular mesangial cell proliferation via Wnt/β-catenin pathway. Methods The rat glomerular mesangial cells (HBZY-1) were incubated in conditioned ADSC medium. Cell cycle was analyzed with flow cytometry; the proliferation rate of HBZY-1 and the expression levels of relative genes and proteins of Wnt signaling pathway were measured using RNA interference, quantitative real-time PCR and Western blotting, respectively. Results HBZY-1 proliferation was significantly inhibited under the action of conditioned ADSC medium, whereas dickkopf WNT signaling pathway inhibitor 1 (DKK1) mRNA level was up-regulated. Fibronectin and TGF-β1 mRNA expression as well as β-catenin and Bcl-2 protein levels of HBZY-1 were significantly down-regulated. DKK1 gene expression level in ADSCs was significantly higher than that of HBZY-1. After RNA interference, DKK1 expression level in ADSCs was markedly inhibited, yet the β-catenin protein level was notably elevated. The β-catenin and Bcl-2 protein levels of HBZY-1 were also significantly raised in HBZY-1 after cultured with conditioned medium containing ADSCs treated with RNA interference. Conclusion Wnt/β-catenin may be a potential signaling pathway involved in the regulative effect of ADSCs on glomerular mesangial cell proliferation.

Salicylic Acid Interferes with Tobacco Mosaic Virus Replication via a Novel Salicylhydroxamic Acid-Sensitive Mechanism.

PubMed Central

Chivasa, S.; Murphy, A. M.; Naylor, M.; Carr, J. P.

1997-01-01

Salicylic acid (SA) induces resistance to all plant pathogens, including bacteria, fungi, and viruses, but the mechanism by which SA engenders resistance to viruses is not known. Pretreatment of tobacco mosaic virus (TMV)-susceptible (nn genotype) tobacco tissue with SA reduced the levels of viral RNAs and viral coat protein accumulating after inoculation with TMV. Viral RNAs were not affected equally, suggesting that SA treatment interferes with TMV replication. Salicylhydroxamic acid (SHAM), an inhibitor of the mitochondrial alternative oxidase, antagonized both SA-induced resistance to TMV in nn genotype plants and SA-induced acquired resistance in resistant (NN genotype) tobacco. SHAM did not inhibit induction of the PR-1 pathogenesis-related protein or induction of resistance to Erwinia carotovora or Botrytis cinerea by SA. This indicates that SA induces resistance to TMV via a novel SHAM-sensitive signal transduction pathway (potentially involving alternative oxidase), which is distinct from that leading to resistance to bacteria and fungi. PMID:12237364

Silencing of Apis mellifera dorsal genes reveals their role in expression of the antimicrobial peptide defensin-1.

PubMed

Lourenço, Anete Pedro; Florecki, Mônica Mazzei; Simões, Zilá Luz Paulino; Evans, Jay Daniel

2018-04-17

Like all other insects, two key signaling pathways (Toll and Imd) regulate the induction of honey bee immune effectors that target microbial pathogens. Among these effectors are antimicrobial peptides (AMPs) that are presumed to be produced by the NF-κB factors Dorsal and Relish from the Toll and Imd pathways, respectively. Using in silico analysis, we previously proposed that the honey bee AMP defensin-1 was regulated by the Toll pathway, while hymenoptaecin was regulated by Imd and abaecin by both the Toll and Imd pathways. Here we use an RNA interference (RNAi) assay to determine the role of Dorsal in regulating abaecin and defensin-1. Honey bees have two dorsal genes (dorsal-1 and dorsal-2) and two splicing isoforms of dorsal-1 (dorsal-1A and dorsal-1B). Accordingly, we used both single and multiple (double or triple) isoform knockdown strategies to clarify the roles of dorsal proteins and their isoforms. Down-regulation of defensin-1 was observed for dorsal-1A and dorsal-2 knockdowns, but abaecin expression was not affected by dorsal RNAi. We conclude that defensin-1 is regulated by Dorsal (Toll pathway). This article is protected by copyright. All rights reserved. © 2018 The Royal Entomological Society.

Light-mediated control of DNA transcription in yeast

PubMed Central

Hughes, Robert M.; Bolger, Steven; Tapadia, Hersh; Tucker, Chandra L.

2012-01-01

A variety of methods exist for inducible control of DNA transcription in yeast. These include the use of native yeast promoters or regulatory elements that are responsive to small molecules such as galactose, methionine, and copper, or engineered systems that allow regulation by orthogonal small molecules such as estrogen. While chemically regulated systems are easy to use and can yield high levels of protein expression, they often provide imprecise control over protein levels. Moreover, chemically regulated systems can affect many other proteins and pathways in yeast, activating signaling pathways or physiological responses. Here, we describe several methods for light mediated control of DNA transcription in vivo in yeast. We describe methodology for using a red light and phytochrome dependent system to induce transcription of genes under GAL1 promoter control, as well as blue light / cryptochrome dependent systems to control transcription of genes under GAL1 promoter or LexA operator control. Light is dose dependent, inexpensive to apply, easily delivered, and does not interfere with cellular pathways, and thus has significant advantages over chemical systems. PMID:22922268

A Metabolic Probe-Enabled Strategy Reveals Uptake and Protein Targets of Polyunsaturated Aldehydes in the Diatom Phaeodactylum tricornutum

PubMed Central

Wolfram, Stefanie; Wielsch, Natalie; Hupfer, Yvonne; Mönch, Bettina; Lu-Walther, Hui-Wen; Heintzmann, Rainer; Werz, Oliver; Svatoš, Aleš; Pohnert, Georg

2015-01-01

Diatoms are unicellular algae of crucial importance as they belong to the main primary producers in aquatic ecosystems. Several diatom species produce polyunsaturated aldehydes (PUAs) that have been made responsible for chemically mediated interactions in the plankton. PUA-effects include chemical defense by reducing the reproductive success of grazing copepods, allelochemical activity by interfering with the growth of competing phytoplankton and cell to cell signaling. We applied a PUA-derived molecular probe, based on the biologically highly active 2,4-decadienal, with the aim to reveal protein targets of PUAs and affected metabolic pathways. By using fluorescence microscopy, we observed a substantial uptake of the PUA probe into cells of the diatom Phaeodactylum tricornutum in comparison to the uptake of a structurally closely related control probe based on a saturated aldehyde. The specific uptake motivated a chemoproteomic approach to generate a qualitative inventory of proteins covalently targeted by the α,β,γ,δ-unsaturated aldehyde structure element. Activity-based protein profiling revealed selective covalent modification of target proteins by the PUA probe. Analysis of the labeled proteins gave insights into putative affected molecular functions and biological processes such as photosynthesis including ATP generation and catalytic activity in the Calvin cycle or the pentose phosphate pathway. The mechanism of action of PUAs involves covalent reactions with proteins that may result in protein dysfunction and interference of involved pathways. PMID:26496085

Electromagnetic interference in electrical systems of motor vehicles

NASA Astrophysics Data System (ADS)

Dziubiński, M.; Drozd, A.; Adamiec, M.; Siemionek, E.

2016-09-01

Electronic ignition system affects the electronic equipment of the vehicle by electric and magnetic fields. The measurement of radio electromagnetic interference originating from the ignition system affecting the audiovisual test bench was carried out with a variable speed of the ignition system. The paper presents measurements of radio electromagnetic interference in automobiles. In order to determine the level of electromagnetic interference, the audiovisual test bench was equipped with a set of meters for power consumption and assessment of the level of electromagnetic interference. Measurements of the electromagnetic interference level within the audiovisual system were performed on an experimental test bench consisting of the ignition system, starting system and charging system with an alternator and regulator.

Functional Analysis of RNA Interference-Related Soybean Pod Borer (Lepidoptera) Genes Based on Transcriptome Sequences.

PubMed

Meng, Fanli; Yang, Mingyu; Li, Yang; Li, Tianyu; Liu, Xinxin; Wang, Guoyue; Wang, Zhanchun; Jin, Xianhao; Li, Wenbin

2018-01-01

RNA interference (RNAi) is useful for controlling pests of agriculturally important crops. The soybean pod borer (SPB) is the most important soybean pest in Northeastern Asia. In an earlier study, we confirmed that the SPB could be controlled via transgenic plant-mediated RNAi. Here, the SPB transcriptome was sequenced to identify RNAi-related genes, and also to establish an RNAi-of-RNAi assay system for evaluating genes involved in the SPB systemic RNAi response. The core RNAi genes, as well as genes potentially involved in double-stranded RNA (dsRNA) uptake were identified based on SPB transcriptome sequences. A phylogenetic analysis and the characterization of these core components as well as dsRNA uptake related genes revealed that they contain conserved domains essential for the RNAi pathway. The results of the RNAi-of-RNAi assay involving Laccas e 2 (a critical cuticle pigmentation gene) as a marker showed that genes encoding the sid-like ( Sil1 ), scavenger receptor class C ( Src ), and scavenger receptor class B ( Srb3 and Srb4 ) proteins of the endocytic pathway were required for SPB cellular uptake of dsRNA. The SPB response was inferred to contain three functional small RNA pathways (i.e., miRNA, siRNA, and piRNA pathways). Additionally, the SPB systemic RNA response may rely on systemic RNA interference deficient transmembrane channel-mediated and receptor-mediated endocytic pathways. The results presented herein may be useful for developing RNAi-mediated methods to control SPB infestations in soybean.

Functional Analysis of RNA Interference-Related Soybean Pod Borer (Lepidoptera) Genes Based on Transcriptome Sequences

PubMed Central

Meng, Fanli; Yang, Mingyu; Li, Yang; Li, Tianyu; Liu, Xinxin; Wang, Guoyue; Wang, Zhanchun; Jin, Xianhao; Li, Wenbin

2018-01-01

RNA interference (RNAi) is useful for controlling pests of agriculturally important crops. The soybean pod borer (SPB) is the most important soybean pest in Northeastern Asia. In an earlier study, we confirmed that the SPB could be controlled via transgenic plant-mediated RNAi. Here, the SPB transcriptome was sequenced to identify RNAi-related genes, and also to establish an RNAi-of-RNAi assay system for evaluating genes involved in the SPB systemic RNAi response. The core RNAi genes, as well as genes potentially involved in double-stranded RNA (dsRNA) uptake were identified based on SPB transcriptome sequences. A phylogenetic analysis and the characterization of these core components as well as dsRNA uptake related genes revealed that they contain conserved domains essential for the RNAi pathway. The results of the RNAi-of-RNAi assay involving Laccase 2 (a critical cuticle pigmentation gene) as a marker showed that genes encoding the sid-like (Sil1), scavenger receptor class C (Src), and scavenger receptor class B (Srb3 and Srb4) proteins of the endocytic pathway were required for SPB cellular uptake of dsRNA. The SPB response was inferred to contain three functional small RNA pathways (i.e., miRNA, siRNA, and piRNA pathways). Additionally, the SPB systemic RNA response may rely on systemic RNA interference deficient transmembrane channel-mediated and receptor-mediated endocytic pathways. The results presented herein may be useful for developing RNAi-mediated methods to control SPB infestations in soybean. PMID:29773992

A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/β-Catenin Signaling during Rift Valley Fever Virus Infection.

PubMed

Harmon, Brooke; Bird, Sara W; Schudel, Benjamin R; Hatch, Anson V; Rasley, Amy; Negrete, Oscar A

2016-08-15

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. These studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses. Copyright © 2016 Harmon et al.

Dietary exposure of 17-alpha ethinylestradiol modulates physiological endpoints and gene signaling pathways in female largemouth bass (Micropterus salmoides)

PubMed Central

Colli-Dula, Reyna-Cristina; Martyniuk, Christopher J.; Kroll, Kevin J.; Prucha, Melinda S.; Kozuch, Marianne; Barber, David S.; Denslow, Nancy D.

2014-01-01

17alpha-ethinylestradiol (EE2), used for birth control in humans, is a potent estrogen that is found in wastewater at low concentrations (ng/L). EE2 has the ability to interfere with the endocrine system of fish, affecting reproduction which can result in population level effects. The objective of this study was to determine if dietary exposure to EE2 would alter gene expression patterns and key pathways in the liver and ovary and whether these could be associated with reproductive endpoints in female largemouth bass during egg development. Female LMB received 70 ng EE2/g feed (feed administered at 1% of body weight) for 60 days. EE2 dietary exposure significantly reduced plasma vitellogenin concentrations by 70%. Hepatosomatic and gonadosomatic indices were also decreased with EE2 feeding by 38.5% and 40%, respectively. Transcriptomic profiling revealed that there were more changes in steady state mRNA levels in the liver compared to the ovary. Genes associated with reproduction were differentially expressed such as vitellogenin in the liver and aromatase in the gonad. In addition, a set of genes related with oxidative stress (e.g. glutathione reductase and glutathione peroxidase) were identified as altered in the liver and genes associated with the immune system (e.g. complement component 1, and macrophage-inducible C-type lectin) were altered in the gonad. In a follow-up study with 0.2 ng EE2/g feed for 60 days, similar phenotypic and gene expression changes were observed that support these findings with the higher concentrations. This study provides new insights into how dietary exposure to EE2 interferes with endocrine signaling pathways in female LMB during a critical period of reproductive oogenesis. PMID:25203422

A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection

DOE PAGES

Harmon, Brooke; Bird, Sara W.; Schudel, Benjamin R.; ...

2016-05-25

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses Lamore » Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. Lastly, these studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.« less

Dietary exposure of 17-alpha ethinylestradiol modulates physiological endpoints and gene signaling pathways in female largemouth bass (Micropterus salmoides).

PubMed

Colli-Dula, Reyna-Cristina; Martyniuk, Christopher J; Kroll, Kevin J; Prucha, Melinda S; Kozuch, Marianne; Barber, David S; Denslow, Nancy D

2014-11-01

17Alpha-ethinylestradiol (EE2), used for birth control in humans, is a potent estrogen that is found in wastewater at low concentrations (ng/l). EE2 has the ability to interfere with the endocrine system of fish, affecting reproduction which can result in population level effects. The objective of this study was to determine if dietary exposure to EE2 would alter gene expression patterns and key pathways in the liver and ovary and whether these could be associated with reproductive endpoints in female largemouth bass during egg development. Female LMB received 70ng EE2/g feed (administered at 1% of body weight) for 60 days. EE2 dietary exposure significantly reduced plasma vitellogenin concentrations by 70%. Hepatosomatic and gonadosomatic indices were also decreased with EE2 feeding by 38.5% and 40%, respectively. Transcriptomic profiling revealed that there were more changes in steady state mRNA levels in the liver compared to the ovary. Genes associated with reproduction were differentially expressed, such as vitellogenin in the liver and aromatase in the gonad. In addition, a set of genes related with oxidative stress (e.g. glutathione reductase and glutathione peroxidase) were identified as altered in the liver and genes associated with the immune system (e.g. complement component 1, and macrophage-inducible C-type lectin) were altered in the gonad. In a follow-up study with 0.2ng EE2/g feed for 60 days, similar phenotypic and gene expression changes were observed that support these findings with the higher concentrations. This study provides new insights into how dietary exposure to EE2 interferes with endocrine signaling pathways in female LMB during a critical period of reproductive oogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection

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

Harmon, Brooke; Bird, Sara W.; Schudel, Benjamin R.

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses Lamore » Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. Lastly, these studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.« less

Role of Host Type IA Phosphoinositide 3-Kinase Pathway Components in Invasin-Mediated Internalization of Yersinia enterocolitica.

PubMed

Dowd, Georgina C; Bhalla, Manmeet; Kean, Bernard; Thomas, Rowan; Ireton, Keith

2016-06-01

Many bacterial pathogens subvert mammalian type IA phosphoinositide 3-kinase (PI3K) in order to induce their internalization into host cells. How PI3K promotes internalization is not well understood. Also unclear is whether type IA PI3K affects different pathogens through similar or distinct mechanisms. Here, we performed an RNA interference (RNAi)-based screen to identify components of the type IA PI3K pathway involved in invasin-mediated entry of Yersinia enterocolitica, an enteropathogen that causes enteritis and lymphadenitis. The 69 genes targeted encode known upstream regulators or downstream effectors of PI3K. A similar RNAi screen was previously performed with the food-borne bacterium Listeria monocytogenes The results of the screen with Y. enterocolitica indicate that at least nine members of the PI3K pathway are needed for invasin-mediated entry. Several of these proteins, including centaurin-α1, Dock180, focal adhesion kinase (FAK), Grp1, LL5α, LL5β, and PLD2 (phospholipase D2), were recruited to sites of entry. In addition, centaurin-α1, FAK, PLD2, and mTOR were required for remodeling of the actin cytoskeleton during entry. Six of the human proteins affecting invasin-dependent internalization also promote InlB-mediated entry of L. monocytogenes Our results identify several host proteins that mediate invasin-induced effects on the actin cytoskeleton and indicate that a subset of PI3K pathway components promote internalization of both Y. enterocolitica and L. monocytogenes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Natural interference phenomena affecting spaceborne receivers

NASA Technical Reports Server (NTRS)

Stacey, J. M.

1984-01-01

Earth orbiting microwave receivers which are vulnerable to the interference from natural sources, mainly, the Sun and the Moon, are discussed. The irradiance from the Sun affects microwave receivers in two ways: (1) the infrared component of the irradiance causes nonuniform heating in metal structures and produces distortions that affect electrical performance; and (2) the graybody radiation component of the solar irradiance enters the collecting aperture of the antenna and the feed ports of the calibration circuits. The graybody radiation operates to degrade the signal to noise ratios and vitiate the internal calibration accuracy. The magnitudes of interference from the Sun and the Moon are analyzed and mathematical expressions are derived which serve to quantify the expected interference levels.

Four types of interference competition and their impacts on the ecology and evolution of size-structured populations and communities.

PubMed

Zhang, Lai; Andersen, Ken H; Dieckmann, Ulf; Brännström, Åke

2015-09-07

We investigate how four types of interference competition - which alternatively affect foraging, metabolism, survival, and reproduction - impact the ecology and evolution of size-structured populations. Even though all four types of interference competition reduce population biomass, interference competition at intermediate intensity sometimes significantly increases the abundance of adult individuals and the population׳s reproduction rate. We find that foraging and metabolic interference evolutionarily favor smaller maturation size when interference is weak and larger maturation size when interference is strong. The evolutionary response to survival interference and reproductive interference is always larger maturation size. We also investigate how the four types of interference competition impact the evolutionary dynamics and resultant diversity and trophic structure of size-structured communities. Like other types of trait-mediated competition, all four types of interference competition can induce disruptive selection and thus promote initial diversification. Even though foraging interference and reproductive interference are more potent in promoting initial diversification, they catalyze the formation of diverse communities with complex trophic structure only at high levels of interference intensity. By contrast, survival interference does so already at intermediate levels, while reproductive interference can only support relatively smaller communities with simpler trophic structure. Taken together, our results show how the type and intensity of interference competition jointly affect coexistence patterns in structured population models. Copyright © 2015 Elsevier Ltd. All rights reserved.

Measurement of affective and activity pain interference using the Brief Pain Inventory (BPI): Cancer and Leukemia Group B 70903.

PubMed

Atkinson, Thomas M; Halabi, Susan; Bennett, Antonia V; Rogak, Lauren; Sit, Laura; Li, Yuelin; Kaplan, Ellen; Basch, Ethan

2012-11-01

The Brief Pain Inventory (BPI) was designed to yield separate scores for pain intensity and interference. It has been proposed that the pain interference factor can be further broken down into unique factors of affective (e.g., mood) and activity (e.g., work) interference. The purpose of this analysis was to confirm this affective/activity interference dichotomy. A retrospective confirmatory factor analysis was completed for a sample of 184 individuals diagnosed with castrate-resistant prostate cancer (age 40-86, mean = 65.46, 77% White non-Hispanic) who had been administered the BPI as part of Cancer and Leukemia Group B trial 9480. A one-factor model was compared against two-factor and three-factor models that were developed based on the design of the instrument. Root mean squared error of approximation (0.075), comparative fit index (0.971), and change in chi-square, given the corresponding change in degrees of freedom (13.33, P < 0.05) values for the three-factor model (i.e., pain intensity, activity interference, and affective interference), were statistically superior in comparison with the one- and two-factor models. This three-factor structure was found to be invariant across age, mean prostate-specific antigen, and hemoglobin levels. These results confirm that the BPI can be used to quantify the degree to which pain separately interferes with affective and activity aspects of a patient's everyday life. These findings will provide clinical trialists, pharmaceutical sponsors, and regulators with confidence in the flexibility of the BPI as they consider the use of this instrument to assist with understanding the patient experience as it relates to treatment. Wiley Periodicals, Inc.

Disentangling Intracycle Interferences in Photoelectron Momentum Distributions Using Orthogonal Two-Color Laser Fields

NASA Astrophysics Data System (ADS)

Xie, Xinhua; Wang, Tian; Yu, ShaoGang; Lai, XuanYang; Roither, Stefan; Kartashov, Daniil; Baltuška, Andrius; Liu, XiaoJun; Staudte, André; Kitzler, Markus

2017-12-01

We use orthogonally polarized two-color (OTC) laser pulses to separate quantum paths in the multiphoton ionization of Ar atoms. Our OTC pulses consist of 400 and 800 nm light at a relative intensity ratio of 10 ∶1 . We find a hitherto unobserved interference in the photoelectron momentum distribution, which exhibits a strong dependence on the relative phase of the OTC pulse. Analysis of model calculations reveals that the interference is caused by quantum pathways from nonadjacent quarter cycles.

Modeling Interpersonal Correlates of Condomless Anal Sex among Gay and Bisexual Men: An Application of Attachment Theory.

PubMed

Starks, Tyrel J; Castro, Michael A; Castiblanco, Juan P; Millar, Brett M

2017-05-01

The existing literature has identified that beliefs about the interpersonal meaning of condom use are a significant predictor of condomless anal sex (CAS). Some have suggested that condom use in this context may function as a form of nonverbal communication. This study utilized attachment theory as a framework and tested a hypothesized model linking adult attachment to CAS through communication skills and condom expectancies. An online survey was completed by 122 single, HIV-negative gay and bisexual (GB) men living in the U.S. They completed measures of adult attachment (anxious and avoidant), condom expectancies regarding intimacy and pleasure interference, communication skills, self-assessed mate value, and recent CAS with casual partners. There was a significant, positive bivariate association between anxious attachment and receptive CAS. In path model analyses, two over-arching pathways emerged. In the other-oriented pathway, anxious attachment, self-perceived mate value, and emotional communication predicted the belief that condoms interfere with intimacy. In turn, intimacy interference expectancies were positively associated with the odds of receptive CAS. In the self-oriented pathway, assertive communication skills mediated a link between avoidant attachment and the belief that condoms interfere with sexual pleasure. Pleasure interference expectancies were positively associated with the odds of insertive CAS. The findings highlight the importance of relational or interpersonal concerns in sexual risk-taking among single GB men. Attachment theory may serve as a framework for organizing these interpersonal correlates of CAS. Results are consistent with the conceptualization of condom use as a form of nonverbal attachment-related behavior. Implications for sexual health and risk-reduction interventions are explored in this context.

Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

PubMed

Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

2016-11-01

Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

Escaping the recent past: Which stimulus dimensions influence proactive interference?

PubMed Central

Craig, Kimberly S.; Berman, Marc G.; Jonides, John; Lustig, Cindy

2013-01-01

Proactive interference occurs when information from the past disrupts current processing and is a major source of confusion and errors in short-term memory (Wickens, Born & Allen, 1963). The present investigation examines potential boundary conditions for interference, testing the hypothesis that potential competitors must be similar along task-relevant dimensions to influence proactive interference effects. We manipulated both the type of task being completed (Experiments 1, 2 and 3) and dimensions of similarity irrelevant to the current task (Experiments 4 and 5) to determine how the recent presentation of a probe item would affect the speed with which participants could reject that item. Experiments 1, 2 and 3 contrasted short-term memory judgments, which require temporal information, with semantic and perceptual judgments, for which temporal information is irrelevant. In Experiments 4 and 5, task-irrelevant information (perceptual similarity) was manipulated within the recent probes task. We found that interference from past items affected short-term memory (STM) task performance but did not affect performance in semantic or perceptual judgment tasks. Conversely, similarity along a nominally-irrelevant perceptual dimension did not affect the magnitude of interference in STM tasks. Results are consistent with the view that items in STM are represented by noisy codes consisting of multiple dimensions, and that interference occurs when items are similar to each other and thus compete along the dimensions relevant to target selection. PMID:23297049

Escaping the recent past: which stimulus dimensions influence proactive interference?

PubMed

Craig, Kimberly S; Berman, Marc G; Jonides, John; Lustig, Cindy

2013-07-01

Proactive interference occurs when information from the past disrupts current processing and is a major source of confusion and errors in short-term memory (STM; Wickens, Born, & Allen, Journal of Verbal Learning and Verbal Behavior, 2:440-445, 1963). The present investigation examines potential boundary conditions for interference, testing the hypothesis that potential competitors must be similar along task-relevant dimensions to influence proactive interference effects. We manipulated both the type of task being completed (Experiments 1, 2, and 3) and dimensions of similarity irrelevant to the current task (Experiments 4 and 5) to determine how the recent presentation of a probe item would affect the speed with which participants could reject that item. Experiments 1, 2, and 3 contrasted STM judgments, which require temporal information, with semantic and perceptual judgments, for which temporal information is irrelevant. In Experiments 4 and 5, task-irrelevant information (perceptual similarity) was manipulated within the recent probes task. We found that interference from past items affected STM task performance but did not affect performance in semantic or perceptual judgment tasks. Conversely, similarity along a nominally irrelevant perceptual dimension did not affect the magnitude of interference in STM tasks. Results are consistent with the view that items in STM are represented by noisy codes consisting of multiple dimensions and that interference occurs when items are similar to each other and, thus, compete along the dimensions relevant to target selection.

Positive Affect and Pain: Mediators of the Within-Day Relation Linking Sleep Quality to Activity Interference in Fibromyalgia

PubMed Central

Kothari, Dhwani J.; Davis, Mary C.; Yeung, Ellen W.; Tennen, Howard A.

2017-01-01

Fibromyalgia (FM) is a chronic pain condition often resulting in functional impairments. Nonrestorative sleep is a prominent symptom of FM that is related to disability, but the day-to-day mechanisms relating the prior night’s sleep quality to next day reports of disability have not been examined. The current study examined the within-day relations among early-morning reports of sleep quality last night, late-morning reports of pain and positive and negative affect, and end-of-day reports of activity interference. Specifically, we tested whether pain, positive affect, and negative affect mediated the association between sleep quality and subsequent activity interference. Data were drawn from electronic diary reports, collected from 220 FM patients for 21 consecutive days. The direct and mediated effects at the within-person level were estimated with Multilevel Structural Equation Modeling. Results showed that pain and positive affect mediated the relation between sleep quality and activity interference. Early-morning reports of poor sleep quality last night predicted elevated levels of pain and lower levels of positive affect at late-morning, which, in turn, predicted elevated end-of-day activity interference. Of note, positive affect was a stronger mediator than pain, and negative affect was not a significant mediator. In summary, the findings identify two parallel mechanisms, pain and positive affect, through which the prior night’s sleep quality predicts disability the next day in FM patients. Further, results highlight the potential utility of boosting positive affect following a poor night’s sleep as one means of preserving daily function in FM. PMID:25679472

Enhanced susceptibility of cancer cells to oncolytic rhabdo-virotherapy by expression of Nodamura virus protein B2 as a suppressor of RNA interference.

PubMed

Bastin, Donald; Aitken, Amelia S; Pelin, Adrian; Pikor, Larissa A; Crupi, Mathieu J F; Huh, Michael S; Bourgeois-Daigneault, Marie-Claude; Bell, John C; Ilkow, Carolina S

2018-06-19

Antiviral responses are barriers that must be overcome for efficacy of oncolytic virotherapy. In mammalian cells, antiviral responses involve the interferon pathway, a protein-signaling cascade that alerts the immune system and limits virus propagation. Tumour-specific defects in interferon signaling enhance viral infection and responses to oncolytic virotherapy, but many human cancers are still refractory to oncolytic viruses. Given that invertebrates, fungi and plants rely on RNA interference pathways for antiviral protection, we investigated the potential involvement of this alternative antiviral mechanism in cancer cells. Here, we detected viral genome-derived small RNAs, indicative of RNAi-mediated antiviral responses, in human cancer cells. As viruses may encode suppressors of the RNA interference pathways, we engineered an oncolytic vesicular stomatitis virus variant to encode the Nodamura virus protein B2, a known inhibitor of RNAi-mediated immune responses. B2-expressing oncolytic virus showed enhanced viral replication and cytotoxicity, impaired viral genome cleavage and altered microRNA processing in cancer cells. Our data establish the improved therapeutic potential of our novel virus which targets the RNAi-mediated antiviral defense of cancer cells.

Asian citrus psyllid RNAi pathway - RNAi evidence

USDA-ARS?s Scientific Manuscript database

In silico analyses of the draft genome of Diaphorina citri, the Asian citrus psyllid, for genes within the Ribonucleic acid interference(RNAi), pathway was successful. The psyllid is the vector of the plant-infecting bacterium, Candidatus Liberibacter asiaticus (CLas), which is linked to citrus gree...

High resolution Chromatin Immunoprecipitation (ChIP) sequencing reveals novel bindings targets and prognostic role for SOX11 in Mantle cell lymphoma

PubMed Central

Kuo, Pei-Yu; Leshchenko, Violetta V.; Fazzari, Melissa J.; Perumal, Deepak; Gellen, Tobias; He, Tianfang; Iqbal, Javeed; Baumgartner-Wennerholm, Stefanie; Nygren, Lina; Zhang, Fan; Zhang, Weijia; Suh, K. Stephen; Goy, Andre; Yang, David T.; Chan, Wing-Chung; Kahl, Brad S.; Verma, Amit K.; Gascoyne, Randy D.; Kimby, Eva; Sander, Birgitta; Ye, B. Hilda; Melnick, Ari M.; Parekh, Samir

2015-01-01

SOX11 (Sex determining region Y-box 11) expression is specific for MCL as compared to other Non-Hodgkin's lymphomas. However, the function and direct binding targets of SOX11 in MCL are largely unknown. We used high-resolution ChIP-Seq to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11 target genes. qCHIP and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency (BCCA). Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11 target genes may help explain the impact of SOX11 expression on patient outcomes. PMID:24681958

RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis

PubMed Central

Mooney, Claire M.; Jimenez-Mateos, Eva M.; Engel, Tobias; Mooney, Catherine; Diviney, Mairead; Venø, Morten T.; Kjems, Jørgen; Farrell, Michael A.; O’Brien, Donncha F.; Delanty, Norman; Henshall, David C.

2017-01-01

The nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice. Status epilepticus led to increased protein levels of Up-frameshift suppressor 1 homolog (Upf1) within the mouse hippocampus. Upf1 protein levels were also higher in resected hippocampus from patients with intractable temporal lobe epilepsy. Immunoprecipitation of Upf1-bound RNA from the cytoplasmic and synaptosomal compartments followed by RNA sequencing identified unique populations of NMD-associated transcripts and altered levels after status epilepticus, including known substrates such as Arc as well as novel targets including Inhba and Npas4. Finally, long-term video-EEG recordings determined that pharmacologic interference in the NMD pathway after status epilepticus reduced the later occurrence of spontaneous seizures in mice. These findings suggest compartment-specific recruitment and differential loading of transcripts by NMD pathway components may contribute to the process of epileptogenesis. PMID:28128343

Pain patients' experiences of validation and invalidation from physicians before and after multimodal pain rehabilitation: Associations with pain, negative affectivity, and treatment outcome.

PubMed

Edlund, Sara M; Wurm, Matilda; Holländare, Fredrik; Linton, Steven J; Fruzzetti, Alan E; Tillfors, Maria

2017-10-01

Validating and invalidating responses play an important role in communication with pain patients, for example regarding emotion regulation and adherence to treatment. However, it is unclear how patients' perceptions of validation and invalidation relate to patient characteristics and treatment outcome. The aim of this study was to investigate the occurrence of subgroups based on pain patients' perceptions of validation and invalidation from their physicians. The stability of these perceptions and differences between subgroups regarding pain, pain interference, negative affectivity and treatment outcome were also explored. A total of 108 pain patients answered questionnaires regarding perceived validation and invalidation, pain severity, pain interference, and negative affectivity before and after pain rehabilitation treatment. Two cluster analyses using perceived validation and invalidation were performed, one on pre-scores and one on post-scores. The stability of patient perceptions from pre- to post-treatment was investigated, and clusters were compared on pain severity, pain interference, and negative affectivity. Finally, the connection between perceived validation and invalidation and treatment outcome was explored. Three clusters emerged both before and after treatment: (1) low validation and heightened invalidation, (2) moderate validation and invalidation, and (3) high validation and low invalidation. Perceptions of validation and invalidation were generally stable over time, although there were individuals whose perceptions changed. When compared to the other two clusters, the low validation/heightened invalidation cluster displayed significantly higher levels of pain interference and negative affectivity post-treatment but not pre-treatment. The whole sample significantly improved on pain interference and depression, but treatment outcome was independent of cluster. Unexpectedly, differences between clusters on pain interference and negative affectivity were only found post-treatment. This appeared to be due to the pre- and post-heightened invalidation clusters not containing the same individuals. Therefore, additional analyses were conducted to investigate the individuals who changed clusters. Results showed that patients scoring high on negative affectivity ended up in the heightened invalidation cluster post-treatment. Taken together, most patients felt understood when communicating with their rehabilitation physician. However, a smaller group of patients experienced the opposite: low levels of validation and heightened levels of invalidation. This group stood out as more problematic, reporting greater pain interference and negative affectivity when compared to the other groups after treatment. Patient perceptions were typically stable over time, but some individuals changed cluster, and these movements seemed to be related to negative affectivity and pain interference. These results do not support a connection between perceived validation and invalidation from physicians (meeting the patients pre- and post-treatment) and treatment outcome. Overall, our results suggest that there is a connection between negative affectivity and pain interference in the patients, and perceived validation and invalidation from the physicians. In clinical practice, it is important to pay attention to comorbid psychological problems and level of pain interference, since these factors may negatively influence effective communication. A focus on decreasing invalidating responses and/or increasing validating responses might be particularly important for patients with high levels of psychological problems and pain interference. Copyright © 2017. Published by Elsevier B.V.

Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.

PubMed

Gat-Viks, Irit; Chevrier, Nicolas; Wilentzik, Roni; Eisenhaure, Thomas; Raychowdhury, Raktima; Steuerman, Yael; Shalek, Alex K; Hacohen, Nir; Amit, Ido; Regev, Aviv

2013-04-01

Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.

Renal epithelial cells can release ATP by vesicular fusion

PubMed Central

Bjaelde, Randi G.; Arnadottir, Sigrid S.; Overgaard, Morten T.; Leipziger, Jens; Praetorius, Helle A.

2013-01-01

Renal epithelial cells have the ability to release nucleotides as paracrine factors. In the intercalated cells of the collecting duct, ATP is released by connexin30 (cx30), which is selectively expressed in this cell type. However, ATP is released by virtually all renal epithelia and the aim of the present study was to identify possible alternative nucleotide release pathways in a renal epithelial cell model. We used MDCK (type1) cells to screen for various potential ATP release pathways. In these cells, inhibition of the vesicular H+-ATPases (bafilomycin) reduced both the spontaneous and hypotonically (80%)-induced nucleotide release. Interference with vesicular fusion using N-ethylamide markedly reduced the spontaneous nucleotide release, as did interference with trafficking from the endoplasmic reticulum to the Golgi apparatus (brefeldin A1) and vesicular transport (nocodazole). These findings were substantiated using a siRNA directed against SNAP-23, which significantly reduced spontaneous ATP release. Inhibition of pannexin and connexins did not affect the spontaneous ATP release in this cell type, which consists of ~90% principal cells. TIRF-microscopy of either fluorescently-labeled ATP (MANT-ATP) or quinacrine-loaded vesicles, revealed that spontaneous release of single vesicles could be promoted by either hypoosmolality (50%) or ionomycin. This vesicular release decreased the overall cellular fluorescence by 5.8 and 7.6% respectively. In summary, this study supports the notion that spontaneous and induced ATP release can occur via exocytosis in renal epithelial cells. PMID:24065923

Molecular interactions and immune responses between Maize fine streak virus and the leafhopper vector Graminella nigrifrons through differential expression and RNA interference.

PubMed

Chen, Y; Redinbaugh, M G; Michel, A P

2015-06-01

Graminella nigrifrons is the only known vector for Maize fine streak virus (MFSV). In this study, we used real-time quantitative PCR to compare the expression profiles of transcripts that putatively function in the insect immune response: four peptidoglycan recognition proteins (PGRP-SB1, -SD, -LC and LB), Toll, spaetzle, defensin, Dicer-2 (Dcr-2), Argonaut-2 (Ago-2) and Arsenic resistance protein 2 (Ars-2). Except for PGRP-LB and defensin, transcripts involved in humoral pathways were significantly suppressed in G. nigrifrons fed on MFSV-infected maize. The abundance of three RNA interference (RNAi) pathway transcripts (Dcr-2, Ago-2, Ars-2) was significantly lower in nontransmitting relative to transmitting G. nigrifrons. Injection with double-stranded RNA (dsRNA) encoding segments of the PGRP-LC and Dcr-2 transcripts effectively reduced transcript levels by 90 and 75% over 14 and 22 days, respectively. MFSV acquisition and transmission were not significantly affected by injection of either dsRNA. Knock-down of PGRP-LC resulted in significant mortality (greater than 90%) at 27 days postinjection, and resulted in more abnormal moults relative to those injected with Dcr-2 or control dsRNA. The use of RNAi to silence G. nigrifrons transcripts will facilitate the study of gene function and pathogen transmission, and may provide approaches for developing novel targets of RNAi-based pest control. © 2015 The Royal Entomological Society.

Negative Affectivity, Role Stress, and Work-Family Conflict.

ERIC Educational Resources Information Center

Stoeva, Albena Z.; Chiu, Randy K.; Greenhaus, Jeffrey H.

2002-01-01

Measures of job and family stress and negative affectivity were completed by 148 (of 400) Hong Kong civil service employees. Persons with high negative affectivity experience more work and family stress. Job stress was associated with extensive interference of work with family, and family stress with extensive interference of family with work.…

Tissue Specific and Hormonal Regulation of Gene Expression

DTIC Science & Technology

1997-08-01

interference assays were performed. These assays identify DNA bases that, when modified, interfere with the binding of the nuclear factor to the hCRH promoter...thymidine residues. The DNA bases that when modified affected the binding of the protein are noted with arrows, and their location in the hCRH...indicated. B. Methylation interference. The fragments were partially methylated using dimethyl sulfate. The DNA bases that when modified affected the

Pathogen and Pest Responses Are Altered Due to RNAi-Mediated Knockdown of GLYCOALKALOID METABOLISM 4 in Solanum tuberosum.

PubMed

Paudel, Jamuna Risal; Davidson, Charlotte; Song, Jun; Maxim, Itkin; Aharoni, Asaph; Tai, Helen H

2017-11-01

Steroidal glycoalkaloids (SGAs) are major secondary metabolites constitutively produced in cultivated potato Solanum tuberosum, and α-solanine and α-chaconine are the most abundant SGAs. SGAs are toxic to humans at high levels but their role in plant protection against pests and pathogens is yet to be established. In this study, levels of SGAs in potato were reduced by RNA interference (RNAi)-mediated silencing of GLYCOALKALOID METABOLISM 4 (GAME4)-a gene encoding cytochrome P450, involved in an oxidation step in the conversion of cholesterol to SGA aglycones. Two GAME4 RNAi lines, T8 and T9, were used to investigate the effects of manipulation of the SGA biosynthetic pathway in potato. Growth and development of an insect pest, Colorado potato beetle (CPB), were affected in these lines. While no effect on CPB leaf consumption or weight gain was observed, early instar larval death and accelerated development of the insect was found while feeding on leaves of GAME4 RNAi lines. Modulation of SGA biosynthetic pathway in GAME4 RNAi plants was associated with a larger alteration to the metabolite profile, including increased levels of one or both the steroidal saponins or phytoecdysteroids, which could affect insect mortality as well as development time. Colonization by Verticillium dahliae on GAME4 RNAi plants was also tested. There were increased pathogen levels in the T8 GAME4 RNAi line but not in the T9. Metabolite differences between T8 and T9 were found and may have contributed to differences in V. dahliae infection. Drought responses created by osmotic stress were not affected by modulation of SGA biosynthetic pathway in potato.

Contribution of CoA ligases to benzenoid biosynthesis in petunia flowers.

PubMed

Klempien, Antje; Kaminaga, Yasuhisa; Qualley, Anthony; Nagegowda, Dinesh A; Widhalm, Joshua R; Orlova, Irina; Shasany, Ajit Kumar; Taguchi, Goro; Kish, Christine M; Cooper, Bruce R; D'Auria, John C; Rhodes, David; Pichersky, Eran; Dudareva, Natalia

2012-05-01

Biosynthesis of benzoic acid from Phe requires shortening of the side chain by two carbons, which can occur via the β-oxidative or nonoxidative pathways. The first step in the β-oxidative pathway is cinnamoyl-CoA formation, likely catalyzed by a member of the 4-coumarate:CoA ligase (4CL) family that converts a range of trans-cinnamic acid derivatives into the corresponding CoA thioesters. Using a functional genomics approach, we identified two potential CoA-ligases from petunia (Petunia hybrida) petal-specific cDNA libraries. The cognate proteins share only 25% amino acid identity and are highly expressed in petunia corollas. Biochemical characterization of the recombinant proteins revealed that one of these proteins (Ph-4CL1) has broad substrate specificity and represents a bona fide 4CL, whereas the other is a cinnamate:CoA ligase (Ph-CNL). RNA interference suppression of Ph-4CL1 did not affect the petunia benzenoid scent profile, whereas downregulation of Ph-CNL resulted in a decrease in emission of benzylbenzoate, phenylethylbenzoate, and methylbenzoate. Green fluorescent protein localization studies revealed that the Ph-4CL1 protein is localized in the cytosol, whereas Ph-CNL is in peroxisomes. Our results indicate that subcellular compartmentalization of enzymes affects their involvement in the benzenoid network and provide evidence that cinnamoyl-CoA formation by Ph-CNL in the peroxisomes is the committed step in the β-oxidative pathway.

Contribution of CoA Ligases to Benzenoid Biosynthesis in Petunia Flowers[W

PubMed Central

Klempien, Antje; Kaminaga, Yasuhisa; Qualley, Anthony; Nagegowda, Dinesh A.; Widhalm, Joshua R.; Orlova, Irina; Shasany, Ajit Kumar; Taguchi, Goro; Kish, Christine M.; Cooper, Bruce R.; D’Auria, John C.; Rhodes, David; Pichersky, Eran; Dudareva, Natalia

2012-01-01

Biosynthesis of benzoic acid from Phe requires shortening of the side chain by two carbons, which can occur via the β-oxidative or nonoxidative pathways. The first step in the β-oxidative pathway is cinnamoyl-CoA formation, likely catalyzed by a member of the 4-coumarate:CoA ligase (4CL) family that converts a range of trans-cinnamic acid derivatives into the corresponding CoA thioesters. Using a functional genomics approach, we identified two potential CoA-ligases from petunia (Petunia hybrida) petal-specific cDNA libraries. The cognate proteins share only 25% amino acid identity and are highly expressed in petunia corollas. Biochemical characterization of the recombinant proteins revealed that one of these proteins (Ph-4CL1) has broad substrate specificity and represents a bona fide 4CL, whereas the other is a cinnamate:CoA ligase (Ph-CNL). RNA interference suppression of Ph-4CL1 did not affect the petunia benzenoid scent profile, whereas downregulation of Ph-CNL resulted in a decrease in emission of benzylbenzoate, phenylethylbenzoate, and methylbenzoate. Green fluorescent protein localization studies revealed that the Ph-4CL1 protein is localized in the cytosol, whereas Ph-CNL is in peroxisomes. Our results indicate that subcellular compartmentalization of enzymes affects their involvement in the benzenoid network and provide evidence that cinnamoyl-CoA formation by Ph-CNL in the peroxisomes is the committed step in the β-oxidative pathway. PMID:22649270

Apicobasal domain identities of expanding tubular membranes depend on glycosphingolipid biosynthesis.

PubMed

Zhang, Hongjie; Abraham, Nessy; Khan, Liakot A; Hall, David H; Fleming, John T; Göbel, Verena

2011-09-18

Metazoan internal organs are assembled from polarized tubular epithelia that must set aside an apical membrane domain as a lumenal surface. In a global Caenorhabditis elegans tubulogenesis screen, interference with several distinct fatty-acid-biosynthetic enzymes transformed a contiguous central intestinal lumen into multiple ectopic lumens. We show that multiple-lumen formation is caused by apicobasal polarity conversion, and demonstrate that in situ modulation of lipid biosynthesis is sufficient to reversibly switch apical domain identities on growing membranes of single post-mitotic cells, shifting lumen positions. Follow-on targeted lipid-biosynthesis pathway screens and functional genetic assays were designed to identify a putative single causative lipid species. They demonstrate that fatty-acid biosynthesis affects polarity through sphingolipid synthesis, and reveal ceramide glucosyltransferases (CGTs) as end-point biosynthetic enzymes in this pathway. Our findings identify glycosphingolipids, CGT products and obligate membrane lipids, as critical determinants of in vivo polarity and indicate that they sort new components to the expanding apical membrane.

Apicobasal domain identities of expanding tubular membranes depend on glycosphingolipid biosynthesis

PubMed Central

Zhang, Hongjie; Abraham, Nessy; Khan, Liakot A.; Hall, David H.; Fleming, John T.; Gobel, Verena

2011-01-01

Metazoan internal organs are assembled from polarized tubular epithelia that must set aside an apical membrane domain as a lumenal surface. In a global Caenorhabditis elegans tubulogenesis screen, interference with several distinct fatty-acid-biosynthetic enzymes transformed a contiguous central intestinal lumen into multiple ectopic lumens. We show that multiple-lumen formation is caused by apicobasal polarity conversion, and demonstrate that in situ modulation of lipid biosynthesis is sufficient to reversibly switch apical domain identities on growing membranes of single postmitotic cells, shifting lumen positions. Follow-on targeted lipid-biosynthesis pathway screens and functional genetic assays were designed to identify a putative single causative lipid species. They demonstrate that fatty-acid biosynthesis affects polarity via sphingolipid synthesis, and reveal ceramideglucosyltransferases (CGTs) as endpoint biosynthetic enzymes in this pathway. Our findings identify glycosphingolipids (GSLs), CGT products and obligate membrane lipids, as critical determinants of in vivo polarity and suggest they sort new components to the expanding apical membrane. PMID:21926990

Clathrin light chains are required for the gyrating-clathrin recycling pathway and thereby promote cell migration.

PubMed

Majeed, Sophia R; Vasudevan, Lavanya; Chen, Chih-Ying; Luo, Yi; Torres, Jorge A; Evans, Timothy M; Sharkey, Andrew; Foraker, Amy B; Wong, Nicole M L; Esk, Christopher; Freeman, Theresa A; Moffett, Ashley; Keen, James H; Brodsky, Frances M

2014-05-23

The clathrin light chain (CLC) subunits participate in several membrane traffic pathways involving both clathrin and actin, through binding the actin-organizing huntingtin-interacting proteins (Hip). However, CLCs are dispensable for clathrin-mediated endocytosis of many cargoes. Here we observe that CLC depletion affects cell migration through Hip binding and reduces surface expression of β1-integrin by interference with recycling following normal endocytosis of inactive β1-integrin. CLC depletion and expression of a modified CLC also inhibit the appearance of gyrating (G)-clathrin structures, known mediators of rapid recycling of transferrin receptor from endosomes. Expression of the modified CLC reduces β1-integrin and transferrin receptor recycling, as well as cell migration, implicating G-clathrin in these processes. Supporting a physiological role for CLC in migration, the CLCb isoform of CLC is upregulated in migratory human trophoblast cells during uterine invasion. Together, these studies establish CLCs as mediating clathrin-actin interactions needed for recycling by G-clathrin during migration.

A Data Analysis Pipeline Accounting for Artifacts in Tox21 Quantitative High-Throughput Screening Assays

PubMed Central

Hsieh, Jui-Hua; Sedykh, Alexander; Huang, Ruili; Xia, Menghang; Tice, Raymond R.

2015-01-01

A main goal of the U.S. Tox21 program is to profile a 10K-compound library for activity against a panel of stress-related and nuclear receptor signaling pathway assays using a quantitative high-throughput screening (qHTS) approach. However, assay artifacts, including nonreproducible signals and assay interference (e.g., autofluorescence), complicate compound activity interpretation. To address these issues, we have developed a data analysis pipeline that includes an updated signal noise–filtering/curation protocol and an assay interference flagging system. To better characterize various types of signals, we adopted a weighted version of the area under the curve (wAUC) to quantify the amount of activity across the tested concentration range in combination with the assay-dependent point-of-departure (POD) concentration. Based on the 32 Tox21 qHTS assays analyzed, we demonstrate that signal profiling using wAUC affords the best reproducibility (Pearson's r = 0.91) in comparison with the POD (0.82) only or the AC50 (i.e., half-maximal activity concentration, 0.81). Among the activity artifacts characterized, cytotoxicity is the major confounding factor; on average, about 8% of Tox21 compounds are affected, whereas autofluorescence affects less than 0.5%. To facilitate data evaluation, we implemented two graphical user interface applications, allowing users to rapidly evaluate the in vitro activity of Tox21 compounds. PMID:25904095

A Data Analysis Pipeline Accounting for Artifacts in Tox21 Quantitative High-Throughput Screening Assays.

PubMed

Hsieh, Jui-Hua; Sedykh, Alexander; Huang, Ruili; Xia, Menghang; Tice, Raymond R

2015-08-01

A main goal of the U.S. Tox21 program is to profile a 10K-compound library for activity against a panel of stress-related and nuclear receptor signaling pathway assays using a quantitative high-throughput screening (qHTS) approach. However, assay artifacts, including nonreproducible signals and assay interference (e.g., autofluorescence), complicate compound activity interpretation. To address these issues, we have developed a data analysis pipeline that includes an updated signal noise-filtering/curation protocol and an assay interference flagging system. To better characterize various types of signals, we adopted a weighted version of the area under the curve (wAUC) to quantify the amount of activity across the tested concentration range in combination with the assay-dependent point-of-departure (POD) concentration. Based on the 32 Tox21 qHTS assays analyzed, we demonstrate that signal profiling using wAUC affords the best reproducibility (Pearson's r = 0.91) in comparison with the POD (0.82) only or the AC(50) (i.e., half-maximal activity concentration, 0.81). Among the activity artifacts characterized, cytotoxicity is the major confounding factor; on average, about 8% of Tox21 compounds are affected, whereas autofluorescence affects less than 0.5%. To facilitate data evaluation, we implemented two graphical user interface applications, allowing users to rapidly evaluate the in vitro activity of Tox21 compounds. © 2015 Society for Laboratory Automation and Screening.

Interference of Apoptosis by Hepatitis B Virus

PubMed Central

2017-01-01

Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective. PMID:28820498

Easy regulation of metabolic flux in Escherichia coli using an endogenous type I-E CRISPR-Cas system.

PubMed

Chang, Yizhao; Su, Tianyuan; Qi, Qingsheng; Liang, Quanfeng

2016-11-15

Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a recently developed powerful tool for gene regulation. In Escherichia coli, the type I CRISPR system expressed endogenously shall be easy for internal regulation without causing metabolic burden in compared with the widely used type II system, which expressed dCas9 as an additional plasmid. By knocking out cas3 and activating the expression of CRISPR-associated complex for antiviral defense (Cascade), we constructed a native CRISPRi system in E. coli. Downregulation of the target gene from 6 to 82% was demonstrated using green fluorescent protein. Regulation of the citrate synthase gene (gltA) in the TCA cycle affected host metabolism. The effect of metabolic flux regulation was demonstrated by the poly-3-hydroxbutyrate (PHB) accumulation in vivo. By regulating native gltA in E. coli using an engineered endogenous type I-E CRISPR system, we redirected metabolic flux from the central metabolic pathway to the PHB synthesis pathway. This study demonstrated that the endogenous type I-E CRISPR-Cas system is an easy and effective method for regulating internal metabolic pathways, which is useful for product synthesis.

Global effects of the CSR-1 RNA interference pathway on the transcriptional landscape.

PubMed

Cecere, Germano; Hoersch, Sebastian; O'Keeffe, Sean; Sachidanandam, Ravi; Grishok, Alla

2014-04-01

Argonaute proteins and their small RNA cofactors short interfering RNAs are known to inhibit gene expression at the transcriptional and post-transcriptional levels. In Caenorhabditis elegans, the Argonaute CSR-1 binds thousands of endogenous siRNAs (endo-siRNAs) that are antisense to germline transcripts. However, its role in gene expression regulation remains controversial. Here we used genome-wide profiling of nascent RNA transcripts and found that the CSR-1 RNA interference pathway promoted sense-oriented RNA polymerase II transcription. Moreover, a loss of CSR-1 function resulted in global increase in antisense transcription and ectopic transcription of silent chromatin domains, which led to reduced chromatin incorporation of centromere-specific histone H3. On the basis of these findings, we propose that the CSR-1 pathway helps maintain the directionality of active transcription, thereby propagating the distinction between transcriptionally active and silent genomic regions.

Recent advances in therapeutic recruitment of mammalian RNAi and bacterial CRISPR-Cas DNA interference pathways as emerging antiviral strategies.

PubMed

Chin, Wei-Xin; Ang, Swee Kim; Chu, Justin Jang Hann

2017-01-01

In invertebrate eukaryotes and prokaryotes, respectively, the RNAi and clustered regularly interspaced short palindromic repeats-CRISPR-associated (CRISPR-Cas) pathways are highly specific and efficient RNA and DNA interference systems, and are well characterised as potent antiviral systems. It has become possible to recruit or reconstitute these pathways in mammalian cells, where they can be directed against desired host or viral targets. The RNAi and CRISPR-Cas systems can therefore yield ideal antiviral therapeutics, capable of specific and efficient viral inhibition with minimal off-target effects, but development of such therapeutics can be slow. This review covers recent advances made towards developing RNAi or CRISPR-Cas strategies for clinical use. These studies address the delivery, toxicity or target design issues that typically plague the in vivo or clinical use of these technologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

PKR is a novel functional direct player that coordinates skeletal muscle differentiation via p38MAPK/AKT pathways.

PubMed

Alisi, A; Spaziani, A; Anticoli, S; Ghidinelli, M; Balsano, C

2008-03-01

Myogenic differentiation is a highly orchestrated multistep process controlled by extracellular growth factors that modulate largely unknown signals into the cell affecting the muscle-transcription program. P38MAPK-dependent signalling, as well as PI3K/Akt pathway, has a key role in the control of muscle gene expression at different stages during the myogenic process. P38MAPK affects the activities of transcription factors, such as MyoD and myogenin, and contributes, together with PI3K/Akt pathway, to control the early and late steps of myogenic differentiation. The aim of our work was to better define the role of PKR, a dsRNA-activated protein kinase, as potential component in the differentiation program of C2C12 murine myogenic cells and to correlate its activity with p38MAPK and PI3K/Akt myogenic regulatory pathways. Here, we demonstrate that PKR is an essential component of the muscle development machinery and forms a functional complex with p38MAPK and/or Akt, contributing to muscle differentiation of committed myogenic cells in vitro. Inhibition of endogenous PKR activity by a specific (si)RNA and a PKR dominant-negative interferes with the myogenic program of C2C12 cells, causing a delay in activation of myogenic specific genes and inducing the formation of thinner myofibers. In addition, the construction of three PKR mutants allowed us to demonstrate that both N and C-terminal regions of PKR are critical for the interaction with p38MAPK and Akt. The novel discovered complex permits PKR to timely regulate the inhibition/activation of p38MAPK and Akt, controlling in this way the different steps characterizing skeletal muscle differentiation.

Apparent hyperthyroidism caused by biotin-like interference from IgM anti-streptavidin antibodies.

PubMed

Lam, Leo; Bagg, Warwick; Smith, Geoff; Chiu, Weldon; Middleditch, Martin James; Lim, Julie Ching-Hsia; Kyle, Campbell Vance

2018-05-29

Exclusion of analytical interference is important when there is discrepancy between clinical and laboratory findings. However, interferences on immunoassays are often mistaken as isolated laboratory artefacts. We characterized and report the mechanism of a rare cause of interference in two patients that caused erroneous thyroid function tests, and also affects many other biotin dependent immunoassays. Patient 1 was a 77 y female with worsening fatigue while taking carbimazole over several years. Her thyroid function tests however, were not suggestive of hypothyroidism. Patient 2 was a 25 y female also prescribed carbimazole for apparent primary hyperthyroidism. Despite an elevated FT4, the lowest TSH on record was 0.17mIU/L. In both cases, thyroid function tests performed by an alternative method were markedly different. Further characterization of both patients' serum demonstrated analytical interference on many immunoassays using the biotin-streptavidin interaction. Sandwich assays (e.g. TSH, FSH, TNT, beta-HCG) were falsely low, while competitive assays (e.g. FT4, FT3, TBII) were falsely high. Pre-incubation of serum with streptavidin microparticles removed the analytical interference, initially suggesting the cause of interference was biotin, however, neither patient had been taking biotin. Instead, a ~100kDa IgM immunoglobulin with high affinity to streptavidin was isolated from each patient's serum. The findings confirm IgM anti-streptavidin antibodies as the cause of analytical interference. We describe two patients with apparent hyperthyroidism as a result of analytical interference caused by IgM anti-streptavidin antibodies. Analytical interference identified on one immunoassay should raise the possibility of other affected results. Characterization of interference may help to identify other potentially affected immunoassays. In the case of anti-streptavidin antibodies, the pattern of interference mimics that due to biotin ingestion; however, the degree of interference varies between individual assays and between patients.

Topoisomerase II Mediates Meiotic Crossover Interference

PubMed Central

Zhang, Liangran; Wang, Shunxin; Yin, Shen; Hong, Soogil; Kim, Keun P.; Kleckner, Nancy

2014-01-01

Summary Spatial patterning is a ubiquitous feature of biological systems. Meiotic crossovers provide an interesting example, defined by the classical phenomenon of crossover interference. Here, analysis of crossover patterns in budding yeast identifies a molecular pathway for interference. Topoisomerase II (Topo II) plays a central role, thus identifying a new function for this critical molecule. SUMOylation [of TopoII and axis component Red1] and ubiquitin-mediated removal of SUMOylated proteins are also required. These and other findings support the hypothesis that crossover interference involves accumulation, relief and redistribution of mechanical stress along the protein/DNA meshwork of meiotic chromosome axes, with TopoII required to adjust spatial relationships among DNA segments. PMID:25043020

The Fano-type transmission and field enhancement in heterostructures composed of epsilon-near-zero materials and truncated photonic crystals

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

Zhang, Zhi-fang; Jiang, Hai-tao, E-mail: davies2000@163.com, E-mail: jiang-haitao@tongji.edu.cn; Li, Yun-hui

2013-11-11

The Fano-type interference effect is studied in the heterostructure composed of an epsilon-near-zero (ENZ) material and a truncated photonic crystal for transverse magnetic polarized light. In the Fano-type interference effect, the ENZ material provides narrow reflection pathway and the photonic crystal provides broadband reflection pathway. The boundary condition across the ENZ interface and the confinement effect provided by the photonic crystal can enhance the electric fields in the ENZ material greatly. The field enhancements, together with the asymmetric property of Fano-type spectrum, possess potential applications for significantly lowering the threshold of nonlinear processes such as optical switching and bistability.

Catheter ablation as a treatment of atrioventricular block.

PubMed

Tuohy, Stephen; Saliba, Walid; Pai, Manjunath; Tchou, Patrick

2018-01-01

Symptomatic second-degree atrioventricular (AV) block is typically treated by implantation of a pacemaker. An otherwise healthy AV conduction system can nevertheless develop AV block due to interference from junctional extrasystoles. When present with a high burden, these can produce debilitating symptoms from AV block despite an underlying normal AV node and His-Purkinje system properties. The purpose of this study was to describe a catheter ablation approach for alleviating symptomatic AV block due to a ventricular nodal pathway interfering with AV conduction. Common clinical monitoring techniques such as Holter and event recorders were used. Standard electrophysiological study techniques using multipolar recording and ablation catheters were utilized during procedures. A 55-year-old woman presented with highly symptomatic, high-burden second-degree AV block due to concealed and manifest junctional premature beats. Electrophysiological characteristics indicated interference of AV conduction due to a concealed ventricular nodal pathway as the cause of the AV block. The patient's AV nodal and His-Purkinje system conduction characteristics were otherwise normal. Radiofrequency catheter ablation of the pathway was successful in restoring normal AV conduction and eliminating her clinical symptoms. Pathways inserting into the AV junction can interfere with AV conduction. When present at a high burden, this type of AV block can be highly symptomatic. Catheter ablation techniques can be used to alleviate this type of AV block and restore normal AV conduction. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

mSEL-1L deficiency affects vasculogenesis and neural stem cell lineage commitment.

PubMed

Cardano, Marina; Diaferia, Giuseppe R; Conti, Luciano; Baronchelli, Simona; Sessa, Alessandro; Broccoli, Vania; Barbieri, Andrea; De Blasio, Pasquale; Biunno, Ida

2018-04-01

mSEL-1L is a highly conserved ER-resident type I protein, involved in the degradation of misfolded peptides through the ubiquitin-proteasome system (UPS), a pathway known to control the plasticity of the vascular smooth muscle cells (VSMC) phenotype and survival. In this article, we demonstrate that mSEL-1L deficiency interferes with the murine embryonic vascular network, showing particular irregularities in the intracranic and intersomitic neurovascular units and in the cerebral capillary microcirculation. During murine embryogenesis, mSEL-1L is expressed in cerebral areas known to harbor progenitor neural cells, while in the adult brain the protein is specifically restricted to the stem cell niches, co-localizing with Sox2 and Nestin. Null mice are characterized by important defects in the development of telenchephalic regions, revealing conspicuous aberration in neural stem cell lineage commitment. Moreover, mSEL-1L depletion in vitro and in vivo appears to affect the harmonic differentiation of the NSCs, by negatively influencing the corticogenesis processes. Overall, the data presented suggests that the drastic phenotypic characteristics exhibited in mSEL-1L null mice can, in part, be explained by the negative influence it plays on Notch1 signaling pathway. © 2017 Wiley Periodicals, Inc.

Movement interference in autism-spectrum disorder.

PubMed

Gowen, E; Stanley, J; Miall, R C

2008-03-07

Movement interference occurs when concurrently observing and executing incompatible actions and is believed to be due to co-activation of conflicting populations of mirror neurons. It has also been suggested that mirror neurons contribute towards the imitation of observed actions. However, the exact neural substrate of imitation may depend on task demands: a processing route for goal-directed meaningful actions may be distinct from one for non-goal-directed actions. A more controversial role proposed for these neurons is in theory of mind processing, along with the subsequent suggestion that impairment in the mirror neuron circuit can contribute to autism-spectrum disorder (ASD) where individuals have theory of mind deficits. We have therefore examined movement interference in nine ASD participants and nine matched controls while performing actions congruent and incongruent with observed meaningless arm movements. We hypothesised that if the mirror neuron system was impaired, reduced interference should be observed in the ASD group. However, control and ASD participants demonstrated an equivalent interference effect in an interpersonal condition, with greater movement variability in the incongruent compared to the congruent condition. A component of movement interference which is independent of congruency did differ between groups: ASD participants made generally more variable movements for the interpersonal task than for biological dot-motion task, while the reverse was true for the control participants. We interpret these results as evidence that the ASD participant group either rely to a greater extent on the goal-directed imitation pathway, supporting claims that they have a specific deficit of the non-goal-directed imitation pathway, or exhibit reduced visuomotor integration.

Release from Proactive Interference: Insufficiency of an Attentional Account

ERIC Educational Resources Information Center

MacLeod, Colin M.

1975-01-01

If an attentional cue affects retroactive interference, perhaps a similar mechanism underlies release from proactive interference. This study tested this hypothesis by inserting an attentional cue before the final trial in Wickens' paradigm. (Author/RK)

A new criterion to evaluate water vapor interference in protein secondary structural analysis by FTIR spectroscopy.

PubMed

Zou, Ye; Ma, Gang

2014-06-04

Second derivative and Fourier self-deconvolution (FSD) are two commonly used techniques to resolve the overlapped component peaks from the often featureless amide I band in Fourier transform infrared (FTIR) curve-fitting approach for protein secondary structural analysis. Yet, the reliability of these two techniques is greatly affected by the omnipresent water vapor in the atmosphere. Several criteria are currently in use as quality controls to ensure the protein absorption spectrum is negligibly affected by water vapor interference. In this study, through a second derivative study of liquid water, we first argue that the previously established criteria cannot guarantee a reliable evaluation of water vapor interference due to a phenomenon that we refer to as sample's absorbance-dependent water vapor interference. Then, through a comparative study of protein and liquid water, we show that a protein absorption spectrum can still be significantly affected by water vapor interference even though it satisfies the established criteria. At last, we propose to use the comparison between the second derivative spectra of protein and liquid water as a new criterion to better evaluate water vapor interference for more reliable second derivative and FSD treatments on the protein amide I band.

Stroop Color-Word Interference Test: Normative data for Spanish-speaking pediatric population.

PubMed

Rivera, D; Morlett-Paredes, A; Peñalver Guia, A I; Irías Escher, M J; Soto-Añari, M; Aguayo Arelis, A; Rute-Pérez, S; Rodríguez-Lorenzana, A; Rodríguez-Agudelo, Y; Albaladejo-Blázquez, N; García de la Cadena, C; Ibáñez-Alfonso, J A; Rodriguez-Irizarry, W; García-Guerrero, C E; Delgado-Mejía, I D; Padilla-López, A; Vergara-Moragues, E; Barrios Nevado, M D; Saracostti Schwartzman, M; Arango-Lasprilla, J C

2017-01-01

To generate normative data for the Stroop Word-Color Interference test in Spanish-speaking pediatric populations. The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the Stroop Word-Color Interference test as part of a larger neuropsychological battery. The Stroop Word, Stroop Color, Stroop Word-Color, and Stroop Interference scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. The final multiple linear regression models showed main effects for age on all scores, except on Stroop Interference for Guatemala, such that scores increased linearly as a function of age. Age2 affected Stroop Word scores for all countries, Stroop Color scores for Ecuador, Mexico, Peru, and Spain; Stroop Word-Color scores for Ecuador, Mexico, and Paraguay; and Stroop Interference scores for Cuba, Guatemala, and Spain. MLPE affected Stroop Word scores for Chile, Mexico, and Puerto Rico; Stroop Color scores for Mexico, Puerto Rico, and Spain; Stroop Word-Color scores for Ecuador, Guatemala, Mexico, Puerto Rico and Spain; and Stroop-Interference scores for Ecuador, Mexico, and Spain. Sex affected Stroop Word scores for Spain, Stroop Color scores for Mexico, and Stroop Interference for Honduras. This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate approach to interpret the Stroop Word-Color Interference test in pediatric populations.

The Influence of Postnatal Psychiatric Disorder on Child Development

PubMed Central

Stein, Alan; Lehtonen, Annukka; Harvey, Allison G.; Nicol-Harper, Rosie; Craske, Michelle

2009-01-01

There is considerable evidence that maternal postnatal psychiatric disorder has an adverse influence on infant development. In attempting to examine the pathways of intergenerational transmission, most research has concentrated on genetic factors or on maternal behaviours during mother-child interaction and attachment. However, researchers have largely ignored the possible role of maternal cognition underlying behaviour, especially the thought and attentional processes involved in psychiatric disorders. This paper argues that a particular form of maternal cognition, namely ‘preoccupation’, is one key, but under-recognised, mechanism in the transmission of psychiatric disturbance. We propose that preoccupation interferes with specific aspects of mental functioning, especially attention and responsivity to the environment. This impairs the mother's parenting capacities and adversely affects mother-child interaction and child development. PMID:19023230

Deep Brain Stimulation

PubMed Central

Lyketsos, Constantine G.; Pendergrass, Jo Cara; Lozano, Andres M.

2012-01-01

Recent studies have identified an association between memory deficits and defects of the integrated neuronal cortical areas known collectively as the default mode network. It is conceivable that the amyloid deposition or other molecular abnormalities seen in patients with Alzheimer’s disease may interfere with this network and disrupt neuronal circuits beyond the localized brain areas. Therefore, Alzheimer’s disease may be both a degenerative disease and a broader system-level disorder affecting integrated neuronal pathways involved in memory. In this paper, we describe the rationale and provide some evidence to support the study of deep brain stimulation of the hippocampal fornix as a novel treatment to improve neuronal circuitry within these integrated networks and thereby sustain memory function in early Alzheimer’s disease. PMID:23346514

Learning and memory deficits consequent to reduction of the fragile X mental retardation protein result from metabotropic glutamate receptor-mediated inhibition of cAMP signaling in Drosophila.

PubMed

Kanellopoulos, Alexandros K; Semelidou, Ourania; Kotini, Andriana G; Anezaki, Maria; Skoulakis, Efthimios M C

2012-09-19

Loss of the RNA-binding fragile X protein [fragile X mental retardation protein (FMRP)] results in a spectrum of cognitive deficits, the fragile X syndrome (FXS), while aging individuals with decreased protein levels present with a subset of these symptoms and tremor. The broad range of behavioral deficits likely reflects the ubiquitous distribution and multiple functions of the protein. FMRP loss is expected to affect multiple neuronal proteins and intracellular signaling pathways, whose identity and interactions are essential in understanding and ameliorating FXS symptoms. We used heterozygous mutants and targeted RNA interference-mediated abrogation in Drosophila to uncover molecular pathways affected by FMRP reduction. We present evidence that FMRP loss results in excess metabotropic glutamate receptor (mGluR) activity, attributable at least in part to elevation of the protein in affected neurons. Using high-resolution behavioral, genetic, and biochemical analyses, we present evidence that excess mGluR upon FMRP attenuation is linked to the cAMP decrement reported in patients and models, and underlies olfactory associative learning and memory deficits. Furthermore, our data indicate positive transcriptional regulation of the fly fmr1 gene by cAMP, via protein kinase A, likely through the transcription factor CREB. Because the human Fmr1 gene also contains CREB binding sites, the interaction of mGluR excess and cAMP signaling defects we present suggests novel combinatorial pharmaceutical approaches to symptom amelioration upon FMRP attenuation.

Plasmonic EIT-like switching in bright-dark-bright plasmon resonators.

PubMed

Chen, Junxue; Wang, Pei; Chen, Chuncong; Lu, Yonghua; Ming, Hai; Zhan, Qiwen

2011-03-28

In this paper we report the study of the electromagnetically induced transparency (EIT)-like transmission in the bright-dark-bright plasmon resonators. It is demonstrated that the interferences between the dark plasmons excited by two bright plasmon resonators can be controlled by the incident light polarization. The constructive interference strengthens the coupling between the bright and dark resonators, leading to a more prominent EIT-like transparency window of the metamaterial. In contrary, destructive interference suppresses the coupling between the bright and dark resonators, destroying the interference pathway that forms the EIT-like transmission. Based on this observation, the plasmonic EIT switching can be realized by changing the polarization of incident light. This phenomenon may find applications in optical switching and plasmon-based information processing.

Amorphous Silica Particles Relevant in Food Industry Influence Cellular Growth and Associated Signaling Pathways in Human Gastric Carcinoma Cells.

PubMed

Wittig, Anja; Gehrke, Helge; Del Favero, Giorgia; Fritz, Eva-Maria; Al-Rawi, Marco; Diabaté, Silvia; Weiss, Carsten; Sami, Haider; Ogris, Manfred; Marko, Doris

2017-01-13

Nanostructured silica particles are commonly used in biomedical and biotechnical fields, as well as, in cosmetics and food industry. Thus, their environmental and health impacts are of great interest and effects after oral uptake are only rarely investigated. In the present study, the toxicological effects of commercially available nano-scaled silica with a nominal primary diameter of 12 nm were investigated on the human gastric carcinoma cell line GXF251L. Besides the analysis of cytotoxic and proliferative effects and the comparison with effects of particles with a nominal primary diameter of 200 nm, emphasis was also given to their influence on the cellular epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPK) signaling pathways-both of them deeply involved in the regulation of cellular processes like cell cycle progression, differentiation or proliferation. The investigated silica nanoparticles (NPs) were found to stimulate cell proliferation as measured by microscopy and the sulforhodamine B assay. In accordance, the nuclear level of the proliferation marker Ki-67 was enhanced in a concentration-dependent manner. At high particle concentrations also necrosis was induced. Finally, silica NPs affected the EGFR and MAPK pathways at various levels dependent on concentration and time. However, classical activation of the EGFR, to be reflected by enhanced levels of phosphorylation, could be excluded as major trigger of the proliferative stimulus. After 45 min of incubation the level of phosphorylated EGFR did not increase, whereas enhanced levels of total EGFR protein were observed. These results indicate interference with the complex homeostasis of the EGFR protein, whereby up to 24 h no impact on the transcription level was detected. In addition, downstream on the level of the MAP kinases ERK1/2 short term incubation appeared to affect total protein levels without clear increase in phosphorylation. Depending on the concentration range, enhanced levels of ERK1/2 phosphorylation were only observed after 24 h of incubation. Taken together, the present study demonstrates the potential of the tested silica particles to enhance the growth of gastric carcinoma cells. Although interference with the EGFR/MAPK cascade is observed, additional mechanisms are likely to be involved in the onset of the proliferative stimulus.

Disruption of Akt kinase activation is important for immunosuppression induced by measles virus.

PubMed

Avota, E; Avots, A; Niewiesk, S; Kane, L P; Bommhardt, U; ter Meulen, V; Schneider-Schaulies, S

2001-06-01

Surface-contact-mediated signaling induced by the measles virus (MV) fusion and hemagglutinin glycoproteins is necessary and sufficient to induce T-cell unresponsiveness in vitro and in vivo. To define the intracellular pathways involved, we analyzed interleukin (IL)-2R signaling in primary human T cells and in Kit-225 cells. Unlike IL-2-dependent activation of JAK/STAT pathways, activation of Akt kinase was impaired after MV contact both in vitro and in vivo. MV interference with Akt activation was important for immunosuppression, as expression of a catalytically active Akt prevented negative signaling by the MV glycoproteins. Thus, we show here that MV exploits a novel strategy to interfere with T-cell activation during immunosuppression.

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation.

PubMed

Demuth, Ilja; Digweed, Martin; Concannon, Patrick

2004-11-11

DNA interstrand crosslinks (ICLs) are critical lesions for the mammalian cell since they affect both DNA strands and block transcription and replication. The repair of ICLs in the mammalian cell involves components of different repair pathways such as nucleotide-excision repair and the double-strand break/homologous recombination repair pathways. However, the mechanistic details of mammalian ICL repair have not been fully delineated. We describe here the complete coding sequence and the genomic organization of hSNM1B, one of at least three human homologs of the Saccharomyces cerevisiae PSO2 gene. Depletion of hSNM1B by RNA interference rendered cells hypersensitive to ICL-inducing agents. This requirement for hSNM1B in the cellular response to ICL has been hypothesized before but never experimentally verified. In addition, siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair. Monoubiquitination of FANCD2, a key step in the FANC/BRCA pathway, is not affected in hSNM1B-depleted HeLa cells, indicating that hSNM1B is probably not a part of the Fanconi anemia core complex. Nonetheless, similarities in the phenotype of hSNM1B-depleted cells and cultured cells from patients suffering from Fanconi anemia make hSNM1B a candidate for one of the as yet unidentified Fanconi anemia genes not involved in monoubiquitination of FANCD2.

Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans.

PubMed

Yang, H-C; Chen, T-L; Wu, Y-H; Cheng, K-P; Lin, Y-H; Cheng, M-L; Ho, H-Y; Lo, S J; Chiu, D T-Y

2013-05-02

Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively.

Emotion and sex of facial stimuli modulate conditional automaticity in behavioral and neuronal interference in healthy men.

PubMed

Kohn, Nils; Fernández, Guillén

2017-12-06

Our surrounding provides a host of sensory input, which we cannot fully process without streamlining and automatic processing. Levels of automaticity differ for different cognitive and affective processes. Situational and contextual interactions between cognitive and affective processes in turn influence the level of automaticity. Automaticity can be measured by interference in Stroop tasks. We applied an emotional version of the Stroop task to investigate how stress as a contextual factor influences the affective valence-dependent level of automaticity. 120 young, healthy men were investigated for behavioral and brain interference following a stress induction or control procedure in a counter-balanced cross-over-design. Although Stroop interference was always observed, sex and emotion of the face strongly modulated interference, which was larger for fearful and male faces. These effects suggest higher automaticity when processing happy and also female faces. Supporting behavioral patterns, brain data show lower interference related brain activity in executive control related regions in response to happy and female faces. In the absence of behavioral stress effects, congruent compared to incongruent trials (reverse interference) showed little to no deactivation under stress in response to happy female and fearful male trials. These congruency effects are potentially based on altered context- stress-related facial processing that interact with sex-emotion stereotypes. Results indicate that sex and facial emotion modulate Stroop interference in brain and behavior. These effects can be explained by altered response difficulty as a consequence of the contextual and stereotype related modulation of automaticity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Benzo[a]pyrene affects Jurkat T cells in the activated state via the antioxidant response element dependent Nrf2 pathway leading to decreased IL-2 secretion and redirecting glutamine metabolism

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

Murugaiyan, Jayaseelan; Rockstroh, Maxie; Wagner, Juliane

2013-06-15

There is a clear evidence that environmental pollutants, such as benzo[a]pyrene (B[a]P), can have detrimental effects on the immune system, whereas the underlying mechanisms still remain elusive. Jurkat T cells share many properties with native T lymphocytes and therefore are an appropriate model to analyze the effects of environmental pollutants on T cells and their activation. Since environmental compounds frequently occur at low, not acute toxic concentrations, we analyzed the effects of two subtoxic concentrations, 50 nM and 5 μM, on non- and activated cells. B[a]P interferes directly with the stimulation process as proven by an altered IL-2 secretion. Furthermore,more » B[a]P exposure results in significant proteomic changes as shown by DIGE analysis. Pathway analysis revealed an involvement of the AhR independent Nrf2 pathway in the altered processes observed in unstimulated and stimulated cells. A participation of the Nrf2 pathway in the change of IL-2 secretion was confirmed by exposing cells to the Nrf2 activator tBHQ. tBHQ and 5 μM B[a]P caused similar alterations of IL-2 secretion and glutamine/glutamate metabolism. Moreover, the proteome changes in unstimulated cells point towards a modified regulation of the cytoskeleton and cellular stress response, which was proven by western blotting. Additionally, there is a strong evidence for alterations in metabolic pathways caused by B[a]P exposure in stimulated cells. Especially the glutamine/glutamate metabolism was indicated by proteome pathway analysis and validated by metabolite measurements. The detrimental effects were slightly enhanced in stimulated cells, suggesting that stimulated cells are more vulnerable to the environmental pollutant model compound B[a]P. - Highlights: • B[a]P affects the proteome of Jurkat T cells also at low concentrations. • Exposure to B[a]P (50 nM, 5 μM) did not change Jurkat T cell viability. • Both B[a]P concentrations altered the IL-2 secretion of stimulated cells. • 608 different protein spots of Jurkat T cells were quantified using 2-DE-DIGE. • Pathway analysis identified Nrf2 and AhR pathway as regulated.« less

Emotional task management: neural correlates of switching between affective and non-affective task-sets

PubMed Central

Reeck, Crystal

2015-01-01

Although task-switching has been investigated extensively, its interaction with emotionally salient task content remains unclear. Prioritized processing of affective stimulus content may enhance accessibility of affective task-sets and generate increased interference when switching between affective and non-affective task-sets. Previous research has demonstrated that more dominant task-sets experience greater switch costs, as they necessitate active inhibition during performance of less entrenched tasks. Extending this logic to the affective domain, the present experiment examined (a) whether affective task-sets are more dominant than non-affective ones, and (b) what neural mechanisms regulate affective task-sets, so that weaker, non-affective task-sets can be executed. While undergoing functional magnetic resonance imaging, participants categorized face stimuli according to either their gender (non-affective task) or their emotional expression (affective task). Behavioral results were consistent with the affective task dominance hypothesis: participants were slower to switch to the affective task, and cross-task interference was strongest when participants tried to switch from the affective to the non-affective task. These behavioral costs of controlling the affective task-set were mirrored in the activation of a right-lateralized frontostriatal network previously implicated in task-set updating and response inhibition. Connectivity between amygdala and right ventrolateral prefrontal cortex was especially pronounced during cross-task interference from affective features. PMID:25552571

[Construction and selection of effective mouse Smad6 recombinant lenti-virus interference vectors].

PubMed

Yu, Jing; Qi, Mengchun; Deng, Jiupeng; Liu, Gang; Chen, Huaiqing

2010-10-01

This experiment was designed to construct mouse Smad6 recombinant RNA interference vectors and determine their interference effects on bone marrow mesenchymal stem cells (BMSCs). Three recombinant Smad6 RNA interference vectors were constructed by molecular clone techniques with a lenti-virus vector expressing green fluorescent protein (GFP), and the correctness of recombinant vectors was verified by DNA sequencing. Mouse BMSCs were used for transfection experiments and BMP-2 was in use for osteogenic induction of MSCs. The transfection efficiency of recombinant vectors was examined by Laser confocal scanning microscope and the interference effect of recombinant vectors on Smad6 gene expression was determined by real-time RT-PCR and Western blot, respectively. Three Smad6 recombinant RNA interference vectors were successfully constructed and their correctness was proved by DNA sequencing. After transfection, GFPs were effectively expressed in MSCs and all of three recombinant vectors gained high transfection efficiency (> 95%). Both real-time PCR and Western blot examination indicated that among three recombinant vectors, No. 2 Svector had the best interference effect and the interference effect was nearly 91% at protein level. In conclusion, Mouse recombinant Smad6 RNA interference (RNAi) vector was successfully constructed and it provided an effective tool for further studies on BMP signal pathways.

Using RNA Interference to Reveal Genetic Vulnerabilities in Human Cancer Cells

DTIC Science & Technology

2005-07-01

pl of RNase/DNase free water and performed PCR amplification in 50pl reaction volumes using Invitrogen’s Platinum® Pfx DNA Polymerase . To obtain a...destroyed1’ 2. This pathway, known as RNA interference (RNAi), has been exploited in organisms ranging from plants to fungi to animals for...experimentally alter its targeting capability. Indeed such strategies have previously succeeded in both plants and animals23󈧜. My initial studies

Quantum coherence spectroscopy reveals complex dynamics in bacterial light-harvesting complex 2 (LH2).

PubMed

Harel, Elad; Engel, Gregory S

2012-01-17

Light-harvesting antenna complexes transfer energy from sunlight to photosynthetic reaction centers where charge separation drives cellular metabolism. The process through which pigments transfer excitation energy involves a complex choreography of coherent and incoherent processes mediated by the surrounding protein and solvent environment. The recent discovery of coherent dynamics in photosynthetic light-harvesting antennae has motivated many theoretical models exploring effects of interference in energy transfer phenomena. In this work, we provide experimental evidence of long-lived quantum coherence between the spectrally separated B800 and B850 rings of the light-harvesting complex 2 (LH2) of purple bacteria. Spectrally resolved maps of the detuning, dephasing, and the amplitude of electronic coupling between excitons reveal that different relaxation pathways act in concert for optimal transfer efficiency. Furthermore, maps of the phase of the signal suggest that quantum mechanical interference between different energy transfer pathways may be important even at ambient temperature. Such interference at a product state has already been shown to enhance the quantum efficiency of transfer in theoretical models of closed loop systems such as LH2.

Quantum coherence spectroscopy reveals complex dynamics in bacterial light-harvesting complex 2 (LH2)

PubMed Central

Harel, Elad; Engel, Gregory S.

2012-01-01

Light-harvesting antenna complexes transfer energy from sunlight to photosynthetic reaction centers where charge separation drives cellular metabolism. The process through which pigments transfer excitation energy involves a complex choreography of coherent and incoherent processes mediated by the surrounding protein and solvent environment. The recent discovery of coherent dynamics in photosynthetic light-harvesting antennae has motivated many theoretical models exploring effects of interference in energy transfer phenomena. In this work, we provide experimental evidence of long-lived quantum coherence between the spectrally separated B800 and B850 rings of the light-harvesting complex 2 (LH2) of purple bacteria. Spectrally resolved maps of the detuning, dephasing, and the amplitude of electronic coupling between excitons reveal that different relaxation pathways act in concert for optimal transfer efficiency. Furthermore, maps of the phase of the signal suggest that quantum mechanical interference between different energy transfer pathways may be important even at ambient temperature. Such interference at a product state has already been shown to enhance the quantum efficiency of transfer in theoretical models of closed loop systems such as LH2. PMID:22215585

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

PubMed Central

Mleczko-Sanecka, Katarzyna; Roche, Franziska; Rita da Silva, Ana; Call, Debora; D’Alessio, Flavia; Ragab, Anan; Lapinski, Philip E.; Ummanni, Ramesh; Korf, Ulrike; Oakes, Christopher; Damm, Georg; D’Alessandro, Lorenza A.; Klingmüller, Ursula; King, Philip D.; Boutros, Michael; Hentze, Matthias W.

2014-01-01

The hepatic hormone hepcidin is a key regulator of systemic iron metabolism. Its expression is largely regulated by 2 signaling pathways: the “iron-regulated” bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways. To obtain broader insights into cellular processes that modulate hepcidin transcription and to provide a resource to identify novel genetic modifiers of systemic iron homeostasis, we designed an RNA interference (RNAi) screen that monitors hepcidin promoter activity after the knockdown of 19 599 genes in hepatocarcinoma cells. Interestingly, many of the putative hepcidin activators play roles in signal transduction, inflammation, or transcription, and affect hepcidin transcription through BMP-responsive elements. Furthermore, our work sheds light on new components of the transcriptional machinery that maintain steady-state levels of hepcidin expression and its responses to the BMP- and interleukin-6–triggered signals. Notably, we discover hepcidin suppression mediated via components of Ras/RAF MAPK and mTOR signaling, linking hepcidin transcriptional control to the pathways that respond to mitogen stimulation and nutrient status. Thus using a combination of RNAi screening, reverse phase protein arrays, and small molecules testing, we identify links between the control of systemic iron homeostasis and critical liver processes such as regeneration, response to injury, carcinogenesis, and nutrient metabolism. PMID:24385536

The role of PACT in the RNA silencing pathway

PubMed Central

Lee, Yoontae; Hur, Inha; Park, Seong-Yeon; Kim, Young-Kook; Suh, Mi Ra; Kim, V Narry

2006-01-01

Small RNA-mediated gene silencing (RNA silencing) has emerged as a major regulatory pathway in eukaryotes. Identification of the key factors involved in this pathway has been a subject of rigorous investigation in recent years. In humans, small RNAs are generated by Dicer and assembled into the effector complex known as RNA-induced silencing complex (RISC) by multiple factors including hAgo2, the mRNA-targeting endonuclease, and TRBP (HIV-1 TAR RNA-binding protein), a dsRNA-binding protein that interacts with both Dicer and hAgo2. Here we describe an additional dsRNA-binding protein known as PACT, which is significant in RNA silencing. PACT is associated with an ∼500 kDa complex that contains Dicer, hAgo2, and TRBP. The interaction with Dicer involves the third dsRNA-binding domain (dsRBD) of PACT and the N-terminal region of Dicer containing the helicase motif. Like TRBP, PACT is not required for the pre-microRNA (miRNA) cleavage reaction step. However, the depletion of PACT strongly affects the accumulation of mature miRNA in vivo and moderately reduces the efficiency of small interfering RNA-induced RNA interference. Our study indicates that, unlike other RNase III type proteins, human Dicer may employ two different dsRBD-containing proteins that facilitate RISC assembly. PMID:16424907

Caenorhabditis elegans ABCRNAi transporters interact genetically with rde-2 and mut-7.

PubMed

Sundaram, Prema; Han, Wang; Cohen, Nancy; Echalier, Benjamin; Albin, John; Timmons, Lisa

2008-02-01

RNA interference (RNAi) mechanisms are conserved and consist of an interrelated network of activities that not only respond to exogenous dsRNA, but also perform endogenous functions required in the fine tuning of gene expression and in maintaining genome integrity. Not surprisingly, RNAi functions have widespread influences on cellular function and organismal development. Previously, we observed a reduced capacity to mount an RNAi response in nine Caenorhabditis elegans mutants that are defective in ABC transporter genes (ABC(RNAi) mutants). Here, we report an exhaustive study of mutants, collectively defective in 49 different ABC transporter genes, that allowed for the categorization of one additional transporter into the ABC(RNAi) gene class. Genetic complementation tests reveal functions for ABC(RNAi) transporters in the mut-7/rde-2 branch of the RNAi pathway. These second-site noncomplementation interactions suggest that ABC(RNAi) proteins and MUT-7/RDE-2 function together in parallel pathways and/or as multiprotein complexes. Like mut-7 and rde-2, some ABC(RNAi) mutants display transposon silencing defects. Finally, our analyses reveal a genetic interaction network of ABC(RNAi) gene function with respect to this part of the RNAi pathway. From our results, we speculate that the coordinated activities of ABC(RNAi) transporters, through their effects on endogenous RNAi-related mechanisms, ultimately affect chromosome function and integrity.

Caenorhabditis elegans ABCRNAi Transporters Interact Genetically With rde-2 and mut-7

PubMed Central

Sundaram, Prema; Han, Wang; Cohen, Nancy; Echalier, Benjamin; Albin, John; Timmons, Lisa

2008-01-01

RNA interference (RNAi) mechanisms are conserved and consist of an interrelated network of activities that not only respond to exogenous dsRNA, but also perform endogenous functions required in the fine tuning of gene expression and in maintaining genome integrity. Not surprisingly, RNAi functions have widespread influences on cellular function and organismal development. Previously, we observed a reduced capacity to mount an RNAi response in nine Caenorhabditis elegans mutants that are defective in ABC transporter genes (ABCRNAi mutants). Here, we report an exhaustive study of mutants, collectively defective in 49 different ABC transporter genes, that allowed for the categorization of one additional transporter into the ABCRNAi gene class. Genetic complementation tests reveal functions for ABCRNAi transporters in the mut-7/rde-2 branch of the RNAi pathway. These second-site noncomplementation interactions suggest that ABCRNAi proteins and MUT-7/RDE-2 function together in parallel pathways and/or as multiprotein complexes. Like mut-7 and rde-2, some ABCRNAi mutants display transposon silencing defects. Finally, our analyses reveal a genetic interaction network of ABCRNAi gene function with respect to this part of the RNAi pathway. From our results, we speculate that the coordinated activities of ABCRNAi transporters, through their effects on endogenous RNAi-related mechanisms, ultimately affect chromosome function and integrity. PMID:18245353

Proactive interference effects on sentence production

PubMed Central

FERREIRA, VICTOR S.; FIRATO, CARLA E.

2007-01-01

Proactive interference refers to recall difficulties caused by prior similar memory-related processing. Information-processing approaches to sentence production predict that retrievability affects sentence form: Speakers may word sentences so that material that is difficult to retrieve is spoken later. In this experiment, speakers produced sentence structures that could include an optional that, thereby delaying the mention of a subsequent noun phrase. This subsequent noun phrase was either (1) conceptually similar to three previous noun phrases in the same sentence, leading to greater proactive interference, or (2) conceptually dissimilar, leading to less proactive interference. Speakers produced more thats (and were more disfluencies) before conceptually similar noun phrases, suggesting that retrieval difficulties during sentence production affect the syntactic structures of sentences that speakers produce. PMID:12613685

Metabolites in vertebrate Hedgehog signaling.

PubMed

Roberg-Larsen, Hanne; Strand, Martin Frank; Krauss, Stefan; Wilson, Steven Ray

2014-04-11

The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field. Copyright © 2014 Elsevier Inc. All rights reserved.

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases.

PubMed

De Luca, Ciro; Virtuoso, Assunta; Maggio, Nicola; Papa, Michele

2017-10-12

Blood coagulation factors and other proteins, with modulatory effects or modulated by the coagulation cascade have been reported to affect the pathophysiology of the central nervous system (CNS). The protease-activated receptors (PARs) pathway can be considered the central hub of this regulatory network, mainly through thrombin or activated protein C (aPC). These proteins, in fact, showed peculiar properties, being able to interfere with synaptic homeostasis other than coagulation itself. These specific functions modulate neuronal networks, acting both on resident (neurons, astrocytes, and microglia) as well as circulating immune system cells and the extracellular matrix. The pleiotropy of these effects is produced through different receptors, expressed in various cell types, in a dose- and time-dependent pattern. We reviewed how these pathways may be involved in neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases), multiple sclerosis, ischemic stroke and post-ischemic epilepsy, CNS cancer, addiction, and mental health. These data open up a new path for the potential therapeutic use of the agonist/antagonist of these proteins in the management of several central nervous system diseases.

JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy

PubMed Central

Raffaello, Anna; Milan, Giulia; Masiero, Eva; Carnio, Silvia; Lee, Donghoon

2010-01-01

The size of skeletal muscle cells is precisely regulated by intracellular signaling networks that determine the balance between overall rates of protein synthesis and degradation. Myofiber growth and protein synthesis are stimulated by the IGF-1/Akt/mammalian target of rapamycin (mTOR) pathway. In this study, we show that the transcription factor JunB is also a major determinant of whether adult muscles grow or atrophy. We found that in atrophying myotubes, JunB is excluded from the nucleus and that decreasing JunB expression by RNA interference in adult muscles causes atrophy. Furthermore, JunB overexpression induces hypertrophy without affecting satellite cell proliferation and stimulated protein synthesis independently of the Akt/mTOR pathway. When JunB is transfected into denervated muscles, fiber atrophy is prevented. JunB blocks FoxO3 binding to atrogin-1 and MuRF-1 promoters and thus reduces protein breakdown. Therefore, JunB is important not only in dividing populations but also in adult muscle, where it is required for the maintenance of muscle size and can induce rapid hypertrophy and block atrophy. PMID:20921137

Fluorescence-based high-throughput screening of dicer cleavage activity.

PubMed

Podolska, Katerina; Sedlak, David; Bartunek, Petr; Svoboda, Petr

2014-03-01

Production of small RNAs by ribonuclease III Dicer is a key step in microRNA and RNA interference pathways, which employ Dicer-produced small RNAs as sequence-specific silencing guides. Further studies and manipulations of microRNA and RNA interference pathways would benefit from identification of small-molecule modulators. Here, we report a study of a fluorescence-based in vitro Dicer cleavage assay, which was adapted for high-throughput screening. The kinetic assay can be performed under single-turnover conditions (35 nM substrate and 70 nM Dicer) in a small volume (5 µL), which makes it suitable for high-throughput screening in a 1536-well format. As a proof of principle, a small library of bioactive compounds was analyzed, demonstrating potential of the assay.

RELATIONSHIP BETWEEN PERCEPTION AND LEARNING IN THE MENTALLY RETARDED.

ERIC Educational Resources Information Center

JOHNSON, G. ORVILLE

SUPPORTIVE EVIDENCE IS GIVEN AGAINST PERCEPTUAL DISORDERS CREATING INTERFERENCE IN LEARNING. THE CONTENTION THAT A PERCEPTUAL FIGURE GROUND DISTURBANCE NECESSARILY INTERFERES WITH THE LEARNING PROCESS IS NOT SUPPORTED BY THE EVIDENCE. THERE ARE INDICATIONS, HOWEVER, THAT BACKGROUND INTERFERENCE SEEMS TO AFFECT SOME CHILDREN MORE THAN OTHERS. TWO…

Is Family-to-Work Interference Related to Co-Workers' Work Outcomes?

ERIC Educational Resources Information Center

ten Brummelhuis, Lieke L.; Bakker, Arnold B.; Euwema, Martin C.

2010-01-01

Previous studies have convincingly shown that employees' family lives can affect their work outcomes. We investigate whether family-to-work interference (FWI) experienced by the employee also affects the work outcomes of a co-worker. We predict that the employee's FWI has an effect on the co-worker's outcomes through the crossover of positive and…

Pifithrin-α provides neuroprotective effects at the level of mitochondria independently of p53 inhibition.

PubMed

Neitemeier, Sandra; Ganjam, Goutham K; Diemert, Sebastian; Culmsee, Carsten

2014-12-01

Impaired mitochondrial integrity and function are key features of intrinsic death pathways in neuronal cells. Therefore, key regulators of intrinsic death pathways acting upstream of mitochondria are potential targets for therapeutic approaches of neuroprotection. The tumor suppressor p53 is a well-established regulator of cellular responses towards different kinds of lethal stress, including oxidative stress. Recent reports suggested that p53 may affect mitochondrial integrity and function through both, transcriptional activation of mitochondria-targeted pro-death proteins and direct effects at the mitochondrial membrane. In the present study, we compared the effects of pharmacological inhibition of p53 by pifithrin-α with those of selective p53 gene silencing by RNA interference. Using MTT assay and real-time cell impedance measurements we confirmed the protective effect of both strategies against glutamate-induced oxidative stress in immortalized mouse hippocampal HT-22 neurons. Further, we observed full restoration of mitochondrial membrane potential and inhibition of glutamate-induced mitochondrial fragmentation by pifithrin-α which was, in contrast, not achieved by p53 gene silencing. Downregulation of p53 by siRNA decreased p53 transcriptional activity and reduced expression levels of p21 mRNA, while pifithrin-α did not affect these endpoints. These results suggest a neuroprotective effect of pifithrin-α which occurred at the level of mitochondria and independently of p53 inhibition.

The near demise and subsequent revival of classical genetics for investigating Caenorhabditis elegans embryogenesis: RNAi meets next-generation DNA sequencing.

PubMed

Bowerman, Bruce

2011-10-01

Molecular genetic investigation of the early Caenorhabditis elegans embryo has contributed substantially to the discovery and general understanding of the genes, pathways, and mechanisms that regulate and execute developmental and cell biological processes. Initially, worm geneticists relied exclusively on a classical genetics approach, isolating mutants with interesting phenotypes after mutagenesis and then determining the identity of the affected genes. Subsequently, the discovery of RNA interference (RNAi) led to a much greater reliance on a reverse genetics approach: reducing the function of known genes with RNAi and then observing the phenotypic consequences. Now the advent of next-generation DNA sequencing technologies and the ensuing ease and affordability of whole-genome sequencing are reviving the use of classical genetics to investigate early C. elegans embryogenesis.

Evolution at increased error rate leads to the coexistence of multiple adaptive pathways in an RNA virus.

PubMed

Cabanillas, Laura; Arribas, María; Lázaro, Ester

2013-01-16

When beneficial mutations present in different genomes spread simultaneously in an asexual population, their fixation can be delayed due to competition among them. This interference among mutations is mainly determined by the rate of beneficial mutations, which in turn depends on the population size, the total error rate, and the degree of adaptation of the population. RNA viruses, with their large population sizes and high error rates, are good candidates to present a great extent of interference. To test this hypothesis, in the current study we have investigated whether competition among beneficial mutations was responsible for the prolonged presence of polymorphisms in the mutant spectrum of an RNA virus, the bacteriophage Qβ, evolved during a large number of generations in the presence of the mutagenic nucleoside analogue 5-azacytidine. The analysis of the mutant spectra of bacteriophage Qβ populations evolved at artificially increased error rate shows a large number of polymorphic mutations, some of them with demonstrated selective value. Polymorphisms distributed into several evolutionary lines that can compete among them, making it difficult the emergence of a defined consensus sequence. The presence of accompanying deleterious mutations, the high degree of recurrence of the polymorphic mutations, and the occurrence of epistatic interactions generate a highly complex interference dynamics. Interference among beneficial mutations in bacteriophage Qβ evolved at increased error rate permits the coexistence of multiple adaptive pathways that can provide selective advantages by different molecular mechanisms. In this way, interference can be seen as a positive factor that allows the exploration of the different local maxima that exist in rugged fitness landscapes.

Discordant Analytical Results Caused by Biotin Interference on Diagnostic Immunoassays in a Pediatric Hospital.

PubMed

Ali, Mahesheema; Rajapakshe, Deepthi; Cao, Liyun; Devaraj, Sridevi

2017-09-01

Recent studies have reported that biotin interferes with certain immunoassays. In this study, we evaluated the analytical interference of biotin on immunoassays that use streptavidin-biotin in our pediatric hospital. We tested the effect of different concentrations of biotin (1.5-200 ng/ml) on TSH, Prolactin, Ferritin, CK-MB, β-hCG, Troponin I, LH, FSH, Cortisol, Anti-HAV antibody (IgG and IgM), assays on Ortho Clinical Diagnostic Vitros 5600 Analyzer. Biotin (up to 200 ng/mL) did not significantly affect Troponin I and HAV assays. Biotin (up to 12.5 ng/ml) resulted in <10% bias in CK-MB, β-hCG, AFP, Cortisol, Ferritin assays and biotin >6.25 ng/mL significantly affected TSH (>20% bias) assay. Prolactin was significantly affected even at low levels (Biotin 1.5 ng/mL). Thus, we recommend educating physicians about biotin interference in common immunoassays and adding an electronic disclaimer. © 2017 by the Association of Clinical Scientists, Inc.

CRISPR interference and priming varies with individual spacer sequences

PubMed Central

Xue, Chaoyou; Seetharam, Arun S.; Musharova, Olga; Severinov, Konstantin; J. Brouns, Stan J.; Severin, Andrew J.; Sashital, Dipali G.

2015-01-01

CRISPR–Cas (clustered regularly interspaced short palindromic repeats-CRISPR associated) systems allow bacteria to adapt to infection by acquiring ‘spacer’ sequences from invader DNA into genomic CRISPR loci. Cas proteins use RNAs derived from these loci to target cognate sequences for destruction through CRISPR interference. Mutations in the protospacer adjacent motif (PAM) and seed regions block interference but promote rapid ‘primed’ adaptation. Here, we use multiple spacer sequences to reexamine the PAM and seed sequence requirements for interference and priming in the Escherichia coli Type I-E CRISPR–Cas system. Surprisingly, CRISPR interference is far more tolerant of mutations in the seed and the PAM than previously reported, and this mutational tolerance, as well as priming activity, is highly dependent on spacer sequence. We identify a large number of functional PAMs that can promote interference, priming or both activities, depending on the associated spacer sequence. Functional PAMs are preferentially acquired during unprimed ‘naïve’ adaptation, leading to a rapid priming response following infection. Our results provide numerous insights into the importance of both spacer and target sequences for interference and priming, and reveal that priming is a major pathway for adaptation during initial infection. PMID:26586800

Negative Transfer and Positive Interference: Some Confusion in Introductory Psychology Textbooks.

ERIC Educational Resources Information Center

Reid, Edward

1981-01-01

Discusses weakness in 11 introductory psychology textbooks in distinguishing between the terms proactive behavior and negative transfer. Negative transfer relates to a detrimental effect of prior experience on the learning of a new task, whereas proactive interference concerns a detrimental affect of prior interference on the recall of a second…

A Rasch analysis of the Brief Pain Inventory Interference subscale reveals three dimensions and an age bias.

PubMed

Walton, David M; Beattie, Tyler; Putos, Joseph; MacDermid, Joy C

2016-06-01

The Brief Pain Inventory is composed of two quantifiable scales: pain severity and pain interference. The reported factor structure of the interference subscale is not consistent in the extant literature, with no clear choice between a single- or two-factor structure. Here, we report on the results of Rasch-based analysis of the interference subscale using a large population-based ambulatory patient database (the Quebec Pain Registry). Observational cohort. A total of 1,000 responses were randomly drawn from a total database of 5,654 for this analysis. Both the original 7-item and an expanded 10-item version (Tyler 2002) of the interference subscale were evaluated. Rasch analysis revealed significant misfit of both versions of the scale, with the original 7-item version outperforming the expanded 10-item version. Analysis of dimensionality revealed that both versions showed improved model fit when considered two subscales (affective and physical interference) with the item on sleep interference removed or considered separately. Additionally, significant uniform differential item functioning was identified for 6 of the 7 original items when the sample was stratified by age above or below 55 years. The interference subscale achieved adequate model fit when considered as two separate subscales with age as a mediator of response, while interpreting the sleep interference item separately. A transformation matrix revealed that in all cases, ordinal-level change at the extreme ends of the scale appears to be more meaningful than does a similar change at the midpoints. The Interference subscale of the BPI should be interpreted as two separate subscales (Affective Interference, Physical Interference) with the sleep item removed or interpreted separately for optimal fit to the Rasch model. Implications for research and clinical use are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Emotional task management: neural correlates of switching between affective and non-affective task-sets.

PubMed

Reeck, Crystal; Egner, Tobias

2015-08-01

Although task-switching has been investigated extensively, its interaction with emotionally salient task content remains unclear. Prioritized processing of affective stimulus content may enhance accessibility of affective task-sets and generate increased interference when switching between affective and non-affective task-sets. Previous research has demonstrated that more dominant task-sets experience greater switch costs, as they necessitate active inhibition during performance of less entrenched tasks. Extending this logic to the affective domain, the present experiment examined (a) whether affective task-sets are more dominant than non-affective ones, and (b) what neural mechanisms regulate affective task-sets, so that weaker, non-affective task-sets can be executed. While undergoing functional magnetic resonance imaging, participants categorized face stimuli according to either their gender (non-affective task) or their emotional expression (affective task). Behavioral results were consistent with the affective task dominance hypothesis: participants were slower to switch to the affective task, and cross-task interference was strongest when participants tried to switch from the affective to the non-affective task. These behavioral costs of controlling the affective task-set were mirrored in the activation of a right-lateralized frontostriatal network previously implicated in task-set updating and response inhibition. Connectivity between amygdala and right ventrolateral prefrontal cortex was especially pronounced during cross-task interference from affective features. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Phyllanthus Suppresses Prostate Cancer Cell, PC-3, Proliferation and Induces Apoptosis through Multiple Signalling Pathways (MAPKs, PI3K/Akt, NFκB, and Hypoxia).

PubMed

Tang, Yin-Quan; Jaganath, Indubala; Manikam, Rishya; Sekaran, Shamala Devi

2013-01-01

Phyllanthus is a traditional medicinal plant that has been found to have antihepatitis, antibacterial, and anticancer properties. The present studies were to investigate the in vitro molecular mechanisms of anticancer effects of Phyllanthus (P. amarus, P. niruri, P. urinaria, and P. watsonii) plant extracts in human prostate adenocarcinoma. The cancer ten-pathway reporter array was performed and revealed that the expression of six pathway reporters were significantly decreased (Wnt, NFκB, Myc/Max, hypoxia, MAPK/ERK, and MAPK/JNK) in PC-3 cells after treatment with Phyllanthus extracts. Western blot was conducted and identified several signalling molecules that were affected in the signalling pathways including pan-Ras, c-Raf, RSK, Elk1, c-Jun, JNK1/2, p38 MAPK, c-myc, DSH, β-catenin, Akt, HIF-1α, GSK3β, NFκB p50 and p52, Bcl-2, Bax, and VEGF, in treated PC-3 cells. A proteomics-based approach, 2D gel electrophoresis, was performed, and mass spectrometry (MS/MS) results revealed that there were 72 differentially expressed proteins identified in treated PC-3 cells and were involved in tumour cell adhesion, apoptosis, glycogenesis and glycolysis, metastasis, angiogenesis, and protein synthesis and energy metabolism. Overall, these findings suggest that Phyllanthus can interfere with multiple signalling cascades involved in tumorigenesis and be used as a potential therapeutic candidate for treatment of cancer.

An early secretory pathway mediated by GNOM-LIKE 1 and GNOM is essential for basal polarity establishment in Arabidopsis thaliana

DOE PAGES

Doyle, Siamsa M.; Haeger, Ash; Vain, Thomas; ...

2015-02-02

Spatial regulation of the plant hormone indole-3-acetic acid (IAA, or auxin) is essential for plant development. Auxin gradient establishment is mediated by polarly localized auxin transporters, including PIN-FORMED (PIN) proteins. Their localization and abundance at the plasma membrane are tightly regulated by endomembrane machinery, especially the endocytic and recycling pathways mediated by the ADP ribosylation factor guanine nucleotide exchange factor (ARF-GEF) GNOM. We assessed the role of the early secretory pathway in establishing PIN1 polarity in Arabidopsis thaliana by pharmacological and genetic approaches. We identified the compound endosidin 8 (ES8), which selectively interferes with PIN1 basal polarity without altering themore » polarity of apical proteins. ES8 alters the auxin distribution pattern in the root and induces a strong developmental phenotype, including reduced root length. The ARF-GEF–defective mutants gnom-like 1 ( gnl1-1) and gnom ( van7) are significantly resistant to ES8. The compound does not affect recycling or vacuolar trafficking of PIN1 but leads to its intracellular accumulation, resulting in loss of PIN1 basal polarity at the plasma membrane. In conclusion, our data confirm a role for GNOM in endoplasmic reticulum (ER)–Golgi trafficking and reveal that a GNL1/GNOM-mediated early secretory pathway selectively regulates PIN1 basal polarity establishment in a manner essential for normal plant development.« less

The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition*S

PubMed Central

Dissanayake, Samudra K.; Wade, Michael; Johnson, Carrie E.; O’Connell, Michael P.; Leotlela, Poloko D.; French, Amanda D.; Shah, Kavita V.; Hewitt, Kyle J.; Rosenthal, Devin T.; Indig, Fred E.; Jiang, Yuan; Nickoloff, Brian J.; Taub, Dennis D.; Trent, Jeffrey M.; Moon, Randall T.; Bittner, Michael; Weeraratna, Ashani T.

2008-01-01

We have shown that Wnt5A increases the motility of melanoma cells. To explore cellular pathways involving Wnt5A, we compared gain-of-function (WNT5A stable transfectants) versus loss-of-function (siRNA knockdown) of WNT5A by microarray analysis. Increasing WNT5A suppressed the expression of several genes, which were re-expressed after small interference RNA-mediated knockdown of WNT5A. Genes affected by WNT5A include KISS-1, a metastasis suppressor, and CD44, involved in tumor cell homing during metastasis. This could be validated at the protein level using both small interference RNA and recombinant Wnt5A (rWnt5A). Among the genes up-regulated by WNT5A was the gene vimentin, associated with an epithelial to mesenchymal transition (EMT), which involves decreases in E-cadherin, due to up-regulation of the transcriptional repressor, Snail. rWnt5A treatment increases Snail and vimentin expression, and decreases E-cadherin, even in the presence of dominant-negativeTCF4, suggesting that this activation is independent of Wnt/β-catenin signaling. Because Wnt5A can signal via protein kinase C (PKC), the role of PKC in Wnt5A-mediated motility and EMT was also assessed using PKC inhibition and activation studies. Treating cells expressing low levels of Wnt5A with phorbol ester increased Snail expression inhibiting PKC in cells expressing high levels of Wnt5A decreased Snail. Furthermore, inhibition of PKC before Wnt5A treatment blocked Snail expression, implying that Wnt5A can potentiate melanoma metastasis via the induction of EMT in a PKC-dependent manner. PMID:17426020

Intracellular bacteria interfere with dendritic cell functions: role of the type I interferon pathway.

PubMed

Gorvel, Laurent; Textoris, Julien; Banchereau, Romain; Ben Amara, Amira; Tantibhedhyangkul, Wiwit; von Bargen, Kristin; Ka, Mignane B; Capo, Christian; Ghigo, Eric; Gorvel, Jean-Pierre; Mege, Jean-Louis

2014-01-01

Dendritic cells (DCs) orchestrate host defenses against microorganisms. In infectious diseases due to intracellular bacteria, the inefficiency of the immune system to eradicate microorganisms has been attributed to the hijacking of DC functions. In this study, we selected intracellular bacterial pathogens with distinct lifestyles and explored the responses of monocyte-derived DCs (moDCs). Using lipopolysaccharide as a control, we found that Orientia tsutsugamushi, the causative agent of scrub typhus that survives in the cytosol of target cells, induced moDC maturation, as assessed by decreased endocytosis activity, the ability to induce lymphocyte proliferation and the membrane expression of phenotypic markers. In contrast, Coxiella burnetii, the agent of Q fever, and Brucella abortus, the agent of brucellosis, both of which reside in vacuolar compartments, only partly induced the maturation of moDCs, as demonstrated by a phenotypic analysis. To analyze the mechanisms used by C. burnetii and B. abortus to alter moDC activation, we performed microarray and found that C. burnetii and B. abortus induced a specific signature consisting of TLR4, TLR3, STAT1 and interferon response genes. These genes were down-modulated in response to C. burnetii and B. abortus but up-modulated in moDCs activated by lipopolysaccharide and O. tsutsugamushi. This transcriptional alteration was associated with the defective interferon-β production. This study demonstrates that intracellular bacteria specifically affect moDC responses and emphasizes how C. burnetii and B. abortus interfere with moDC activation and the antimicrobial immune response. We believe that comparing infection by several bacterial species may be useful for defining new pathways and biomarkers and for developing new treatment strategies.

Prenatal bisphenol A (BPA) exposure alters the transcriptome of the neonate rat amygdala in a sex-specific manner: a CLARITY-BPA consortium study.

PubMed

Arambula, Sheryl E; Jima, Dereje; Patisaul, Heather B

2018-03-01

Bisphenol A (BPA) is a widely recognized endocrine disruptor prevalent in many household items. Because experimental and epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, even at levels below the current US FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, there is concern that early life exposure may alter neurodevelopment. The current study was conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and examined the full amygdalar transcriptome on postnatal day (PND) 1, with the hypothesis that prenatal BPA exposure would alter the expression of genes and pathways fundamental to sex-specific affective behaviors. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (2.5, 25, 250, 2500, or 25000μg/kg bw/day), a reference estrogen (0.05 or 0.5μg ethinyl estradiol (EE 2 )/kg bw/day), or vehicle. PND 1 amygdalae were microdissected and gene expression was assessed with qRT-PCR (all exposure groups) and RNAseq (vehicle, 25 and 250μg BPA, and 0.5μg EE 2 groups only). Our results demonstrate that that prenatal BPA exposure can disrupt the transcriptome of the neonate amygdala, at doses below the FDA NOAEL, in a sex-specific manner and indicate that the female amygdala may be more sensitive to BPA exposure during fetal development. We also provide additional evidence that developmental BPA exposure can interfere with estrogen, oxytocin, and vasopressin signaling pathways in the developing brain and alter signaling pathways critical for synaptic organization and transmission. Copyright © 2017 Elsevier B.V. All rights reserved.

An Environmental Sentinel Biomonitor System for Drinking Water Protection

DTIC Science & Technology

2008-12-01

threat chemicals. Potential interferences include chemicals commonly used for drinking water disinfection (chlorine and chloramine ), byproducts of...range. Of the potential interferences tested, the ECIS test was affected only by the disinfectants chlorine and chloramine ; chlorine is typically...Industrial and Potential Interfering Chemicals Used to Evaluate ESB System Toxicity Sensors TICs Potential Interferences Acrylonitrile Chloramine

Handling of uncertainty due to interference fringe in FT-NIR transmittance spectroscopy - Performance comparison of interference elimination techniques using glucose-water system

NASA Astrophysics Data System (ADS)

Beganović, Anel; Beć, Krzysztof B.; Henn, Raphael; Huck, Christian W.

2018-05-01

The applicability of two elimination techniques for interferences occurring in measurements with cells of short pathlength using Fourier transform near-infrared (FT-NIR) spectroscopy was evaluated. Due to the growing interest in the field of vibrational spectroscopy in aqueous biological fluids (e.g. glucose in blood), aqueous solutions of D-(+)-glucose were prepared and split into a calibration set and an independent validation set. All samples were measured with two FT-NIR spectrometers at various spectral resolutions. Moving average smoothing (MAS) and fast Fourier transform filter (FFT filter) were applied to the interference affected FT-NIR spectra in order to eliminate the interference pattern. After data pre-treatment, partial least squares regression (PLSR) models using different NIR regions were constructed using untreated (interference affected) spectra and spectra treated with MAS and FFT filter. The prediction of the independent validation set revealed information about the performance of the utilized interference elimination techniques, as well as the different NIR regions. The results showed that the combination band of water at approx. 5200 cm-1 is of great importance since its performance was superior to the one of the so-called first overtone of water at approx. 6800 cm-1. Furthermore, this work demonstrated that MAS and FFT filter are fast and easy-to-use techniques for the elimination of interference fringes in FT-NIR transmittance spectroscopy.

Frequency Hopping, Multiple Frequency-Shift Keying, Coding, and Optimal Partial-Band Jamming.

DTIC Science & Technology

1982-08-01

receivers appropriate for these two strategies. Each receiver is noncoherent (a coherent receiver is generally impractical) and implements hard...Advances in Coding and Modulation for Noncoherent Channels Affected by Fading, Partial Band, and Multiple- . Access Interference, in A. J. Viterbi...Modulation for Noncoherent Channels Affected by Fading, Partial Band, and Multiple-Access interference, in A. J. Viterbi, ed., Advances in Coumunication

Influence of acute promyelocytic leukemia therapeutic drugs on nuclear pore complex density and integrity.

PubMed

Lång, Anna; Øye, Alexander; Eriksson, Jens; Rowe, Alexander D; Lång, Emma; Bøe, Stig Ove

2018-05-15

During cell division, a large number of nuclear proteins are released into the cytoplasm due to nuclear envelope breakdown. Timely nuclear import of these proteins following exit from mitosis is critical for establishment of the G1 nuclear environment. Dysregulation of post-mitotic nuclear import may affect the fate of newly divided stem or progenitor cells and may lead to cancer. Acute promyelocytic leukemia (APL) is a malignant disorder that involves a defect in blood cell differentiation at the promyelocytic stage. Recent studies suggest that pharmacological concentrations of the APL therapeutic drugs, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), affect post-mitotic nuclear import of the APL-associated oncoprotein PML/RARA. In the present study, we have investigated the possibility that ATRA and ATO affect post-mitotic nuclear import through interference with components of the nuclear import machinery. We observe reduced density and impaired integrity of nuclear pore complexes after ATRA and/or ATO exposure. Using a post-mitotic nuclear import assay, we demonstrate distinct import kinetics among different nuclear import pathways while nuclear import rates were similar in the presence or absence of APL therapeutic drugs. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

The potential of targeting Ras proteins in lung cancer.

PubMed

McCormick, Frank

2015-04-01

The Ras pathway is a major driver in lung adenocarcinoma: over 75% of all cases harbor mutations that activate this pathway. While spectacular clinical successes have been achieved by targeting activated receptor tyrosine kinases in this pathway, little, if any, significant progress has been achieved targeting Ras proteins themselves or cancers driven by oncogenic Ras mutants. New approaches to drug discovery, new insights into Ras function, new ways of attacking undruggable proteins through RNA interference and new ways of harnessing the immune system could change this landscape in the relatively near future.

Involvement of 2-C-methyl-D-erythritol-4-phosphate pathway in biosynthesis of aphidicolin-like tetracyclic diterpene of Scoparia dulcis.

PubMed

Nkembo, Marguerite Kasidimoko; Lee, Jung-Bum; Nakagiri, Takeshi; Hayashi, Toshimitsu

2006-05-01

Specific inhibitors of the MVA pathway (pravastatin) and the MEP pathway (fosmidomycin) were used to interfere with the biosynthetic flux which leads to the production of aphidicolin-like diterpene in leaf organ cultures of Scoparia dulcis. Treatment of leaf organs with fosmidomycin resulted in dose dependent inhibition of chlorophylls, carotenoids, scopadulcic acid B (SDB) and phytol production, and no effect on sterol production was observed. In response to the pravastatin treatment, a significant decrease in sterol and perturbation of SDB production was observed.

Word reading practice reduces Stroop interference in children.

PubMed

Protopapas, Athanassios; Vlahou, Eleni L; Moirou, Despoina; Ziaka, Laoura

2014-05-01

Stroop interference is thought to index reading automaticity and is expected to increase with reading practice and to decrease with improved color naming. We investigated the effects of practice in word reading and color naming on interference in 92 adults and 109 children in Grades 4-5. For children, interference was reduced after reading practice with color words. In neither group was interference affected by practice in color naming of neutral stimuli. These findings are consistent with a direct negative relationship between reading ability and interference and challenge the automaticity account in favor of a blocking mechanism whereby interference is determined by the delay to inhibit the reading response rather than by the efficiency of color naming. Copyright © 2014 Elsevier B.V. All rights reserved.

Aspects of a Distinct Cytotoxicity of Selenium Salts and Organic Selenides in Living Cells with Possible Implications for Drug Design.

PubMed

Estevam, Ethiene Castellucci; Witek, Karolina; Faulstich, Lisa; Nasim, Muhammad Jawad; Latacz, Gniewomir; Domínguez-Álvarez, Enrique; Kieć-Kononowicz, Katarzyna; Demasi, Marilene; Handzlik, Jadwiga; Jacob, Claus

2015-07-31

Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant.

Regulation and function of DNA methylation in plants and animals

PubMed Central

He, Xin-Jian; Chen, Taiping; Zhu, Jian-Kang

2011-01-01

DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt piwi-interacting small RNAs. DNA methylation status is dynamically regulated by DNA methylation and demethylation reactions. In plants, active DNA demethylation relies on the repressor of silencing 1 family of bifunctional DNA glycosylases, which remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, initiating a base excision repair (BER) pathway. In animals, multiple mechanisms of active DNA demethylation have been proposed, including a deaminase- and DNA glycosylase-initiated BER pathway. New information concerning the effects of various histone modifications on the establishment and maintenance of DNA methylation has broadened our understanding of the regulation of DNA methylation. The function of DNA methylation in plants and animals is also discussed in this review. PMID:21321601

The Cost of Learning: Interference Effects in Memory Development

PubMed Central

Darby, Kevin P.; Sloutsky, Vladimir M.

2015-01-01

Learning often affects future learning and memory for previously learned information by exerting either facilitation or interference effects. Several theoretical accounts of interference effects have been proposed, each making different developmental predictions. This research examines interference effects across development, with the goal of better understanding mechanisms of interference and of memory development. Preschool-aged children and adults participated in a three-phased associative learning paradigm containing stimuli that were either unique or repeated across phases. Both age groups demonstrated interference effects, but only for repeated items. Whereas proactive interference effects were comparable across age groups, retroactive interference reached catastrophic-like levels in children. Additionally, retroactive interference increased in adults when contextual differences between phases were minimized (Experiment 2), and decreased in adults who were more successful at encoding repeated pairs of stimuli during a training phase (Experiment 3). These results are discussed with respect to theories of memory and memory development. PMID:25688907

Interference effects on vibration-mediated tunneling through interacting degenerate molecular states.

PubMed

Zhong, X; Cao, J C

2009-07-22

We study the combined effects of quantum electronic interference and Coulomb interaction on electron transport through near-degenerate molecular states with strong electron-vibration interaction. It is found that quantum electronic interference strongly affects the current and its noise properties. In particular, destructive interference induces pronounced negative differential conductances (NDCs) accompanying the vibrational excited states, and such NDC characters are not related to asymmetric tunnel coupling and are robust to the damping of a thermal bath. In a certain transport regime, the non-equilibrium vibration distribution even shows a peculiar sub-Poissonian behavior, which is enhanced by quantum electronic interference.

Effect of the synthetic cannabinoid HU-210 on quorum sensing and on the production of quorum sensing-mediated virulence factors by Vibrio harveyi.

PubMed

Soni, Divya; Smoum, Reem; Breuer, Aviva; Mechoulam, Raphael; Steinberg, Doron

2015-08-12

Bacterial populations communicate through the cell density-dependent mechanism of quorum sensing (QS). Vibrio harveyi, one of the best studied model organisms for QS, was used to explore effects of the synthetic cannabinoid HU-210 on QS and different QS-regulated physiological processes in bacteria. Analysis of QS-regulated bioluminescence in wild-type and mutant strains of V. harveyi revealed that HU-210 affects the autoinducer-2 (AI-2) pathway, one of three known QS cascades of V. harveyi. Furthermore, QS-mediated biofilm formation and swimming motility in the mutant strain BB152 (AI-1(-), AI-2(+)) were significantly reduced in the presence of HU-210. HU-210 inhibited QS-mediated virulence factor production without any inhibitory effect on bacterial growth. It also alters the expression of several genes, which are regulated by QS, specifically downregulating the genes of the AI-2 QS cascade. First evidence is being provided for interference of bacterial signal-transduction systems by a synthetic cannabinoid. The effect of HU-210 was specific to the AI-2 cascade in V. harveyi. AI-2 is known as a "universal autoinducer" and interference with its activity opens a broad spectrum of applications for synthetic cannabinoids in future research as a potential anti-QS agent.

In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

PubMed Central

Miller, Peter G.; Al-Shahrour, Fatima; Hartwell, Kimberly A.; Chu, Lisa P.; Järås, Marcus; Puram, Rishi V.; Puissant, Alexandre; Callahan, Kevin P.; Ashton, John; McConkey, Marie E.; Poveromo, Luke P.; Cowley, Glenn S.; Kharas, Michael G.; Labelle, Myriam; Shterental, Sebastian; Fujisaki, Joji; Silberstein, Lev; Alexe, Gabriela; Al-Hajj, Muhammad A.; Shelton, Christopher A.; Armstrong, Scott A.; Root, David E.; Scadden, David T.; Hynes, Richard O.; Mukherjee, Siddhartha; Stegmaier, Kimberly; Jordan, Craig T.; Ebert, Benjamin L.

2013-01-01

SUMMARY We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. PMID:23770013

The over expression of long non-coding RNA ANRIL promotes epithelial-mesenchymal transition by activating the ATM-E2F1 signaling pathway in pancreatic cancer: An in vivo and in vitro study.

PubMed

Chen, Shi; Zhang, Jia-Qiang; Chen, Jiang-Zhi; Chen, Hui-Xing; Qiu, Fu-Nan; Yan, Mao-Lin; Chen, Yan-Ling; Peng, Cheng-Hong; Tian, Yi-Feng; Wang, Yao-Dong

2017-09-01

This study aims to investigate the roles of lncRNA ANRIL in epithelial-mesenchymal transition (EMT) by regulating the ATM-E2F1 signaling pathway in pancreatic cancer (PC). PC rat models were established and ANRIL overexpression and interference plasmids were transfected. The expression of ANRIL, EMT markers (E-cadherin, N-cadherin and Vimentin) and ATM-E2F1 signaling pathway-related proteins (ATM, E2F1, INK4A, INK4B and ARF) were detected. Small molecule drugs were applied to activate and inhibit the ATM-E2F1 signaling pathway. Transwell assay and the scratch test were adopted to detect cell invasion and migration abilities. ANRIL expression in the PC cells was higher than in normal pancreatic duct epithelial cells. In the PC rat models and PC cells, ANRIL interference promoted the expressions of INK4B, INK4A, ARF and E-cadherin, while reduced N-cadherin and Vimentin expression. Over-expressed ANRIL decreased the expression of INK4B, INK4A, ARF and E-cadherin, but raised N-cadherin and Vimentin expressions. By inhibiting the ATM-E2F1 signaling pathway in PC cells, E-cadherin expression increased but N-cadherin and Vimentin expressions decreased. After ANRIL was silenced or the ATM-E2F1 signaling pathway inhibited, PC cell migration and invasion abilities were decreased. In conclusion, over-expression of lncRNA ANRIL can promote EMT of PC cells by activating the ATM-E2F1 signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Naturally occurring phenolic acids modulate TPA-induced activation of EGFR, AP-1, and STATs in mouse epidermis.

PubMed

Cichocki, Michał; Dałek, Miłosz; Szamałek, Mateusz; Baer-Dubowska, Wanda

2014-01-01

Epidermal growth factor receptor (EGFR) plays an important role in epithelial carcinogenesis and appears to be involved in STATs activation. In this study we investigated the possible interference of naturally occurring phenolic acids with EGFR, activator protein-1 (AP-1), and signal transducers and activators of transcription (STATs) pathways activated by topical application of tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Balb/c mice epidermis. Pretreatment with tannic or chlorogenic acid resulted in a significant decrease in the phosphorylation of EGFR Y-1068 and Y-1173 tyrosine residues, which was accompanied by reduced activation of AP-1. Tannic acid decreased also the c-Jun AP-1 subunit level and binding to TPA response element (TRE) (3- and 2-fold in comparison with TPA-treated group respectively). Simultaneous reduction of JNK activity might be responsible for reduced activation of AP-1. In contrast to these more complex phenolics, protocatechuic acid increased the activity of JNK and was also the most efficient inhibitor of STATs activation. These results indicate that naturally occurring phenolic acids, by decreasing EGFR, AP-1, and STATs activation, may modulate other elements both upstream and downstream in these pathways and thus inhibit the tumor development. Although more complex phenolics affect mainly the EGFR/AP-1 pathway, STATs seem to be the most important targets for simple compounds, such as protocatechuic acid.

Systems Biology of Tissue-Specific Response to Anaplasma phagocytophilum Reveals Differentiated Apoptosis in the Tick Vector Ixodes scapularis

PubMed Central

Ayllón, Nieves; Villar, Margarita; Galindo, Ruth C.; Kocan, Katherine M.; Šíma, Radek; López, Juan A.; Vázquez, Jesús; Alberdi, Pilar; Cabezas-Cruz, Alejandro; Kopáček, Petr; de la Fuente, José

2015-01-01

Anaplasma phagocytophilum is an emerging pathogen that causes human granulocytic anaplasmosis. Infection with this zoonotic pathogen affects cell function in both vertebrate host and the tick vector, Ixodes scapularis. Global tissue-specific response and apoptosis signaling pathways were characterized in I. scapularis nymphs and adult female midguts and salivary glands infected with A. phagocytophilum using a systems biology approach combining transcriptomics and proteomics. Apoptosis was selected for pathway-focused analysis due to its role in bacterial infection of tick cells. The results showed tissue-specific differences in tick response to infection and revealed differentiated regulation of apoptosis pathways. The impact of bacterial infection was more pronounced in tick nymphs and midguts than in salivary glands, probably reflecting bacterial developmental cycle. All apoptosis pathways described in other organisms were identified in I. scapularis, except for the absence of the Perforin ortholog. Functional characterization using RNA interference showed that Porin knockdown significantly increases tick colonization by A. phagocytophilum. Infection with A. phagocytophilum produced complex tissue-specific alterations in transcript and protein levels. In tick nymphs, the results suggested a possible effect of bacterial infection on the inhibition of tick immune response. In tick midguts, the results suggested that A. phagocytophilum infection inhibited cell apoptosis to facilitate and establish infection through up-regulation of the JAK/STAT pathway. Bacterial infection inhibited the intrinsic apoptosis pathway in tick salivary glands by down-regulating Porin expression that resulted in the inhibition of Cytochrome c release as the anti-apoptotic mechanism to facilitate bacterial infection. However, tick salivary glands may promote apoptosis to limit bacterial infection through induction of the extrinsic apoptosis pathway. These dynamic changes in response to A. phagocytophilum in I. scapularis tissue-specific transcriptome and proteome demonstrated the complexity of the tick response to infection and will contribute to characterize gene regulation in ticks. PMID:25815810

Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans

PubMed Central

Yang, H-C; Chen, T-L; Wu, Y-H; Cheng, K-P; Lin, Y-H; Cheng, M-L; Ho, H-Y; Lo, S J; Chiu, D T-Y

2013-01-01

Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively. PMID:23640458

Long non-coding RNA MEG3 inhibits the proliferation and metastasis of oral squamous cell carcinoma by regulating the WNT/β-catenin signaling pathway.

PubMed

Liu, Zongxiang; Wu, Cui; Xie, Nina; Wang, Penglai

2017-10-01

This study aimed to investigate how long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) inhibits the growth and metastasis of oral squamous cell carcinoma (OSCC) by regulating WNT/β-catenin signaling pathway in order to explore the antitumor effect of MEG3 and to provide a potential molecular target for the treatment of OSCC. The RT-qPCR technique was used to quantitatively analyze the expression of MEG3 in cancer and adjacent tissues collected from the patients after surgery. Using the Lipofectamine method, the MEG3 overexpression vector and the siRNA interference vector were constructed and transfected into SCC15 and Cal27 cells, respectively, followed by cell proliferation, apoptosis and metastasis analyses. The semi-quantitative analysis of the expression of the β-catenin protein in transfected cells was performed by the western blot analysis, and the activity of the WNT/β-catenin signaling pathway was analyzed using the TOP/FOP flash reporters. In addition, the cells were treated with decitabine to investigate the correlation between the MEG3 expression and the DNA methylation. Results showed that the expression level of MEG3 was significantly decreased in OSCC (p<0.05) and overexpression of MEG3 inhibited the proliferation and metastasis of cancer cells and promoted apoptosis. Importantly, MEG3 played a role as a tumor suppressor by inhibiting the WNT/β-catenin signaling pathway. In addition, the expression of the MEG3 was significantly affected by the degree of DNA methylation. It was concluded that the lncRNA MEG3 can inhibit the growth and metastasis of OSCC by negatively regulating the WNT/β-catenin signaling pathway.

Solid-state carrier-envelope phase stabilization via quantum interference control of injected photocurrents.

PubMed

Roos, P A; Li, Xiaoqin; Smith, R P; Pipis, Jessica A; Fortier, T M; Cundiff, S T

2005-04-01

We demonstrate carrier-envelope phase stabilization of a mode-locked Ti:sapphire laser by use of quantum interference control of injected photocurrents in a semiconductor. No harmonic generation is required for this stabilization technique. Instead, interference between coexisting single- and two-photon absorption pathways in the semiconductor provides a phase comparison between different spectral components. The phase comparison, and the detection of the photocurrent that it produces, both occur within a single low-temperature-grown gallium arsenide sample. The carrier-envelope offset beat note fidelity is 30 dB in a 10-kHz resolution bandwidth. The out-of-loop phase-noise level is essentially identical to the best previous measurements with the standard self-referencing technique.

Interference Mitigation Effects on Synthetic Aperture Radar Coherent Data Products

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

Musgrove, Cameron

For synthetic aperture radars radio frequency interference from sources external to the radar system and techniques to mitigate the interference can degrade the quality of the image products. Usually the radar system designer will try to balance the amount of mitigation for an acceptable amount of interference to optimize the image quality. This dissertation examines the effect of interference mitigation upon coherent data products of fine resolution, high frequency synthetic aperture radars using stretch processing. Novel interference mitigation techniques are introduced that operate on single or multiple apertures of data that increase average coherence compared to existing techniques. New metricsmore » are applied to evaluate multiple mitigation techniques for image quality and average coherence. The underlying mechanism for interference mitigation techniques that affect coherence is revealed.« less

STAT3 inhibition as a therapeutic strategy for leukemia.

PubMed

Kanna, Rubashruti; Choudhary, Gaurav; Ramachandra, Nandini; Steidl, Ulrich; Verma, Amit; Shastri, Aditi

2017-11-22

Leukemia is characterized by selective overgrowth of malignant hematopoietic stem cells (HSC's) that interfere with HSC differentiation. Cytoreductive chemotherapy can kill rapidly dividing cancerous cells but cannot eradicate the malignant HSC pool leading to relapses. Leukemic stem cells have several dysregulated pathways and the Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) pathway are prominent among them. STAT3 is an important transcription factor that regulates cell growth, proliferation, and inhibits apoptosis. High STAT3 expression in leukemia has been associated with an increased risk for relapse and decreased overall survival. Multiple strategies for interfering with STAT3 activity in leukemic cells include inhibition of STAT3 phosphorylation, interfering with STAT3 interactions, preventing nuclear transfer, inhibiting transcription and causing interference in STAT: DNA binding. A better understanding of key interactions and upstream mediators of STAT3 activity will help facilitate the development of effective cancer therapies and may result in durable remissions.

High-order corrections on the laser cooling limit in the Lamb-Dicke regime.

PubMed

Yi, Zhen; Gu, Wen-Ju

2017-01-23

We investigate corrections on the cooling limit of high-order Lamb-Dicke (LD) parameters in the double electromagnetically induced transparency (EIT) cooling scheme. Via utilizing quantum interferences, the single-phonon heating mechanism vanishes and the system evolves to a double dark state, from which we will obtain the mechanical occupation on the single-phonon excitation state. In addition, the further correction induced by two-phonon heating transitions is included to achieve a more accurate cooling limit. There exist two pathways of two-phonon heating transitions: direct two-phonon excitation from the dark state and further excitation from the single-phonon excited state. By adding up these two parts of correction, the obtained analytical predictions show a well consistence with numerical results. Moreover, we find that the two pathways can destructively interfere with each other, leading to the elimination of two-phonon heating transitions and achieving a lower cooling limit.

Zinc chelation decreases IFN-β-induced STAT1 upregulation and iNOS expression in RAW 264.7 macrophages.

PubMed

Reiber, Cathleen; Brieger, Anne; Engelhardt, Gabriela; Hebel, Silke; Rink, Lothar; Haase, Hajo

2017-12-01

One consequence of lipopolysaccharide (LPS)-induced stimulation of macrophages is the release of Interferon (IFN)-β, and subsequently the activation of the JAK-STAT1 pathway, resulting in the expression of inducible nitric oxide synthase (iNOS). Free intracellular zinc ions (Zn 2+ ) have a profound impact as a second messenger in LPS-dependent gene expression. Previous work had indicated a Zn 2+ -dependent upregulation of STAT1 mRNA in response to LPS and IFN-β, potentially affecting STAT1-dependent downstream signaling upon pre-incubation with these agents. The aim of the present study was to investigate the long-term influence of Zn 2+ chelation on cellular STAT1 levels and their effect on protein levels and activity of iNOS. The LPS- and IFN-β-mediated increase of STAT1 mRNA and protein levels was abrogated by chelation of Zn 2+ with the membrane permeable chelator N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) in RAW 264.7 macrophages. After 48h pre-incubation together with IFN-β, TPEN also led to reduced nitric monoxide formation in response to a second stimulation with LPS. Nonetheless, the latter was observed regardless of any pre-incubation with IFN-β, suggesting that the effect of treatment with TPEN negatively affects iNOS induction independently from cellular STAT1 levels. In conclusion, long term Zn 2+ chelation does affect STAT1 protein expression, but interferes with NO production by a different, yet unknown pathway not involving STAT1. However, as there are many additional STAT1-dependent genes, there might still be effects on targets other than iNOS. Copyright © 2017 Elsevier GmbH. All rights reserved.

Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling.

PubMed

Farquharson, Colin; Ahmed, S Faisal

2013-04-01

Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. Despite attempts to promote growth and control disease, there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action. Thus, there is an urgent need to consider better and alternative forms of therapy that are directed specifically at the mechanism of the insult which leads to abnormal bone health. Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling. Therefore, in this review, we will focus on the premise that SOCS2 signaling represents a critical pathway in growth plate chondrocytes through which pro-inflammatory cytokines alter both GH/IGF-1 signaling and cellular function.

[Effects of hypothalamic microinjections of 6-hydroxydopamine (6-OHDA) on estral cycle and morphology of the genital tract in the female rat (author's transl)].

PubMed

Sala, M A; Oteui, J T; Benedetti, W I

1975-01-01

To determine whether central catecholaminergic pathways are involved in the neural contral of gonadotrophin secretion, they were interrupted at the hypothalamic level by microinjections of 6-hydroxydopamine (6-OHDA). The effects on ovulation, estral cycle and ovarian and uterine histology were studied. Microinjections of 50 mug of 6-OHDA hydrobromyde were made bilaterally into the anterolateral hypothalamus in a group of rats. Another group was injected with 25 mug of 6-OHDA, while a control group recieved an equivalent volume (5 mul) of saline with ascorbic acid. Animals injected with 50 mug of 6-OHDA showed blockade of ovulation, vaginal cytology characteristics of persistent estrous, polyfollicular ovaries and enlarged uteri with hypertrophic endometrial glands. In the group injected with 25 mug, similiar effects were demonstrated, but the number of affected animals was smaller than that in the 50 mug group. Control animals dit not show modifications, either in estral cycle or in ovarian and uterine histology. These results suggest that 6-OHDA injected into the anterolateral hypothalmus interferes with catecholaminergic pathways that participate in the neural control of ovulation.

The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration

PubMed Central

Altmann, Christine

2018-01-01

Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be part of diabetic retinopathy. Microglia, the resident monocytes of the retina, are activated due to a complex interplay between the different cell types of the retina and diverse pathological pathways. The trigger for developing diabetic retinopathy is diabetes-induced hyperglycemia, accompanied by leukostasis and vascular leakages. Transcriptional changes in activated microglia, mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and extracellular signal–regulated kinase (ERK) signaling pathways, results in release of various pro-inflammatory mediators, including cytokines, chemokines, caspases and glutamate. Activated microglia additionally increased proliferation and migration. Among other consequences, these changes in microglia severely affected retinal neurons, causing increased apoptosis and subsequent thinning of the nerve fiber layer, resulting in visual loss. New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients. PMID:29301251

Prolonged effect of the stratospheric pathway in linking Barents-Kara Sea sea ice variability to the midlatitude circulation in a simplified model

NASA Astrophysics Data System (ADS)

Zhang, Pengfei; Wu, Yutian; Smith, Karen L.

2018-01-01

To better understand the dynamical mechanism that accounts for the observed lead-lag correlation between the early winter Barents-Kara Sea (BKS) sea ice variability and the later winter midlatitude circulation response, a series of experiments are conducted using a simplified atmospheric general circulation model with a prescribed idealized near-surface heating over the BKS. A prolonged effect is found in the idealized experiments following the near-surface heating and can be explicitly attributed to the stratospheric pathway and the long time scale in the stratosphere. The analysis of the Eliassen-Palm flux shows that, as a result of the imposed heating and linear constructive interference, anomalous upward propagating planetary-scale waves are excited and weaken the stratospheric polar vortex. This stratospheric response persists for approximately 1-2 months accompanied by downward migration to the troposphere and the surface. This downward migration largely amplifies and extends the low-level jet deceleration in the midlatitudes and cold air advection over central Asia. The idealized model experiments also suggest that the BKS region is the most effective in affecting the midlatitude circulation than other regions over the Arctic.

Calcium delivery and storage in plant leaves: exploring the link with water flow.

PubMed

Gilliham, Matthew; Dayod, Maclin; Hocking, Bradleigh J; Xu, Bo; Conn, Simon J; Kaiser, Brent N; Leigh, Roger A; Tyerman, Stephen D

2011-04-01

Calcium (Ca) is a unique macronutrient with diverse but fundamental physiological roles in plant structure and signalling. In the majority of crops the largest proportion of long-distance calcium ion (Ca(2+)) transport through plant tissues has been demonstrated to follow apoplastic pathways, although this paradigm is being increasingly challenged. Similarly, under certain conditions, apoplastic pathways can dominate the proportion of water flow through plants. Therefore, tissue Ca supply is often found to be tightly linked to transpiration. Once Ca is deposited in vacuoles it is rarely redistributed, which results in highly transpiring organs amassing large concentrations of Ca ([Ca]). Meanwhile, the nutritional flow of Ca(2+) must be regulated so it does not interfere with signalling events. However, water flow through plants is itself regulated by Ca(2+), both in the apoplast via effects on cell wall structure and stomatal aperture, and within the symplast via Ca(2+)-mediated gating of aquaporins which regulates flow across membranes. In this review, an integrated model of water and Ca(2+) movement through plants is developed and how this affects [Ca] distribution and water flow within tissues is discussed, with particular emphasis on the role of aquaporins.

[Haemolysis and turbidity influence on three analysis methods of quantitative determination of total and conjugated bilirubin on ADVIA 1650].

PubMed

Gobert De Paepe, E; Munteanu, G; Schischmanoff, P O; Porquet, D

2008-01-01

Plasma bilirubin testing is crucial to prevent the occurrence of neonatal kernicterus. Haemolysis may occur during sampling and interfere with bilirubin determination. Moreover, lipidic infusions may induce plasma lipemia and also interfere with bilirubin measurement. We evaluated the interference of haemolysis and lipemia with three methods of total and direct bilirubin measurement adaptated on an Advia 1650 analyser (Siemens Medical Solutions Diagnostics) : Synermed (Sofibel), Bilirubin 2 (Siemens) and Bilirubin Auto FS (Diasys). The measurement of total bilirubin was little affected by haemolysis with all three methods. The Bilirubin 2 (Siemens) method was the less sensitive to haemolysis even at low bilirubin levels. The measurement of conjugated bilirubin was significantly altered by low heamoglobin concentrations for Bilirubin Auto FS(R) (30 microM or 0,192 g/100 mL haemoglobin) and for Synermed (60 microM or 0,484 g/100 mL haemoglobin). In marked contrast, we found no haemoglobin interference with the Direct Bilirubin 2 reagent which complied with the method validation criteria from the French Society for Biological Chemistry. The lipemia up to 2 g/L of Ivelip did not affect neither the measurement of total bilirubin for all three methods nor the measurement of conjugated bilirubin with the Diasys and Siemens reagents. However, we observed a strong interference starting at 0,5 g/L of Ivelip with the Synermed reagent. Our data suggest that both Siemens and Diasys methods allow to measure accurately total and conjugated bilirubin in hemolytic and lipemic samples, nevertheless, the Siemens methodology is less affected by these interferences.

Polyhydroxylated [60]fullerene binds specifically to functional recognition sites on a monomeric and a dimeric ubiquitin

NASA Astrophysics Data System (ADS)

Zanzoni, Serena; Ceccon, Alberto; Assfalg, Michael; Singh, Rajesh K.; Fushman, David; D'Onofrio, Mariapina

2015-04-01

The use of nanoparticles (NPs) in biomedical applications requires an in-depth understanding of the mechanisms by which NPs interact with biomolecules. NPs associating with proteins may interfere with protein-protein interactions and affect cellular communication pathways, however the impact of NPs on biomolecular recognition remains poorly characterized. In this respect, particularly relevant is the study of NP-induced functional perturbations of proteins implicated in the regulation of key biochemical pathways. Ubiquitin (Ub) is a prototypical protein post-translational modifier playing a central role in numerous essential biological processes. To contribute to the understanding of the interactions between this universally distributed biomacromolecule and NPs, we investigated the adsorption of polyhydroxylated [60]fullerene on monomeric Ub and on a minimal polyubiquitin chain in vitro at atomic resolution. Site-resolved chemical shift and intensity perturbations of Ub's NMR signals, together with 15N spin relaxation rate changes, exchange saturation transfer effects, and fluorescence quenching data were consistent with the reversible formation of soluble aggregates incorporating fullerenol clusters. The specific interaction epitopes were identified, coincident with functional recognition sites in a monomeric and lysine48-linked dimeric Ub. Fullerenol appeared to target the open state of the dynamic structure of a dimeric Ub according to a conformational selection mechanism. Importantly, the protein-NP association prevented the enzyme-catalyzed synthesis of polyubiquitin chains. Our findings provide an experiment-based insight into protein/fullerenol recognition, with implications in functional biomolecular communication, including regulatory protein turnover, and for the opportunity of therapeutic intervention in Ub-dependent cellular pathways.The use of nanoparticles (NPs) in biomedical applications requires an in-depth understanding of the mechanisms by which NPs interact with biomolecules. NPs associating with proteins may interfere with protein-protein interactions and affect cellular communication pathways, however the impact of NPs on biomolecular recognition remains poorly characterized. In this respect, particularly relevant is the study of NP-induced functional perturbations of proteins implicated in the regulation of key biochemical pathways. Ubiquitin (Ub) is a prototypical protein post-translational modifier playing a central role in numerous essential biological processes. To contribute to the understanding of the interactions between this universally distributed biomacromolecule and NPs, we investigated the adsorption of polyhydroxylated [60]fullerene on monomeric Ub and on a minimal polyubiquitin chain in vitro at atomic resolution. Site-resolved chemical shift and intensity perturbations of Ub's NMR signals, together with 15N spin relaxation rate changes, exchange saturation transfer effects, and fluorescence quenching data were consistent with the reversible formation of soluble aggregates incorporating fullerenol clusters. The specific interaction epitopes were identified, coincident with functional recognition sites in a monomeric and lysine48-linked dimeric Ub. Fullerenol appeared to target the open state of the dynamic structure of a dimeric Ub according to a conformational selection mechanism. Importantly, the protein-NP association prevented the enzyme-catalyzed synthesis of polyubiquitin chains. Our findings provide an experiment-based insight into protein/fullerenol recognition, with implications in functional biomolecular communication, including regulatory protein turnover, and for the opportunity of therapeutic intervention in Ub-dependent cellular pathways. Electronic supplementary information (ESI) available: Experimental details. Fig. S1. Characterization of fullerenol by dynamic light scattering. Fig. S2. Size-exclusion chromatography. Fig. S3. 15N R1 spin relaxation rates of Ub and Ub2 upon subsequent additions of fullerenol. See DOI: 10.1039/c5nr00539f

Influence of Fano interference and incoherent processes on optical bistability in a four-level quantum dot nanostructure

NASA Astrophysics Data System (ADS)

Seyyed, Hossein Asadpour; G, Solookinejad; M, Panahi; E Ahmadi, Sangachin

2016-03-01

Role of Fano interference and incoherent pumping field on optical bistability in a four-level designed InGaN/GaN quantum dot nanostructure embedded in a unidirectional ring cavity are analyzed. It is found that intensity threshold of optical bistability can be manipulated by Fano interference. It is shown that incoherent pumping fields make the threshold of optical bistability behave differently by Fano interference. Moreover, in the presence of Fano interference the medium becomes phase-dependent. Therefore, the relative phase of applied fields can affect the behaviors of optical bistability and intensity threshold can be controlled easily.

RNA interference-mediated intrinsic antiviral immunity in invertebrates.

PubMed

Nayak, Arabinda; Tassetto, Michel; Kunitomi, Mark; Andino, Raul

2013-01-01

In invertebrates such as insects and nematodes, RNA interference (RNAi) provides RNA-based protection against viruses. This form of immunity restricts viral replication and dissemination from infected cells and viruses, in turn, have evolved evasion mechanisms or RNAi suppressors to counteract host defenses. Recent advances indicate that, in addition to RNAi, other related small RNA pathways contribute to antiviral functions in invertebrates. This has led to a deeper understanding of fundamental aspects of small RNA-based antiviral immunity in invertebrates and its contribution to viral spread and pathogenesis.

Effects of SARA on oxygen-glucose deprivation in PC12 cell line.

PubMed

Wang, Jiao-Qi; He, Jin-Ting; Du, Zhen-Wu; Li, Zong-Shu; Liu, Yong-Feng; Mang, Jing; Xu, Zhong-Xin

2013-05-01

Ischemic stroke is a major composition of cerebrovascular disease, seriously threatening to human health in the world. Activin A (ActA), belonging to transforming growth factor-beta (TGF-β) super family, plays an important role in the hypoxic-ischemic brain injury through ActA/Smads pathway. While as an essential phosphorylation assistor in TGF-β signaling, the functions and mechanisms of smad anchor for receptor activation (SARA) in ischemic brain injury remain poorly understood. To solve this problem and explore the pathological processes of ischemic stroke, we used an Oxygen-Glucose deprivation (OGD) model in nerve growth factor-induced differentiated rattus PC12 pheochromocytoma cells and down regulated the expressions of SARA by RNA interference technology. Our results showed that the repression of SARA before OGD exposure reduced the expressions of Smad2, 3, 4 mRNA and the phosphorylation rate of Smad2 protein, but it did not affect the mRNA expressions of Smad7. After OGD treatment, ActA/Smads pathway was activated and the expression of SARA in the SARA pre-repression group was significantly up-regulated. The pre-repression of SARA increased the sensitivities of nerve-like cells to OGD damage. Moreover, the mRNA expression of Smad7 which was supposed to participate in the negative feedback of ActA/Smads pathway was also elevated due to OGD injury. Taken together, these results suggest a positive role of SARA in assisting the phosphorylation of Smad2 and maintaining the neuron protective effect of ActA/Smads pathway.

Reprogrammed Glucose Metabolic Pathways of Inhibitor-Tolerant Yeast

USDA-ARS?s Scientific Manuscript database

Representative inhibitory compounds such as furfural and 5-hydroxymethylfurfural generated from lignocellulosic biomass pretreatment inhibit yeast growth and interfere with the subsequent ethanol fermentation. Evolutionary engineering under laboratory settings is a powerful tool that can be used to ...

Reprogrammed glucose metabolic pathways of inhibitor-tolerant yeast

USDA-ARS?s Scientific Manuscript database

Representative inhibitory compounds such as furfural and 5-hydroxymethylfurfural generated from lignocellulosic biomass pretreatment inhibit yeast growth and interfere with the subsequent ethanol fermentation. Evolutionary engineering under laboratory settings is a powerful tool that can be used to...

RNA Interference Restricts Rift Valley Fever Virus in Multiple Insect Systems.

PubMed

Dietrich, Isabelle; Jansen, Stephanie; Fall, Gamou; Lorenzen, Stephan; Rudolf, Martin; Huber, Katrin; Heitmann, Anna; Schicht, Sabine; Ndiaye, El Hadji; Watson, Mick; Castelli, Ilaria; Brennan, Benjamin; Elliott, Richard M; Diallo, Mawlouth; Sall, Amadou A; Failloux, Anna-Bella; Schnettler, Esther; Kohl, Alain; Becker, Stefanie C

2017-01-01

The emerging bunyavirus Rift Valley fever virus (RVFV) is transmitted to humans and livestock by a large number of mosquito species. RNA interference (RNAi) has been characterized as an important innate immune defense mechanism used by mosquitoes to limit replication of positive-sense RNA flaviviruses and togaviruses; however, little is known about its role against negative-strand RNA viruses such as RVFV. We show that virus-specific small RNAs are produced in infected mosquito cells, in Drosophila melanogaster cells, and, most importantly, also in RVFV vector mosquitoes. By addressing the production of small RNAs in adult Aedes sp. and Culex quinquefasciatus mosquitoes, we showed the presence of virus-derived Piwi-interacting RNAs (piRNAs) not only in Aedes sp. but also in C. quinquefasciatus mosquitoes, indicating that antiviral RNA interference in C. quinquefasciatus mosquitoes is similar to the described activities of RNAi in Aedes sp. mosquitoes. We also show that these have antiviral activity, since silencing of RNAi pathway effectors enhances viral replication. Moreover, our data suggest that RVFV does not encode a suppressor of RNAi. These findings point toward a significant role of RNAi in the control of RVFV in mosquitoes. IMPORTANCE Rift Valley fever virus (RVFV; Phlebovirus , Bunyaviridae ) is an emerging zoonotic mosquito-borne pathogen of high relevance for human and animal health. Successful strategies of intervention in RVFV transmission by its mosquito vectors and the prevention of human and veterinary disease rely on a better understanding of the mechanisms that govern RVFV-vector interactions. Despite its medical importance, little is known about the factors that govern RVFV replication, dissemination, and transmission in the invertebrate host. Here we studied the role of the antiviral RNA interference immune pathways in the defense against RVFV in natural vector mosquitoes and mosquito cells and draw comparisons to the model insect Drosophila melanogaster . We found that RVFV infection induces both the exogenous small interfering RNA (siRNA) and piRNA pathways, which contribute to the control of viral replication in insects. Furthermore, we demonstrate the production of virus-derived piRNAs in Culex quinquefasciatus mosquitoes. Understanding these pathways and the targets within them offers the potential of the development of novel RVFV control measures in vector-based strategies.

RNA Interference Restricts Rift Valley Fever Virus in Multiple Insect Systems

PubMed Central

Jansen, Stephanie; Fall, Gamou; Lorenzen, Stephan; Rudolf, Martin; Huber, Katrin; Heitmann, Anna; Schicht, Sabine; Ndiaye, El Hadji; Watson, Mick; Castelli, Ilaria; Elliott, Richard M.; Diallo, Mawlouth; Sall, Amadou A.; Failloux, Anna-Bella; Schnettler, Esther

2017-01-01

ABSTRACT The emerging bunyavirus Rift Valley fever virus (RVFV) is transmitted to humans and livestock by a large number of mosquito species. RNA interference (RNAi) has been characterized as an important innate immune defense mechanism used by mosquitoes to limit replication of positive-sense RNA flaviviruses and togaviruses; however, little is known about its role against negative-strand RNA viruses such as RVFV. We show that virus-specific small RNAs are produced in infected mosquito cells, in Drosophila melanogaster cells, and, most importantly, also in RVFV vector mosquitoes. By addressing the production of small RNAs in adult Aedes sp. and Culex quinquefasciatus mosquitoes, we showed the presence of virus-derived Piwi-interacting RNAs (piRNAs) not only in Aedes sp. but also in C. quinquefasciatus mosquitoes, indicating that antiviral RNA interference in C. quinquefasciatus mosquitoes is similar to the described activities of RNAi in Aedes sp. mosquitoes. We also show that these have antiviral activity, since silencing of RNAi pathway effectors enhances viral replication. Moreover, our data suggest that RVFV does not encode a suppressor of RNAi. These findings point toward a significant role of RNAi in the control of RVFV in mosquitoes. IMPORTANCE Rift Valley fever virus (RVFV; Phlebovirus, Bunyaviridae) is an emerging zoonotic mosquito-borne pathogen of high relevance for human and animal health. Successful strategies of intervention in RVFV transmission by its mosquito vectors and the prevention of human and veterinary disease rely on a better understanding of the mechanisms that govern RVFV-vector interactions. Despite its medical importance, little is known about the factors that govern RVFV replication, dissemination, and transmission in the invertebrate host. Here we studied the role of the antiviral RNA interference immune pathways in the defense against RVFV in natural vector mosquitoes and mosquito cells and draw comparisons to the model insect Drosophila melanogaster. We found that RVFV infection induces both the exogenous small interfering RNA (siRNA) and piRNA pathways, which contribute to the control of viral replication in insects. Furthermore, we demonstrate the production of virus-derived piRNAs in Culex quinquefasciatus mosquitoes. Understanding these pathways and the targets within them offers the potential of the development of novel RVFV control measures in vector-based strategies. PMID:28497117

Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets

PubMed Central

Svitek, Nicholas; Gerhauser, Ingo; Goncalves, Christophe; Grabski, Elena; Döring, Marius; Kalinke, Ulrich; Anderson, Danielle E.; Cattaneo, Roberto

2014-01-01

ABSTRACT The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus Morbillivirus interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties. IMPORTANCE The V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors. PMID:24371065

Morbillivirus control of the interferon response: relevance of STAT2 and mda5 but not STAT1 for canine distemper virus virulence in ferrets.

PubMed

Svitek, Nicholas; Gerhauser, Ingo; Goncalves, Christophe; Grabski, Elena; Döring, Marius; Kalinke, Ulrich; Anderson, Danielle E; Cattaneo, Roberto; von Messling, Veronika

2014-03-01

The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus Morbillivirus interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties. The V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors.

Effects of additional interfering signals on adaptive array performance

NASA Technical Reports Server (NTRS)

Moses, Randolph L.

1989-01-01

The effects of additional interference signals on the performance of a fully adaptive array are considered. The case where the number of interference signals exceeds the number of array degrees of freedom is addressed. It is shown how performance is affected as a function of the number of array elements, the number of interference signals, and the directivity of the array antennas. By using directive auxiliary elements, the performance of the array can be as good as the performance when the additional interference signals are not present.

Examining the Effect of Interference on Short-Term Memory Recall of Arabic Abstract and Concrete Words Using Free, Cued, and Serial Recall Paradigms

ERIC Educational Resources Information Center

Alduais, Ahmed Mohammed Saleh; Almukhaizeem, Yasir Saad

2015-01-01

Purpose: To see if there is a correlation between interference and short-term memory recall and to examine interference as a factor affecting memory recalling of Arabic and abstract words through free, cued, and serial recall tasks. Method: Four groups of undergraduates in King Saud University, Saudi Arabia participated in this study. The first…

Extracting binaural information from simultaneous targets and distractors: Effects of amplitude modulation and asynchronous envelopes

PubMed Central

Stellmack, Mark A.; Byrne, Andrew J.; Viemeister, Neal F.

2010-01-01

When different components of a stimulus carry different binaural information, processing of binaural information in a target component is often affected. The present experiments examine whether such interference is affected by amplitude modulation and the relative phase of modulation of the target and distractors. In all experiments, listeners attempted to discriminate interaural time differences of a target stimulus in the presence of distractor stimuli with ITD=0. In Experiment 1, modulation of the distractors but not the target reduced interference between components. In Experiment 2, synthesized musical notes exhibited little binaural interference when there were slight asynchronies between different streams of notes (31 or 62 ms). The remaining experiments suggested that the reduction in binaural interference in the previous experiments was due neither to the complex spectra of the synthesized notes nor to greater detectability of the target in the presence of modulated distractors. These data suggest that this interference is reduced when components are modulated in ways that result in the target appearing briefly in isolation, not because of segregation cues. These data also suggest that modulation and asynchronies between modulators that might be encountered in real-world listening situations are adequate to reduce binaural interference to inconsequential levels. PMID:20815459

Physiological and Subjective Evaluation of the Temperate Battle Dress Uniform (TBDU) and Three Other Uniforms Worn by Men and Women in Tropical Climatic Conditions

DTIC Science & Technology

1983-05-01

worn in the heat affects thermal comfort and with an added solar heat load subsequently interferes with the ability to dissipate stored body heat...worn in the heat affects thermal comfort and with an added solar heat load subsequently interferes with the ability to dissipate stored body heat...ratio; thermal comfort ; evaporative cooling; permeability; physiological responses mA]X .................................... INTRODUCTION The Temperate

Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells.

PubMed

Shi, Xiarong; Burkart, Alison; Nicoloro, Sarah M; Czech, Michael P; Straubhaar, Juerg; Corvera, Silvia

2008-11-07

Adipocyte function is crucial for the control of whole body energy homeostasis. Pathway analysis of differentiating 3T3-L1 adipocytes reveals that major metabolic pathways induced during differentiation involve mitochondrial function. However, it is not clear why differentiated white adipocytes require enhanced respiratory chain activity relative to pre-adipocytes. To address this question, we used small interference RNA to interfere with the induction of the transcription factor Tfam, which is highly induced between days 2 and 4 of differentiation and is crucial for replication of mitochondrial DNA. Interference with Tfam resulted in cells with decreased respiratory chain capacity, reflected by decreased basal oxygen consumption, and decreased mitochondrial ATP synthesis, but no difference in many other adipocyte functions or expression levels of adipose-specific genes. However, insulin-stimulated GLUT4 translocation to the cell surface and subsequent glucose transport are impaired in Tfam knockdown cells. Paradoxically, insulin-stimulated Akt phosphorylation is significantly enhanced in these cells. These studies reveal independent links between mitochondrial function, insulin signaling, and glucose transport, in which impaired respiratory chain activity enhances insulin signaling to Akt phosphorylation, but impairs GLUT4 translocation. These results indicate that mitochondrial respiratory chain dysfunction in adipocytes can cause impaired insulin responsiveness of GLUT4 translocation by a mechanism downstream of the Akt protein kinase.

All Fatigue is Not Created Equal: The Association of Fatigue and Its Subtypes on Pain Interference in Orofacial Pain.

PubMed

Boggero, Ian A; Rojas-Ramirez, Marcia V; Carlson, Charles R

2017-03-01

Fatigue is known to be a pathway through which depression, psychological distress, pain intensity, and sleep disturbance influence pain interference, but the independent effects of fatigue on pain interference after controlling for these variables remains unknown. In addition, no study to date has tested whether fatigue subtypes of general fatigue, mental fatigue, emotional fatigue, physical fatigue, or vigor differentially predict pain interference. The current study tested these associations using archival medical data of 2133 chronic orofacial pain patients, who completed a battery of psychological questionnaires at the time of their first appointment at an orofacial pain clinic. Hierarchical linear regression analysis revealed that after controlling for depression, psychological distress, sleep disturbance, pain intensity, and demographic variables, fatigue predicted higher pain interference (B=0.70, SE=0.17, P<0.001, η=0.01). Physical fatigue (B=1.70, SE=0.48, P<0.001, η=0.01) and vigor (B=-3.24, SE=0.47, P<0.001, η=0.03) were independently associated with pain interference after controlling for the aforementioned variables. The findings suggest that fatigue is an important independent predictor of pain interference and not merely a mediator. These findings also suggest that not all fatigue is created equal. Interventions aimed at reducing pain interference should target specific fatigue symptoms of physical fatigue and vigor. Future research investigating the independent associations of fatigue subtypes on pain outcomes may help clarify the nature of the interrelationships between pain and fatigue.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

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

Rimon, Gilad; Sidhu, Ranjinder S.; Lauver, D. Adam

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A{sub 2} formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we reportmore » the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.« less

Locata Performance Evaluation in the Presence of Wide- and Narrow-Band Interference

NASA Astrophysics Data System (ADS)

Khan, Faisal A.; Rizos, Chris; Dempster, Andrew G.

Classically difficult positioning environments often call for augmentation technology to assist the GPS, or more generally the Global Navigation Satellite System (GNSS) technology. The ground-based ranging technology offers augmentation, and even replacement, to GPS in such environments. However, like any other system relying on wireless technology, a Locata positioning network also faces issues in the presence of RF interference (RFI). This problem is magnified due to the fact that Locata operates in the licence-free 2·4 GHz Industrial, Scientific and Medical (ISM) band. The licence-free nature of this band attracts a much larger number of devices using a wider range of signal types than for licensed bands, resulting in elevation of the noise floor. Also, harmonics from out-of-band signals can act as potential interferers. WiFi devices operating in this band have been identified as the most likely potential interferer, due partially to their use of the whole ISM band, but also because Locata applications often also may use a wireless network. This paper evaluates the performance of Locata in the presence of both narrow- and wide-band interfering signals. Effects of received interference on both raw measurements and final solutions are reported and analysed. Test results show that Locata performance degrades in the presence of received interference. It is also identified that high levels of received interference can affect Locata carriers even if the interference is not in co-frequency situation with the affected carrier. Finally, Locata characteristics have been identified which can be exploited to mitigate RFI issues.

Identifying pathways affected by cancer mutations.

PubMed

Iengar, Prathima

2017-12-16

Mutations in 15 cancers, sourced from the COSMIC Whole Genomes database, and 297 human pathways, arranged into pathway groups based on the processes they orchestrate, and sourced from the KEGG pathway database, have together been used to identify pathways affected by cancer mutations. Genes studied in ≥15, and mutated in ≥10 samples of a cancer have been considered recurrently mutated, and pathways with recurrently mutated genes have been considered affected in the cancer. Novel doughnut plots have been presented which enable visualization of the extent to which pathways and genes, in each pathway group, are targeted, in each cancer. The 'organismal systems' pathway group (including organism-level pathways; e.g., nervous system) is the most targeted, more than even the well-recognized signal transduction, cell-cycle and apoptosis, and DNA repair pathway groups. The important, yet poorly-recognized, role played by the group merits attention. Pathways affected in ≥7 cancers yielded insights into processes affected. Copyright © 2017 Elsevier Inc. All rights reserved.

Two-Electron Transfer Pathways.

PubMed

Lin, Jiaxing; Balamurugan, D; Zhang, Peng; Skourtis, Spiros S; Beratan, David N

2015-06-18

The frontiers of electron-transfer chemistry demand that we develop theoretical frameworks to describe the delivery of multiple electrons, atoms, and ions in molecular systems. When electrons move over long distances through high barriers, where the probability for thermal population of oxidized or reduced bridge-localized states is very small, the electrons will tunnel from the donor (D) to acceptor (A), facilitated by bridge-mediated superexchange interactions. If the stable donor and acceptor redox states on D and A differ by two electrons, it is possible that the electrons will propagate coherently from D to A. While structure-function relations for single-electron superexchange in molecules are well established, strategies to manipulate the coherent flow of multiple electrons are largely unknown. In contrast to one-electron superexchange, two-electron superexchange involves both one- and two-electron virtual intermediate states, the number of virtual intermediates increases very rapidly with system size, and multiple classes of pathways interfere with one another. In the study described here, we developed simple superexchange models for two-electron transfer. We explored how the bridge structure and energetics influence multielectron superexchange, and we compared two-electron superexchange interactions to single-electron superexchange. Multielectron superexchange introduces interference between singly and doubly oxidized (or reduced) bridge virtual states, so that even simple linear donor-bridge-acceptor systems have pathway topologies that resemble those seen for one-electron superexchange through bridges with multiple parallel pathways. The simple model systems studied here exhibit a richness that is amenable to experimental exploration by manipulating the multiple pathways, pathway crosstalk, and changes in the number of donor and acceptor species. The features that emerge from these studies may assist in developing new strategies to deliver multiple electrons in condensed-phase redox systems, including multiple-electron redox species, multimetallic/multielectron redox catalysts, and multiexciton excited states.

An update on mobile phones interference with medical devices.

PubMed

Mahmoud Pashazadeh, Ali; Aghajani, Mahdi; Nabipour, Iraj; Assadi, Majid

2013-10-01

Mobile phones' electromagnetic interference with medical devices is an important issue for the medical safety of patients who are using life-supporting medical devices. This review mainly focuses on mobile phones' interference with implanted medical devices and with medical equipment located in critical areas of hospitals. A close look at the findings reveals that mobile phones may adversely affect the functioning of medical devices, and the specific effect and the degree of interference depend on the applied technology and the separation distance. According to the studies' findings and the authors' recommendations, besides mitigating interference, using mobile phones at a reasonable distance from medical devices and developing technology standards can lead to their effective use in hospital communication systems.

Affective neural response to restricted interests in Autism Spectrum Disorders

PubMed Central

Cascio, Carissa J.; Foss-Feig, Jennifer H.; Heacock, Jessica; Schauder, Kimberly B.; Loring, Whitney A.; Rogers, Baxter P.; Pryweller, Jennifer R.; Newsom, Cassandra R.; Cockhren, Jurnell; Cao, Aize; Bolton, Scott

2013-01-01

Background Restricted interests are a class of repetitive behavior in autism spectrum disorders (ASD) whose intensity and narrow focus often contribute to significant interference with daily functioning. While numerous neuroimaging studies have investigated executive circuits as putative neural substrates of repetitive behavior, recent work implicates affective neural circuits in restricted interests. We sought to explore the role of affective neural circuits and determine how restricted interests are distinguished from hobbies or interests in typical development. Methods We compared a group of children with ASD to a typically developing (TD) group of children with strong interests or hobbies, employing parent report, an operant behavioral task, and functional imaging with personalized stimuli based on individual interests. Results While performance on the operant task was similar between the two groups, parent report of intensity and interference of interests was significantly higher in the ASD group. Both the ASD and TD groups showed increased BOLD response in widespread affective neural regions to pictures of their own interest. When viewing pictures of other children's interests, the TD group showed a similar pattern, whereas BOLD response in the ASD group was much more limited. Increased BOLD response in the insula and anterior cingulate cortex distinguished the ASD from the TD group, and parent report of the intensity and interference with daily life of the child's restricted interest predicted insula response. Conclusions While affective neural network response and operant behavior are comparable in typical and restricted interests, the narrowness of focus that clinically distinguishes restricted interests in ASD is reflected in more interference in daily life and aberrantly enhanced insula and anterior cingulate response to individuals’ own interests in the ASD group. These results further support the involvement of affective neural networks in repetitive behaviors in ASD. PMID:24117668

Sensing coherent phonons with two-photon interference

NASA Astrophysics Data System (ADS)

Ding, Ding; Yin, Xiaobo; Li, Baowen

2018-02-01

Detecting coherent phonons pose different challenges compared to coherent photons due to the much stronger interaction between phonons and matter. This is especially true for high frequency heat carrying phonons, which are intrinsic lattice vibrations experiencing many decoherence events with the environment, and are thus generally assumed to be incoherent. Two photon interference techniques, especially coherent population trapping (CPT) and electromagnetically induced transparency (EIT), have led to extremely sensitive detection, spectroscopy and metrology. Here, we propose the use of two photon interference in a three-level system to sense coherent phonons. Unlike prior works which have treated phonon coupling as damping, we account for coherent phonon coupling using a full quantum-mechanical treatment. We observe strong asymmetry in absorption spectrum in CPT and negative dispersion in EIT susceptibility in the presence of coherent phonon coupling which cannot be accounted for if only pure phonon damping is considered. Our proposal has application in sensing heat carrying coherent phonons effects and understanding coherent bosonic multi-pathway interference effects in three coupled oscillator systems.

Testing the distinctiveness of visual imagery and motor imagery in a reach paradigm.

PubMed

Gabbard, Carl; Ammar, Diala; Cordova, Alberto

2009-01-01

We examined the distinctiveness of motor imagery (MI) and visual imagery (VI) in the context of perceived reachability. The aim was to explore the notion that the two visual modes have distinctive processing properties tied to the two-visual-system hypothesis. The experiment included an interference tactic whereby participants completed two tasks at the same time: a visual or motor-interference task combined with a MI or VI-reaching task. We expected increased error would occur when the imaged task and the interference task were matched (e.g., MI with the motor task), suggesting an association based on the assumption that the two tasks were in competition for space on the same processing pathway. Alternatively, if there were no differences, dissociation could be inferred. Significant increases in the number of errors were found when the modalities for the imaged (both MI and VI) task and the interference task were matched. Therefore, it appears that MI and VI in the context of perceived reachability recruit different processing mechanisms.

Kondo blockade due to quantum interference in single-molecule junctions

PubMed Central

Mitchell, Andrew K.; Pedersen, Kim G. L.; Hedegård, Per; Paaske, Jens

2017-01-01

Molecular electronics offers unique scientific and technological possibilities, resulting from both the nanometre scale of the devices and their reproducible chemical complexity. Two fundamental yet different effects, with no classical analogue, have been demonstrated experimentally in single-molecule junctions: quantum interference due to competing electron transport pathways, and the Kondo effect due to entanglement from strong electronic interactions. Here we unify these phenomena, showing that transport through a spin-degenerate molecule can be either enhanced or blocked by Kondo correlations, depending on molecular structure, contacting geometry and applied gate voltages. An exact framework is developed, in terms of which the quantum interference properties of interacting molecular junctions can be systematically studied and understood. We prove that an exact Kondo-mediated conductance node results from destructive interference in exchange-cotunneling. Nonstandard temperature dependences and gate-tunable conductance peaks/nodes are demonstrated for prototypical molecular junctions, illustrating the intricate interplay of quantum effects beyond the single-orbital paradigm. PMID:28492236

Novel Spectrophotometric Method for the Assay of Captopril in Dosage Forms using 2,6-Dichloroquinone-4-Chlorimide

PubMed Central

El-Enany, Nahed; Belal, Fathalla; Rizk, Mohamed

2008-01-01

A simple spectrophotometric method was developed for the determination of captopril (CPL) in pharmaceutical preparations. The method is based on coupling captopril with 2,6-dichloroquinone-4-chlorimide (DCQ) in dimethylsulphoxide. The yellow reaction product was measured at 443 nm. The absorbance–concentration plot was rectilinear over the range of 10-50 μg/mL with minimum detection limit (LOD) of 0.66 μg/mL and a quantification limit (LOQ) of 2.0 μg/mL. The different experimental parameters affecting the development and stability of the color were carefully studied and optimized. The proposed method was successfully applied to the analysis of commercial tablets and the results were in good agreement with those obtained using official and reference spectrophotometric methods. Hydrochlorothiazide which is frequently co-formulated with CPL did not interfere with the assay. A proposal of the reaction pathway was presented. PMID:23675082

An Evolutionarily Conserved Innate Immunity Protein Interaction Network*

PubMed Central

De Arras, Lesly; Seng, Amara; Lackford, Brad; Keikhaee, Mohammad R.; Bowerman, Bruce; Freedman, Jonathan H.; Schwartz, David A.; Alper, Scott

2013-01-01

The innate immune response plays a critical role in fighting infection; however, innate immunity also can affect the pathogenesis of a variety of diseases, including sepsis, asthma, cancer, and atherosclerosis. To identify novel regulators of innate immunity, we performed comparative genomics RNA interference screens in the nematode Caenorhabditis elegans and mouse macrophages. These screens have uncovered many candidate regulators of the response to lipopolysaccharide (LPS), several of which interact physically in multiple species to form an innate immunity protein interaction network. This protein interaction network contains several proteins in the canonical LPS-responsive TLR4 pathway as well as many novel interacting proteins. Using RNAi and overexpression studies, we show that almost every gene in this network can modulate the innate immune response in mouse cell lines. We validate the importance of this network in innate immunity regulation in vivo using available mutants in C. elegans and mice. PMID:23209288

Craving love? Enduring grief activates brain's reward center.

PubMed

O'Connor, Mary-Frances; Wellisch, David K; Stanton, Annette L; Eisenberger, Naomi I; Irwin, Michael R; Lieberman, Matthew D

2008-08-15

Complicated Grief (CG) occurs when an individual experiences prolonged, unabated grief. The neural mechanisms distinguishing CG from Noncomplicated Grief (NCG) are unclear, but hypothesized mechanisms include both pain-related activity (related to the social pain of loss) and reward-related activity (related to attachment behavior). Bereaved women (11 CG, 12 NCG) participated in an event-related functional magnetic resonance imaging scan, during grief elicitation with idiographic stimuli. Analyses revealed that whereas both CG and NCG participants showed pain-related neural activity in response to reminders of the deceased, only those with CG showed reward-related activity in the nucleus accumbens (NA). This NA cluster was positively correlated with self-reported yearning, but not with time since death, participant age, or positive/negative affect. This study supports the hypothesis that attachment activates reward pathways. For those with CG, reminders of the deceased still activate neural reward activity, which may interfere with adapting to the loss in the present.

Study on ground water characteristics and the effects of discharged effluents from textile units at Karur District.

PubMed

Kannan, V; Ramesh, R; Sasikumar, C

2005-04-01

A study was made on the physico-chemical characteristics of water samples mixed with effluent discharged from textile industries at Chellandipalayam (Site--I), Senaparatti (Site--II) and Pasupathipalayam (Sites--III and IV) revealed the elevated levels of Ca, Mg, Na, Cr, K, Ni, Cu, Zn, CO3, SO4, NO3 and Cl- . The concentrations of these ions exceeded the limit prescribed by ISI. The increase in the concentrations of ions was revealed by higher values of electrical conductivity (EC). Water at these sites was found to be hard, brackish and unsuitable for drinking purpose. In all these sites, the seed germination of rice alone was significantly affected among the other crops tested. Irrigation of crops with ground water notably lowered the quantity of reserve food in rice, wheat (starch), and sugarcane (sugar), indicating the interference of their metabolic pathway by polluted ground water.

Female Partners of Men With Peyronie's Disease Have Impaired Sexual Function, Satisfaction, and Mood, While Degree of Sexual Interference Is Associated With Worse Outcomes.

PubMed

Davis, Seth N P; Ferrar, Saskia; Sadikaj, Gentiana; Gerard, Marina; Binik, Yitzchak M; Carrier, Serge

2016-07-01

Peyronie's disease (PD) causes penile deformity and can result in sexual dysfunction and psychological distress. Currently, nothing is known about the psychosexual impact on the partners of men with PD. Research carried out on the partners of men with other chronic illnesses suggests that the partners of men with PD might have increased rates of sexual dysfunction and decreased sexual satisfaction. To examine (i) sexual functioning, sexual satisfaction, negative affect, and relationship satisfaction of men with PD and their female partners and (ii) the effect of male-perceived sexual interference on partners' outcomes. Forty-four men diagnosed with PD and their female partners completed a questionnaire package. Each partner filled out the Revised Dyadic Adjustment Scale, the Positive and Negative Affect Scale, the Global Measure of Sexual Satisfaction, and the Female Sexual Function Index (women) or the International Index of Erectile Function (men). Overall, partners of men with PD were found to have decreased sexual function, sexual satisfaction, and mood compared with population-based norms. Men and their partners showed non-distressed levels of relationship satisfaction. The degree to which PD interfered with sexual activity was an important correlate of outcomes. Increased sexual interference was associated with lower sexual function and satisfaction for the person experiencing interference. Sexual interference also was associated with negative affect and relationship satisfaction in partners and the person experiencing interference. PD is associated with negative psychosexual and psychosocial effects on those with the disease and their partners. As a result, assessment and intervention should include the two members of the couple. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Evolutionarily Engineered Ethanologenic Yeast Detoxifies Lignocellulosic Biomass Conversion Inhibitors by Reprogrammed Pathways

USDA-ARS?s Scientific Manuscript database

Lignocellulosic biomass conversion inhibitors furfural and HMF inhibit microbial growth and interfere with subsequent fermentation of ethanol, posing significant challenges for a sustainable cellulosic ethanol conversion industry. Numerous yeast genes were found to be associated with the inhibitor ...

Intraindividual Coupling of Daily Stressors and Cognitive Interference in Old Age

PubMed Central

Mogle, Jacqueline; Sliwinski, Martin J.

2011-01-01

Objectives. The current study examined emotional and cognitive reactions to daily stress. We examined the psychometric properties of a short cognitive interference measure and how cognitive interference was associated with measures of daily stress and negative affect (NA) between persons and within persons over time. Methods. A sample of 87 older adults (Mage = 83, range = 70–97, 28% male) completed measures of daily stress, cognitive interference, and NA on 6 days within a 14-day period. Results. The measure yielded a single-factor solution with good reliability both between and within persons. At the between-person level, NA accounted for the effects of daily stress on individual differences in cognitive interference. At the within-person level, NA and daily stress were unique predictors of cognitive interference. Furthermore, the within-person effect of daily stress on cognitive interference decreased significantly with age. Discussion. These results support theoretical work regarding associations among stress, NA, and cognitive interference, both across persons and within persons over time. PMID:21743045

The effect of electromagnetic interference from mobile communication on the performance of intensive care ventilators.

PubMed

Jones, R P; Conway, D H

2005-08-01

Electromagnetic interference produced by wireless communication can affect medical devices and hospital policies exist to address this risk. During the transfer of ventilated patients, these policies may be compromised by essential communication between base and receiving hospitals. Local wireless networks (e.g. Bluetooth) may reduce the 'spaghetti syndrome' of wires and cables seen on intensive care units, but also generate electromagnetic interference. The aim of this study was to investigate these effects on displayed and actual ventilator performance. Five ventilators were tested: Drager Oxylog 2000, BREAS LTV-1000, Respironics BiPAP VISION, Puritan Bennett 7200 and 840. Electromagnetic interference was generated by three devices: Simoco 8020 radio handset, Nokia 7210 and Nokia 6230 mobile phone, Nokia 6230 communicating via Bluetooth with a Palm Tungsten T Personal Digital Assistant. We followed the American National Standard Recommended Practice for On-Site, Ad Hoc Testing (ANSI C63) for electromagnetic interference. We used a ventilator tester, to simulate healthy adult lungs and measure ventilator performance. The communication device under test was moved in towards each ventilator from a distance of 1 m in six axes. Alarms or error codes on the ventilator were recorded, as was ventilator performance. All ventilators tested, except for the Respironics VISION, showed a display error when subjected to electromagnetic interference from the Nokia phones and Simoco radio. Ventilator performance was only affected by the radio which caused the Puritan Bennett 840 to stop functioning completely. The transfer ventilators' performance were not affected by radio or mobile phone, although the mobile phone did trigger a low-power alarm. Effects on intensive care ventilators included display reset, with the ventilator restoring normal display function within 2 s, and low-power/low-pressure alarms. Bluetooth transmission had no effect on the function of all the ventilators tested. In a clinical setting, high-power-output devices such as a two-way radio may cause significant interference in ventilator function. Medium-power-output devices such as mobile phones may cause minor alarm triggers. Low-power-output devices such as Bluetooth appear to cause no interference with ventilator function.

Individual differences in the Simon effect are underpinned by differences in the competitive dynamics in the basal ganglia: An experimental verification and a computational model.

PubMed

Stocco, Andrea; Murray, Nicole L; Yamasaki, Brianna L; Renno, Taylor J; Nguyen, Jimmy; Prat, Chantel S

2017-07-01

Cognitive control is thought to be made possible by the activity of the prefrontal cortex, which selectively uses task-specific representations to bias the selection of task-appropriate responses over more automated, but inappropriate, ones. Recent models have suggested, however, that prefrontal representations are in turn controlled by the basal ganglia. In particular, neurophysiological considerations suggest that the basal ganglia's indirect pathway plays a pivotal role in preventing irrelevant information from being incorporated into a task, thus reducing response interference due to the processing of inappropriate stimuli dimensions. Here, we test this hypothesis by showing that individual differences in a non-verbal cognitive control task (the Simon task) are correlated with performance on a decision-making task (the Probabilistic Stimulus Selection task) that tracks the contribution of the indirect pathway. Specifically, the higher the effect of the indirect pathway, the smaller was the behavioral costs associated with suppressing interference in incongruent trials. Additionally, it was found that this correlation was driven by individual differences in incongruent trials only (with little effect on congruent ones) and specific to the indirect pathway (with almost no correlation with the effect of the direct pathways). Finally, it is shown that this pattern of results is precisely what is predicted when competitive dynamics of the basal ganglia are added to the selective attention component of a simple model of the Simon task, thus showing that our experimental results can be fully explained by our initial hypothesis. Published by Elsevier B.V.

Malfunction of medical equipment as a result of mains borne interference.

PubMed

Railton, R; Currie, G D; Corner, G A; Evans, A L

1993-08-01

Medical equipment has become more intelligent as the manufacturers have incorporated the latest microprocessor based technology. Equipment malfunction can be caused at any time by inherent errors in the control program but it is particularly important that this is designed to cope with the effects of electrical interference which, in addition, may cause corruption of the software. We have considered interference found in the mains supply in the hospital environment. Using a test protocol with appropriate interference simulators, a wide range of medical equipment was removed temporarily from use and its immunity to electrical mains borne interference tested. Battery operated mains rechargeable devices were unaffected by mains voltage variations including drop-outs and sags whereas mains powered devices were affected to varying degrees of severity. In particular, repetitive drop-outs caused loss of power due to fuse blowing in some life support equipment. Impulses affected 25% and pulse bursts 50% of the equipment tested with some evidence that the more recent designs coped better. The EEC Directive on electro-medical compatibility compliance may cause the design of equipment to be improved but hospitals will have to cope with the above problems in their existing equipment for many years to come.

The UV-absorber benzophenone-4 alters transcripts of genes involved in hormonal pathways in zebrafish (Danio rerio) eleuthero-embryos and adult males

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

Zucchi, Sara; Bluethgen, Nancy; University of Basel, Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, CH-4056 Basel

Benzophenone-4 (BP-4) is frequently used as UV-absorber in cosmetics and materials protection. Despite its frequent detection in the aquatic environment potential effects on aquatic life are unknown. In this study, we evaluate the effects of BP-4 in eleuthero-embryos and in the liver, testis and brain of adult male fish on the transcriptional level by focusing on target genes involved in hormonal pathways to provide a more complete toxicological profile of this important UV-absorber. Eleuthero-embryos and males of zebrafish were exposed up to 3 days after hatching and for 14 days, respectively, to BP-4 concentrations between 30 and 3000 {mu}g/L. Inmore » eleuthero-embryos transcripts of vtg1, vtg3, esr1, esr2b, hsd17ss3, cyp19b cyp19a, hhex and pax8 were induced at 3000 {mu}g/L BP-4, which points to a low estrogenic activity and interference with early thyroid development, respectively. In adult males BP-4 displayed multiple effects on gene expression in different tissues. In the liver vtg1, vtg3, esr1 and esr2b were down-regulated, while in the brain, vtg1, vtg3 and cyp19b transcripts were up-regulated. In conclusion, the transcription profile revealed that BP-4 interferes with the expression of genes involved in hormonal pathways and steroidogenesis. The effects of BP-4 differ in life stages and adult tissues and point to an estrogenic activity in eleuthero-embryos and adult brain, and an antiestrogenic activity in the liver. The results indicate that BP-4 interferes with the sex hormone system of fish, which is important for the risk assessment of this UV-absorber.« less

Bisphenol A alternatives bisphenol S and bisphenol F interfere with thyroid hormone signaling pathway in vitro and in vivo.

PubMed

Zhang, Yin-Feng; Ren, Xiao-Min; Li, Yuan-Yuan; Yao, Xiao-Fang; Li, Chuan-Hai; Qin, Zhan-Fen; Guo, Liang-Hong

2018-06-01

The wide use of the alternatives to bisphenol A (BPA) has raised concerns about their potential toxicities. Considering the disrupting activity of BPA on thyroid hormone (TH) signaling, we investigated whether bisphenol S (BPS) and bisphenol F (BPF), two leading alternatives, could interfere with TH signaling pathway using a series of assays in vitro and in vivo. In the fluorescence competitive binding assay, we found BPS and BPF, like BPA, bound to TH receptors (TRα and TRβ), with the binding potencies an order of magnitude lower than BPA (BPA > BPF > BPS). Molecular docking data also show their binding potencies to TRs. In the coactivator recruitment assay, BPS and BPF recruited coactivator to TRβ but not TRα, with weaker potencies than BPA. Correspondingly, agonistic actions of the three bisphenols in the absence or presence of T3 were observed in the TR-mediated reporter gene transcription assay. Also, all the three bisphenols induced TH-dependent GH3 cell proliferation, whereas BPA and BPF inhibited T3 induction in the presence of T3. As for in vivo assay, the three bisphenols like T3 induced TH-response gene transcription in Pelophylax nigromaculatus tadpoles, but in the presence of T3 altered T3-induced gene transcription in a biphasic concentration-response manner. These results for the first time demonstrate that BPS and BPF, like BPA, have potential to interfere with TH signaling pathway, i.e., they generally activate TH signaling in the absence of T3, but in the presence of TH, display agonistic or/and antagonistic actions under certain condition. Our study highlights the potential risks of BPS and BPF as BPA alternatives. Copyright © 2017 Elsevier Ltd. All rights reserved.

A novel anti-inflammatory mechanism of high density lipoprotein through up-regulating annexin A1 in vascular endothelial cells.

PubMed

Pan, Bing; Kong, Jinge; Jin, Jingru; Kong, Jian; He, Yubin; Dong, Shuying; Ji, Liang; Liu, Donghui; He, Dan; Kong, Liming; Jin, David K; Willard, Belinda; Pennathur, Subramaniam; Zheng, Lemin

2016-06-01

High density lipoprotein (HDL) as well as annexin A1 have been reported to be associated with cardiovascular protection. However, the correlation between HDL and annexin A1 was still unknown. In this study, HDL increased endothelial annexin A1 and prevented the decrease of annexin A1 in TNF-α-activated endothelial cells in vitro and in vivo, and above effects were attenuated after knockdown of annexin A1. Annexin A1 modulation affected HDL-mediated inhibition of monocyte adhesion to TNF-α-activated endothelium (45.2±13.7% decrease for annexin A1 RNA interference; 78.7±16.3% decrease for anti-Annexin A1 antibody blocking; 11.2±6.9% increase for Ad-ANXA1 transfection). Additionally, HDL up-regulated annexin A1 through scavenger receptor class B type I, involving ERK, p38MAPK, Akt and PKC signaling pathways, and respective inhibitors of these pathways attenuated HDL-induced annexin A1 expression as well as impaired HDL-mediated inhibition of monocyte-endothelial cell adhesion. Apolipoprotein AI also increased annexin A1 and activated similar signaling pathways. Endothelial annexin A1 from apolipoprotein AI knockout mice was decreased in comparison to that from wild type mice. Finally, HDL-induced annexin A1 inhibited cell surface VCAM-1, ICAM-1 and E-selectin, and secretion of MCP-1, IL-8, VCAM-1 and E-selectin, thereby inhibiting monocyte adhesion. Copyright © 2016 Elsevier B.V. All rights reserved.

The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway.

PubMed

Vasilcanu, Daiana; Girnita, Ada; Girnita, Leonard; Vasilcanu, Radu; Axelson, Magnus; Larsson, Olle

2004-10-14

The insulin-like growth factor-1 receptor (IGF-1R) is crucial for many functions in neoplastic cells, for example, antiapoptosis. Recently, we demonstrated that the cyclolignan PPP efficiently inhibited phosphorylation of IGF-1R without interfering with insulin receptor activity. PPP preferentially reduced phosphorylated Akt, as compared to phosphorylated Erk1/2, and caused apoptosis. Now, we aimed to investigate how PPP inhibits the IGF-1R tyrosine kinase (IGF-1RTK) and the PI3K/Akt apoptotic pathway. Using a baculovirus driven IGF-1RTK we found that PPP interfered with tyrosine phosphorylation in the activation loop of the kinase domain. Specifically, it blocked phosphorylation of tyrosine (Y) 1136, while sparing the two others (Y1131 and Y1135). To explore the impact of inhibition of Y1136 on Akt phosphorylation we transfected P6 cells (overexpressing IGF-1R) and malignant melanoma cells with different IGF-1R mutants, including Y1136F (tyrosine replaced by phenylalanine). Y1136F was found to strongly decrease IGF-1 stimulated phosphorylation of Akt. Conversely, Akt phosphorylation was weakly affected in the Y1131F transfectant. Taken together, our data suggest that the preferential inhibition of phosphorylated Akt, after PPP treatment, may be due to specific inhibition of Y1136. PPP was proven not to interfere directly with Akt or any of its downstream molecules in the apoptotic pathway.

Interference and Noise in and Adjacent to the Loran-C Spectrum at Airports

DOT National Transportation Integrated Search

1980-05-01

Electrical noise and interference in the LORAN-C frequency band was measured at two rural airports in Vermont and a major airport in Boston, Mass. The purpose of the test program was to determine the potential interfering sources that could affect th...

Sequence-specific inhibition of Dicer measured with a force-based microarray for RNA ligands.

PubMed

Limmer, Katja; Aschenbrenner, Daniela; Gaub, Hermann E

2013-04-01

Malfunction of protein translation causes many severe diseases, and suitable correction strategies may become the basis of effective therapies. One major regulatory element of protein translation is the nuclease Dicer that cuts double-stranded RNA independently of the sequence into pieces of 19-22 base pairs starting the RNA interference pathway and activating miRNAs. Inhibiting Dicer is not desirable owing to its multifunctional influence on the cell's gene regulation. Blocking specific RNA sequences by small-molecule binding, however, is a promising approach to affect the cell's condition in a controlled manner. A label-free assay for the screening of site-specific interference of small molecules with Dicer activity is thus needed. We used the Molecular Force Assay (MFA), recently developed in our lab, to measure the activity of Dicer. As a model system, we used an RNA sequence that forms an aptamer-binding site for paromomycin, a 615-dalton aminoglycoside. We show that Dicer activity is modulated as a function of concentration and incubation time: the addition of paromomycin leads to a decrease of Dicer activity according to the amount of ligand. The measured dissociation constant of paromomycin to its aptamer was found to agree well with literature values. The parallel format of the MFA allows a large-scale search and analysis for ligands for any RNA sequence.

HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner.

PubMed

Rabachini, Tatiana; Boccardo, Enrique; Andrade, Rubiana; Perez, Katia Regina; Nonogaki, Suely; Cuccovia, Iolanda Midea; Villa, Luisa Lina

2018-04-27

Human Papillomavirus (HPV) infection is the main risk factor for the development and progression of cervical cancer. HPV-16 E6 and E7 expression is essential for induction and maintenance of the transformed phenotype. These oncoproteins interfere with the function of several intracellular proteins, including those controlling the PI3K/AKT/mTOR pathway in which Phospolipase D (PLD) and Phosphatidic acid (PA) play a critical role. PLD activity was measured in primary human keratinocytes transduced with retroviruses expressing HPV-16 E6, E7 or E7 mutants. The cytostatic effect of rapamycin, a well-known mTOR inhibitor with potential clinical applications, was evaluated in monolayer and organotypic cultures. HPV-16 E7 expression in primary human keratinocytes leads to an increase in PLD expression and activity. Moreover, this activation is dependent on the ability of HPV-16 E7 to induce retinoblastoma protein (pRb) degradation. We also show that cells expressing HPV-16 E7 or silenced for pRb acquire resistance to the antiproliferative effect of rapamycin. This is the first indication that HPV oncoproteins can affect PLD activity. Since PA can interfere with the ability of rapamycin to bind mTOR, the use of combined strategies to target mTOR and PLD activity might be considered to treat HPV-related malignancies.

Non-pathogenic rhizobacteria interfere with the attraction of parasitoids to aphid-induced plant volatiles via jasmonic acid signalling.

PubMed

Pineda, Ana; Soler, Roxina; Weldegergis, Berhane T; Shimwela, Mpoki M; VAN Loon, Joop J A; Dicke, Marcel

2013-02-01

Beneficial soil-borne microbes, such as mycorrhizal fungi or rhizobacteria, can affect the interactions of plants with aboveground insects at several trophic levels. While the mechanisms of interactions with herbivorous insects, that is, the second trophic level, are starting to be understood, it remains unknown how plants mediate the interactions between soil microbes and carnivorous insects, that is, the third trophic level. Using Arabidopsis thaliana Col-0 and the aphid Myzus persicae, we evaluate here the underlying mechanisms involved in the plant-mediated interaction between the non-pathogenic rhizobacterium Pseudomonas fluorescens and the parasitoid Diaeretiella rapae, by combining ecological, chemical and molecular approaches. Rhizobacterial colonization modifies the composition of the blend of herbivore-induced plant volatiles. The volatile blend from rhizobacteria-treated aphid-infested plants is less attractive to an aphid parasitoid, in terms of both olfactory preference behaviour and oviposition, than the volatile blend from aphid-infested plants without rhizobacteria. Importantly, the effect of rhizobacteria on both the emission of herbivore-induced volatiles and parasitoid response to aphid-infested plants is lost in an Arabidopsis mutant (aos/dde2-2) that is impaired in jasmonic acid production. By modifying the blend of herbivore-induced plant volatiles that depend on the jasmonic acid-signalling pathway, root-colonizing microbes interfere with the attraction of parasitoids of leaf herbivores. © 2012 Blackwell Publishing Ltd.

Neural mechanisms of interference control in working memory: effects of interference expectancy and fluid intelligence.

PubMed

Burgess, Gregory C; Braver, Todd S

2010-09-20

A critical aspect of executive control is the ability to limit the adverse effects of interference. Previous studies have shown activation of left ventrolateral prefrontal cortex after the onset of interference, suggesting that interference may be resolved in a reactive manner. However, we suggest that interference control may also operate in a proactive manner to prevent effects of interference. The current study investigated the temporal dynamics of interference control by varying two factors - interference expectancy and fluid intelligence (gF) - that could influence whether interference control operates proactively versus reactively. A modified version of the recent negatives task was utilized. Interference expectancy was manipulated across task blocks by changing the proportion of recent negative (interference) trials versus recent positive (facilitation) trials. Furthermore, we explored whether gF affected the tendency to utilize specific interference control mechanisms. When interference expectancy was low, activity in lateral prefrontal cortex replicated prior results showing a reactive control pattern (i.e., interference-sensitivity during probe period). In contrast, when interference expectancy was high, bilateral prefrontal cortex activation was more indicative of proactive control mechanisms (interference-related effects prior to the probe period). Additional results suggested that the proactive control pattern was more evident in high gF individuals, whereas the reactive control pattern was more evident in low gF individuals. The results suggest the presence of two neural mechanisms of interference control, with the differential expression of these mechanisms modulated by both experimental (e.g., expectancy effects) and individual difference (e.g., gF) factors.

Age-differences in the temporal properties of proactive interference in working memory.

PubMed

Samrani, George; Bäckman, Lars; Persson, Jonas

2017-12-01

The inability to suppress irrelevant information has been suggested as a primary cause of proactive interference (PI), and this deficit may be enhanced in aging. The current study examines age differences and temporal boundaries of PI, by manipulating lure distances in a verbal 2-back working memory task. Both younger and older adults showed effects of interference for proximal 3- and 4-back lures, and this effect was greater for older adults. Whereas younger adults showed less interference during 4-back compared to 3-back lures, in both reaction times and accuracy, older adults improved only in accuracy. For distant lures, when the time between the 1st presentation of an item to its reappearance as a lure item was longer (e.g., 5- to 10-back lures), younger adults were no longer affected by PI. However, older adults were affected by PI throughout all distant lures, up to the most distant lure (9-/10-back). The results suggest that older adults were less successful in resolving interference from both proximal and distant familiar lures. Further, younger adults were able to overcome the effects of PI completely after a specific lure distance. The age differences in temporal properties of PI may therefore highlight a unique component linked to impaired interference control and aging. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Agent-patient similarity affects sentence structure in language production: evidence from subject omissions in Mandarin

PubMed Central

Hsiao, Yaling; Gao, Yannan; MacDonald, Maryellen C.

2014-01-01

Interference effects from semantically similar items are well-known in studies of single word production, where the presence of semantically similar distractor words slows picture naming. This article examines the consequences of this interference in sentence production and tests the hypothesis that in situations of high similarity-based interference, producers are more likely to omit one of the interfering elements than when there is low semantic similarity and thus low interference. This work investigated language production in Mandarin, which allows subject noun phrases to be omitted in discourse contexts in which the subject entity has been previously mentioned in the discourse. We hypothesize that Mandarin speakers omit the subject more often when the subject and the object entities are conceptually similar. A corpus analysis of simple transitive sentences found higher rates of subject omission when both the subject and object were animate (potentially yielding similarity-based interference) than when the subject was animate and object was inanimate. A second study manipulated subject-object animacy in a picture description task and replicated this result: participants omitted the animate subject more often when the object was also animate than when it was inanimate. These results suggest that similarity-based interference affects sentence forms, particularly when the agent of the action is mentioned in the sentence. Alternatives and mechanisms for this effect are discussed. PMID:25278915

Golgi-associated Rab14, a new regulator for Chlamydia trachomatis infection outcome.

PubMed

Capmany, Anahí; Leiva, Natalia; Damiani, María Teresa

2011-09-01

Chlamydia trachomatis is the causing agent of the most frequent bacterial sexually-transmitted diseases worldwide and is an underlying cause of chronic pelvic inflammatory diseases and cervical cancer. It is an obligate intracellular bacterium that establishes a close relationship with the Golgi complex and parasites the biosynthetic machinery of host cells. In a recent study, we have demonstrated that Rab14, a newly-described Golgi-associated Rab, is involved in the delivery of sphingolipids to the growing bacteria-containing vacuole. The interference with Rab14-controlled trafficking pathways delays chlamydial inclusion enlargement, decreases bacterial lipid uptake, negatively impact on bacterial differentiation, and reduces bacterial progeny and infectivity. C. trachomatis manipulation of host trafficking pathways for the acquisition of endogenously-biosynthesized nutrients arises as one of the characteristics of this highly evolved pathogen. The development of therapeutic strategies targeted to interfere with bacterium-host cell interaction is a new challenge for pharmacological approaches to control chlamydial infections.

Golgi-associated Rab14, a new regulator for Chlamydia trachomatis infection outcome

PubMed Central

Capmany, Anahí; Leiva, Natalia

2011-01-01

Chlamydia trachomatis is the causing agent of the most frequent bacterial sexually-transmitted diseases worldwide and is an underlying cause of chronic pelvic inflammatory diseases and cervical cancer. It is an obligate intracellular bacterium that establishes a close relationship with the Golgi complex and parasites the biosynthetic machinery of host cells. In a recent study, we have demonstrated that Rab14, a newly-described Golgi-associated Rab, is involved in the delivery of sphingolipids to the growing bacteria-containing vacuole. The interference with Rab14-controlled trafficking pathways delays chlamydial inclusion enlargement, decreases bacterial lipid uptake, negatively impact on bacterial differentiation, and reduces bacterial progeny and infectivity. C. trachomatis manipulation of host trafficking pathways for the acquisition of endogenously-biosynthesized nutrients arises as one of the characteristics of this highly evolved pathogen. The development of therapeutic strategies targeted to interfere with bacterium-host cell interaction is a new challenge for pharmacological approaches to control chlamydial infections. PMID:22046472

The geometric phase controls ultracold chemistry

DOE PAGES

Kendrick, B. K.; Hazra, Jisha; Balakrishnan, N.

2015-07-30

In this study, the geometric phase is shown to control the outcome of an ultracold chemical reaction. The control is a direct consequence of the sign change on the interference term between two scattering pathways (direct and looping), which contribute to the reactive collision process in the presence of a conical intersection (point of degeneracy between two Born–Oppenheimer electronic potential energy surfaces). The unique properties of the ultracold energy regime lead to an effective quantization of the scattering phase shift enabling maximum constructive or destructive interference between the two pathways. By taking the O + OH → H + Omore » 2 reaction as an illustrative example, it is shown that inclusion of the geometric phase modifies ultracold reaction rates by nearly two orders of magnitude. Interesting experimental control possibilities include the application of external electric and magnetic fields that might be used to exploit the geometric phase effect reported here and experimentally switch on or off the reactivity.« less

Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies.

PubMed

Deng, Yan; Wang, Chi Chiu; Choy, Kwong Wai; Du, Quan; Chen, Jiao; Wang, Qin; Li, Lu; Chung, Tony Kwok Hung; Tang, Tao

2014-04-01

During recent decades there have been remarkable advances in biology, in which one of the most important discoveries is RNA interference (RNAi). RNAi is a specific post-transcriptional regulatory pathway that can result in silencing gene functions. Efforts have been done to translate this new discovery into clinical applications for disease treatment. However, technical difficulties restrict the development of RNAi, including stability, off-target effects, immunostimulation and delivery problems. Researchers have attempted to surmount these barriers and improve the bioavailability and safety of RNAi-based therapeutics by optimizing the chemistry and structure of these molecules. This paper aimed to describe the principles of RNA interference, review the therapeutic potential in various diseases and discuss the new strategies for in vivo delivery of RNAi to overcome the challenges. Copyright © 2013 Elsevier B.V. All rights reserved.

Work-home interference among nurses: reciprocal relationships with job demands and health.

PubMed

van der Heijden, Beatrice I J M; Demerouti, Evangelia; Bakker, Arnold B

2008-06-01

This paper is a report of a study with three aims: (i) to investigate whether emotional, quantitative and physical demands have a causal, negative impact on nurses' health; (ii) to examine whether work-home interference can explain this effect, by playing a mediating role; and (iii) to test the so-called loss spiral hypothesis claiming that nurses' health problems lead to even higher job demands and more work-home interference over time. While many scholars have thought in terms of the stressor-->work-home interference-->strain model, the validity of a model that includes opposite pathways needs to be tested. A questionnaire was completed twice, with a 1-year time interval by 753 (63.4%) Registered Nurses working in hospitals, 183 (15.4%) working in nursing homes, and 251 (21.1%) working in home care institutions. The first measurement took place between October 2002 and June 2003. Our findings strongly support the idea of cross-lagged, reciprocal relationships between job demands and general health over time. The reciprocal model with work-home interference as an intervening variable (including reciprocal relationships between job demands, work-home interference and general health) showed a good fit to the data, and proved to be superior to both the causality and reversed causation models. The higher nurses' job demands, the higher is their level of work-home interference and the more likely is a general health deterioration over time, in turn giving rise to higher job demands and work-home interference, which may even aggravate the nurses' general health, and so on.

Exogenous sample contamination. Sources and interference.

PubMed

Cornes, Michael P

2016-12-01

Clinical laboratory medicine is involved in the vast majority of patient care pathways. It has been estimated that pathology results inform 60-70% of critical patient care decisions. The primary goal of the laboratory is to produce precise and accurate results which reflect the true situation in vivo. It is not surprising that interference occurs in laboratory analysis given the complexity of some of the assays used to perform them. Interference is defined as "the effect of a substance upon any step in the determination of the concentration or catalytic activity of the metabolite". Exogenous interferences are defined as those that derive from outside of the body and are therefore not normally found in a specimen and can cause either a positive or negative bias in analytical results. Interferences in analysis can come from various sources and can be classified as endogenous or exogenous. Exogenous substances could be introduced at any point in the sample journey. The laboratory must take responsibility for the quality of results produced. It has a responsibility to have processes in place to identify and minimise the occurrence and effect contamination and interference. To do this well the laboratory needs to work with clinicians and manufacturers. Failure to identify an erroneous result could have an impact on patient care, patient safety and also on hospital budgets. However it is not always easy to recognise interferences. This review summarises the types and sources of exogenous interference and some steps to minimise the impact they have. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Small Interfering RNA Pathway Modulates Initial Viral Infection in Midgut Epithelium of Insect after Ingestion of Virus.

PubMed

Lan, Hanhong; Chen, Hongyan; Liu, Yuyan; Jiang, Chaoyang; Mao, Qianzhuo; Jia, Dongsheng; Chen, Qian; Wei, Taiyun

2016-01-15

Numerous viruses are transmitted in a persistent manner by insect vectors. Persistent viruses establish their initial infection in the midgut epithelium, from where they disseminate to the midgut visceral muscles. Although propagation of viruses in insect vectors can be controlled by the small interfering RNA (siRNA) antiviral pathway, whether the siRNA pathway can control viral dissemination from the midgut epithelium is unknown. Infection by a rice virus (Southern rice black streaked dwarf virus [SRBSDV]) of its incompetent vector (the small brown planthopper [SBPH]) is restricted to the midgut epithelium. Here, we show that the siRNA pathway is triggered by SRBSDV infection in continuously cultured cells derived from the SBPH and in the midgut of the intact insect. Knockdown of the expression of the core component Dicer-2 of the siRNA pathway by RNA interference strongly increased the ability of SRBSDV to propagate in continuously cultured SBPH cells and in the midgut epithelium, allowing viral titers in the midgut epithelium to reach the threshold (1.99 × 10(9) copies of the SRBSDV P10 gene/μg of midgut RNA) needed for viral dissemination into the SBPH midgut muscles. Our results thus represent the first elucidation of the threshold for viral dissemination from the insect midgut epithelium. Silencing of Dicer-2 further facilitated the transmission of SRBSDV into rice plants by SBPHs. Taken together, our results reveal the new finding that the siRNA pathway can control the initial infection of the insect midgut epithelium by a virus, which finally affects the competence of the virus's vector. Many viral pathogens that cause significant global health and agricultural problems are transmitted via insect vectors. The first bottleneck in viral infection, the midgut epithelium, is a principal determinant of the ability of an insect species to transmit a virus. Southern rice black streaked dwarf virus (SRBSDV) is restricted exclusively to the midgut epithelium of an incompetent vector, the small brown planthopper (SBPH). Here, we show that silencing of the core component Dicer-2 of the small interfering RNA (siRNA) pathway increases viral titers in the midgut epithelium past the threshold (1.99 × 10(9) copies of the SRBSDV P10 gene/μg of midgut RNA) for viral dissemination into the midgut muscles and then into the salivary glands, allowing the SBPH to become a competent vector of SRBSDV. This result is the first evidence that the siRNA antiviral pathway has a direct role in the control of viral dissemination from the midgut epithelium and that it affects the competence of the virus's vector. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Small Interfering RNA Pathway Modulates Initial Viral Infection in Midgut Epithelium of Insect after Ingestion of Virus

PubMed Central

Lan, Hanhong; Chen, Hongyan; Liu, Yuyan; Jiang, Chaoyang; Mao, Qianzhuo; Jia, Dongsheng; Chen, Qian

2015-01-01

ABSTRACT Numerous viruses are transmitted in a persistent manner by insect vectors. Persistent viruses establish their initial infection in the midgut epithelium, from where they disseminate to the midgut visceral muscles. Although propagation of viruses in insect vectors can be controlled by the small interfering RNA (siRNA) antiviral pathway, whether the siRNA pathway can control viral dissemination from the midgut epithelium is unknown. Infection by a rice virus (Southern rice black streaked dwarf virus [SRBSDV]) of its incompetent vector (the small brown planthopper [SBPH]) is restricted to the midgut epithelium. Here, we show that the siRNA pathway is triggered by SRBSDV infection in continuously cultured cells derived from the SBPH and in the midgut of the intact insect. Knockdown of the expression of the core component Dicer-2 of the siRNA pathway by RNA interference strongly increased the ability of SRBSDV to propagate in continuously cultured SBPH cells and in the midgut epithelium, allowing viral titers in the midgut epithelium to reach the threshold (1.99 × 109 copies of the SRBSDV P10 gene/μg of midgut RNA) needed for viral dissemination into the SBPH midgut muscles. Our results thus represent the first elucidation of the threshold for viral dissemination from the insect midgut epithelium. Silencing of Dicer-2 further facilitated the transmission of SRBSDV into rice plants by SBPHs. Taken together, our results reveal the new finding that the siRNA pathway can control the initial infection of the insect midgut epithelium by a virus, which finally affects the competence of the virus's vector. IMPORTANCE Many viral pathogens that cause significant global health and agricultural problems are transmitted via insect vectors. The first bottleneck in viral infection, the midgut epithelium, is a principal determinant of the ability of an insect species to transmit a virus. Southern rice black streaked dwarf virus (SRBSDV) is restricted exclusively to the midgut epithelium of an incompetent vector, the small brown planthopper (SBPH). Here, we show that silencing of the core component Dicer-2 of the small interfering RNA (siRNA) pathway increases viral titers in the midgut epithelium past the threshold (1.99 × 109 copies of the SRBSDV P10 gene/μg of midgut RNA) for viral dissemination into the midgut muscles and then into the salivary glands, allowing the SBPH to become a competent vector of SRBSDV. This result is the first evidence that the siRNA antiviral pathway has a direct role in the control of viral dissemination from the midgut epithelium and that it affects the competence of the virus's vector. PMID:26537672

Synaptic control of local translation: the plot thickens with new characters.

PubMed

Thomas, María Gabriela; Pascual, Malena Lucía; Maschi, Darío; Luchelli, Luciana; Boccaccio, Graciela Lidia

2014-06-01

The production of proteins from mRNAs localized at the synapse ultimately controls the strength of synaptic transmission, thereby affecting behavior and cognitive functions. The regulated transcription, processing, and transport of mRNAs provide dynamic control of the dendritic transcriptome, which includes thousands of messengers encoding multiple cellular functions. Translation is locally modulated by synaptic activity through a complex network of RNA-binding proteins (RBPs) and various types of non-coding RNAs (ncRNAs) including BC-RNAs, microRNAs, piwi-interacting RNAs, and small interference RNAs. The RBPs FMRP and CPEB play a well-established role in synaptic translation, and additional regulatory factors are emerging. The mRNA repressors Smaug, Nanos, and Pumilio define a novel pathway for local translational control that affects dendritic branching and spines in both flies and mammals. Recent findings support a role for processing bodies and related synaptic mRNA-silencing foci (SyAS-foci) in the modulation of synaptic plasticity and memory formation. The SyAS-foci respond to different stimuli with changes in their integrity thus enabling regulated mRNA release followed by translation. CPEB, Pumilio, TDP-43, and FUS/TLS form multimers through low-complexity regions related to prion domains or polyQ expansions. The oligomerization of these repressor RBPs is mechanistically linked to the aggregation of abnormal proteins commonly associated with neurodegeneration. Here, we summarize the current knowledge on how specificity in mRNA translation is achieved through the concerted action of multiple pathways that involve regulatory ncRNAs and RBPs, the modification of translation factors, and mRNA-silencing foci dynamics.

Disturbances in Response Inhibition and Emotional Processing as Potential Pathways to Violence in Schizophrenia: A High-Density Event-Related Potential Study

PubMed Central

Krakowski, Menahem I.; De Sanctis, Pierfilippo; Foxe, John J.; Hoptman, Matthew J.; Nolan, Karen; Kamiel, Stephanie; Czobor, Pal

2016-01-01

Objective: Increased susceptibility to emotional triggers and poor response inhibition are important in the etiology of violence in schizophrenia. Our goal was to evaluate abnormalities in neurophysiological mechanisms underlying response inhibition and emotional processing in violent patients with schizophrenia (VS) and 3 different comparison groups: nonviolent patients (NV), healthy controls (HC) and nonpsychotic violent subjects (NPV). Methods: We recorded high-density Event-Related Potentials (ERPs) and behavioral responses during an Emotional Go/NoGo Task in 35 VS, 24 NV, 28 HC and 31 NPV subjects. We also evaluated psychiatric symptoms and impulsivity. Results: The neural and behavioral deficits in violent patients were most pronounced when they were presented with negative emotional stimuli: They responded more quickly than NV when they made commission errors (ie, failure of inhibition), and evidenced N2 increases and P3 decreases. In contrast, NVs showed little change in reaction time or ERP amplitude with emotional stimuli. These N2 and P3 amplitude changes in VSs showed a strong association with greater impulsivity. Besides these group specific changes, VSs shared deficits with NV, mostly N2 reduction, and with violent nonpsychotic subjects, particularly P3 reduction. Conclusion: Negative affective triggers have a strong impact on violent patients with schizophrenia which may have both behavioral and neural manifestations. The resulting activation could interfere with response inhibition. The affective disruption of response inhibition, identified in this study, may index an important pathway to violence in schizophrenia and suggest new modes of treatment. PMID:26895845

CRISPRi-sRNA: Transcriptional-Translational Regulation of Extracellular Electron Transfer in Shewanella oneidensis.

PubMed

Cao, Yingxiu; Li, Xiaofei; Li, Feng; Song, Hao

2017-09-15

Extracellular electron transfer (EET) in Shewanella oneidensis MR-1, which is one of the most well-studied exoelectrogens, underlies many microbial electrocatalysis processes, including microbial fuel cells, microbial electrolysis cells, and microbial electrosynthesis. However, regulating the efficiency of EET remains challenging due to the lack of efficient genome regulation tools that regulate gene expression levels in S. oneidensis. Here, we systematically established a transcriptional regulation technology, i.e., clustered regularly interspaced short palindromic repeats interference (CRISPRi), in S. oneidensis MR-1 using green fluorescent protein (GFP) as a reporter. We used this CRISPRi technology to repress the expression levels of target genes, individually and in combination, in the EET pathways (e.g., the MtrCAB pathway and genes affecting the formation of electroactive biofilms in S. oneidensis), which in turn enabled the efficient regulation of EET efficiency. We then established a translational regulation technology, i.e., Hfq-dependent small regulatory RNA (sRNA), in S. oneidensis by repressing the GFP reporter and mtrA, which is a critical gene in the EET pathways in S. oneidensis. To achieve coordinated transcriptional and translational regulation at the genomic level, the CRISPRi and Hfq-dependent sRNA systems were incorporated into a single plasmid harbored in a recombinant S. oneidensis strain, which enabled an even higher efficiency of mtrA gene repression in the EET pathways than that achieved by the CRISPRi and Hfq-dependent sRNA system alone, as exhibited by the reduced electricity output. Overall, we developed a combined CRISPRi-sRNA method that enabled the synergistic transcriptional and translational regulation of target genes in S. oneidensis. This technology involving CRISPRi-sRNA transcriptional-translational regulation of gene expression at the genomic level could be applied to other microorganisms.

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians.

PubMed

Fraguas, Susanna; Barberán, Sara; Iglesias, Marta; Rodríguez-Esteban, Gustavo; Cebrià, Francesc

2014-05-01

During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/β-catenin and Hh signaling pathways in re-establishing anterior-posterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/β-catenin pathway, together with expression analysis of brain- and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phases - an early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/β-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.

Induction of glutathione synthesis and heme oxygenase 1 by the flavonoids butein and phloretin is mediated through the ERK/Nrf2 pathway and protects against oxidative stress.

PubMed

Yang, Ya-Chen; Lii, Chong-Kuei; Lin, Ai-Hsuan; Yeh, Yu-Wen; Yao, Hsien-Tsung; Li, Chien-Chun; Liu, Kai-Li; Chen, Haw-Wen

2011-12-01

Butein and phloretin are chalcones that are members of the flavonoid family of polyphenols. Flavonoids have well-known antioxidant and anti-inflammatory activities. In rat primary hepatocytes, we examined whether butein and phloretin affect tert-butylhydroperoxide (tBHP)-induced oxidative damage and the possible mechanism(s) involved. Treatment with butein and phloretin markedly attenuated tBHP-induced peroxide formation, and this amelioration was reversed by l-buthionine-S-sulfoximine [a glutamate cysteine ligase (GCL) inhibitor] and zinc protoporphyrin [a heme oxygenase 1 (HO-1) inhibitor]. Butein and phloretin induced both HO-1 and GCL protein and mRNA expression and increased intracellular glutathione (GSH) and total GSH content. Butein treatment activated the ERK1/2 signaling pathway and increased Nrf2 nuclear translocation, Nrf2 nuclear protein-DNA binding activity, and ARE-luciferase reporter activity. The roles of the ERK signaling pathway and Nrf2 in butein-induced HO-1 and GCL catalytic subunit (GCLC) expression were determined by using RNA interference directed against ERK2 and Nrf2. Both siERK2 and siNrf2 abolished butein-induced HO-1 and GCLC protein expression. These results suggest the involvement of ERK2 and Nrf2 in the induction of HO-1 and GCLC by butein. In an animal study, phloretin was shown to increase GSH content and HO-1 expression in rat liver and decrease carbon tetrachloride-induced hepatotoxicity. In conclusion, we demonstrate that butein and phloretin up-regulate HO-1 and GCL expression through the ERK2/Nrf2 pathway and protect hepatocytes against oxidative stress. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of PHENYLALANINE AMMONIA LYASE ( PAL) knockdown on cell wall composition, biomass digestibility, and biotic and abiotic stress responses in Brachypodium

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

Cass, Cynthia L.; Peraldi, Antoine; Dowd, Patrick F.

The phenylpropanoid pathway in plants synthesizes a variety of structural and defence compounds, and is an important target in efforts to reduce cell wall lignin for improved biomass conversion to biofuels. Little is known concerning the trade-offs in grasses when perturbing the function of the first gene family in the pathway, PHENYLALANINE AMMONIA LYASE ( PAL). Therefore, PAL isoforms in the model grass Brachypodium distachyon were targeted, by RNA interference (RNAi), and large reductions (up to 85%) in stem tissue transcript abundance for two of the eight putative BdPAL genes were identified. The cell walls of stems of BdPAL-knockdown plantsmore » had reductions of 43% in lignin and 57% in cell wall-bound ferulate, and a nearly 2-fold increase in the amounts of polysaccharide-derived carbohydrates released by thermochemical and hydrolytic enzymic partial digestion. PAL-knockdown plants exhibited delayed development and reduced root growth, along with increased susceptibilities to the fungal pathogens Fusarium culmorum and Magnaporthe oryzae. Surprisingly, these plants generally had wild-type (WT) resistances to caterpillar herbivory, drought, and ultraviolet light. RNA sequencing analyses revealed that the expression of genes associated with stress responses including ethylene biosynthesis and signalling were significantly altered in PAL knocked-down plants under non-challenging conditions. These data reveal that, although an attenuation of the phenylpropanoid pathway increases carbohydrate availability for biofuel, it can adversely affect plant growth and disease resistance to fungal pathogens. Lastly, the data identify notable differences between the stress responses of these monocot pal mutants versus Arabidopsis (a dicot) pal mutants and provide insights into the challenges that may arise when deploying phenylpropanoid pathway-altered bioenergy crops.« less

Expression of a bacterial 3-dehydroshikimate dehydratase reduces lignin content and improves biomass saccharification efficiency

DOE PAGES

Eudes, Aymerick; Sathitsuksanoh, Noppadon; Baidoo, Edward E. K.; ...

2015-01-13

Lignin confers recalcitrance to plant biomass used as feedstocks in agro-processing industries or as source of renewable sugars for the production of bioproducts. The metabolic steps for the synthesis of lignin building blocks belong to the shikimate and phenylpropanoid pathways. Genetic engineering efforts to reduce lignin content typically employ gene knockout or gene silencing techniques to constitutively repress one of these metabolic pathways. Recently, new strategies have emerged offering better spatiotemporal control of lignin deposition, including the expression of enzymes that interfere with the normal process for cell wall lignification. In this study, we report that expression of a 3-dehydroshikimatemore » dehydratase (QsuB from Corynebacterium glutamicum) reduces lignin deposition in Arabidopsis cell walls. QsuB was targeted to the plastids to convert 3-dehydroshikimate – an intermediate of the shikimate pathway – into protocatechuate. Compared to wild-type plants, lines expressing QsuB contain higher amounts of protocatechuate, p-coumarate, p-coumaraldehyde and p-coumaryl alcohol, and lower amounts of coniferaldehyde, coniferyl alcohol, sinapaldehyde and sinapyl alcohol. 2D-NMR spectroscopy and pyrolysis-gas chromatography/mass spectrometry (pyro-GC/MS) reveal an increase of p-hydroxyphenyl units and a reduction of guaiacyl units in the lignin of QsuB lines. Size-exclusion chromatography indicates a lower degree of lignin polymerization in the transgenic lines. Therefore, our data show that the expression of QsuB primarily affects the lignin biosynthetic pathway. Finally, biomass from these lines exhibits more than a twofold improvement in saccharification efficiency. We conclude that the expression of QsuB in plants, in combination with specific promoters, is a promising gain-of-function strategy for spatiotemporal reduction of lignin in plant biomass.« less

Effects of PHENYLALANINE AMMONIA LYASE ( PAL) knockdown on cell wall composition, biomass digestibility, and biotic and abiotic stress responses in Brachypodium

DOE PAGES

Cass, Cynthia L.; Peraldi, Antoine; Dowd, Patrick F.; ...

2015-06-19

The phenylpropanoid pathway in plants synthesizes a variety of structural and defence compounds, and is an important target in efforts to reduce cell wall lignin for improved biomass conversion to biofuels. Little is known concerning the trade-offs in grasses when perturbing the function of the first gene family in the pathway, PHENYLALANINE AMMONIA LYASE ( PAL). Therefore, PAL isoforms in the model grass Brachypodium distachyon were targeted, by RNA interference (RNAi), and large reductions (up to 85%) in stem tissue transcript abundance for two of the eight putative BdPAL genes were identified. The cell walls of stems of BdPAL-knockdown plantsmore » had reductions of 43% in lignin and 57% in cell wall-bound ferulate, and a nearly 2-fold increase in the amounts of polysaccharide-derived carbohydrates released by thermochemical and hydrolytic enzymic partial digestion. PAL-knockdown plants exhibited delayed development and reduced root growth, along with increased susceptibilities to the fungal pathogens Fusarium culmorum and Magnaporthe oryzae. Surprisingly, these plants generally had wild-type (WT) resistances to caterpillar herbivory, drought, and ultraviolet light. RNA sequencing analyses revealed that the expression of genes associated with stress responses including ethylene biosynthesis and signalling were significantly altered in PAL knocked-down plants under non-challenging conditions. These data reveal that, although an attenuation of the phenylpropanoid pathway increases carbohydrate availability for biofuel, it can adversely affect plant growth and disease resistance to fungal pathogens. Lastly, the data identify notable differences between the stress responses of these monocot pal mutants versus Arabidopsis (a dicot) pal mutants and provide insights into the challenges that may arise when deploying phenylpropanoid pathway-altered bioenergy crops.« less

RNAi pathways contribute to developmental history-dependent phenotypic plasticity in C. elegans

PubMed Central

Hall, Sarah E.; Chirn, Gung-Wei; Lau, Nelson C.; Sengupta, Piali

2013-01-01

Early environmental experiences profoundly influence adult phenotypes through complex mechanisms that are poorly understood. We previously showed that adult Caenorhabditis elegans that transiently passed through the stress-induced dauer larval stage (post-dauer adults) exhibit significant changes in gene expression profiles, chromatin states, and life history traits when compared with adults that bypassed the dauer stage (control adults). These wild-type, isogenic animals of equivalent developmental stages exhibit different signatures of molecular marks that reflect their distinct developmental trajectories. To gain insight into the mechanisms that contribute to these developmental history-dependent phenotypes, we profiled small RNAs from post-dauer and control adults by deep sequencing. RNA interference (RNAi) pathways are known to regulate genome-wide gene expression both at the chromatin and post-transcriptional level. By quantifying changes in endogenous small interfering RNA (endo-siRNA) levels in post-dauer as compared with control animals, our analyses identified a subset of genes that are likely targets of developmental history-dependent reprogramming through a complex RNAi-mediated mechanism. Mutations in specific endo-siRNA pathways affect expected gene expression and chromatin state changes for a subset of genes in post-dauer animals, as well as disrupt their increased brood size phenotype. We also find that both chromatin state and endo-siRNA distribution in dauers are unique, and suggest that remodeling in dauers provides a template for the subsequent establishment of adult post-dauer profiles. Our results indicate a role for endo-siRNA pathways as a contributing mechanism to early experience-dependent phenotypic plasticity in adults, and describe how developmental history can program adult physiology and behavior via epigenetic mechanisms. PMID:23329696

29 CFR 779.507 - Fourteen-year minimum.

Code of Federal Regulations, 2010 CFR

2010-07-01

... RETAILERS OF GOODS OR SERVICES Other Provisions Which May Affect Retail Enterprises Child Labor Provisions... interfere with the minors' schooling and to conditions which will not interfere with their health and well... in a limited number of occupations where the work is performed outside school hours and is confined...

47 CFR 73.810 - Third adjacent channel interference.

Code of Federal Regulations, 2014 CFR

2014-10-01

... reception of the input signal of any TV translator, TV booster, FM translator or FM booster station; or (iii... authorized and operating LPFM stations, FM translators and FM booster stations. Interference will be... power FM, FM translator or FM booster station to such affected station and to the Commission. (ii) A...

47 CFR 73.810 - Third adjacent channel interference.

Code of Federal Regulations, 2013 CFR

2013-10-01

... reception of the input signal of any TV translator, TV booster, FM translator or FM booster station; or (iii... authorized and operating LPFM stations, FM translators and FM booster stations. Interference will be... power FM, FM translator or FM booster station to such affected station and to the Commission. (ii) A...

Effects of Semantic and Orthographic Interference on Prose Recall.

ERIC Educational Resources Information Center

Burton, John K.; And Others

"Levels of processing" is an explanatory framework postulating that differences in memory processing quality or effort affect the duration of the memory trace. Using recall (immediate, one week, or two week) for connected discourse processed under three semantic and three orthographic interference conditions, as well as a noninterference…

Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection

PubMed Central

Garcia, Victor; Feldman, Marcus W.; Regoes, Roland R.

2016-01-01

During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV’s genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains –an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction– could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies. PMID:26829720

A redox proteomics approach to investigate the mode of action of nanomaterials

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

Riebeling, Christian; Wiemann, Martin; Schnekenburger, Jürgen

2016-05-15

Numbers of engineered nanomaterials (ENMs) are steadily increasing. Therefore, alternative testing approaches with reduced costs and high predictivity suitable for high throughput screening and prioritization are urgently needed to ensure a fast and effective development of safe products. In parallel, extensive research efforts are targeted to understanding modes of action of ENMs, which may also support the development of new predictive assays. Oxidative stress is a widely accepted paradigm associated with different adverse outcomes of ENMs. It has frequently been identified in in vitro and in vivo studies and different assays have been developed for this purpose. Fluorescent dye basedmore » read-outs are most frequently used for cell testing in vitro but may be limited due to possible interference of the ENMs. Recently, other assays have been put forward such as acellular determination of ROS production potential using methods like electron spin resonance, antioxidant quantification or the use of specific sensors. In addition, Omics based approaches have gained increasing attention. In particular, redox proteomics can combine the assessment of oxidative stress with the advantage of getting more detailed mechanistic information. Here we propose a comprehensive testing strategy for assessing the oxidative stress potential of ENMs, which combines acellular methods and fast in vitro screening approaches, as well as a more involved detailed redox proteomics approach. This allows for screening and prioritization in a first tier and, if required, also for unraveling mechanistic details down to compromised signaling pathways. - Highlights: • Oxidative stress is a general paradigm for nanomaterial hazard mechanism of action. • Reactive oxygen species generation can be predicted using acellular assays. • Cellular assays based on fluorescence suffer from interference by nanomaterials. • Protein carbonylation is an irreversible and predictive mark of oxidative stress. • Proteomics of carbonylation indicates affected pathways and mechanism of action.« less

"The mute who can sing": a cortical stimulation study on singing.

PubMed

Roux, Franck-Emmanuel; Borsa, Stefano; Démonet, Jean-François

2009-02-01

In an attempt to identify cortical areas involved in singing in addition to language areas, the authors used a singing task during direct cortical mapping in 5 patients who were amateur singers and had undergone surgery for brain tumors. The organization of the cortical areas involved in language and singing was analyzed in relation with these surgical data. One left-handed and 4 right-handed patients with brain tumors in left (2 cases) and right (3 cases) hemispheres and no significant language or singing deficits underwent surgery with the "awake surgery" technique. All patients had a special interest in singing and were involved in amateur singing activities. They were tested using naming, reading, and singing tasks. Outside primary sensorimotor areas, singing interferences were rare and were exclusively localized in small cortical areas (< 1 cm(2)). A clear distinction was found between speech and singing in the Broca region. In the Broca region, no singing interference was found in areas in which interference in naming and reading tasks were detected. Conversely, a specific singing interference was found in nondominant middle frontal gyri in one patient. This interference consisted of abrupt singing arrest without apparent face, mouth, and tongue contraction. Finally, nonspecific singing interferences were found in the right and left precentral gyri in all patients (probably by interference in final articulatory mechanisms of singing). Dissociations between speech and singing found outside primary sensorimotor areas showed that these 2 functions use, in some cortical stages, different cerebral pathways.

When Learning Disturbs Memory – Temporal Profile of Retroactive Interference of Learning on Memory Formation

PubMed Central

Sosic-Vasic, Zrinka; Hille, Katrin; Kröner, Julia; Spitzer, Manfred; Kornmeier, Jürgen

2018-01-01

Introduction: Consolidation is defined as the time necessary for memory stabilization after learning. In the present study we focused on effects of interference during the first 12 consolidation minutes after learning. Participants had to learn a set of German – Japanese word pairs in an initial learning task and a different set of German – Japanese word pairs in a subsequent interference task. The interference task started in different experimental conditions at different time points (0, 3, 6, and 9 min) after the learning task and was followed by subsequent cued recall tests. In a control experiment the interference periods were replaced by rest periods without any interference. Results: The interference task decreased memory performance by up to 20%, with negative effects at all interference time points and large variability between participants concerning both the time point and the size of maximal interference. Further, fast learners seem to be more affected by interference than slow learners. Discussion: Our results indicate that the first 12 min after learning are highly important for memory consolidation, without a general pattern concerning the precise time point of maximal interference across individuals. This finding raises doubts about the generalized learning recipes and calls for individuality of learning schedules. PMID:29503621

Suppression of allene oxide synthase 3 in potato increases degree of arbuscular mycorrhizal fungal colonization.

PubMed

Morcillo, Rafael Jorge León; Navarrete, María Isabel Tamayo; Bote, Juan Antonio Ocampo; Monguio, Salomé Prat; García-Garrido, José Manuel

2016-01-15

Arbuscular mycorrhizal (AM) is a mutually beneficial interaction among higher plants and soil fungi of the phylum Glomeromycota. Numerous studies have pointed that jasmonic acid plays an important role in the development of the intraradical fungus. This compound belongs to a group of biologically active compounds known as oxylipins which are derived from the oxidative metabolism of polyunsaturated fatty acids. Studies of the regulatory role played by oxylipins in AM colonization have generally focused on jasmonates, while few studies exist on the 9-LOX pathway of oxylipins during AM formation. Here, the cDNA of Allene oxide synthase 3 (AOS3), a key enzyme in the 9-LOX pathway, was used in the RNA interference (RNAi) system to transform potato plants in order to suppress its expression. Results show increases in AOS3 gene expression and 9-LOX products in roots of wild type potato mycorrhizal plants. The suppression of AOS3 gene expression increases the percentage of root with mycorrhizal colonization at early stages of AM formation. AOS3 RNA interference lead to an induction of LOXA and 13-LOX genes, a reduction in AOS3 derived 9-LOX oxylipin compounds and an increase in jasmonic acid content, suggesting compensation between 9 and 13-LOX pathways. The results in a whole support the hypothesis of a regulatory role for the 9-LOX oxylipin pathway during mycorrhization. Copyright © 2015 Elsevier GmbH. All rights reserved.

A quantitative adverse outcome pathway model for thyroid axis disruption in Xenopus laevis tadpoles

EPA Science Inventory

The development of Xenopus laevis tadpoles is tightly controlled by the thyroid hormones tetraiodothyronine (T4) and triiodothyronine (T3). Toxicity testing efforts have shown that several compounds interfere with development in X. laevis tadpoles by disrupting the thyroid axis a...

Experimental Evidence for Quantum Interference and Vibrationally Induced Decoherence in Single-Molecule Junctions

NASA Astrophysics Data System (ADS)

Ballmann, Stefan; Härtle, Rainer; Coto, Pedro B.; Elbing, Mark; Mayor, Marcel; Bryce, Martin R.; Thoss, Michael; Weber, Heiko B.

2012-08-01

We analyze quantum interference and decoherence effects in single-molecule junctions both experimentally and theoretically by means of the mechanically controlled break junction technique and density-functional theory. We consider the case where interference is provided by overlapping quasidegenerate states. Decoherence mechanisms arising from electronic-vibrational coupling strongly affect the electrical current flowing through a single-molecule contact and can be controlled by temperature variation. Our findings underline the universal relevance of vibrations for understanding charge transport through molecular junctions.

Experimental evidence for quantum interference and vibrationally induced decoherence in single-molecule junctions.

PubMed

Ballmann, Stefan; Härtle, Rainer; Coto, Pedro B; Elbing, Mark; Mayor, Marcel; Bryce, Martin R; Thoss, Michael; Weber, Heiko B

2012-08-03

We analyze quantum interference and decoherence effects in single-molecule junctions both experimentally and theoretically by means of the mechanically controlled break junction technique and density-functional theory. We consider the case where interference is provided by overlapping quasidegenerate states. Decoherence mechanisms arising from electronic-vibrational coupling strongly affect the electrical current flowing through a single-molecule contact and can be controlled by temperature variation. Our findings underline the universal relevance of vibrations for understanding charge transport through molecular junctions.

Effect of subacute exposure to lead and estrogen on immature pre-weaning rat leukocytes

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

Villagra, R.; Tchernitchin, N.N.; Tchernitchin, A.N.

1997-02-01

Lead is an environmental pollutant known to cause damage to human health, affecting specially the central nervous system, reproductive organs, the immune system and kidney. From the perspective or reproduction, lead affects both men and women. Reported effects in women include infertility, miscarriage, pre-eclampsia, pregnancy hypertension and premature delivery. In experimental animals, lead affects female reproductive organs through different mechanisms. The heavy metal may interact at the enzyme level. It may interfere with the action of reproductive hormones at the target organ, modifying the activity of estrogen receptors in the pregnant uterus and inhibiting responses where estrogens play a role.more » Lead may induce imprinting mechanism, causing persistent changes in uterine estrogen receptors and ovary LH receptors following perinatal exposure. Finally, it may interfere at the level of hypothalamus-pituitary, decreasing pituitary response to growth hormone releasing factor, affecting levels of FSH and LH and increasing blood levels of glucocorticoids, which modify the action of estrogens in the uterus. This study examines the mechanisms of lead-induced interference with female reproductive and immune functions. 33 refs., 2 figs., 2 tabs.« less

Genetic analysis of gravity signal transduction in roots

NASA Astrophysics Data System (ADS)

Masson, Patrick; Strohm, Allison; Baldwin, Katherine

To grow downward into the soil, roots use gravity as a guide. Specialized cells, named stato-cytes, enable this directional growth response by perceiving gravity. Located in the columella region of the cap, these cells sense a reorientation of the root within the gravity field through the sedimentation of, and/or tension/pressure exerted by, dense amyloplasts. This process trig-gers a gravity signal transduction pathway that leads to a fast alkalinization of the cytoplasm and a change in the distribution of the plasma membrane-associated auxin-efflux carrier PIN3. The latter protein is uniformly distributed within the plasma membrane on all sides of the cell in vertically oriented roots. However, it quickly accumulates at the bottom side upon gravis-timulation. This process correlates with a preferential transport of auxin to the bottom side of the root cap, resulting in a lateral gradient across the tip. This gradient is then transported to the elongation zone where it promotes differential cellular elongation, resulting in downward curvature. We isolated mutations that affect gravity signal transduction at a step that pre-cedes cytoplasmic alkalinization and/or PIN3 relocalization and lateral auxin transport across the cap. arg1 and arl2 mutations identify a common genetic pathway that is needed for all three gravity-induced processes in the cap statocytes, indicating these genes function early in the pathway. On the other hand, adk1 affects gravity-induced PIN3 relocalization and lateral auxin transport, but it does not interfere with cytoplasmic alkalinization. ARG1 and ARL2 encode J-domain proteins that are associated with membranes of the vesicular trafficking path-way whereas ADK1 encodes adenosine kinase, an enzyme that converts adenosine derived from nucleic acid metabolism and the AdoMet cycle into AMP, thereby alleviating feedback inhibi-tion of this important methyl-donor cycle. Because mutations in ARG1 (and ARL2) do not completely eliminate gravitropism, we sought genetic enhancers of arg1 as a way to identify new gravity signal transducers. Two of these modifiers, named mar1 and mar2, were found to affect genes that encode two subunits of the plastidic outer-membrane protein import complex, TOC75 and TOC132, respectively. mar2 did not affect the ultrastructure of amyloplasts in the statocytes nor did it alter their ability to sediment in response to gravistimulation, suggesting a role for the outer membrane of the amyloplasts in gravity signal transduction (reviewed in Stanga et al., 2009, Plant Signal Behavior 4(10): 1-9). The contribution of TOC132 in gravity signal transduction is being investigated by analyzing the regions of this protein that are needed for the pathway, and investigating the contribution of a putative TOC132-interacting protein in gravity signal transduction. We have also isolated additional putative enhancers of arg1-2 in the hope of identifying new plastid-associated gravity signal transducers, and have initiated a screen for genetic enhancers of mar2 to seek new transducers in the ARG1 branch of the pathway.

Antitumor Lipids--Structure, Functions, and Medical Applications.

PubMed

Kostadinova, Aneliya; Topouzova-Hristova, Tanya; Momchilova, Albena; Tzoneva, Rumiana; Berger, Martin R

2015-01-01

Cell proliferation and metastasis are considered hallmarks of tumor progression. Therefore, efforts have been made to develop novel anticancer drugs that inhibit both the proliferation and the motility of tumor cells. Synthetic antitumor lipids (ATLs), which are chemically divided into two main classes, comprise (i) alkylphospholipids (APLs) and (ii) alkylphosphocholines (APCs). They represent a new entity of drugs with distinct antiproliferative properties in tumor cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell, instead, they incorporate into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signaling pathways. Recently, it has been shown that the most commonly studied APLs inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected and are potent sensitizers of conventional chemo- and radiotherapy, as well as of electrical field therapy. APLs resist catabolic degradation to a large extent, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. They are internalized in the cell membrane via raft domains and cause downstream reactions as inhibition of cell growth and migration, cell cycle arrest, actin stress fibers collapse, and apoptosis. This review summarizes the in vitro, in vivo, and clinical trials of most common ATLs and their mode of action at molecular and biochemical levels. © 2015 Elsevier Inc. All rights reserved.

Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens

PubMed Central

Meliopoulos, Victoria A.; Andersen, Lauren E.; Birrer, Katherine F.; Simpson, Kaylene J.; Lowenthal, John W.; Bean, Andrew G. D.; Stambas, John; Stewart, Cameron R.; Tompkins, S. Mark; van Beusechem, Victor W.; Fraser, Iain; Mhlanga, Musa; Barichievy, Samantha; Smith, Queta; Leake, Devin; Karpilow, Jon; Buck, Amy; Jona, Ghil; Tripp, Ralph A.

2012-01-01

Influenza virus encodes only 11 viral proteins but replicates in a broad range of avian and mammalian species by exploiting host cell functions. Genome-wide RNA interference (RNAi) has proven to be a powerful tool for identifying the host molecules that participate in each step of virus replication. Meta-analysis of findings from genome-wide RNAi screens has shown influenza virus to be dependent on functional nodes in host cell pathways, requiring a wide variety of molecules and cellular proteins for replication. Because rapid evolution of the influenza A viruses persistently complicates the effectiveness of vaccines and therapeutics, a further understanding of the complex host cell pathways coopted by influenza virus for replication may provide new targets and strategies for antiviral therapy. RNAi genome screening technologies together with bioinformatics can provide the ability to rapidly identify specific host factors involved in resistance and susceptibility to influenza virus, allowing for novel disease intervention strategies.—Meliopoulos, V. A., Andersen, L. E., Birrer, K. F., Simpson, K. J., Lowenthal, J. W., Bean, A. G. D., Stambas, J., Stewart, C. R., Tompkins, S. M., van Beusechem, V. W., Fraser, I., Mhlanga, M., Barichievy, S., Smith, Q., Leake, D., Karpilow, J., Buck, A., Jona, G., Tripp, R. A. Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens. PMID:22247330

Interference effects on commonly used memory tasks.

PubMed

Brophy, Linda M; Jackson, Martin; Crowe, Simon F

2009-02-01

This paper reports two studies which investigated the effect of interference on delayed recall scores of the WMS-III and other commonly used memory measures. In Study 1, participants completed the immediate and delayed components of the WMS-III, with or without the introduction of conceptually similar memory tasks between the recall trials. In Study 2, this order of administration was reversed, with the WMS-III subtests used as the interference items. The results indicated that the introduction of interference items during the delay negatively affected delayed recall performance on almost all sub-tests. In addition, equal effects of proactive and retroactive interference were demonstrated. These findings raise concerns regarding the standardization process for memory tasks and highlight the need to consider interference effects in clinical practice, and stand as a caution in the use of memory-related materials during the delay interval in memory testing.

The balance of protein expression and degradation: an ESCRTs point of view.

PubMed

Babst, Markus; Odorizzi, Greg

2013-08-01

Endosomal sorting complexes required for transport (ESCRTs) execute the biogenesis of late endosomal multivesicular bodies (MVBs). The ESCRT pathway has traditionally been viewed as a means by which transmembrane proteins are degraded in vacuoles/lysosomes. More recent studies aimed at understanding the broader functions of ESCRTs have uncovered unexpected links with pathways that control cellular metabolism. Central to this communication is TORC1, the kinase complex that controls many of the catabolic and anabolic systems. The connection between TORC1 activity and ESCRTs allows cells to quickly adapt to the stress of nutrient limitations until the longer-term autophagic pathway is activated. Increasing evidence also points to ESCRTs regulating RNA interference (RNAi) pathways that control translation. Copyright © 2013 Elsevier Ltd. All rights reserved.

A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis.

PubMed

Han, Xiang Hua; Jin, Yong-Ri; Seto, Marianne; Yoon, Jeong Kyo

2011-03-25

R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/β-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loop-helix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/β-catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/β-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/β-catenin signaling pathway.

A WNT/β-Catenin Signaling Activator, R-spondin, Plays Positive Regulatory Roles during Skeletal Myogenesis*

PubMed Central

Han, Xiang Hua; Jin, Yong-Ri; Seto, Marianne; Yoon, Jeong Kyo

2011-01-01

R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/β-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loop-helix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/β-catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/β-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/β-catenin signaling pathway. PMID:21252233

Chloroquine Inhibits Dengue Virus Type 2 Replication in Vero Cells but Not in C6/36 Cells

PubMed Central

Farias, Kleber Juvenal Silva; Machado, Paula Renata Lima; da Fonseca, Benedito Antônio Lopes

2013-01-01

Dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. Since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. Chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal pH, was used in the in vitro treatment of Vero and C6/36 cells infected with dengue virus type 2 (DENV-2). Real-time RT-PCR and plaque assays were used to quantify the DENV-2 load in infected Vero and C6/36 cells after chloroquine treatment. Our results showed that a dose of 50 μg/ml of chloroquine was not toxic to the cells and induced a statistically significant inhibition of virus production in infected Vero cells when compared to untreated cells. In C6/36 cells, chloroquine does not induce a statistically significant difference in viral replication when compared to untreated cells, showing that this virus uses an unlikely pathway of penetration in these cells, and results were also confirmed by the plaque assay (PFU). These data suggest that the inhibition of virus infection induced by chloroquine is due to interference with acidic vesicles in mammalian cells. PMID:23431254

Chloroquine inhibits dengue virus type 2 replication in Vero cells but not in C6/36 cells.

PubMed

Farias, Kleber Juvenal Silva; Machado, Paula Renata Lima; da Fonseca, Benedito Antônio Lopes

2013-01-01

Dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. Since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. Chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal pH, was used in the in vitro treatment of Vero and C6/36 cells infected with dengue virus type 2 (DENV-2). Real-time RT-PCR and plaque assays were used to quantify the DENV-2 load in infected Vero and C6/36 cells after chloroquine treatment. Our results showed that a dose of 50 μg/ml of chloroquine was not toxic to the cells and induced a statistically significant inhibition of virus production in infected Vero cells when compared to untreated cells. In C6/36 cells, chloroquine does not induce a statistically significant difference in viral replication when compared to untreated cells, showing that this virus uses an unlikely pathway of penetration in these cells, and results were also confirmed by the plaque assay (PFU). These data suggest that the inhibition of virus infection induced by chloroquine is due to interference with acidic vesicles in mammalian cells.

Nanometer Scale Titanium Surface Texturing Are Detected by Signaling Pathways Involving Transient FAK and Src Activations

PubMed Central

Zambuzzi, Willian F.; Bonfante, Estevam A.; Jimbo, Ryo; Hayashi, Mariko; Andersson, Martin; Alves, Gutemberg; Takamori, Esther R.; Beltrão, Paulo J.; Coelho, Paulo G.; Granjeiro, José M.

2014-01-01

Background It is known that physico/chemical alterations on biomaterial surfaces have the capability to modulate cellular behavior, affecting early tissue repair. Such surface modifications are aimed to improve early healing response and, clinically, offer the possibility to shorten the time from implant placement to functional loading. Since FAK and Src are intracellular proteins able to predict the quality of osteoblast adhesion, this study evaluated the osteoblast behavior in response to nanometer scale titanium surface texturing by monitoring FAK and Src phosphorylations. Methodology Four engineered titanium surfaces were used for the study: machined (M), dual acid-etched (DAA), resorbable media microblasted and acid-etched (MBAA), and acid-etch microblasted (AAMB). Surfaces were characterized by scanning electron microscopy, interferometry, atomic force microscopy, x-ray photoelectron spectroscopy and energy dispersive X-ray spectroscopy. Thereafter, those 4 samples were used to evaluate their cytotoxicity and interference on FAK and Src phosphorylations. Both Src and FAK were investigated by using specific antibody against specific phosphorylation sites. Principal Findings The results showed that both FAK and Src activations were differently modulated as a function of titanium surfaces physico/chemical configuration and protein adsorption. Conclusions It can be suggested that signaling pathways involving both FAK and Src could provide biomarkers to predict osteoblast adhesion onto different surfaces. PMID:24999733

Fidelity of metal insertion into hydrogenases.

PubMed

Magalon, A; Blokesch, M; Zehelein, E; Böck, A

2001-06-15

The fidelity of metal incorporation into the active center of hydrogenase 3 from Escherichia coli was studied by analyzing the inhibition of the maturation pathway by zinc and other transition metals. Hydrogenase maturation of wild-type cells was significantly affected only by concentrations of zinc or cadmium higher than 200 microM, whereas a mutant with a lesion in the nickel uptake system displayed a total blockade of the proteolytic processing of the precursor form into the mature form of the large subunit after growth in the presence of 10 microM Zn(2+). The precursor could not be processed in vitro by the maturation endopeptidase even in the presence of an excess of nickel ions. Evidence is presented that zinc does not interfere with the incorporation of iron into the metal center. Precursor of the large subunit accumulated in nickel proficient cells formed a transient substrate complex with the cognate endoprotease HycI whereas that of zinc-supplemented cells did not. The results show that zinc can intrude the nickel-dependent maturation pathway only when nickel uptake is blocked. Under this condition zinc appears to be incorporated at the nickel site of the large subunit and delivers a precursor not amenable to proteolytic processing since the interaction with the endoprotease is blocked.

Innate immunity mediated longevity and longevity induced by germ cell removal converge on the C-type lectin domain protein IRG-7

PubMed Central

Yunger, Elad; Safra, Modi; Levi-Ferber, Mor; Haviv-Chesner, Anat

2017-01-01

In C. elegans, removal of the germline triggers molecular events in the neighboring intestine, which sends an anti-aging signal to the rest of the animal. In this study, we identified an innate immunity related gene, named irg-7, as a novel mediator of longevity in germlineless animals. We consider irg-7 to be an integral downstream component of the germline longevity pathway because its expression increases upon germ cell removal and its depletion interferes with the activation of the longevity-promoting transcription factors DAF-16 and DAF-12 in germlineless animals. Furthermore, irg-7 activation by itself sensitizes the animals' innate immune response and extends the lifespan of animals exposed to live bacteria. This lifespan-extending pathogen resistance relies on the somatic gonad as well as on many genes previously associated with the reproductive longevity pathway. This suggests that these genes are also relevant in animals with an intact gonad, and can affect their resistance to pathogens. Altogether, this study demonstrates the tight association between germline homeostasis and the immune response of animals, and raises the possibility that the reproductive system can act as a signaling center to divert resources towards defending against putative pathogen attacks. PMID:28196094

The Class II Trehalose 6-phosphate Synthase Gene PvTPS9 Modulates Trehalose Metabolism in Phaseolus vulgaris Nodules

PubMed Central

Barraza, Aarón; Contreras-Cubas, Cecilia; Estrada-Navarrete, Georgina; Reyes, José L.; Juárez-Verdayes, Marco A.; Avonce, Nelson; Quinto, Carmen; Díaz-Camino, Claudia; Sanchez, Federico

2016-01-01

Legumes form symbioses with rhizobia, producing nitrogen-fixing nodules on the roots of the plant host. The network of plant signaling pathways affecting carbon metabolism may determine the final number of nodules. The trehalose biosynthetic pathway regulates carbon metabolism and plays a fundamental role in plant growth and development, as well as in plant-microbe interactions. The expression of genes for trehalose synthesis during nodule development suggests that this metabolite may play a role in legume-rhizobia symbiosis. In this work, PvTPS9, which encodes a Class II trehalose-6-phosphate synthase (TPS) of common bean (Phaseolus vulgaris), was silenced by RNA interference in transgenic nodules. The silencing of PvTPS9 in root nodules resulted in a reduction of 85% (± 1%) of its transcript, which correlated with a 30% decrease in trehalose contents of transgenic nodules and in untransformed leaves. Composite transgenic plants with PvTPS9 silenced in the roots showed no changes in nodule number and nitrogen fixation, but a severe reduction in plant biomass and altered transcript profiles of all Class II TPS genes. Our data suggest that PvTPS9 plays a key role in modulating trehalose metabolism in the symbiotic nodule and, therefore, in the whole plant. PMID:27847509

Modulation of motor behavior by dopamine and the D1-like dopamine receptor AmDOP2 in the honey bee

PubMed Central

Mustard, Julie A.; Pham, Priscilla M.; Smith, Brian H.

2009-01-01

Determining the specific molecular pathways through which dopamine affects behavior has been complicated by the presence of multiple dopamine receptor subtypes that couple to different second messenger pathways. The observation of freely moving adult bees in an arena was used to investigate the role of dopamine signaling in regulating the behavior of the honey bee. Dopamine or the dopamine receptor antagonist flupenthixol was injected into the hemolymph of worker honey bees. Significant differences between treated and control bees were seen for all behaviors (walking, stopped, upside down, grooming, flying and fanning), and behavioral shifts were dependent on drug dosage and time after injection. To examine the role of dopamine signaling through a specific dopamine receptor in the brain, RNA interference was used to reduce expression levels of a D1-like receptor, AmDOP2. Injection of Amdop2 dsRNA into the mushroom bodies reduced the levels of Amdop2 mRNA and produced significant changes in the amount of time honey bees spent performing specific behaviors with reductions in time spent walking offset by increases in grooming or time spent stopped. Taken together these results establish that dopamine plays an important role in regulating motor behavior of the honey bee. PMID:19945462

Modulation of motor behavior by dopamine and the D1-like dopamine receptor AmDOP2 in the honey bee.

PubMed

Mustard, Julie A; Pham, Priscilla M; Smith, Brian H

2010-04-01

Determining the specific molecular pathways through which dopamine affects behavior has been complicated by the presence of multiple dopamine receptor subtypes that couple to different second messenger pathways. The observation of freely moving adult bees in an arena was used to investigate the role of dopamine signaling in regulating the behavior of the honey bee. Dopamine or the dopamine receptor antagonist flupenthixol was injected into the hemolymph of worker honey bees. Significant differences between treated and control bees were seen for all behaviors (walking, stopped, upside down, grooming, flying and fanning), and behavioral shifts were dependent on drug dosage and time after injection. To examine the role of dopamine signaling through a specific dopamine receptor in the brain, RNA interference was used to reduce expression levels of a D1-like receptor, AmDOP2. Injection of Amdop2 dsRNA into the mushroom bodies reduced the levels of Amdop2 mRNA and produced significant changes in the amount of time honey bees spent performing specific behaviors with reductions in time spent walking offset by increases in grooming or time spent stopped. Taken together these results establish that dopamine plays an important role in regulating motor behavior of the honey bee. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Dopamine treatment and cognitive functioning in individuals with Parkinson's disease: the "cognitive flexibility" hypothesis seems to work.

PubMed

Costa, Alberto; Peppe, Antonella; Mazzù, Ilenia; Longarzo, Mariachiara; Caltagirone, Carlo; Carlesimo, Giovanni A

2014-01-01

Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis). To investigate above hypotheses in individuals with Parkinson's disease (PD). Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) "off" condition, about 18 hours after dopamine dose and (ii) "on" condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs. Passing from the "off" to the "on" state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P < 0.05); no significant effect was found on low-flexibility tasks. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals.

Distinct Behaviour of Sorafenib in Experimental Cachexia-Inducing Tumours: The Role of STAT3

PubMed Central

Busquets, Sílvia; López-Soriano, Francisco J.; Argilés, Josep M.

2014-01-01

The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC). The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin-1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways. PMID:25436606

The emerging role of class-3 semaphorins and their neuropilin receptors in oncology

PubMed Central

Nasarre, Patrick; Gemmill, Robert M; Drabkin, Harry A

2014-01-01

The semaphorins, discovered over 20 years ago, are a large family of secreted or transmembrane and glycophosphatidylinositol -anchored proteins initially identified as axon guidance molecules crucial for the development of the nervous system. It has now been established that they also play important roles in organ development and function, especially involving the immune, respiratory, and cardiovascular systems, and in pathological disorders, including cancer. During tumor progression, semaphorins can have both pro- and anti-tumor functions, and this has created complexities in our understanding of these systems. Semaphorins may affect tumor growth and metastases by directly targeting tumor cells, as well as indirectly by interacting with and influencing cells from the micro-environment and vasculature. Mechanistically, semaphorins, through binding to their receptors, neuropilins and plexins, affect pathways involved in cell adhesion, migration, invasion, proliferation, and survival. Importantly, neuropilins also act as co-receptors for several growth factors and enhance their signaling activities, while class 3 semaphorins may interfere with this. In this review, we focus on the secreted class 3 semaphorins and their neuropilin co-receptors in cancer, including aspects of their signaling that may be clinically relevant. PMID:25285016

Attention and positive affect: temporal switching or spatial broadening?

PubMed

Phaf, R Hans

2015-04-01

Evolutionary reasoning and computation suggest that positive affect is associated with higher attentional flexibility than negative affect, even when affectively neutral material is processed. The affective modulation of interference in the Eriksen flanker task seems, however, more readily explained by a spatial broadening of attention due to positive affect. It is argued here that these results should also be interpreted in terms of an increased switching over time between flankers and target (i.e., flexibility). The two hypotheses were contrasted with positive and negative mood inductions in a masked-flanker task. The interval (Stimulus Onset Asynchrony; SOA) with which the masked flankers preceded the target letter was parametrically varied. In contrast to what is found with simultaneous non-masked flanker presentation, masking produced larger interference with negative than with positive moods. In addition, a crossover interaction between mood and SOA emerged. These results seem incompatible with a spatial broadening account and support an affective modulation account in terms of flexibility.

Effect of TPA and HTLV-1 Tax on BRCA1 and ERE controlled genes expression.

PubMed

Jabareen, Azhar; Abu-Jaafar, Aya; Abou-Kandil, Ammar; Huleihel, Mahmoud

2017-07-18

Interference with the expression and/or functions of the multifunctional tumor suppressor BRCA1 leads to a high risk of breast and ovarian cancers. BRCA1 expression is usually activated by the estrogen (E2) liganded ERα receptor. Activated ERα is considered as a potent transcription factor which activates various genes expression by 2 pathways. A classical pathway, ERα binds directly to E2-responsive elements (EREs) in the promoters of the responsive genes and a non-classical pathway where ERα indirectly binds with the appropriate gene promoter. In our previous study, HTLV-1Tax was found to strongly inhibit ERα induced BRCA1 expression while stimulating ERα induced ERE dependent genes. TPA is a strong PKC activator which found to induce the expression of HTLV-1. Here we examined the effect of TPA on the expression of BRCA1 and genes controlled by ERE region in MCF-7 cells and on Tax activity on these genes. Our results showed strong stimulatory effect of TPA on both BRCA1 and ERE expression without treatment with E2. Tax did not show any significant effect on these TPA activities. It seems that TPA activation of BRCA1 and ERE expression is dependent on PKC activity but not through the NFκB pathway. However, 53BP1 may be involved in this TPA activity because its overexpression significantly reduced the TPA stimulatory effect on BRCA1 and ERE expression. Additionally, our Chip assay results probably exclude possible involvement of ERα pathway in this TPA activity because TPA did not interfere with the binding of ERα to both BRCA1 promoter and ERE region.

Harnessing RNA interference to develop neonatal therapies: from Nobel Prize winning discovery to proof of concept clinical trials.

PubMed

DeVincenzo, John P

2009-10-01

A revolution in the understanding of RNA biological processing and control is leading to revolutionary new concepts in human therapeutics. It has become increasingly clear that the so called "non-coding RNA" exerts specific and profound functional control on regulation of protein production and indeed controls the expression of all genes. Harnessing this naturally-occurring RNA-mediated regulation of protein production has immense human therapeutic potential. These processes are collectively known as RNA interference (RNAi). RNAi is a recently discovered, naturally-occurring intracellular process that regulates gene expression through the silencing of specific mRNAs. Methods of harnessing this natural pathway are being developed that allow the catalytic degradation of targeted mRNAs using specifically designed complementary small inhibitory RNAs (siRNA). siRNAs are being chemically modified to acquire drug-like properties. Numerous recent high profile publications have provided proofs of concept that RNA interference may be useful therapeutically. Much of the design of these siRNAs can be accomplished bioinformatically, thus potentially expediting drug discovery and opening new avenues of therapy for many uncommon, orphan, or emerging diseases. This makes this approach very attractive for developing therapies targeting orphan diseases including neonatal diseases. Theoretically, any disease that can be ameliorated through knockdown of any endogenous or exogenous protein is a potential therapeutic target for RNAi-based therapeutics. Lung diseases are particularly attractive targets for RNAi therapeutics since the affected cells' location increases their accessibility to topical administration of siRNA, for example by aerosol. Respiratory viral infections and chronic lung disease are examples of such diseases. RNAi therapeutics have been shown to be active against RSV, parainfluenza and human metapneumoviruses in vitro and in vivo resulting in profound antiviral effects. The first proof of concept test of efficacy of an RNAi-based therapeutic in man has been initiated. A discussion of the science behind RNA interference is followed by a presentation of the potential practical issues in applying this technology to neonatal respiratory viral diseases. RNAi may offer new strategies for the treatment of a variety of orphan diseases including neonatal diseases, RSV infections, and other respiratory viruses.

Sleep can reduce proactive interference.

PubMed

Abel, Magdalena; Bäuml, Karl-Heinz T

2014-01-01

Sleep has repeatedly been connected to processes of memory consolidation. While extensive research indeed documents beneficial effects of sleep on memory, little is yet known about the role of sleep for interference effects in episodic memory. Although two prior studies reported sleep to reduce retroactive interference, no sleep effect has previously been found for proactive interference. Here we applied a study format differing from that employed by the prior studies to induce a high degree of proactive interference, and asked participants to encode a single list or two interfering lists of paired associates via pure study cycles. Testing occurred after 12 hours of diurnal wakefulness or nocturnal sleep. Consistent with the prior work, we found sleep in comparison to wake did not affect memory for the single list, but reduced retroactive interference. In addition we found sleep reduced proactive interference, and reduced retroactive and proactive interference to the same extent. The finding is consistent with the view that arising benefits of sleep are caused by the reactivation of memory contents during sleep, which has been suggested to strengthen and stabilise memories. Such stabilisation may make memories less susceptible to competition from interfering memories at test and thus reduce interference effects.

Link Scheduling Algorithm with Interference Prediction for Multiple Mobile WBANs

PubMed Central

Le, Thien T. T.

2017-01-01

As wireless body area networks (WBANs) become a key element in electronic healthcare (e-healthcare) systems, the coexistence of multiple mobile WBANs is becoming an issue. The network performance is negatively affected by the unpredictable movement of the human body. In such an environment, inter-WBAN interference can be caused by the overlapping transmission range of nearby WBANs. We propose a link scheduling algorithm with interference prediction (LSIP) for multiple mobile WBANs, which allows multiple mobile WBANs to transmit at the same time without causing inter-WBAN interference. In the LSIP, a superframe includes the contention access phase using carrier sense multiple access with collision avoidance (CSMA/CA) and the scheduled phase using time division multiple access (TDMA) for non-interfering nodes and interfering nodes, respectively. For interference prediction, we define a parameter called interference duration as the duration during which disparate WBANs interfere with each other. The Bayesian model is used to estimate and classify the interference using a signal to interference plus noise ratio (SINR) and the number of neighboring WBANs. The simulation results show that the proposed LSIP algorithm improves the packet delivery ratio and throughput significantly with acceptable delay. PMID:28956827

Comparison of conventional and adaptive wall wind tunnel results with regard to Reynolds number effects

NASA Technical Reports Server (NTRS)

Stanewsky, E.; Freimuth, P.

1989-01-01

A comparison of results from conventional and adaptive wall wind tunnels with regard to Reynolds number effects was carried out. The special objective of this comparison was to confirm or reject earlier conclusions, soley based on conventional wind tunnel results, concerning the influence of viscous effects on the characteristics of partially open wind tunnel walls, hence wall interference. The following postulations could be confirmed: (1) certain classes of supercritical airfoils exhibit a non-linear increase in lift which is, at least in part, related to viscous-inviscid interactions on the airfoil. This non-linear lift characteristic can erroneously be suppressed by sidewall interference effects in addition to being affected by changes in Reynolds number. Adaptive walls seem to relieve the influence of sidewall interference; (2) the degree of (horizontal) wall interference effects can be significantly affected by changes in Reynolds number, thus appearing as true Reynolds number effects; (3) perforated wall characteristics seem much more susceptible to viscous changes than the characteristics of slotted walls; here, blockage interference may be most severely influenced by viscous changes; and (4) real Reynolds number effects are present on the CAST 10-2/DOA 2 airfoil; they were shown to be appreciable also by the adaptive wall wind tunnel tests.

Motivational Interference in Study-Leisure Conflicts: How Opportunity Costs Affect the Self-Regulation of University Students

ERIC Educational Resources Information Center

Grund, Axel; Fries, Stefan

2012-01-01

We examined the effects of motivational interference resulting from tempting action alternatives among a sample of university students with respect to a new measure of different motivational qualities. Participants imagined themselves in a typical study-leisure conflict and provided information about their internal conflict experience in two…

Selective Interference on the Holistic Processing of Faces in Working Memory

ERIC Educational Resources Information Center

Cheung, Olivia S.; Gauthier, Isabel

2010-01-01

Faces and objects of expertise compete for early perceptual processes and holistic processing resources (Gauthier, Curran, Curby, & Collins, 2003). Here, we examined the nature of interference on holistic face processing in working memory by comparing how various types of loads affect selective attention to parts of face composites. In dual…

Acquired tolerance and in situ detoxification of furfural and HMF through glucose metabolic pathways by Saccharomyces cerevisiae

USDA-ARS?s Scientific Manuscript database

Lignocellulosic biomass conversion inhibitors furfural and HMF inhibit microbial growth and interfere with subsequent fermentation of ethanol. Numerous yeast genes were found to be associated with the inhibitor tolerance. However, little is known about system mechanisms of the tolerance and detoxi...

Different Loci of Semantic Interference in Picture Naming vs. Word-Picture Matching Tasks.

PubMed

Harvey, Denise Y; Schnur, Tatiana T

2016-01-01

Naming pictures and matching words to pictures belonging to the same semantic category impairs performance relative to when stimuli come from different semantic categories (i.e., semantic interference). Despite similar semantic interference phenomena in both picture naming and word-picture matching tasks, the locus of interference has been attributed to different levels of the language system - lexical in naming and semantic in word-picture matching. Although both tasks involve access to shared semantic representations, the extent to which interference originates and/or has its locus at a shared level remains unclear, as these effects are often investigated in isolation. We manipulated semantic context in cyclical picture naming and word-picture matching tasks, and tested whether factors tapping semantic-level (generalization of interference to novel category items) and lexical-level processes (interactions with lexical frequency) affected the magnitude of interference, while also assessing whether interference occurs at a shared processing level(s) (transfer of interference across tasks). We found that semantic interference in naming was sensitive to both semantic- and lexical-level processes (i.e., larger interference for novel vs. old and low- vs. high-frequency stimuli), consistent with a semantically mediated lexical locus. Interference in word-picture matching exhibited stable interference for old and novel stimuli and did not interact with lexical frequency. Further, interference transferred from word-picture matching to naming. Together, these experiments provide evidence to suggest that semantic interference in both tasks originates at a shared processing stage (presumably at the semantic level), but that it exerts its effect at different loci when naming pictures vs. matching words to pictures.

Different Loci of Semantic Interference in Picture Naming vs. Word-Picture Matching Tasks

PubMed Central

Harvey, Denise Y.; Schnur, Tatiana T.

2016-01-01

Naming pictures and matching words to pictures belonging to the same semantic category impairs performance relative to when stimuli come from different semantic categories (i.e., semantic interference). Despite similar semantic interference phenomena in both picture naming and word-picture matching tasks, the locus of interference has been attributed to different levels of the language system – lexical in naming and semantic in word-picture matching. Although both tasks involve access to shared semantic representations, the extent to which interference originates and/or has its locus at a shared level remains unclear, as these effects are often investigated in isolation. We manipulated semantic context in cyclical picture naming and word-picture matching tasks, and tested whether factors tapping semantic-level (generalization of interference to novel category items) and lexical-level processes (interactions with lexical frequency) affected the magnitude of interference, while also assessing whether interference occurs at a shared processing level(s) (transfer of interference across tasks). We found that semantic interference in naming was sensitive to both semantic- and lexical-level processes (i.e., larger interference for novel vs. old and low- vs. high-frequency stimuli), consistent with a semantically mediated lexical locus. Interference in word-picture matching exhibited stable interference for old and novel stimuli and did not interact with lexical frequency. Further, interference transferred from word-picture matching to naming. Together, these experiments provide evidence to suggest that semantic interference in both tasks originates at a shared processing stage (presumably at the semantic level), but that it exerts its effect at different loci when naming pictures vs. matching words to pictures. PMID:27242621

Haloarcula hispanica CRISPR authenticates PAM of a target sequence to prime discriminative adaptation

PubMed Central

Li, Ming; Wang, Rui; Xiang, Hua

2014-01-01

The prokaryotic immune system CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated genes) adapts to foreign invaders by acquiring their short deoxyribonucleic acid (DNA) fragments as spacers, which guide subsequent interference to foreign nucleic acids based on sequence matching. The adaptation mechanism avoiding acquiring ‘self’ DNA fragments is poorly understood. In Haloarcula hispanica, we previously showed that CRISPR adaptation requires being primed by a pre-existing spacer partially matching the invader DNA. Here, we further demonstrate that flanking a fully-matched target sequence, a functional PAM (protospacer adjacent motif) is still required to prime adaptation. Interestingly, interference utilizes only four PAM sequences, whereas adaptation-priming tolerates as many as 23 PAM sequences. This relaxed PAM selectivity explains how adaptation-priming maximizes its tolerance of PAM mutations (that escape interference) while avoiding mis-targeting the spacer DNA within CRISPR locus. We propose that the primed adaptation, which hitches and cooperates with the interference pathway, distinguishes target from non-target by CRISPR ribonucleic acid guidance and PAM recognition. PMID:24803673

Interference in acetylene intersystem crossing acts as the molecular analog of Young's double-slit experiment

PubMed Central

de Groot, Mattijs; Field, Robert W.; Buma, Wybren J.

2009-01-01

We report on an experimental approach that reveals crucial details of the composition of singlet-triplet mixed eigenstates in acetylene. Intersystem crossing in this prototypical polyatomic molecule embodies the mixing of the lowest excited singlet state (S1) with 3 triplet states (T1, T2, and T3). Using high-energy (157-nm) photons from an F2 laser to record excited-state photoelectron spectra, we have decomposed the mixed eigenstates into their S1, T3, T2, and T1 constituent parts. One example of the interpretive power that ensues from the selective sensitivity of the experiment to the individual electronic state characters is the discovery and examination of destructive interference between two doorway-mediated intersystem crossing pathways. This observation of an interference effect in nonradiative decay opens up possibilities for rational coherent control over molecular excited state dynamics. PMID:19179288

Assessing effects of cholera vaccination in the presence of interference.

PubMed

Perez-Heydrich, Carolina; Hudgens, Michael G; Halloran, M Elizabeth; Clemens, John D; Ali, Mohammad; Emch, Michael E

2014-09-01

Interference occurs when the treatment of one person affects the outcome of another. For example, in infectious diseases, whether one individual is vaccinated may affect whether another individual becomes infected or develops disease. Quantifying such indirect (or spillover) effects of vaccination could have important public health or policy implications. In this article we use recently developed inverse-probability weighted (IPW) estimators of treatment effects in the presence of interference to analyze an individually-randomized, placebo-controlled trial of cholera vaccination that targeted 121,982 individuals in Matlab, Bangladesh. Because these IPW estimators have not been employed previously, a simulation study was also conducted to assess the empirical behavior of the estimators in settings similar to the cholera vaccine trial. Simulation study results demonstrate the IPW estimators can yield unbiased estimates of the direct, indirect, total, and overall effects of vaccination when there is interference provided the untestable no unmeasured confounders assumption holds and the group-level propensity score model is correctly specified. Application of the IPW estimators to the cholera vaccine trial indicates the presence of interference. For example, the IPW estimates suggest on average 5.29 fewer cases of cholera per 1000 person-years (95% confidence interval 2.61, 7.96) will occur among unvaccinated individuals within neighborhoods with 60% vaccine coverage compared to neighborhoods with 32% coverage. Our analysis also demonstrates how not accounting for interference can render misleading conclusions about the public health utility of vaccination. © 2014, The International Biometric Society.

Modulation of the nuclear factor-kappa B (NF-κB) signalling pathway by glutamine in peritoneal macrophages of a murine model of protein malnutrition.

PubMed

da Silva Lima, Fabiana; Rogero, Marcelo Macedo; Ramos, Mayara Caldas; Borelli, Primavera; Fock, Ricardo Ambrósio

2013-06-01

Protein malnutrition affects resistance to infection by impairing the inflammatory response, modifying the function of effector cells, such as macrophages. Recent studies have revealed that glutamine-a non-essential amino acid, which could become conditionally essential in some situations like trauma, infection, post-surgery and sepsis-is able to modulate the synthesis of cytokines. The aim of this study was to evaluate the effect of glutamine on the expression of proteins involved in the nuclear factor-kappa B (NF-κB) signalling pathway of peritoneal macrophages from malnourished mice. Two-month-old male Balb/c mice were submitted to protein-energy malnutrition (n = 10) with a low-protein diet containing 2 % protein, whereas control mice (n = 10) were fed a 12 % protein-containing diet. The haemogram and analysis of plasma glutamine and corticosterone were evaluated. Peritoneal macrophages were pre-treated in vitro with glutamine (0, 0.6, 2 and 10 mmol/L) for 24 h and then stimulated with 1.25 μg LPS for 30 min, and the synthesis of TNF-α and IL-1α and the expression of proteins related to the NF-κB pathway were evaluated. Malnourished animals had anaemia, leucopoenia, lower plasma glutamine and increased corticosterone levels. TNF-α production of macrophages stimulated with LPS was significantly lower in cells from malnourished animals when cultivated in supraphysiological (2 and 10 mmol/L) concentrations of glutamine. Further, glutamine has a dose-dependent effect on the activation of macrophages, in both groups, when stimulated with LPS, inducing a decrease in TNF-α and IL-1α production and negatively modulating the NF-κB signalling pathway. These data lead us to infer that the protein malnutrition state interferes with the activation of macrophages and that higher glutamine concentrations, in vitro, have the capacity to act negatively in the NF-κB signalling pathway.

Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma.

PubMed

McGuire, Mary F; Sriram Iyengar, M; Mercer, David W

2012-04-01

Although trauma is the leading cause of death for those below 45years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. In the node/molecular analysis of the first 24h from trauma, PSA uncovered seven molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which three molecules had not been previously associated with any shock/trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships--activation, expression, inhibition, and transcription--and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction mechanisms may be most effective within a certain time period and for a specific functional relationship. Copyright © 2011 Elsevier Inc. All rights reserved.

Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma

PubMed Central

McGuire, Mary F.; Iyengar, M. Sriram; Mercer, David W.

2012-01-01

Motivation Although trauma is the leading cause of death for those below 45 years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. Results In the node/molecular analysis of the first 24 hours from trauma, PSA uncovered 7 molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which 3 molecules had not been previously associated with any shock / trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships – activation, expression, inhibition, and transcription – and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction mechanisms may be most effective within a certain time period and for a specific functional relationship. PMID:22200681

Electronic quenching of O({sup 1}D) by Xe: Oscillations in the product angular distribution and their dependence on collision energy

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

Garofalo, Lauren A.; Smith, Mica C.; Dagdigian, Paul J., E-mail: pjdagdigian@jhu.edu

2015-08-07

The dynamics of the O({sup 1}D) + Xe electronic quenching reaction was investigated in a crossed beam experiment at four collision energies. Marked large-scale oscillations in the differential cross sections were observed for the inelastic scattering products, O({sup 3}P) and Xe. The shape and relative phases of the oscillatory structure depend strongly on collision energy. Comparison of the experimental results with time-independent scattering calculations shows qualitatively that this behavior is caused by Stueckelberg interferences, for which the quantum phases of the multiple reaction pathways accessible during electronic quenching constructively and destructively interfere.

Targeted Elimination of Peroxisomes During Viral Infection: Lessons from HIV and Other Viruses.

PubMed

Wong, Cheung Pang; Xu, Zaikun; Power, Christopher; Hobman, Tom C

2018-05-01

Peroxisomes are membrane-bound organelles that are best known for their roles in lipid metabolism. Mounting evidence indicates that they are also important nodes for antiviral signaling. While research over the past few decades has revealed effective viral strategies to block antiviral signalling pathways from the plasma membrane, mitochondria and/or the nucleus, until recently, very little was known about how viruses interfere with peroxisome-based antiviral signaling. In this essay, we review how viruses use a variety of strategies to interfere with peroxisome biogenesis, a phenomenon that has implications for evasion of the host immune system as well as pathogenesis.

The RNA-induced silencing complex: a versatile gene-silencing machine.

PubMed

Pratt, Ashley J; MacRae, Ian J

2009-07-03

RNA interference is a powerful mechanism of gene silencing that underlies many aspects of eukaryotic biology. On the molecular level, RNA interference is mediated by a family of ribonucleoprotein complexes called RNA-induced silencing complexes (RISCs), which can be programmed to target virtually any nucleic acid sequence for silencing. The ability of RISC to locate target RNAs has been co-opted by evolution many times to generate a broad spectrum of gene-silencing pathways. Here, we review the fundamental biochemical and biophysical properties of RISC that facilitate gene targeting and describe the various mechanisms of gene silencing known to exploit RISC activity.

Backbone and sidechain methyl Ile (δ1), Leu and Val chemical shift assignments of RDE-4 (1-243), an RNA interference initiation protein in C. elegans.

PubMed

Chiliveri, Sai Chaitanya; Kumar, Sonu; Marelli, Udaya Kiran; Deshmukh, Mandar V

2012-10-01

The RNAi pathway of several organisms requires presence of double stranded RNA binding proteins for functioning of Dicer in gene regulation. In C. elegans, a double stranded RNA binding protein, RDE-4 (385 aa, 44 kDa) recognizes long exogenous dsRNA and initiates the RNAi pathway. We have achieved complete backbone and stereospecific methyl sidechain Ile (δ1), Leu and Val chemical shifts of first 243 amino acids of RDE-4, namely RDE-4ΔC.

Affective neural response to restricted interests in autism spectrum disorders.

PubMed

Cascio, Carissa J; Foss-Feig, Jennifer H; Heacock, Jessica; Schauder, Kimberly B; Loring, Whitney A; Rogers, Baxter P; Pryweller, Jennifer R; Newsom, Cassandra R; Cockhren, Jurnell; Cao, Aize; Bolton, Scott

2014-01-01

Restricted interests are a class of repetitive behavior in autism spectrum disorders (ASD) whose intensity and narrow focus often contribute to significant interference with daily functioning. While numerous neuroimaging studies have investigated executive circuits as putative neural substrates of repetitive behavior, recent work implicates affective neural circuits in restricted interests. We sought to explore the role of affective neural circuits and determine how restricted interests are distinguished from hobbies or interests in typical development. We compared a group of children with ASD to a typically developing (TD) group of children with strong interests or hobbies, employing parent report, an operant behavioral task, and functional imaging with personalized stimuli based on individual interests. While performance on the operant task was similar between the two groups, parent report of intensity and interference of interests was significantly higher in the ASD group. Both the ASD and TD groups showed increased BOLD response in widespread affective neural regions to the pictures of their own interest. When viewing pictures of other children's interests, the TD group showed a similar pattern, whereas BOLD response in the ASD group was much more limited. Increased BOLD response in the insula and anterior cingulate cortex distinguished the ASD from the TD group, and parent report of the intensity and interference with daily life of the child's restricted interest predicted insula response. While affective neural network response and operant behavior are comparable in typical and restricted interests, the narrowness of focus that clinically distinguishes restricted interests in ASD is reflected in more interference in daily life and aberrantly enhanced insula and anterior cingulate response to individuals' own interests in the ASD group. These results further support the involvement of affective neural networks in repetitive behaviors in ASD. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

Lateralized dual task interference in left-handers: initial value differences do not affect the outcome.

PubMed

McBride, D M; Cherry, B J; Kee, D W; Neale, P L

1995-07-01

The study was conducted to clarify factors involved in dual-task finger-tapping interference. Left-handers, as assessed by hand-writing preference and left-hand baseline tapping advantage, tapped both alone and while solving anagrams. Even though the left-hand baseline tapping advantage was experimentally removed on some (adjusted) trials, greater left- than right-hand tapping interference was observed during concurrent task performance. This result coupled with previous findings for right-handed subjects [Kee and Cherry, Neuropsychologia, Vol. 28, pp. 313-316, 1990] indicates that lateralized interference effects are not merely due to initial baseline tapping differences as proposed by Willis and Goodwin [Neuropsychologia, Vol. 25, pp. 719-724, 1987].

Constructive and Destructive Interference in Nonadiabatic Tunneling via Conical Intersections

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

Xie, Changjian; Kendrick, Brian K.; Yarkony, David R.

As a manifestation of the molecular Aharonov–Bohm effect, tunneling-facilitated dissociation under a conical intersection (CI) requires the inclusion of the geometric phase (GP) to ensure a single-valued adiabatic wave function encircling the CI. Here, we demonstrate using a simple two-dimensional model that the GP induces destructive interference for vibrational states with even quanta in the coupling mode, but it leads to constructive interference for those with odd quanta. The interference patterns are manifested in tunneling wave functions and clearly affect the tunneling lifetime. Furthermore, we show that the inclusion of the diagonal Born–Oppenheimer correction is necessary for agreement with exactmore » results.« less

Constructive and Destructive Interference in Nonadiabatic Tunneling via Conical Intersections

DOE PAGES

Xie, Changjian; Kendrick, Brian K.; Yarkony, David R.; ...

2017-03-31

As a manifestation of the molecular Aharonov–Bohm effect, tunneling-facilitated dissociation under a conical intersection (CI) requires the inclusion of the geometric phase (GP) to ensure a single-valued adiabatic wave function encircling the CI. Here, we demonstrate using a simple two-dimensional model that the GP induces destructive interference for vibrational states with even quanta in the coupling mode, but it leads to constructive interference for those with odd quanta. The interference patterns are manifested in tunneling wave functions and clearly affect the tunneling lifetime. Furthermore, we show that the inclusion of the diagonal Born–Oppenheimer correction is necessary for agreement with exactmore » results.« less

Confirmatory factor analysis of 2 versions of the Brief Pain Inventory in an ambulatory population indicates that sleep interference should be interpreted separately.

PubMed

Walton, David M; Putos, Joseph; Beattie, Tyler; MacDermid, Joy C

2016-07-01

The Brief Pain Inventory (BPI-SF) is a widely-used generic pain interference scale, however its factor structure remains unclear. An expanded 10-item version of the Interference subscale has been proposed, but the additional value of the 3 extra items has not been rigorously evaluated. The purpose of this study was to evaluate and contrast the factorial and concurrent validity of the original 7-item and 10-item versions of the BPI-SF in a large heterogeneous sample of patients with chronic pain. Exploratory and confirmatory factor analyses were conducted on independent subsets of the sample, and concurrent correlations with scales capturing similar constructs were evaluated. Two independent exploratory factor analyses (n=500 each) supported a single interference factor in both the 7- and 10-item versions, while confirmatory factor analysis (N=1000) suggested that a 2-factor structure (Physical and Affective) provided better fit. A 3-factor model, where sleep interference was the third factor, improved in model fit further. There was no significant difference in model fit between the 7- and 10-item versions. Concurrent associations with measures of general health, pain intensity and pain-related cognitions were all in the anticipated direction and magnitude and were not different by version of the BPI-SF. The addition of 3 extra items to the original 7-item Interference subscale of the BPI-SF did not improve psychometric properties. The combined results lead us to endorse a 3-factor structure (Physical, Affective, and Sleep Interference) as the more statistically and conceptually sound option. Copyright © 2016 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Proactive Interference Slows Recognition by Eliminating Fast Assessments of Familiarity

ERIC Educational Resources Information Center

Oztekin, Ilke; McElree, Brian

2007-01-01

The response-signal speed-accuracy tradeoff (SAT) procedure was used to investigate how proactive interference (PI) affects retrieval from working memory. Participants were presented with 6-item study lists, followed immediately by a recognition probe. A variant of a release from PI design was used: All items in a list were from the same semantic…

Impaired Inhibition of Prepotent Motor Tendencies in Friedreich Ataxia Demonstrated by the Simon Interference Task

ERIC Educational Resources Information Center

Corben, L. A.; Akhlaghi, H.; Georgiou-Karistianis, N.; Bradshaw, J. L.; Egan, G. F.; Storey, E.; Churchyard, A. J.; Delatycki, M. B.

2011-01-01

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We recently demonstrated that people with FRDA have impairment in motor planning--most likely because of pathology affecting the cerebral cortex and/or cerebello-cortical projections. We used the Simon interference task to examine how effective 13 individuals with…

Developmental Change in Proactive Interference across the Life Span: Evidence from Two Working Memory Tasks

ERIC Educational Resources Information Center

Loosli, Sandra V.; Rahm, Benjamin; Unterrainer, Josef M.; Weiller, Cornelius; Kaller, Christoph P.

2014-01-01

Working memory (WM) as the ability to temporarily maintain and manipulate various kinds of information is known to be affected by proactive interference (PI) from previously relevant contents, but studies on developmental changes in the susceptibility to PI are scarce. In the present study, we investigated life span development of item-specific…

Hyper-modulation of brain networks by the amygdala among women with Borderline Personality Disorder: Network signatures of affective interference during cognitive processing.

PubMed

Soloff, Paul H; Abraham, Kristy; Ramaseshan, Karthik; Burgess, Ashley; Diwadkar, Vaibhav A

2017-05-01

Emotion dysregulation is a core characteristic of patients with Borderline Personality Disorder (BPD), and is often attributed to an imbalance in fronto-limbic network function. Hyperarousal of amygdala, especially in response to negative affective stimuli, results in affective interference with cognitive processing of executive functions. Clinical consequences include the impulsive-aggression, suicidal and self-injurious behaviors which characterize BPD. Dysfunctional interactions between amygdala and its network targets have not been well characterized during cognitive task performance. Using psychophysiological interaction analysis (PPI), we mapped network profiles of amygdala interaction with key regulatory regions during a Go No-Go task, modified to use negative, positive and neutral Ekman faces as targets. Fifty-six female subjects, 31 BPD and 25 healthy controls (HC), completed the affectively valenced Go No-Go task during fMRI scanning. In the negative affective condition, the amygdala exerted greater modulation of its targets in BPD compared to HC subjects in Rt. OFC, Rt. dACC, Rt. Parietal cortex, Rt. Basal Ganglia, and Rt. dlPFC. Across the spectrum of affective contrasts, hypermodulation in BPD subjects observed the following ordering: Negative > Neutral > Positive contrast. The amygdala seed exerted modulatory effects on specific target regions important in processing response inhibition and motor impulsiveness. The vulnerability of BPD subjects to affective interference with impulse control may be due to specific network dysfunction related to amygdala hyper-arousal and its effects on prefrontal regulatory regions such as the OFC and dACC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cerebellum: links between development, developmental disorders and motor learning

PubMed Central

Manto, Mario U.; Jissendi, Patrice

2012-01-01

The study of the links and interactions between development and motor learning has noticeable implications for the understanding and management of neurodevelopmental disorders. This is particularly relevant for the cerebellum which is critical for sensorimotor learning. The olivocerebellar pathway is a key pathway contributing to learning of motor skills. Its developmental maturation and remodeling are being unraveled. Advances in genetics have led to major improvements in our appraisal of the genes involved in cerebellar development, especially studies in mutant mice. Cerebellar neurogenesis is compartmentalized in relationship with neurotransmitter fate. The Engrailed-2 gene is a major actor of the specification of cerebellar cell types and late embryogenic morphogenesis. Math1, expressed by the rhombic lip, is required for the genesis of glutamatergic neurons. Mutants deficient for the transcription factor Ptf1a display a lack of Purkinje cells and gabaergic interneurons. Rora gene contributes to the developmental signaling between granule cells and Purkinje neurons. The expression profile of sonic hedgehog in postnatal stages determines the final size/shape of the cerebellum. Genes affecting the development impact upon the physiological properties of the cerebellar circuits. For instance, receptors are developmentally regulated and their action interferes directly with developmental processes. Another field of research which is expanding relates to very preterm neonates. They are at risk for cerebellar lesions, which may themselves impair the developmental events. Very preterm neonates often show sensori-motor deficits, highlighting another major link between impaired developments and learning deficiencies. Pathways playing a critical role in cerebellar development are likely to become therapeutical targets for several neurodevelopmental disorders. PMID:22291620

Neutrality of the canonical NF-kappaB-dependent pathway for human and murine cytomegalovirus transcription and replication in vitro.

PubMed

Benedict, Chris A; Angulo, Ana; Patterson, Ginelle; Ha, Sukwon; Huang, Huang; Messerle, Martin; Ware, Carl F; Ghazal, Peter

2004-01-01

Cytomegalovirus (CMV) is known to rapidly induce activation of nuclear factor kappaB (NF-kappaB) after infection of fibroblast and macrophage cells. NF-kappaB response elements are present in the enhancer region of the CMV major immediate-early promoter (MIEP), and activity of the MIEP is strongly upregulated by NF-kappaB in transient-transfection assays. Here we investigate whether the NF-kappaB-dependent pathway is required for initiating or potentiating human and murine CMV replication in vitro. We show that expression of a dominant negative mutant of the inhibitor of NF-kappaB-alpha (IkappaBalphaM) does not alter the replication kinetics of human or mouse CMV in cultured cells. In addition, mouse embryo fibroblasts genetically deficient for p65/RelA actually showed elevated levels of MCMV replication. Mutation of all NF-kappaB response elements within the enhancer of the MIEP in a recombinant mouse CMV containing the human MIEP (hMCMV-ES), which we have previously shown to replicate in murine fibroblasts with kinetics equivalent to that of wild-type mouse CMV, did not negatively affect replication in fibroblasts. Taken together, these data show that, for CMV replication in cultured fibroblasts activation of the canonical NF-kappaB pathway and binding of NF-kappaB to the MIEP are dispensable, and in the case of p65 may even interfere, thus uncovering a previously unrecognized level of complexity in the host regulatory network governing MIE gene expression in the context of a viral infection.

Evidence of a tick RNAi pathway by comparative genomics and reverse genetics screen of targets with known loss-of-function phenotypes in Drosophila

PubMed Central

Kurscheid, Sebastian; Lew-Tabor, Ala E; Rodriguez Valle, Manuel; Bruyeres, Anthea G; Doogan, Vivienne J; Munderloh, Ulrike G; Guerrero, Felix D; Barrero, Roberto A; Bellgard, Matthew I

2009-01-01

Background The Arthropods are a diverse group of organisms including Chelicerata (ticks, mites, spiders), Crustacea (crabs, shrimps), and Insecta (flies, mosquitoes, beetles, silkworm). The cattle tick, Rhipicephalus (Boophilus) microplus, is an economically significant ectoparasite of cattle affecting cattle industries world wide. With the availability of sequence reads from the first Chelicerate genome project (the Ixodes scapularis tick) and extensive R. microplus ESTs, we investigated evidence for putative RNAi proteins and studied RNA interference in tick cell cultures and adult female ticks targeting Drosophila homologues with known cell viability phenotype. Results We screened 13,643 R. microplus ESTs and I. scapularis genome reads to identify RNAi related proteins in ticks. Our analysis identified 31 RNAi proteins including a putative tick Dicer, RISC associated (Ago-2 and FMRp), RNA dependent RNA polymerase (EGO-1) and 23 homologues implicated in dsRNA uptake and processing. We selected 10 R. microplus ESTs with >80% similarity to D. melanogaster proteins associated with cell viability for RNAi functional screens in both BME26 R. microplus embryonic cells and female ticks in vivo. Only genes associated with proteasomes had an effect on cell viability in vitro. In vivo RNAi showed that 9 genes had significant effects either causing lethality or impairing egg laying. Conclusion We have identified key RNAi-related proteins in ticks and along with our loss-of-function studies support a functional RNAi pathway in R. microplus. Our preliminary studies indicate that tick RNAi pathways may differ from that of other Arthropods such as insects. PMID:19323841

Viruses and neurodegeneration

PubMed Central

2013-01-01

Neurodegenerative diseases (NDs) are chronic degenerative diseases of the central nervous system (CNS), which affect 37 million people worldwide. As the lifespan increases, the NDs are the fourth leading cause of death in the developed countries and becoming increasingly prevalent in developing countries. Despite considerable research, the underlying mechanisms remain poorly understood. Although the large majority of studies do not show support for the involvement of pathogenic aetiology in classical NDs, a number of emerging studies show support for possible association of viruses with classical neurodegenerative diseases in humans. Space does not permit for extensive details to be discussed here on non-viral-induced neurodegenerative diseases in humans, as they are well described in literature. Viruses induce alterations and degenerations of neurons both directly and indirectly. Their ability to attack the host immune system, regions of nervous tissue implies that they can interfere with the same pathways involved in classical NDs in humans. Supporting this, many similarities between classical NDs and virus-mediated neurodegeneration (non-classical) have been shown at the anatomic, sub-cellular, genomic and proteomic levels suggesting that viruses can explain neurodegenerative disorders mechanistically. The main objective of this review is to provide readers a detailed snapshot of similarities viral and non-viral neurodegenerative diseases share, so that mechanistic pathways of neurodegeneration in human NDs can be clearly understood. Viruses can guide us to unveil these pathways in human NDs. This will further stimulate the birth of new concepts in the biological research, which is needed for gaining deeper insights into the treatment of human NDs and delineate mechanisms underlying neurodegeneration. PMID:23724961

Topological Interference Management for K-User Downlink Massive MIMO Relay Network Channel.

PubMed

Selvaprabhu, Poongundran; Chinnadurai, Sunil; Li, Jun; Lee, Moon Ho

2017-08-17

In this paper, we study the emergence of topological interference alignment and the characterizing features of a multi-user broadcast interference relay channel. We propose an alternative transmission strategy named the relay space-time interference alignment (R-STIA) technique, in which a K -user multiple-input-multiple-output (MIMO) interference channel has massive antennas at the transmitter and relay. Severe interference from unknown transmitters affects the downlink relay network channel and degrades the system performance. An additional (unintended) receiver is introduced in the proposed R-STIA technique to overcome the above problem, since it has the ability to decode the desired signals for the intended receiver by considering cooperation between the receivers. The additional receiver also helps in recovering and reconstructing the interference signals with limited channel state information at the relay (CSIR). The Alamouti space-time transmission technique and minimum mean square error (MMSE) linear precoder are also used in the proposed scheme to detect the presence of interference signals. Numerical results show that the proposed R-STIA technique achieves a better performance in terms of the bit error rate (BER) and sum-rate compared to the existing broadcast channel schemes.

Topological Interference Management for K-User Downlink Massive MIMO Relay Network Channel

PubMed Central

Li, Jun; Lee, Moon Ho

2017-01-01

In this paper, we study the emergence of topological interference alignment and the characterizing features of a multi-user broadcast interference relay channel. We propose an alternative transmission strategy named the relay space-time interference alignment (R-STIA) technique, in which a K-user multiple-input-multiple-output (MIMO) interference channel has massive antennas at the transmitter and relay. Severe interference from unknown transmitters affects the downlink relay network channel and degrades the system performance. An additional (unintended) receiver is introduced in the proposed R-STIA technique to overcome the above problem, since it has the ability to decode the desired signals for the intended receiver by considering cooperation between the receivers. The additional receiver also helps in recovering and reconstructing the interference signals with limited channel state information at the relay (CSIR). The Alamouti space-time transmission technique and minimum mean square error (MMSE) linear precoder are also used in the proposed scheme to detect the presence of interference signals. Numerical results show that the proposed R-STIA technique achieves a better performance in terms of the bit error rate (BER) and sum-rate compared to the existing broadcast channel schemes. PMID:28817071

Heterophilic antibody interference affecting multiple hormone assays: Is it due to rheumatoid factor?

PubMed

Mongolu, Shiva; Armston, Annie E; Mozley, Erin; Nasruddin, Azraai

2016-01-01

Assay interference with heterophilic antibodies has been well described in literature. Rheumatoid factor is known to cause similar interference leading to falsely elevated hormone levels when measured by immunometric methods like enzyme-linked immunosorbent assay (ELISA) or multiplex immunoasays (MIA). We report a case of a 60-year-old male patient with a history of rheumatoid arthritis referred to our endocrine clinic for investigation of hypogonadism and was found to have high serum levels of LH, FSH, SHBG, Prolactin, HCG and TSH. We suspected assay interference and further tests were performed. We used Heteroblock tubes and PEG precipitation to eliminate the interference and the hormone levels post treatment were in the normal range. We believe the interference was caused by high serum levels of rheumatoid factor. Although he was treated with thyroxine for 3 years, we believe he may have been treated inappropriately as his Free T4 level was always normal despite high TSH due to assay interference. Our case illustrates the phenomenon of heterophilic antibody interference likely due to high levels of rheumatoid factor. It is essential for clinicians and endocrinologists in particular to be aware of this possibility when making treatment decisions in these groups of patients.

A complex regulatory network coordinating cell cycles during C. elegans development is revealed by a genome-wide RNAi screen.

PubMed

Roy, Sarah H; Tobin, David V; Memar, Nadin; Beltz, Eleanor; Holmen, Jenna; Clayton, Joseph E; Chiu, Daniel J; Young, Laura D; Green, Travis H; Lubin, Isabella; Liu, Yuying; Conradt, Barbara; Saito, R Mako

2014-02-28

The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized ubc-25, a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that ubc-25 acts in a linear pathway with cul-1/Cul1, in parallel to pathways employing cki-1/p27 and lin-35/pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that ubc-25 activity negatively regulates CYE-1/cyclin E protein abundance in vivo. Together, our results show that the ubc-25-mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development. Copyright © 2014 Roy et al.

Epithelial Mesenchymal Transition in Cancer Progression: Prev entive Phytochemicals.

PubMed

Illam, Soorya P; Narayanankutty, Arunaksharan; Mathew, Shaji E; Valsalakumari, Remya; Jacob, Rosemol M; Raghavamenon, Achuthan C

2017-01-01

Epithelial-Mesenchymal Transition (EMT) is the conversion of epithelial cells into mesenchymal phenotype generally observed during embryogenesis and wound healing as well as in malignant transformation. Several signaling pathways and transcription factors associated with EMT have been explored. Dietary phytochemicals that are multi-targeted agents which interfere with these pathways, assume preventive potential against pathologic EMT. The present review aims to provide a detailed description of the nature and characteristics of EMT in physiological and pathophysiological conditions and the scope of phytochemicals in its prevention. Details regarding the initiation, progression as well as prevention of pathologic EMT and metastasis and recent patents on preventive phytochemicals were obtained from PubMed literatures and patent databases. The phenotypic changes during EMT are regulated by transcription factors like Snail, Slug, Twist and Zeb, which are activated through diverse signaling pathways of TGF-β, NF-kB, Wnt and Notch. s phytocompounds that are potent enough to interfere with these signaling pathways, which in turn prevent pathological implications of EMT. Present review also discusses 28 recent patents on those phytocompounds. EMT is a significant pharmacological target for developing preventive agents to combat pathological conditions like malignancy. Many of the phytochemicals cited in this review are being enrolled for different phases of clinical trials for their efficacy. In spite of the major limitations regarding bioavailability, sensitivity and tolerance of these compounds, their synthetic analogs, formulations and efficient drug delivery systems are also being attempted which will hopefully generate productive and promising results in near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Impact of ageing on problem size and proactive interference in arithmetic facts solving.

PubMed

Archambeau, Kim; De Visscher, Alice; Noël, Marie-Pascale; Gevers, Wim

2018-02-01

Arithmetic facts (AFs) are required when solving problems such as "3 × 4" and refer to calculations for which the correct answer is retrieved from memory. Currently, two important effects that modulate the performance in AFs have been highlighted: the problem size effect and the proactive interference effect. The aim of this study is to investigate possible age-related changes of the problem size effect and the proactive interference effect in AF solving. To this end, the performance of young and older adults was compared in a multiplication production task. Furthermore, an independent measure of proactive interference was assessed to further define the architecture underlying this effect in multiplication solving. The results indicate that both young and older adults were sensitive to the effects of interference and of the problem size. That is, both interference and problem size affected performance negatively: the time needed to solve a multiplication problem increases as the level of interference and the size of the problem increase. Regarding the effect of ageing, the problem size effect remains constant with age, indicating a preserved AF network in older adults. Interestingly, sensitivity to proactive interference in multiplication solving was less pronounced in older than in younger adults suggesting that part of the proactive interference has been overcome with age.

Investigating a novel pathway by which pheromone-based mating disruption may protect crops

USDA-ARS?s Scientific Manuscript database

Pheromone-based mating disruption has been a successful, relatively new technology that growers use to reduce key insect populations. Mating disruption systems function by sending out false plumes of the insect sex pheromones – this interferes with the insect’s ability to find a mate, preempting egg...

Prevention of Aminoglycoside Ototoxicity: From the Laboratory to the Clinic

ERIC Educational Resources Information Center

Talaska, Andra E.; Schacht, Jochen

2005-01-01

The search for protection from aminoglycoside ototoxicity is nearly as old as their use as antibiotics. However, only in recent years has focused research on the mechanisms underlying the insults to the inner ear led to coherent attempts at protection, such as antioxidant therapy or interference with cell death signaling pathways. Successful…

A MIXTURE OF THE "ANTIANDROGENS" LINURON AND BUTYL BENZYL PHTHALATE ALTERS SEXUAL DIFFERENTIATION OF THE MALE RAT IN A CUMULATIVE FASHION

EPA Science Inventory

Prenatal exposure to environmental chemicals that interfere with the androgen signaling pathway can cause permanent adverse effects on reproductive development in male rats. The objectives of this study were to 1) determine whether a documented antiandrogen butyl benzyl phthalate...

Interference-Robust Transmission in Wireless Sensor Networks

PubMed Central

Han, Jin-Seok; Lee, Yong-Hwan

2016-01-01

Low-power wireless sensor networks (WSNs) operating in unlicensed spectrum bands may seriously suffer from interference from other coexisting radio systems, such as IEEE 802.11 wireless local area networks. In this paper, we consider the improvement of the transmission performance of low-power WSNs by adjusting the transmission rate and the payload size in response to the change of co-channel interference. We estimate the probability of transmission failure and the data throughput and then determine the payload size to maximize the throughput performance. We investigate that the transmission time maximizing the normalized throughput is not much affected by the transmission rate, but rather by the interference condition. We adjust the transmission rate and the transmission time in response to the change of the channel and interference condition, respectively. Finally, we verify the performance of the proposed scheme by computer simulation. The simulation results show that the proposed scheme significantly improves data throughput compared with conventional schemes while preserving energy efficiency even in the presence of interference. PMID:27854249

Interference-Robust Transmission in Wireless Sensor Networks.

PubMed

Han, Jin-Seok; Lee, Yong-Hwan

2016-11-14

Low-power wireless sensor networks (WSNs) operating in unlicensed spectrum bands may seriously suffer from interference from other coexisting radio systems, such as IEEE 802.11 wireless local area networks. In this paper, we consider the improvement of the transmission performance of low-power WSNs by adjusting the transmission rate and the payload size in response to the change of co-channel interference. We estimate the probability of transmission failure and the data throughput and then determine the payload size to maximize the throughput performance. We investigate that the transmission time maximizing the normalized throughput is not much affected by the transmission rate, but rather by the interference condition. We adjust the transmission rate and the transmission time in response to the change of the channel and interference condition, respectively. Finally, we verify the performance of the proposed scheme by computer simulation. The simulation results show that the proposed scheme significantly improves data throughput compared with conventional schemes while preserving energy efficiency even in the presence of interference.

Dual-task interference in visual working memory: A limitation in storage capacity but not in encoding or retrieval

PubMed Central

Fougnie, Daryl; Marois, René

2009-01-01

The concurrent maintenance of two visual working memory (VWM) arrays can lead to profound interference. It is unclear, however, whether these costs arise from limitations in VWM storage capacity (Fougnie & Marois, 2006), or from interference between the storage of one visual array and encoding or retrieval of another visual array (Cowan & Morey, 2007). Here, we show that encoding a VWM array does not interfere with maintenance of another VWM array unless the two displays exceed maintenance capacity (Experiments 1 and 2). Moreover, manipulating the extent to which encoding and maintenance can interfere with one another had no discernable effect on dual-task performance (Experiment 2). Finally, maintenance of a VWM array was not affected by retrieval of information from another VWM array (Experiment 3). Taken together, these findings demonstrate that dual-task interference between two concurrent VWM tasks is due to a capacity-limited store that is independent from encoding and retrieval processes. PMID:19933566

Language Learning and Control in Monolinguals and Bilinguals

PubMed Central

Bartolotti, James; Marian, Viorica

2012-01-01

Parallel language activation in bilinguals leads to competition between languages. Experience managing this interference may aid novel language learning by improving the ability to suppress competition from known languages. To investigate the effect of bilingualism on the ability to control native-language interference, monolinguals and bilinguals were taught an artificial language designed to elicit between-language competition. Partial activation of interlingual competitors was assessed with eye-tracking and mouse-tracking during a word recognition task in the novel language. Eye-tracking results showed that monolinguals looked at competitors more than bilinguals, and for a longer duration of time. Mouse-tracking results showed that monolinguals’ mouse-movements were attracted to native-language competitors, while bilinguals overcame competitor interference by increasing activation of target items. Results suggest that bilinguals manage cross-linguistic interference more effectively than monolinguals. We conclude that language interference can affect lexical retrieval, but bilingualism may reduce this interference by facilitating access to a newly-learned language. PMID:22462514

Information content and cross-talk in biological signal transduction: An information theory study

NASA Astrophysics Data System (ADS)

Prasad, Ashok; Lyons, Samanthe

2014-03-01

Biological cells respond to chemical cues provided by extra-cellular chemical signals, but many of these chemical signals and the pathways they activate interfere and overlap with one another. How well cells can distinguish between interfering extra-cellular signals is thus an important question in cellular signal transduction. Here we use information theory with stochastic simulations of networks to address the question of what happens to total information content when signals interfere. We find that both total information transmitted by the biological pathway, as well as its theoretical capacity to discriminate between overlapping signals, are relatively insensitive to cross-talk between the extracellular signals, until significantly high levels of cross-talk have been reached. This robustness of information content against cross-talk requires that the average amplitude of the signals are large. We predict that smaller systems, as exemplified by simple phosphorylation relays (two-component systems) in bacteria, should be significantly much less robust against cross-talk. Our results suggest that mammalian signal transduction can tolerate a high amount of cross-talk without degrading information content, while smaller bacterial systems cannot.

Integrating Negative Affect Measures in a Measurement Model: Assessing the Function of Negative Affect as Interference to Self-Regulation

ERIC Educational Resources Information Center

Magno, Carlo

2010-01-01

The present study investigated the composition of negative affect and its function as inhibitory to thought processes such as self-regulation. Negative affect in the present study were composed of anxiety, worry, thought suppression, and fear of negative evaluation. These four factors were selected based on the criteria of negative affect by…

The role of uric acid in the pathogenesis of diabetic retinopathy based on notch pathway.

PubMed

Zhu, Dan-Dan; Wang, Yun-Zhi; Zou, Chen; She, Xin-Ping; Zheng, Zhi

2018-06-19

Uric acid has been proposed as an independent risk factor of diabetic retinopathy. Although Notch signaling was reported to be affected in the presence of high concentrations of uric acid or glucose, the underlying mechanisms of hyperuricemia through the Notch signaling pathway to promote the development of diabetic retinopathy remain unknown. We incubated human retinal endothelial cells (HRECs) with high glucose, high uric acid and high glucose plus high glucose respectively and evaluated the apoptosis rate in different treated cells by Tunel staining. We induced diabetic model by intraperitoneally streptozotocin. Then healthy rats and diabetic rats were given with adenine and oteracil potassium by gavage. Using automatic biochemical analyzer to detect blood glucose, uric acid, urea nitrogen, creatinine levels, to verify the success of modeling. The expression and mRNA levels of ICAM-1, IL-6, MCP-1, TNF-a, receptors Notch 1, ligands Dll 1, Dll 4, Jagged 1, Jagged 2 were detected by RT-PCR and Western-Blot. Notch1 siRNA was used to interfere Notch signaling pathway, the expression and mRNA levels of ICAM-1, IL-6, MCP-1 and TNF-α was detected by RT-PCR and Western blot respectively. In vitro models, the apoptosis of HRECs cells in high uric acid plus high glucose group was the most significant. In vitro and vivo models, detection of inflammatory cytokines revealed that the expression of inflammatory cytokines increased most significantly in high uric acid plus high glucose group. Notch signaling pathway activity was also increased most significantly in high uric acid plus high glucose group. After Notch 1 siRNA transfection in high glucose and high glucose plus uric acid group, the activity of Notch signaling pathway was successfully down-regulated. We found that the apoptosis of HRECs was significantly decreased in cells transfected with Notch 1 siRNA compared to the blank vector group, and the expression of inflammatory cytokines in cells was also significantly decreased. Our study reported that high uric acid can promote the inflammation of the retina and increase the activity of Notch signaling pathway on the basis of high glucose. Hyperuricemia promotes the development of diabetic retinopathy by increasing the activity of Notch signaling pathway. Notch signaling pathway is a potential therapeutic target for diabetic retinopathy. Copyright © 2018. Published by Elsevier Inc.

Appraising the roles of CBLL1 and the ubiquitin/proteasome system for flavivirus entry and replication.

PubMed

Fernandez-Garcia, Maria-Dolores; Meertens, Laurent; Bonazzi, Matteo; Cossart, Pascale; Arenzana-Seisdedos, Fernando; Amara, Ali

2011-03-01

The ubiquitin ligase CBLL1 (also known as HAKAI) has been proposed to be a critical cellular factor exploited by West Nile virus (WNV) for productive infection. CBLL1 has emerged as a major hit in a recent RNA interference screen designed to identify cellular factors required for the early stages of the WNV life cycle. Follow-up experiments showed that HeLa cells knocked down for CBLL1 by a small interfering RNA (siRNA) failed to internalize WNV particles and resisted infection. Furthermore, depletion of a free-ubiquitin pool by the proteasome inhibitor MG132 abolished WNV endocytosis, suggesting that CBLL1 acts in concert with the ubiquitin proteasome system to mediate virus internalization. Here, we examined the effect of CBLL1 knockdown and proteasome inhibitors on infection by WNV and other flaviviruses. We identified new siRNAs that repress the CBLL1 protein and strongly inhibit the endocytosis of Listeria monocytogenes, a bacterial pathogen known to require CBLL1 to invade host cells. Strikingly, however, we detected efficient WNV, dengue virus, and yellow fever virus infection of human cells, despite potent downregulation of CBLL1 by RNA interference. In addition, we found that the proteasome inhibitors MG132 and lactacystin did not affect WNV internalization but strongly repressed flavivirus RNA translation and replication. Together, these data do not support a requirement for CBLL1 during flavivirus entry and rather suggest an essential role of the ubiquitin/proteasome pathway for flavivirus genome amplification.

Dissecting the Yale-Brown Obsessive-Compulsive Scale severity scale to understand the routes for symptomatic improvement in obsessive-compulsive disorder.

PubMed

Costa, Daniel L da Conceição; Barbosa, Veronica S; Requena, Guaraci; Shavitt, Roseli G; Pereira, Carlos A de Bragança; Diniz, Juliana B

2017-10-01

We aimed to investigate which items of the Yale-Brown Obsessive-Compulsive Severity Scale best discriminate the reduction in total scores in obsessive-compulsive disorder patients after 4 and 12 weeks of pharmacological treatment. Data from 112 obsessive-compulsive disorder patients who received fluoxetine (⩽80 mg/day) for 12 weeks were included. Improvement indices were built for each Yale-Brown Obsessive-Compulsive Severity Scale item at two timeframes: from baseline to week 4 and from baseline to week 12. Indices for each item were correlated with the total scores for obsessions and compulsions and then ranked by correlation coefficient. A correlation coefficient ⩾0.7 was used to identify items that contributed significantly to reducing obsessive-compulsive disorder severity. At week 4, the distress items reached the threshold of 0.7 for improvement on the obsession and compulsion subscales although, contrary to our expectations, there was greater improvement in the control items than in the distress items. At week 12, there was greater improvement in the time, interference, and control items than in the distress items. The use of fluoxetine led first to reductions in distress and increases in control over symptoms before affecting the time spent on, and interference from, obsessions and compulsions. Resistance did not correlate with overall improvement. Understanding the pathway of improvement with pharmacological treatment in obsessive-compulsive disorder may provide clues about how to optimize the effects of medication.

Functional basis for complement evasion by staphylococcal superantigen-like 7.

PubMed

Bestebroer, Jovanka; Aerts, Piet C; Rooijakkers, Suzan H M; Pandey, Manoj K; Köhl, Jörg; van Strijp, Jos A G; de Haas, Carla J C

2010-10-01

The human pathogen Staphylococcus aureus has a plethora of virulence factors that promote its colonization and survival in the host. Among such immune modulators are staphylococcal superantigen-like (SSL) proteins, comprising a family of 14 small, secreted molecules that seem to interfere with the host innate immune system. SSL7 has been described to bind immunoglobulin A (IgA) and complement C5, thereby inhibiting IgA-FcαRI binding and serum killing of Escherichia coli. As C5a generation, in contrast to C5b-9-mediated lysis, is crucial for immune defence against staphylococci, we investigated the impact of SSL7 on staphylococcal-induced C5a-mediated effects. Here, we show that SSL7 inhibits C5a generation induced by staphylococcal opsonization, slightly enhanced by its IgA-binding capacity. Moreover, we demonstrate a strong protective activity of SSL7 against staphylococcal clearance in human whole blood. SSL7 strongly inhibited the C5a-induced phagocytosis of S. aureus and oxidative burst in an in vitro whole-blood inflammation model. Furthermore, we found that SSL7 affects all three pathways of complement activation and inhibits the cleavage of C5 by interference of its binding to C5 convertases. Finally, SSL7 effects were also demonstrated in vivo. In a murine model of immune complex peritonitis, SSL7 abrogated the C5a-driven influx of neutrophils in mouse peritoneum. © 2010 Blackwell Publishing Ltd.

Functional basis for complement evasion by staphylococcal superantigen-like 7

PubMed Central

Bestebroer, Jovanka; Aerts, Piet C.; Rooijakkers, Suzan H.M.; Pandey, Manoj K.; Köhl, Jörg; van Strijp, Jos A. G.; de Haas, Carla J. C.

2010-01-01

Summary The human pathogen Staphylococcus aureus has a plethora of virulence factors that promote its colonization and survival in the host. Among such immune modulators are staphylococcal superantigen-like (SSL) proteins, comprising a family of 14 small, secreted molecules that seem to interfere with the host innate immune system. SSL7 has been described to bind immunoglobulin A (IgA) and complement C5, thereby inhibiting IgA-FcαRI binding and serum killing of E. coli. As C5a generation, in contrast to C5b-9-mediated lysis, is crucial for immune defense against staphylococci, we investigated the impact of SSL7 on staphylococcal-induced C5a-mediated effects. Here, we show that SSL7 inhibits C5a generation induced by staphylococcal opsonization, slightly enhanced by its IgA-binding capacity. Moreover, we demonstrate a strong protective activity of SSL7 against staphylococcal clearance in human whole blood. SSL7 strongly inhibited the C5a-induced phagocytosis of S. aureus and oxidative burst in an in vitro whole blood inflammation model. Furthermore, we found that SSL7 affects all three pathways of complement activation and inhibits the cleavage of C5 by interference of its binding to C5 convertases. Finally, SSL7 effects were also demonstrated in vivo. In a murine model of immune complex peritonitis, SSL7 abrogated the C5a-driven influx of neutrophils in mouse peritoneum. PMID:20545943

Advanced glycation end-products and insulin signaling in granulosa cells

PubMed Central

Chatzigeorgiou, Antonios; Papageorgiou, Efstathia; Koundouras, Dimitrios; Koutsilieris, Michael

2016-01-01

Advanced glycation end-products (AGEs) may interfere with insulin intracellular signaling and glucose transport in human granulosa cells, potentially affecting ovarian function, follicular growth, linked with diminished fertility. The potential interaction of AGEs with insulin signaling pathways and glucose transport was investigated in human granulosa KGN cells. KGN cells were cultured with variable concentrations of human glycated albumin (HGA, 50–200 µg/mL) or insulin (100 ng/mL). Combined treatments of KGN cells with insulin (100 ng/mL) and HGA (200 µg/mL) were also performed. p-AKT levels and glucose transporter type 4 (Glut-4) translocation analysis were performed by Western blot. Phosphatidylinositol-3-kinase (PI3K)-specific signaling was checked by using the PI3K-inhibitor, LY294002. p-AKT levels were significantly increased following insulin treatment compared to basal levels or HGA exposure. This insulin-mediated AKT-phosphorylation was PI3K-specific and it was inhibited after combined treatment of insulin and HGA. Furthermore, Glut-4 translocation from the cytoplasm to the membrane compartments of KGN cells was remarkably reduced after the combined treatment of insulin and HGA. The present findings support that AGEs interfere with insulin signaling in granulosa cells and prevent Glut-4 membrane translocation suggesting that intra ovarian AGEs accumulation, from endogenous or exogenous sources, may contribute to the pathophysiology of states characterized with anovulation and insulin resistance such as polycystic ovary syndrome. PMID:25956684

Interference in plant defense and development by non-structural protein NSs of Groundnut bud necrosis virus.

PubMed

Goswami, Suneha; Sahana, Nandita; Pandey, Vanita; Doblas, Paula; Jain, R K; Palukaitis, Peter; Canto, Tomas; Praveen, Shelly

2012-01-01

Groundnut bud necrosis virus (GBNV) infects a large number of leguminous and solanaceous plants. To elucidate the biological function of the non-structural protein encoded by the S RNA of GBNV (NSs), we studied its role in RNA silencing suppression and in viral pathogenesis. Our results demonstrated that GBNV NSs functions as a suppressor of RNA silencing using the agroinfiltration patch assay. An in silico analysis suggested the presence of pro-apoptotic protein Reaper-like sequences in the GBNV NSs, which were known to be present in animal infecting bunyaviruses. Utilizing NSs mutants, we demonstrated that a Leu-rich domain was required for RNA silencing suppression activity, but not the non-overlapping Trp/GH3 motif of the Reaper-like sequence. To investigate the role of NSs in symptom development we generated transgenic tomato expressing the GBNV NSs and showed that the expression of NSs in tomato mimics symptoms induced by infection with GBNV, such as leaf senescence and necrosis. As leaf senescence is controlled by miR319 regulation of the transcription factor TCP1, we assessed the accumulation of both RNAs in transgenic NSs-expressing and GBNV-infected tomato plants. In both types of plants the levels of miR319 decreased, while the levels of TCP1 transcripts increased. We propose that GBNV-NSs affects miRNA biogenesis through its RNA silencing suppressor activity and interferes with TCP1-regulated leaf developmental pathways. Copyright © 2011 Elsevier B.V. All rights reserved.

The protective effect of Hif3a RNA interference and HIF-prolyl hydroxylase inhibition on cardiomyocytes under anoxia-reoxygenation.

PubMed

Drevytska, T; Gonchar, E; Okhai, I; Lynnyk, O; Mankovska, I; Klionsky, D; Dosenko, V

2018-06-01

The aim of this study was to investigate the molecular mechanisms underlying the protective effects of hypoxia-inducible factor (HIF) signaling pathway activation in cardiomyocytes under anoxia-reoxygenation (A/R) injury. In this study, rat neonatal cardiomyocytes were pretreated with anti-Hif3A/Hif-3α siRNA or HIF-prolyl hydroxylase inhibitor prior to A/R injury. Our results showed that both HIF3A silencing and HIF-prolyl hydroxylase inhibition effectively increased the cell viability during A/R, led to changes in mRNA expression of HIF1-target genes, and reduced the loss of mitochondrial membrane potential (Δψ m ). Furthermore, application of anti-Hif3a siRNA led to an increase in mRNA expression of Epo, Igf1, Slc2a1/Glut-1, and Slc2a4/Glut-4. Similar results were observed with HIF-prolyl hydroxylase inhibition, which additionally upregulated the mRNA expression of Epor, Tert, and Pdk1. Hif3a RNA-interference and application of HIF-prolyl hydroxylase inhibitor during A/R modelling led to an increase of Δψ m on 11.5 and 11.9 mV respectively, compared to the control groups. Thus, Hif3a RNA interference and HIF-prolyl hydroxylase inhibition protect cardiomyocytes against A/R injury via the HIF signaling pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

AKAP-Lbc mobilizes a cardiac hypertrophy signaling pathway.

PubMed

Carnegie, Graeme K; Soughayer, Joseph; Smith, F Donelson; Pedroja, Benjamin S; Zhang, Fang; Diviani, Dario; Bristow, Michael R; Kunkel, Maya T; Newton, Alexandra C; Langeberg, Lorene K; Scott, John D

2008-10-24

Elevated catecholamines in the heart evoke transcriptional activation of the Myocyte Enhancer Factor (MEF) pathway to induce a cellular response known as pathological myocardial hypertrophy. We have discovered that the A-Kinase Anchoring Protein (AKAP)-Lbc is upregulated in hypertrophic cardiomyocytes. It coordinates activation and movement of signaling proteins that initiate MEF2-mediated transcriptional reprogramming events. Live-cell imaging, fluorescent kinase activity reporters, and RNA interference techniques show that AKAP-Lbc couples activation of protein kinase D (PKD) with the phosphorylation-dependent nuclear export of the class II histone deacetylase HDAC5. These studies uncover a role for AKAP-Lbc in which increased expression of the anchoring protein selectively amplifies a signaling pathway that drives cardiac myocytes toward a pathophysiological outcome.

Disturbances in Response Inhibition and Emotional Processing as Potential Pathways to Violence in Schizophrenia: A High-Density Event-Related Potential Study.

PubMed

Krakowski, Menahem I; De Sanctis, Pierfilippo; Foxe, John J; Hoptman, Matthew J; Nolan, Karen; Kamiel, Stephanie; Czobor, Pal

2016-07-01

Increased susceptibility to emotional triggers and poor response inhibition are important in the etiology of violence in schizophrenia. Our goal was to evaluate abnormalities in neurophysiological mechanisms underlying response inhibition and emotional processing in violent patients with schizophrenia (VS) and 3 different comparison groups: nonviolent patients (NV), healthy controls (HC) and nonpsychotic violent subjects (NPV). We recorded high-density Event-Related Potentials (ERPs) and behavioral responses during an Emotional Go/NoGo Task in 35 VS, 24 NV, 28 HC and 31 NPV subjects. We also evaluated psychiatric symptoms and impulsivity. The neural and behavioral deficits in violent patients were most pronounced when they were presented with negative emotional stimuli: They responded more quickly than NV when they made commission errors (ie, failure of inhibition), and evidenced N2 increases and P3 decreases. In contrast, NVs showed little change in reaction time or ERP amplitude with emotional stimuli. These N2 and P3 amplitude changes in VSs showed a strong association with greater impulsivity. Besides these group specific changes, VSs shared deficits with NV, mostly N2 reduction, and with violent nonpsychotic subjects, particularly P3 reduction. Negative affective triggers have a strong impact on violent patients with schizophrenia which may have both behavioral and neural manifestations. The resulting activation could interfere with response inhibition. The affective disruption of response inhibition, identified in this study, may index an important pathway to violence in schizophrenia and suggest new modes of treatment. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The Systemic Acquired Resistance Regulator OsNPR1 Attenuates Growth by Repressing Auxin Signaling through Promoting IAA-Amido Synthase Expression1[OPEN

PubMed Central

2016-01-01

Systemic acquired resistance is a long-lasting and broad-spectrum disease resistance to pathogens. Our previous study demonstrated that overexpression of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (OsNPR1), a master gene for systemic acquired resistance in rice (Oryza sativa), greatly enhanced resistance to bacterial blight caused by Xanthomonas oryzae pv oryzae. However, the growth and development of the OsNPR1 overexpression (OsNPR1-OX) plants were restrained, and the mechanism remained elusive. In this study, we dissected the OsNPR1-induced growth inhibition. We found that the OsNPR1-OX lines displayed phenotypes mimicking auxin-defective mutants, with decreases in root system, seed number and weight, internode elongation, and tiller number. Whole-genome expression analysis revealed that genes related to the auxin metabolism and signaling pathway were differentially expressed between the OsNPR1-OX and wild-type plants. Consistently, the indole-3-acetic acid (IAA) content was decreased and the auxin distribution pattern was altered in OsNPR1-OX plants. Importantly, we found that some GH3 family members, in particular OsGH3.8 coding IAA-amido synthetase, were constitutively up-regulated in OsNPR1-OX plants. Decreased OsGH3.8 expression by RNA interference could partially restore IAA level and largely rescue the restrained growth and development phenotypes but did not affect the disease resistance of OsNPR1-OX plants. Taken together, we revealed that OsNPR1 affects rice growth and development by disrupting the auxin pathway at least partially through indirectly up-regulating OsGH3.8 expression. PMID:27378815

A yeast-based genetic screening to identify human proteins that increase homologous recombination.

PubMed

Collavoli, Anita; Comelli, Laura; Rainaldi, Giuseppe; Galli, Alvaro

2008-05-01

To identify new human proteins implicated in homologous recombination (HR), we set up 'a papillae assay' to screen a human cDNA library using the RS112 strain of Saccharomyces cerevisiae containing an intrachromosomal recombination substrate. We isolated 23 cDNAs, 11 coding for complete proteins and 12 for partially deleted proteins that increased HR when overexpressed in yeast. We characterized the effect induced by the overexpression of the complete human proteasome subunit beta 2, the partially deleted proteasome subunits alpha 3 and beta 8, the ribosomal protein L12, the brain abundant membrane signal protein (BASP1) and the human homologue to v-Ha-RAS (HRAS), which elevated HR by 2-6.5-fold over the control. We found that deletion of the RAD52 gene, which has a key role in most HR events, abolished the increase of HR induced by the proteasome subunits and HRAS; by contrast, the RAD52 deletion did not affect the high level of HR due to BASP1 and RPL12. This suggests that the proteins stimulated yeast HR via different mechanisms. Overexpression of the complete beta 2 human proteasome subunit or the partially deleted alpha 3 and beta 8 subunits increased methyl methanesulphonate (MMS) resistance much more in the rad52 Delta mutant than in the wild-type. Overexpression of RPL12 and BASP1 did not affect MMS resistance in both the wild-type and the rad52 Delta mutant, whereas HRAS decreased MMS resistance in the rad52 Delta mutant. The results indicate that these proteins may interfere with the pathway(s) involved in the repair of MMS-induced DNA damage. Finally, we provide further evidence that yeast is a helpful tool to identify human proteins that may have a regulatory role in HR.

The neural basis for writing from dictation in the temporoparietal cortex.

PubMed

Roux, Franck-Emmanuel; Durand, Jean-Baptiste; Réhault, Emilie; Planton, Samuel; Draper, Louisa; Démonet, Jean-François

2014-01-01

Cortical electrical stimulation mapping was used to study neural substrates of the function of writing in the temporoparietal cortex. We identified the sites involved in oral language (sentence reading and naming) and writing from dictation, in order to spare these areas during removal of brain tumours in 30 patients (23 in the left, and 7 in the right hemisphere). Electrostimulation of the cortex impaired writing ability in 62 restricted cortical areas (.25 cm2). These were found in left temporoparietal lobes and were mostly located along the superior temporal gyrus (Brodmann's areas 22 and 42). Stimulation of right temporoparietal lobes in right-handed patients produced no writing impairments. However there was a high variability of location between individuals. Stimulation resulted in combined symptoms (affecting oral language and writing) in fourteen patients, whereas in eight other patients, stimulation-induced pure agraphia symptoms with no oral language disturbance in twelve of the identified areas. Each detected area affected writing in a different way. We detected the various different stages of the auditory-to-motor pathway of writing from dictation: either through comprehension of the dictated sentences (word deafness areas), lexico-semantic retrieval, or phonologic processing. In group analysis, barycentres of all different types of writing interferences reveal a hierarchical functional organization along the superior temporal gyrus from initial word recognition to lexico-semantic and phonologic processes along the ventral and the dorsal comprehension pathways, supporting the previously described auditory-to-motor process. The left posterior Sylvian region supports different aspects of writing function that are extremely specialized and localized, sometimes being segregated in a way that could account for the occurrence of pure agraphia that has long-been described in cases of damage to this region. Copyright © 2013 Elsevier Ltd. All rights reserved.

Obesogens in the aquatic environment: an evolutionary and toxicological perspective.

PubMed

Capitão, Ana; Lyssimachou, Angeliki; Castro, Luís Filipe Costa; Santos, Miguel M

2017-09-01

The rise of obesity in humans is a major health concern of our times, affecting an increasing proportion of the population worldwide. It is now evident that this phenomenon is not only associated with the lack of exercise and a balanced diet, but also due to environmental factors, such as exposure to environmental chemicals that interfere with lipid homeostasis. These chemicals, also known as obesogens, are present in a wide range of products of our daily life, such as cosmetics, paints, plastics, food cans and pesticide-treated food, among others. A growing body of evidences indicates that their action is not limited to mammals. Obesogens also end up in the aquatic environment, potentially affecting its ecosystems. In fact, reports show that some environmental chemicals are able to alter lipid homeostasis, impacting weight, lipid profile, signaling pathways and/or protein activity, of several taxa of aquatic animals. Such perturbations may give rise to physiological disorders and disease. Although largely unexplored from a comparative perspective, the key molecular components implicated in lipid homeostasis have likely appeared early in animal evolution. Therefore, it is not surprising that the obesogen effects are found in other animal groups beyond mammals. Collectively, data indicates that suspected obesogens impact lipid metabolism across phyla that have diverged over 600 million years ago. Thus, a consistent link between environmental chemical exposure and the obesity epidemic has emerged. This review aims to summarize the available information on the effects of putative obesogens in aquatic organisms, considering the similarities and differences of lipid homeostasis pathways among metazoans, thus contributing to a better understanding of the etiology of obesity in human populations. Finally, we identify the knowledge gaps in this field and we set future research priorities. Copyright © 2017 Elsevier Ltd. All rights reserved.

Blood Pressure-Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor.

PubMed

Montenegro, Marcelo F; Sundqvist, Michaela L; Larsen, Filip J; Zhuge, Zhengbing; Carlström, Mattias; Weitzberg, Eddie; Lundberg, Jon O

2017-01-01

Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg -1 ), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg -1 min -1 ) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascular relaxation to nitroprusside and acetylcholine, demonstrating an intact downstream NO-signaling pathway. We conclude that the acute blood pressure-lowering effect of nitrite requires an acidic gastric environment. Future studies will reveal if the cardiovascular complications associated with the use of proton pump inhibitors are linked to interference with the nitrate-nitrite-NO pathway. © 2016 American Heart Association, Inc.

Exploring the effect of sleep and reduced interference on different forms of declarative memory.

PubMed

Schönauer, Monika; Pawlizki, Annedore; Köck, Corinna; Gais, Steffen

2014-12-01

Many studies have found that sleep benefits declarative memory consolidation. However, fundamental questions on the specifics of this effect remain topics of discussion. It is not clear which forms of memory are affected by sleep and whether this beneficial effect is partly mediated by passive protection against interference. Moreover, a putative correlation between the structure of sleep and its memory-enhancing effects is still being discussed. In three experiments, we tested whether sleep differentially affects various forms of declarative memory. We varied verbal content (verbal/nonverbal), item type (single/associate), and recall mode (recall/recognition, cued/free recall) to examine the effect of sleep on specific memory subtypes. We compared within-subject differences in memory consolidation between intervals including sleep, active wakefulness, or quiet meditation, which reduced external as well as internal interference and rehearsal. Forty healthy adults aged 18-30 y, and 17 healthy adults aged 24-55 y with extensive meditation experience participated in the experiments. All types of memory were enhanced by sleep if the sample size provided sufficient statistical power. Smaller sample sizes showed an effect of sleep if a combined measure of different declarative memory scales was used. In a condition with reduced external and internal interference, performance was equal to one with high interference. Here, memory consolidation was significantly lower than in a sleep condition. We found no correlation between sleep structure and memory consolidation. Sleep does not preferentially consolidate a specific kind of declarative memory, but consistently promotes overall declarative memory formation. This effect is not mediated by reduced interference. © 2014 Associated Professional Sleep Societies, LLC.

Deletion of Cytoplasmic Double-Stranded RNA Sensors Does Not Uncover Viral Small Interfering RNA Production in Human Cells.

PubMed

Schuster, Susan; Tholen, Lotte E; Overheul, Gijs J; van Kuppeveld, Frank J M; van Rij, Ronald P

2017-01-01

Antiviral immunity in insects and plants is mediated by the RNA interference (RNAi) pathway in which viral long double-stranded RNA (dsRNA) is processed into small interfering RNAs (siRNAs) by Dicer enzymes. Although this pathway is evolutionarily conserved, its involvement in antiviral defense in mammals is the subject of debate. In vertebrates, recognition of viral RNA induces a sophisticated type I interferon (IFN)-based immune response, and it has been proposed that this response masks or inhibits antiviral RNAi. To test this hypothesis, we analyzed viral small RNA production in differentiated cells deficient in the cytoplasmic RNA sensors RIG-I and MDA5. We did not detect 22-nucleotide (nt) viral siRNAs upon infection with three different positive-sense RNA viruses. Our data suggest that the depletion of cytoplasmic RIG-I-like sensors is not sufficient to uncover viral siRNAs in differentiated cells. IMPORTANCE The contribution of the RNA interference (RNAi) pathway in antiviral immunity in vertebrates has been widely debated. It has been proposed that RNAi possesses antiviral activity in mammalian systems but that its antiviral effect is masked by the potent antiviral interferon response in differentiated mammalian cells. In this study, we show that inactivation of the interferon response is not sufficient to uncover antiviral activity of RNAi in human epithelial cells infected with three wild-type positive-sense RNA viruses.

Analysis of Tyman green detection system based on polarization interference

NASA Astrophysics Data System (ADS)

Huang, Yaolin; Wang, Min; Shao, Xiaoping; Kou, Yuanfeng

2018-02-01

The optical surface deviation of the lens can directly affect the quality of the optical system.In order to effectively and accurately detect the surface shape, an optical surface on-line detection system based on polarization interference technology is designed and developed. The system is based on Tyman-Green interference optical path, join the polarization interference measuring technology. Based on the theoretical derivation of the optical path and the ZEMAX software simulation, the experimental optical path is constructed. The parallel light is used to detect the concave lens. The parallel light is used as the light source, the size of the polarization splitting prism, detection radius of curvature, the relations between and among the size of the lens aperture, a detection range is given.

Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens

PubMed Central

Lazarus, Michael; Shen, Hai-Ying; Cherasse, Yoan; Qu, Wei-Min; Huang, Zhi-Li; Bass, Caroline E.; Winsky-Sommerer, Raphaelle; Semba, Kazue; Fredholm, Bertil B.; Boison, Detlev; Hayaishi, Osamu; Urade, Yoshihiro; Chen, Jiang-Fan

2011-01-01

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A2A receptors (A2ARs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A2ARs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that the A2ARs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness. Caffeine-induced arousal was not affected in rats when A2ARs were focally removed from the NAc core or other A2AR-positive areas of the basal ganglia. Our observations suggest that caffeine promotes arousal by activating pathways that traditionally have been associated with motivational and motor responses in the brain. PMID:21734299

Oncogenomic disruptions in arsenic-induced carcinogenesis

PubMed Central

Ng, Kevin W.; Stewart, Greg L.; Dummer, Trevor J.B.; Lam, Wan L.; Martinez, Victor D

2017-01-01

Chronic exposure to arsenic affects more than 200 million people worldwide, and has been associated with many adverse health effects, including cancer in several organs. There is accumulating evidence that arsenic biotransformation, a step in the elimination of arsenic from the human body, can induce changes at a genetic and epigenetic level, leading to carcinogenesis. At the genetic level, arsenic interferes with key cellular processes such as DNA damage-repair and chromosomal structure, leading to genomic instability. At the epigenetic level, arsenic places a high demand on the cellular methyl pool, leading to global hypomethylation and hypermethylation of specific gene promoters. These arsenic-associated DNA alterations result in the deregulation of both oncogenic and tumour-suppressive genes. Furthermore, recent reports have implicated aberrant expression of non-coding RNAs and the consequential disruption of signaling pathways in the context of arsenic-induced carcinogenesis. This article provides an overview of the oncogenomic anomalies associated with arsenic exposure and conveys the importance of non-coding RNAs in the arsenic-induced carcinogenic process. PMID:28179585

ATM and MET kinases are synthetic lethal with non-genotoxic activation of p53

PubMed Central

Sullivan, Kelly D.; Padilla-Just, Nuria; Henry, Ryan E.; Porter, Christopher C.; Kim, Jihye; Tentler, John J.; Eckhardt, S. Gail; Tan, Aik Choon; DeGregori, James; Espinosa, Joaquín M.

2012-01-01

The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a ‘Synthetic Lethal with Nutlin-3’ genome-wide shRNA screen, which revealed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors enable Nutlin-3 to kill tumor spheroids. These results identify novel pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies. PMID:22660439

Host scavenger receptor SR-BI plays a dual role in the establishment of malaria parasite liver infection.

PubMed

Rodrigues, Cristina D; Hannus, Michael; Prudêncio, Miguel; Martin, Cécilie; Gonçalves, Lígia A; Portugal, Sílvia; Epiphanio, Sabrina; Akinc, Akin; Hadwiger, Philipp; Jahn-Hofmann, Kerstin; Röhl, Ingo; van Gemert, Geert-Jan; Franetich, Jean-François; Luty, Adrian J F; Sauerwein, Robert; Mazier, Dominique; Koteliansky, Victor; Vornlocher, Hans-Peter; Echeverri, Christophe J; Mota, Maria M

2008-09-11

An obligatory step of malaria parasite infection is Plasmodium sporozoite invasion of host hepatocytes, and host lipoprotein clearance pathways have been linked to Plasmodium liver infection. By using RNA interference to screen lipoprotein-related host factors, we show here that the class B, type I scavenger receptor (SR-BI) is the strongest regulator of Plasmodium infection among these factors. Inhibition of SR-BI function reduced P. berghei infection in Huh7 cells, and overexpression of SR-BI led to increased infection. In vivo silencing of liver SR-BI expression in mice and inhibition of SR-BI activity in human primary hepatocytes reduced infection by P. berghei and by P. falciparum, respectively. Heterozygous SR-BI(+/-) mice displayed reduced P. berghei infection rates correlating with liver SR-BI expression levels. Additional analyses revealed that SR-BI plays a dual role in Plasmodium infection, affecting both sporozoite invasion and intracellular parasite development, and may therefore constitute a good target for malaria prophylaxis.

SIRT1 suppresses adipogenesis by activating Wnt/β-catenin signaling in vivo and in vitro

PubMed Central

Zhou, Yuanfei; Song, Tongxing; Peng, Jie; Zhou, Zheng; Wei, Hongkui; Zhou, Rui; Jiang, Siwen; Peng, Jian

2016-01-01

Sirtuin 1 (SIRT1) regulates adipocyte and osteoblast differentiation. However, the underlying mechanism should be investigated. This study revealed that SIRT1 acts as a crucial repressor of adipogenesis. RNA-interference-mediated SIRT1 knockdown or genetic ablation enhances adipogenic potential, whereas SIRT1 overexpression inhibits adipogenesis in mesenchymal stem cells (MSCs). SIRT1 also deacetylates the histones of sFRP1, sFRP2, and Dact1 promoters; inhibits the mRNA expression of sFRP1, sFRP2, and Dact1; activates Wnt signaling pathways; and suppresses adipogenesis. SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis. In mice, the partial absence of SIRT1 promotes the formation of white adipose tissues without affecting the development of the body of mice. Our study described the regulatory role of SIRT1 in Wnt signaling and proposed a regulatory mechanism of adipogenesis. PMID:27776347

Craving love? Enduring grief activates brain’s reward center

PubMed Central

O’Connor, Mary-Frances; Wellisch, David K.; Stanton, Annette L.; Eisenberger, Naomi I.; Irwin, Michael R.; Lieberman, Matthew D.

2008-01-01

Complicated grief (CG) occurs when an individual experiences prolonged, unabated grief. The neural mechanisms distinguishing CG from noncomplicated grief (NCG) are unclear, but hypothesized mechanisms include both pain-related activity (related to the social pain of loss) and reward-related activity (related to attachment behavior). Bereaved women (11 CG, 12 NCG) participated in an event-related functional magnetic resonance imaging scan, during grief elicitation with idiographic stimuli. Analyses revealed that whereas both CG and NCG participants showed pain-related neural activity in response to reminders of the deceased, only those with CG showed reward-related activity in the nucleus accumbens (NA). This NA cluster was positively correlated with self-reported yearning, but not with time since death, participant age, or positive/negative affect. This study supports the hypothesis that attachment activates reward pathways. For those with CG, reminders of the deceased still activate neural reward activity, which may interfere with adapting to the loss in the present. PMID:18559294

Age-related changes in overcoming proactive interference in associative memory: The role of PFC-mediated executive control processes at retrieval.

PubMed

Dulas, Michael R; Duarte, Audrey

2016-05-15

Behavioral evidence has shown age-related impairments in overcoming proactive interference in memory, but it is unclear what underlies this deficit. Imaging studies in the young suggest overcoming interference may require several executive control processes supported by the ventrolateral prefrontal cortex (VLPFC) and dorsolateral PFC (DLPFC). The present functional magnetic resonance imaging (fMRI) study investigated whether age-related changes in dissociable executive control processes underlie deficits in overcoming proactive interference in associative memory during retrieval. Participants were tasked with remembering which associate (face or scene) objects were paired with most recently during study, under conditions of high or low proactive interference. Behavioral results demonstrated that, as interference increased, memory performance decreased similarly across groups, with slight associative memory deficits in older adults. Imaging results demonstrated that, across groups, left mid-VLPFC showed increasing activity with increasing interference, though activity did not distinguish correct from incorrect associative memory responses, suggesting this region may not directly serve in successful resolution of proactive interference, per se. Under conditions of high interference, older adults showed reduced associative memory accuracy effects in the DLPFC and anterior PFC. These results suggest that age-related PFC dysfunction may not be ubiquitous. Executive processes supported by ventral regions that detect mnemonic interference may be less affected than processes supported by dorsal and anterior regions that directly resolve interference. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of conversation interference on annoyance due to aircraft noise

NASA Technical Reports Server (NTRS)

Key, K. F.; Powell, C. A.

1980-01-01

The annoyance and interference effects of aircraft flyover noise on face to face conversation were investigated. Twenty 5 minute sessions, each composed of three flyovers, were presented to each of 20 pairs of female subjects in a simulated living room. Flyovers varied in peak noise level (55-79 dB, A-weighted) and spectrum (low or high frequency components). Subjects engaged in conversation for 10 sessions and in reverie for the other 10 sessions, and completed subjective ratings following every session. Annoyance was affected by noise level, but was not significantly different for the two activities of reverie and conversation. A noise level of 77 db was found unacceptable for conversation by 50 percent of the subjects. Conversation interference was assessed by incidence of increased vocal effort and/or interruption of conversation during flyovers. Although conversation interference increased with noise level, the conversation interference measures did not improve prediction of individual annoyance judgments.

Factors Affecting SOS (Silicon-on-Sapphire) Yield and Reliability.

DTIC Science & Technology

1984-07-01

Figure 47. Nomarski differential interference contrast micrographs at 2000 X. 104 Figure 48. Schematic illustrating procedure for preparing cross...8217When the rotation angle dependence of UV scattering was discovered, additional surface texture characterizations by Nomarski differential-interference...model 9000 f wafer flatness analyzer, an optical interferometric instrument of - adjustable sensitivity. Wafers were mounted on a 2-inch diameter Perkin

Metasurface-Enabled Remote Quantum Interference.

PubMed

Jha, Pankaj K; Ni, Xingjie; Wu, Chihhui; Wang, Yuan; Zhang, Xiang

2015-07-10

An anisotropic quantum vacuum (AQV) opens novel pathways for controlling light-matter interaction in quantum optics, condensed matter physics, etc. Here, we theoretically demonstrate a strong AQV over macroscopic distances enabled by a judiciously designed array of subwavelength-scale nanoantennas-a metasurface. We harness the phase-control ability and the polarization-dependent response of the metasurface to achieve strong anisotropy in the decay rate of a quantum emitter located over distances of hundreds of wavelengths. Such an AQV induces quantum interference among radiative decay channels in an atom with orthogonal transitions. Quantum vacuum engineering with metasurfaces holds promise for exploring new paradigms of long-range light-matter interaction for atom optics, solid-state quantum optics, quantum information processing, etc.

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

NASA Astrophysics Data System (ADS)

Bürli, Roland W.; Thomas, Elizabeth; Beaumont, Vahri

Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

A scabies mite serpin interferes with complement-mediated neutrophil functions and promotes staphylococcal growth.

PubMed

Swe, Pearl M; Fischer, Katja

2014-06-01

Scabies is a contagious skin disease caused by the parasitic mite Sarcoptes scabiei. The disease is highly prevalent worldwide and known to predispose to secondary bacterial infections, in particular by Streptococcus pyogenes and Staphylococcus aureus. Reports of scabies patients co-infected with methicillin resistant S. aureus (MRSA) pose a major concern for serious down-stream complications. We previously reported that a range of complement inhibitors secreted by the mites promoted the growth of S. pyogenes. Here, we show that a recently characterized mite serine protease inhibitor (SMSB4) inhibits the complement-mediated blood killing of S. aureus. Blood killing of S. aureus was measured in whole blood bactericidal assays, counting viable bacteria recovered after treatment in fresh blood containing active complement and phagocytes, treated with recombinant SMSB4. SMSB4 inhibited the blood killing of various strains of S. aureus including methicillin-resistant and methicillin-sensitive isolates. Staphylococcal growth was promoted in a dose-dependent manner. We investigated the effect of SMSB4 on the complement-mediated neutrophil functions, namely phagocytosis, opsonization and anaphylatoxin release, by flow cytometry and in enzyme linked immuno sorbent assays (ELISA). SMSB4 reduced phagocytosis of S. aureus by neutrophils. It inhibited the deposition of C3b, C4b and properdin on the bacteria surface, but did not affect the depositions of C1q and MBL. SMSB4 also inhibited C5 cleavage as indicated by a reduced C5b-9 deposition. We postulate that SMSB4 interferes with the activation of all three complement pathways by reducing the amount of C3 convertase formed. We conclude that SMSB4 interferes with the complement-dependent killing function of neutrophils, thereby reducing opsonization, phagocytosis and further recruitment of neutrophils to the site of infection. As a consequence secreted scabies mites complement inhibitors, such as SMSB4, provide favorable conditions for the onset of S. aureus co-infection in the scabies-infected microenvironment by suppressing the immediate host immune response.

Peptidoglycan recognition protein genes and their roles in the innate immune pathways of the red flour beetle, Tribolium castaneum.

PubMed

Koyama, Hiroaki; Kato, Daiki; Minakuchi, Chieka; Tanaka, Toshiharu; Yokoi, Kakeru; Miura, Ken

2015-11-01

We have previously demonstrated that the functional Toll and IMD innate immune pathways indeed exist in the model beetle, Tribolium castaneum while the beetle's pathways have broader specificity in terms of microbial activation than that of Drosophila. To elucidate the molecular basis of this broad microbial activation, we here focused on potential upstream sensors of the T. castaneum innate immune pathways, peptidoglycan recognition proteins (PGRPs). Our phenotype analyses utilizing RNA interference-based comprehensive gene knockdown followed by bacterial challenge suggested: PGRP-LA functions as a pivotal sensor of the IMD pathway for both Gram-negative and Gram-positive bacteria; PGRP-LC acts as an IMD pathway-associated sensor mainly for Gram-negative bacteria; PGRP-LE also has some roles in Gram-negative bacterial recognition of the IMD pathway. On the other hand, we did not obtain clear phenotype changes by gene knockdown of short-type PGRP genes, probably because of highly inducible nature of these genes. Our results may collectively account for the promiscuous bacterial activation of the T. castaneum innate immune pathways at least in part. Copyright © 2015 Elsevier Inc. All rights reserved.

Activation of Wnt/β-Catenin Pathway in Monocytes Derived from Chronic Kidney Disease Patients

PubMed Central

Al-Chaqmaqchi, Heevy Abdulkareem Musa; Moshfegh, Ali; Dadfar, Elham; Paulsson, Josefin; Hassan, Moustapha; Jacobson, Stefan H.; Lundahl, Joachim

2013-01-01

Patients with chronic kidney disease (CKD) have significantly increased morbidity and mortality resulting from infections and cardiovascular diseases. Since monocytes play an essential role in host immunity, this study was directed to explore the gene expression profile in order to identify differences in activated pathways in monocytes relevant to the pathophysiology of atherosclerosis and increased susceptibility to infections. Monocytes from CKD patients (stages 4 and 5, estimated GFR <20 ml/min/1.73 m2) and healthy donors were collected from peripheral blood. Microarray gene expression profile was performed and data were interpreted by GeneSpring software and by PANTHER tool. Western blot was done to validate the pathway members. The results demonstrated that 600 and 272 genes were differentially up- and down regulated respectively in the patient group. Pathways involved in the inflammatory response were highly expressed and the Wnt/β-catenin signaling pathway was the most significant pathway expressed in the patient group. Since this pathway has been attributed to a variety of inflammatory manifestations, the current findings may contribute to dysfunctional monocytes in CKD patients. Strategies to interfere with this pathway may improve host immunity and prevent cardiovascular complications in CKD patients. PMID:23935909

Questionnaire-based evaluation of mobile phone interference with medical-electrical equipment in Swedish hospitals.

PubMed

Wiinberg, Stig; Samuelsson, Göran; Larsson, Stefan; Nilsson, Barbro; Jönsson, Patrik X; Ivarsson, Bodil; Olofsson, Per-Åke

2017-08-09

National recommendations in Sweden recommend a safety distance of 3 meter (m) between mobile phones and medical-electrical (ME) equipment in hospitals. A questionnaire was used to investigate how often mobile phones were reported to interfere with ME products in clinical practice across Sweden. The results confirmed that ME equipment can be affected by mobile phone use but, the risk of the patient's outcome being affected were minimal; no cases were identified which led to injury or death. In conclusion, the results support recommendations for a general safety distance of 0.5 m between mobile phones and ME equipment in care environments.

Sunitinib Proves Beneficial in Metastatic Kidney Cancer | Center for Cancer Research

Cancer.gov

Many researchers and clinicians consider targeted therapies, such as tyrosine kinase inhibitors and antibody-based drugs, to be a great advance in the treatment of patients with cancer. Unlike older chemotherapy drugs, targeted therapies are designed to direct drugs specifically to cancer cells or to interfere with pathways essential to tumor growth with less toxicity to

Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells.

PubMed

Murakawa, Yasuhiro; Sonoda, Eiichiro; Barber, Louise J; Zeng, Weihua; Yokomori, Kyoko; Kimura, Hiroshi; Niimi, Atsuko; Lehmann, Alan; Zhao, Guang Yu; Hochegger, Helfrid; Boulton, Simon J; Takeda, Shunichi

2007-09-15

Proteasome inhibitors are novel antitumor agents against multiple myeloma and other malignancies. Despite the increasing clinical application, the molecular basis of their antitumor effect has been poorly understood due to the involvement of the ubiquitin-proteasome pathway in multiple cellular metabolisms. Here, we show that treatment of cells with proteasome inhibitors has no significant effect on nonhomologous end joining but suppresses homologous recombination (HR), which plays a key role in DNA double-strand break (DSB) repair. In this study, we treat human cells with proteasome inhibitors and show that the inhibition of the proteasome reduces the efficiency of HR-dependent repair of an artificial HR substrate. We further show that inhibition of the proteasome interferes with the activation of Rad51, a key factor for HR, although it does not affect the activation of ATM, gammaH2AX, or Mre11. These data show that the proteasome-mediated destruction is required for the promotion of HR at an early step. We suggest that the defect in HR-mediated DNA repair caused by proteasome inhibitors contributes to antitumor effect, as HR plays an essential role in cellular proliferation. Moreover, because HR plays key roles in the repair of DSBs caused by chemotherapeutic agents such as cisplatin and by radiotherapy, proteasome inhibitors may enhance the efficacy of these treatments through the suppression of HR-mediated DNA repair pathways.

Studies on the Pathophysiology and Genetic Basis of Migraine

PubMed Central

Gasparini, Claudia F; Sutherland, Heidi G.; Griffiths, Lyn R

2013-01-01

Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people’s daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies. PMID:24403849

Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

PubMed Central

Iliodromitis, Efstathios K; Lazou, Antigone; Görbe, Anikó; Giricz, Zoltán; Schulz, Rainer

2017-01-01

Hypercholesterolaemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolaemia affects the global cardiac gene expression profile, among many other factors, it results in increased myocardial oxidative stress, mitochondrial dysfunction and inflammation triggered apoptosis, all of which may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies have revealed that hyperlcholesterolaemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolaemic animals have been reported to involve dysregulation of the endothelial NOS‐cGMP, reperfusion injury salvage kinase, peroxynitrite‐MMP2 signalling pathways, modulation of ATP‐sensitive potassium channels and apoptotic pathways. In this review article, we summarize the current knowledge on the effect of hypercholesterolaemia on the non‐ischaemic and ischaemic heart as well as on the cardioprotection induced by drugs or ischaemic preconditioning, postconditioning and remote conditioning. Future perspectives concerning the mechanisms and the design of preclinical and clinical trials are highlighted. Linked Articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc PMID:28060997

CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation.

PubMed

Gan, Xueqi; Zhang, Ling; Liu, Beilei; Zhu, Zhuoli; He, Yuting; Chen, Junsheng; Zhu, Junfei; Yu, Haiyang

2018-04-20

Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation. Reactive oxygen species (ROS) is associated with mitochondrial dysfunction and cellular damage. Here, we reported an unexplored role of cyclophilin D (CypD), the major modulator of mitochondrial permeability transition pore (mPTP), and the CypD-mPTP axis in inflammation-induced mitochondrial dysfunction and bone damage. And the protective effects of knocking down CypD by siRNA interference or the addition of cyclosporin A (CsA), an inhibitor of CypD, were evidenced by rescued mitochondrial function and osteogenic function of osteoblast under tumor necrosis factor-α (TNF-α) treatment. These findings provide new insights into the role of CypD-mPTP-dependent mitochondrial pathway in the inflammatory bone injury. The protective effect of CsA or other moleculars affecting the mPTP formation may hold promise as a potential novel therapeutic strategy for inflammation-induced bone damage via mitochondrial pathways.

Oxidized Low-Density Lipoprotein-Activated c-Jun NH2-Terminal Kinase Regulates Manganese Superoxide Dismutase Ubiquitination

PubMed Central

Takabe, Wakako; Li, Rongsong; Ai, Lisong; Yu, Fei; Berliner, Judith A.; Hsiai, Tzung K.

2012-01-01

Objective Oxidized low-density lipoprotein (oxLDL) modulates intracellular redox status and induces apoptosis in endothelial cells. However, the signal pathways and molecular mechanism remain unknown. In this study, we investigated the role of manganese superoxide dismutase (Mn-SOD) on oxLDL-induced apoptosis via c-Jun NH2-terminal kinase (JNK)-mediated ubiquitin/proteasome pathway. Methods and Results OxLDL induced JNK phosphorylation that peaked at 30 minutes in human aortic endothelial cells. Fluorescence-activated cell sorting analysis revealed that oxLDL increased mitochondrial superoxide production by 1.88±0.19-fold and mitochondrial membrane potential by 18%. JNK small interference RNA (siJNK) reduced oxLDL-induced mitochondrial superoxide production by 88.4% and mitochondrial membrane potential by 61.7%. OxLDL did not affect Mn-SOD mRNA expression, but it significantly reduced Mn-SOD protein level, which was restored by siJNK. Immunoprecipitation by ubiquitin antibody revealed that oxLDL increased ubiquitination of Mn-SOD, which was inhibited by siJNK. OxLDL-induced caspase-3 activities were also attenuated by siJNK but were enhanced by Mn-SOD small interfering RNA. Furthermore, overexpression of Mn-SOD abrogated oxLDL-induced caspase-3 activities. Conclusion OxLDL-induced JNK activation regulates mitochondrial redox status and Mn-SOD protein degradation via JNK-dependent ubiquitination, leading to endothelial cell apoptosis. PMID:20139358

Widespread Nanoparticle-Assay Interference: Implications for Nanotoxicity Testing

PubMed Central

Ong, Kimberly J.; MacCormack, Tyson J.; Clark, Rhett J.; Ede, James D.; Ortega, Van A.; Felix, Lindsey C.; Dang, Michael K. M.; Ma, Guibin; Fenniri, Hicham; Veinot, Jonathan G. C.; Goss, Greg G.

2014-01-01

The evaluation of engineered nanomaterial safety has been hindered by conflicting reports demonstrating differential degrees of toxicity with the same nanoparticles. The unique properties of these materials increase the likelihood that they will interfere with analytical techniques, which may contribute to this phenomenon. We tested the potential for: 1) nanoparticle intrinsic fluorescence/absorbance, 2) interactions between nanoparticles and assay components, and 3) the effects of adding both nanoparticles and analytes to an assay, to interfere with the accurate assessment of toxicity. Silicon, cadmium selenide, titanium dioxide, and helical rosette nanotubes each affected at least one of the six assays tested, resulting in either substantial over- or under-estimations of toxicity. Simulation of realistic assay conditions revealed that interference could not be predicted solely by interactions between nanoparticles and assay components. Moreover, the nature and degree of interference cannot be predicted solely based on our current understanding of nanomaterial behaviour. A literature survey indicated that ca. 95% of papers from 2010 using biochemical techniques to assess nanotoxicity did not account for potential interference of nanoparticles, and this number had not substantially improved in 2012. We provide guidance on avoiding and/or controlling for such interference to improve the accuracy of nanotoxicity assessments. PMID:24618833

Attention and memory protection: Interactions between retrospective attention cueing and interference.

PubMed

Makovski, Tal; Pertzov, Yoni

2015-01-01

Visual working memory (VWM) and attention have a number of features in common, but despite extensive research it is still unclear how the two interact. Can focused attention improve VWM precision? Can it protect VWM from interference? Here we used a partial-report, continuous-response orientation memory task to examine how attention and interference affect different aspects of VWM and how they interact with one another. Both attention and interference were orthogonally manipulated during the retention interval. Attention was manipulated by presenting informative retro-cues, whereas interference was manipulated by introducing a secondary interfering task. Mixture-model analyses revealed that retro-cues, compared to uninformative cues, improved all aspects of performance: Attention increased recall precision and decreased guessing rate and swap-errors (reporting a wrong item in memory). Similarly, performing a secondary task impaired all aspects of the VWM task. In particular, an interaction between retro-cue and secondary task interference was found primarily for swap-errors. Together these results suggest that both the quantity and quality of VWM representations are sensitive to attention cueing and interference modulations, and they highlight the role of attention in protecting the feature-location associations needed to access the correct items in memory.

A generalized population dynamics model for reproductive interference with absolute density dependence.

PubMed

Kyogoku, Daisuke; Sota, Teiji

2017-05-17

Interspecific mating interactions, or reproductive interference, can affect population dynamics, species distribution and abundance. Previous population dynamics models have assumed that the impact of frequency-dependent reproductive interference depends on the relative abundances of species. However, this assumption could be an oversimplification inappropriate for making quantitative predictions. Therefore, a more general model to forecast population dynamics in the presence of reproductive interference is required. Here we developed a population dynamics model to describe the absolute density dependence of reproductive interference, which appears likely when encounter rate between individuals is important. Our model (i) can produce diverse shapes of isoclines depending on parameter values and (ii) predicts weaker reproductive interference when absolute density is low. These novel characteristics can create conditions where coexistence is stable and independent from the initial conditions. We assessed the utility of our model in an empirical study using an experimental pair of seed beetle species, Callosobruchus maculatus and Callosobruchus chinensis. Reproductive interference became stronger with increasing total beetle density even when the frequencies of the two species were kept constant. Our model described the effects of absolute density and showed a better fit to the empirical data than the existing model overall.

How Does Vaccinia Virus Interfere With Interferon?

PubMed

Smith, Geoffrey L; Talbot-Cooper, Callum; Lu, Yongxu

2018-01-01

Interferons (IFNs) are secreted glycoproteins that are produced by cells in response to virus infection and other stimuli and induce an antiviral state in cells bearing IFN receptors. In this way, IFNs restrict virus replication and spread before an adaptive immune response is developed. Viruses are very sensitive to the effects of IFNs and consequently have evolved many strategies to interfere with interferon. This is particularly well illustrated by poxviruses, which have large dsDNA genomes and encode hundreds of proteins. Vaccinia virus is the prototypic poxvirus and expresses many proteins that interfere with IFN and are considered in this review. These proteins act either inside or outside the cell and within the cytoplasm or nucleus. They function by restricting the production of IFN by blocking the signaling pathways leading to transcription of IFN genes, stopping IFNs binding to their receptors, blocking IFN-induced signal transduction leading to expression of interferon-stimulated genes (ISGs), or inhibiting the antiviral activity of ISG products. © 2018 Elsevier Inc. All rights reserved.

Optimization of a yeast RNA interference system for controlling gene expression and enabling rapid metabolic engineering.

PubMed

Crook, Nathan C; Schmitz, Alexander C; Alper, Hal S

2014-05-16

Reduction of endogenous gene expression is a fundamental operation of metabolic engineering, yet current methods for gene knockdown (i.e., genome editing) remain laborious and slow, especially in yeast. In contrast, RNA interference allows facile and tunable gene knockdown via a simple plasmid transformation step, enabling metabolic engineers to rapidly prototype knockdown strategies in multiple strains before expending significant cost to undertake genome editing. Although RNAi is naturally present in a myriad of eukaryotes, it has only been recently implemented in Saccharomyces cerevisiae as a heterologous pathway and so has not yet been optimized as a metabolic engineering tool. In this study, we elucidate a set of design principles for the construction of hairpin RNA expression cassettes in yeast and implement RNA interference to quickly identify routes for improvement of itaconic acid production in this organism. The approach developed here enables rapid prototyping of knockdown strategies and thus accelerates and reduces the cost of the design-build-test cycle in yeast.

Nanoscale probing of image-dipole interactions in a metallic nanostructure

PubMed Central

Ropp, Chad; Cummins, Zachary; Nah, Sanghee; Fourkas, John T.; Shapiro, Benjamin; Waks, Edo

2015-01-01

An emitter near a surface induces an image dipole that can modify the observed emission intensity and radiation pattern. These image-dipole effects are generally not taken into account in single-emitter tracking and super-resolved imaging applications. Here we show that the interference between an emitter and its image dipole induces a strong polarization anisotropy and a large spatial displacement of the observed emission pattern. We demonstrate these effects by tracking the emission of a single quantum dot along two orthogonal polarizations as it is deterministically positioned near a silver nanowire. The two orthogonally polarized diffraction spots can be displaced by up to 50 nm, which arises from a Young’s interference effect between the quantum dot and its induced image dipole. We show that the observed spatially varying interference fringe provides a useful measure for correcting image-dipole-induced distortions. These results provide a pathway towards probing and correcting image-dipole effects in near-field imaging applications. PMID:25790228

Effects of Irrelevant Colors on Reading of Color Names: A Controlled Replication of the "Reversed-Stroop" Effect. Progress Report.

ERIC Educational Resources Information Center

Dyer, Frederick N.; Severance, Laurence J.

Gumenik and Glass (1970) claimed to have shown a reversed form of Stroop interference in which implicit naming responses to irrelevant colors delay the reading of color words combined with the colors. In their study, a legibility reduction that did not affect color visibility was interpreted as increasing this interference from color-naming to the…

Electrical interference in non-competitive pacemakers

PubMed Central

Sowton, E.; Gray, K.; Preston, T.

1970-01-01

Patients with 41 implanted non-competitive pacemakers were investigated. A variety of domestic electrical equipment, a motor-car, and a physiotherapy diathermy apparatus were each operated in turn at various ranges from the patient. Interference effects on pacemaker function were assessed on the electrocardiograph. Medtronic demand 5841 pacemakers were stopped by diathermy while Cordis Ectocor pacemakers developed a fast discharge rate. Cordis triggered pacemakers (both Atricor and Ectocor) were sensitive to interference from many items of domestic equipment and the motor car. The Elema EM153 ran at an increased rate when an electric razor was running close to the pacemaker. The Devices demand 2980 and the Medtronic demand 5841 were not affected by the domestic equipment tested. The significance of interference effects is discussed in relation to pacemaker design. Images PMID:5470044

TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis.

PubMed

Flutter, Barry; Nestle, Frank O

2013-12-01

Psoriasis is an inflammatory disease of the skin affecting 2-3% of the population, characterized by a thickening of the epidermis and immune infiltrates throughout the dermis and epidermis, causing skin lesions that can seriously affect quality of life. The study of psoriasis has historically been hampered by the lack of good animal models. Various genetically induced models exist, which have provided some information about possible mechanisms of disease, but these models rely mostly on intrinsic imbalances of homeostasis. However, a mouse model of psoriasiform dermatitis caused by the repeated topical application of Aldara™ containing 5% imiquimod was described in 2009. The mechanisms of action of Aldara™ are complex. Imiquimod is an effective ligand for TLR7 (and TLR8 in humans) and also interferes with adenosine receptor signaling. In addition, isostearic acid present in the Aldara™ vehicle has been shown to be biologically active and of importance for activating the inflammasome. Interestingly, the repetitive application of Aldara™ reveals a complex aetiology involving multiple cell types, cytokines, and inflammatory pathways. In this review, we will dissect the findings of the imiquimod model to date and ask how this model can inform us about the immunological aspects of human disease. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

About the unidirectionality of interference: insight from the musical Stroop effect.

PubMed

Grégoire, Laurent; Perruchet, Pierre; Poulin-Charronnat, Bénédicte

2014-01-01

The asymmetry of interference in a Stroop task usually refers to the well-documented result that incongruent colour words slow colour naming (Stroop effect) but incongruent colours do not slow colour word reading (no reverse Stroop effect). A few other studies have suggested that, more generally, a reverse Stroop effect can be occasionally observed but at the expense of the Stroop effect itself, as if interference was inherently unidirectional, from the stronger to the weaker of the two competing processes. We describe here a situation conducive to a pervasive mutual interference effect. Musicians were exposed to congruent and incongruent note name/note position patterns, and they were asked either to read the word while ignoring the location of the note within the staff, or to name the note while ignoring the note name written inside the note picture. Most of the participants exhibited interference in the two tasks. Overall, this result pattern runs against the still prevalent model of the Stroop phenomenon [Cohen, J. D., Dunbar, K., & McClelland, J. L. (1990). On the control of automatic processes: A parallel distributed processing account of the Stroop effect. Psychological Review, 97(3), 332-361]. However, further analyses lend support to one of the key tenets of the model, namely that the pattern of interference depends on the relative strength of the two competing pathways. The reasons for the impressive differences between the results collected in the present study and in the standard colour-word (or picture-word) paradigms are also examined. We suggest that these differences reveal the importance of stimulus-response contingency in the formation of automatisms.

Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation.

PubMed

Meissner, Kamila A; Lunev, Sergey; Wang, Yuan-Ze; Linzke, Marleen; de Assis Batista, Fernando; Wrenger, Carsten; Groves, Matthew R

2017-01-01

The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target's function in vivo. The current "toolbox" of various methods and techniques to identify a protein's function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts.

PubMed

Tank, Juliane; Lindner, Diana; Wang, Xiaomin; Stroux, Andrea; Gilke, Leona; Gast, Martina; Zietsch, Christin; Skurk, Carsten; Scheibenbogen, Carmen; Klingel, Karin; Lassner, Dirk; Kühl, Uwe; Schultheiss, Heinz-Peter; Westermann, Dirk; Poller, Wolfgang

2014-01-01

Therapeutic targets of broad relevance are likely located in pathogenic pathways common to disorders of various etiologies. Screening for targets of this type revealed CCN genes to be consistently upregulated in multiple cardiomyopathies. We developed RNA interference (RNAi) to silence CCN2 and found this single-target approach to block multiple proinflammatory and profibrotic pathways in activated primary cardiac fibroblasts (PCFBs). The RNAi-strategy was developed in murine PCFBs and then investigated in "individual" human PCFBs grown from human endomyocardial biopsies (EMBs). Screening of short hairpin RNA (shRNA) sequences for high silencing efficacy and specificity yielded RNAi adenovectors silencing CCN2 in murine or human PCFBs, respectively. Comparison of RNAi with CCN2-modulating microRNA (miR) vectors expressing miR-30c or miR-133b showed higher efficacy of RNAi. In murine PCFBs, CCN2 silencing resulted in strongly reduced expression of stretch-induced chemokines (Ccl2, Ccl7, Ccl8), matrix metalloproteinases (MMP2, MMP9), extracellular matrix (Col3a1), and a cell-to-cell contact protein (Cx43), suggesting multiple signal pathways to be linked to CCN2. Immune cell chemotaxis towards CCN2-depleted PCFBs was significantly reduced. We demonstrate here that this RNAi strategy is technically applicable to "individual" human PCFBs, too, but that these display individually strikingly different responses to CCN2 depletion. Either genomically encoded factors or stable epigenetic modification may explain different responses between individual PCFBs. The new RNAi approach addresses a key regulator protein induced in cardiomyopathies. Investigation of this and other molecular therapies in individual human PCBFs may help to dissect differential pathogenic processes between otherwise similar disease entities and individuals. Copyright © 2013 Elsevier Ltd. All rights reserved.

HIV-1 RNAs are Not Part of the Argonaute 2 Associated RNA Interference Pathway in Macrophages.

PubMed

Vongrad, Valentina; Imig, Jochen; Mohammadi, Pejman; Kishore, Shivendra; Jaskiewicz, Lukasz; Hall, Jonathan; Günthard, Huldrych F; Beerenwinkel, Niko; Metzner, Karin J

2015-01-01

MiRNAs and other small noncoding RNAs (sncRNAs) are key players in post-transcriptional gene regulation. HIV-1 derived small noncoding RNAs (sncRNAs) have been described in HIV-1 infected cells, but their biological functions still remain to be elucidated. Here, we approached the question whether viral sncRNAs may play a role in the RNA interference (RNAi) pathway or whether viral mRNAs are targeted by cellular miRNAs in human monocyte derived macrophages (MDM). The incorporation of viral sncRNAs and/or their target RNAs into RNA-induced silencing complex was investigated using photoactivatable ribonucleoside-induced cross-linking and immunoprecipitation (PAR-CLIP) as well as high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP), which capture Argonaute2-bound miRNAs and their target RNAs. HIV-1 infected monocyte-derived macrophages (MDM) were chosen as target cells, as they have previously been shown to express HIV-1 sncRNAs. In addition, we applied small RNA deep sequencing to study differential cellular miRNA expression in HIV-1 infected versus non-infected MDMs. PAR-CLIP and HITS-CLIP data demonstrated the absence of HIV-1 RNAs in Ago2-RISC, although the presence of a multitude of HIV-1 sncRNAs in HIV-1 infected MDMs was confirmed by small RNA sequencing. Small RNA sequencing revealed that 1.4% of all sncRNAs were of HIV-1 origin. However, neither HIV-1 derived sncRNAs nor putative HIV-1 target sequences incorporated into Ago2-RISC were identified suggesting that HIV-1 sncRNAs are not involved in the canonical RNAi pathway nor is HIV-1 targeted by this pathway in HIV-1 infected macrophages.

Differential effects of HTLV-1 Tax oncoprotein on the different estrogen-induced-ER α-mediated transcriptional activities

PubMed Central

Abou-Kandil, Ammar; Eisa, Nora; Jabareen, Azhar; Huleihel, Mahmoud

2016-01-01

ABSTRACT The activated estrogen (E2) receptor α (ERα) is a potent transcription factor that is involved in the activation of various genes by 2 different pathways; a classical and non-classical. In classical pathway, ERα binds directly to E2-responsive elements (EREs) located in the appropriate genes promoters and stimulates their transcription. However, in non-classical pathway, the ERα can indirectly bind with promoters and enhance their activity. For instance, ERα activates BRCA1 expression by interacting with jun/fos complex bound to the AP-1 site in BRCA1 promoter. Interference with the expression and/or functions of BRCA1, leads to high risk of breast or/and ovarian cancer. HTLV-1Tax was found to strongly inhibit BRCA1 expression by preventing the binding of E2–ERα complex to BRCA1 promoter. Here we examined Tax effect on ERα induced activation of genes by the classical pathway by testing its influence on E2-induced expression of ERE promoter-driven luciferase reporter (ERE-Luc). Our findings showed that E2 profoundly stimulated this reporter expression and that HTLV-1Tax significantly induced this stimulation. This result is highly interesting because in our previous study Tax was found to strongly block the E2-ERα-mediated activation of BRCA1 expression. ERα was found to produce a big complex by recruiting various cofactors in the nucleus before binding to the ERE region. We also found that only part of the reqruited cofactors are required for the transcriptional activity of ERα complex. Chip assay revealed that the binding of Tax to the ERα complex, did not interfere with its link to ERE region. PMID:27420286

Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1

PubMed Central

Khare, Vineeta; Lyakhovich, Alex; Dammann, Kyle; Lang, Michaela; Borgmann, Melanie; Tichy, Boris; Pospisilova, Sarka; Luciani, Gloria; Campregher, Christoph; Evstatiev, Rayko; Pflueger, Maren; Hundsberger, Harald; Gasche, Christoph

2013-01-01

Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APCmin polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APCmin polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. PMID:23146664

Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.

PubMed

Khare, Vineeta; Lyakhovich, Alex; Dammann, Kyle; Lang, Michaela; Borgmann, Melanie; Tichy, Boris; Pospisilova, Sarka; Luciani, Gloria; Campregher, Christoph; Evstatiev, Rayko; Pflueger, Maren; Hundsberger, Harald; Gasche, Christoph

2013-01-15

Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. Copyright © 2012 Elsevier Inc. All rights reserved.

Comparison of Dengue Virus Type 2-Specific Small RNAs from RNA Interference-Competent and –Incompetent Mosquito Cells

PubMed Central

Scott, Jaclyn C.; Brackney, Doug E.; Campbell, Corey L.; Bondu-Hawkins, Virginie; Hjelle, Brian; Ebel, Greg D.; Olson, Ken E.; Blair, Carol D.

2010-01-01

The exogenous RNA interference (RNAi) pathway is an important antiviral defense against arboviruses in mosquitoes, and virus-specific small interfering (si)RNAs are key components of this pathway. Understanding the biogenesis of siRNAs in mosquitoes could have important ramifications in using RNAi to control arbovirus transmission. Using deep sequencing technology, we characterized dengue virus type 2 (DENV2)-specific small RNAs produced during infection of Aedes aegypti mosquitoes and A. aegypti Aag2 cell cultures and compared them to those produced in the C6/36 Aedes albopictus cell line. We show that the size and mixed polarity of virus-specific small RNAs from DENV-infected A. aegypti cells indicate that they are products of Dicer-2 (Dcr2) cleavage of long dsRNA, whereas C6/36 cells generate DENV2-specific small RNAs that are longer and predominantly positive polarity, suggesting that they originate from a different small RNA pathway. Examination of virus-specific small RNAs after infection of the two mosquito cell lines with the insect-only flavivirus cell fusing agent virus (CFAV) corroborated these findings. An in vitro assay also showed that Aag2 A. aegypti cells are capable of siRNA production, while C6/36 A. albopictus cells exhibit inefficient Dcr2 cleavage of long dsRNA. Defective expression or function of Dcr2, the key initiator of the RNAi pathway, might explain the comparatively robust growth of arthropod-borne viruses in the C6/36 cell line, which has been used frequently as a surrogate for studying molecular interactions between arboviruses and cells of their mosquito hosts. PMID:21049014

Does Mutual Interference Affect the Feeding Rate of Aphidophagous Coccinellids? A Modeling Perspective.

PubMed

Papanikolaou, Nikos E; Demiris, Nikos; Milonas, Panagiotis G; Preston, Simon; Kypraios, Theodore

2016-01-01

Mutual interference involves direct interactions between individuals of the same species that may alter their foraging success. Larvae of aphidophagous coccinellids typically stay within a patch during their lifetime, displaying remarkable aggregation to their prey. Thus, as larvae are exposed to each other, frequent encounters may affect their foraging success. A study was initiated in order to determine the effect of mutual interference in the coccinellids' feeding rate. One to four 4th larval instars of the fourteen-spotted ladybird beetle Propylea quatuordecimpunctata were exposed for 6 hours into plastic containers with different densities of the black bean aphid, Aphis fabae, on potted Vicia faba plants. The data were used to fit a purely prey-dependent Holling type II model and its alternatives which account for interference competition and have thus far been underutilized, i.e. the Beddington-DeAngelis, the Crowley-Martin and a modified Hassell-Varley model. The Crowley-Martin mechanistic model appeared to be slightly better among the competing models. The results showed that although the feeding rate became approximately independent of predator density at high prey density, some predator dependence in the coccinellid's functional response was observed at the low prey-high predator density combination. It appears that at low prey densities, digestion breaks are negligible so that the predators do waste time interfering with each other, whereas at high prey densities time loss during digestion breaks may fully accommodate the cost of interference, so that the time cost may be negligible.

Strong Overtones Modes in Inelastic Electron Tunneling Spectroscopy with Cross-Conjugated Molecules: A Prediction from Theory

PubMed Central

2013-01-01

Cross-conjugated molecules are known to exhibit destructive quantum interference, a property that has recently received considerable attention in single-molecule electronics. Destructive quantum interference can be understood as an antiresonance in the elastic transmission near the Fermi energy and leading to suppressed levels of elastic current. In most theoretical studies, only the elastic contributions to the current are taken into account. In this paper, we study the inelastic contributions to the current in cross-conjugated molecules and find that while the inelastic contribution to the current is larger than for molecules without interference, the overall behavior of the molecule is still dominated by the quantum interference feature. Second, an ongoing challenge for single molecule electronics is understanding and controlling the local geometry at the molecule-surface interface. With this in mind, we investigate a spectroscopic method capable of providing insight into these junctions for cross-conjugated molecules: inelastic electron tunneling spectroscopy (IETS). IETS has the advantage that the molecule interface is probed directly by the tunneling current. Previously, it has been thought that overtones are not observable in IETS. Here, overtones are predicted to be strong and, in some cases, the dominant spectroscopic features. We study the origin of the overtones and find that the interference features in these molecules are the key ingredient. The interference feature is a property of the transmission channels of the π system only, and consequently, in the vicinity of the interference feature, the transmission channels of the σ system and the π system become equally transmissive. This allows for scattering between the different transmission channels, which serves as a pathway to bypass the interference feature. A simple model calculation is able to reproduce the results obtained from atomistic calculations, and we use this to interpret these findings. PMID:24067128

Effect of radiofrequency energy emitted from monopolar "Bovie" instruments on cardiac implantable electronic devices.

PubMed

Robinson, Thomas N; Varosy, Paul D; Guillaume, Girard; Dunning, James E; Townsend, Nicole T; Jones, Edward L; Paniccia, Alessandro; Stiegmann, Greg V; Weyer, Christopher; Rozner, Marc A

2014-09-01

The monopolar "Bovie" instrument emits radiofrequency energy that can disrupt the function of other implanted electronic devices through a phenomenon termed electromagnetic interference. The purpose of this study was to quantify the electromagnetic interference occurring on cardiac implantable devices (CIEDs) resulting from monopolar instrument use in common, modifiable clinical scenarios. Three anesthetized pigs underwent CIED placement (1 pacemaker and 2 defibrillators). Electromagnetic interference was quantified when changing the monopolar instrument parameters of generator power, generator mode, surgical technique, orientation of active electrode cord, pathway of current vector, and proximity of active electrode to the CIED. Monopolar instrument parameters that decreased the electromagnetic interference occurring on the CIED included decreasing generator power from 60 W to 30 W (p < 0.001), using cut mode rather than coag mode (p < 0.001), using desiccation technique rather than fulguration technique (p < 0.001), orienting the active electrode cord from the feet rather than across the chest wall (p < 0.001), and avoiding the current vector from crossing the CIED system (p < 0.001). Increasing the distance between the active electrode tool and the CIED system decreased electromagnetic interference occurring on the CIED in a dose-response fashion up to a distance of 10 cm (ANOVA, p < 0.001), after which the magnitude of electromagnetic interference remained constant. Electromagnetic interference occurring on CIEDs resulting from monopolar instruments is minimized by decreasing generator power, using cut mode, using desiccation technique, orienting the active electrode cord from the feet, avoiding the current vector for crossing the CIED system, and increasing the distance between the active electrode and the CIED. Surgeons and operating room staff can minimize electromagnetic interference on CIEDs during monopolar instrument use by accounting for these modifiable clinical factors. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Teasing apart retrieval and encoding interference in the processing of anaphors

PubMed Central

Jäger, Lena A.; Benz, Lena; Roeser, Jens; Dillon, Brian W.; Vasishth, Shravan

2015-01-01

Two classes of account have been proposed to explain the memory processes subserving the processing of reflexive-antecedent dependencies. Structure-based accounts assume that the retrieval of the antecedent is guided by syntactic tree-configurational information without considering other kinds of information such as gender marking in the case of English reflexives. By contrast, unconstrained cue-based retrieval assumes that all available information is used for retrieving the antecedent. Similarity-based interference effects from structurally illicit distractors which match a non-structural retrieval cue have been interpreted as evidence favoring the unconstrained cue-based retrieval account since cue-based retrieval interference from structurally illicit distractors is incompatible with the structure-based account. However, it has been argued that the observed effects do not necessarily reflect interference occurring at the moment of retrieval but might equally well be accounted for by interference occurring already at the stage of encoding or maintaining the antecedent in memory, in which case they cannot be taken as evidence against the structure-based account. We present three experiments (self-paced reading and eye-tracking) on German reflexives and Swedish reflexive and pronominal possessives in which we pit the predictions of encoding interference and cue-based retrieval interference against each other. We could not find any indication that encoding interference affects the processing ease of the reflexive-antecedent dependency formation. Thus, there is no evidence that encoding interference might be the explanation for the interference effects observed in previous work. We therefore conclude that invoking encoding interference may not be a plausible way to reconcile interference effects with a structure-based account of reflexive processing. PMID:26106337

Exploring the Effect of Sleep and Reduced Interference on Different Forms of Declarative Memory

PubMed Central

Schönauer, Monika; Pawlizki, Annedore; Köck, Corinna; Gais, Steffen

2014-01-01

Study Objectives: Many studies have found that sleep benefits declarative memory consolidation. However, fundamental questions on the specifics of this effect remain topics of discussion. It is not clear which forms of memory are affected by sleep and whether this beneficial effect is partly mediated by passive protection against interference. Moreover, a putative correlation between the structure of sleep and its memory-enhancing effects is still being discussed. Design: In three experiments, we tested whether sleep differentially affects various forms of declarative memory. We varied verbal content (verbal/nonverbal), item type (single/associate), and recall mode (recall/recognition, cued/free recall) to examine the effect of sleep on specific memory subtypes. We compared within-subject differences in memory consolidation between intervals including sleep, active wakefulness, or quiet meditation, which reduced external as well as internal interference and rehearsal. Participants: Forty healthy adults aged 18–30 y, and 17 healthy adults aged 24–55 y with extensive meditation experience participated in the experiments. Results: All types of memory were enhanced by sleep if the sample size provided sufficient statistical power. Smaller sample sizes showed an effect of sleep if a combined measure of different declarative memory scales was used. In a condition with reduced external and internal interference, performance was equal to one with high interference. Here, memory consolidation was significantly lower than in a sleep condition. We found no correlation between sleep structure and memory consolidation. Conclusions: Sleep does not preferentially consolidate a specific kind of declarative memory, but consistently promotes overall declarative memory formation. This effect is not mediated by reduced interference. Citation: Schönauer M, Pawlizki A, Köck C, Gais S. Exploring the effect of sleep and reduced interference on different forms of declarative memory. SLEEP 2014;37(12):1995-2007. PMID:25325490

Interference studies with two hospital-grade and two home-grade glucose meters.

PubMed

Lyon, Martha E; Baskin, Leland B; Braakman, Sandy; Presti, Steven; Dubois, Jeffrey; Shirey, Terry

2009-10-01

Interference studies of four glucose meters (Nova Biomedical [Waltham, MA] StatStrip [hospital grade], Roche Diagnostics [Indianapolis, IN] Accu-Chek Aviva [home grade], Abbott Diabetes Care [Alameda, CA] Precision FreeStyle Freedom [home grade], and LifeScan [Milpitas, CA] SureStep Flexx [hospital grade]) were evaluated and compared to the clinical laboratory plasma hexokinase reference method (Roche Hitachi 912 chemistry analyzer). These meters were chosen to reflect the continuum of care from hospital to home grade meters commonly seen in North America. Within-run precision was determined using a freshly prepared whole blood sample spiked with concentrated glucose to give three glucose concentrations. Day-to-day precision was evaluated using aqueous control materials supplied by each vendor. Common interferences, including hematocrit, maltose, and ascorbate, were tested alone and in combination with one another on each of the four glucose testing devices at three blood glucose concentrations. Within-run precision for all glucose meters was <5% except for the FreeStyle (up to 7.6%). Between-day precision was <6% for all glucose meters. Ascorbate caused differences (percentage change from a sample without added interfering substances) of >5% with pyrroloquinolinequinone (PQQ)-glucose dehydrogenase-based technologies (Aviva and Freestyle) and the glucose oxidase-based Flexx meter. Maltose strongly affected the PQQ-glucose dehydrogenase-based meter systems. When combinations of interferences (ascorbate, maltose, and hematocrit mixtures) were tested, the extent of the interference was up to 193% (Aviva), 179% (FreeStyle), 25.1% (Flexx), and 5.9% (StatStrip). The interference was most pronounced at low glucose (3.9-4.4 mmol/L). All evaluated glucose meter systems demonstrated varying degrees of interference by hematocrit, ascorbate, and maltose mixtures. PQQ-glucose dehydrogenase-based technologies showed greater susceptibility than glucose oxidase-based systems. However, the modified glucose oxidase-based amperometric method (Nova StatStrip) was less affected in comparison with the glucose oxidase-based photometric method (LifeScan SureStep Flexx).

Investigating saccade programming in the praying mantis Tenodera aridifolia using distracter interference paradigms.

PubMed

Yamawaki, Yoshifumi

2006-10-01

To investigate the saccadic system in the mantis, I applied distracter interference paradigms. These involved presenting the mantis with a fixation target and one or several distracters supposed to affect saccades towards the target. When a single target was presented, a medium-sized target located in its lower visual field elicited higher rates of saccade response. This preference for target size and position was also observed when a target and a distracter were presented simultaneously. That is, the mantis chose and fixated the target rather than a distracter that was much smaller or larger than the target, or was located above the target. Furthermore, the mantis' preference was not affected by increasing the number of distracters. However, the presence of the distracter decreased the occurrence rate of saccade and increased the response time to saccade. I conclude that distracter interference paradigms are an effective way of investigating the visual processing underlying saccade generation in the mantis. Possible mechanisms of saccade generation in the mantis are discussed.

[Research on improving spectrum resolution of optimized Wollaston prism array].

PubMed

Zhang, Peng; Wang, Jian-Rong; Zhang, Guo-Chen; Hou, Wen

2011-11-01

In order to not affect the image quality of interference fringes on the basis of the structure by increasing the structure angle of Wollaston prism to improve spectrum resolution, the authors optimized the structure of Wollaston prism. Calculating the function of the splitting angle and the structure angle, analysis indicated that taking the isosceles triangle prism with the same nature of the second wedge-shaped prism after the Wollaston prism, which makes the o and e light parallel to the optical axis, and alpha=0 degrees, the imaging interference fringes are no longer affected by changes in the splitting angle. Several optimized Wollaston prisms were made as an array to improve the spectral resolution. Experiments used traditional and optimized Wollaston prism array to detect the spectrum of the 980 nm laser. Experimental data showed that using optimized Wollaston prism array gets a clearer contrast of interference fringes, and the spectral data with Fourier transform are more accurate with DSP.

Ageing differentially affects neural processing of different conflict types-an fMRI study.

PubMed

Korsch, Margarethe; Frühholz, Sascha; Herrmann, Manfred

2014-01-01

Interference control and conflict resolution is affected by ageing. There is increasing evidence that ageing does not compromise interference control in general but rather shows distinctive effects on different components of interference control. Different conflict types, [e.g., stimulus-stimulus (S-S) or stimulus-response (S-R) conflicts] trigger different cognitive processes and thus activate different neural networks. In the present functional magnetic resonance imaging (fMRI) study, we used a combined Flanker and Stimulus Response Conflict (SRC) task to investigate the effect of ageing on S-S and S-R conflicts. Behavioral data analysis revealed larger SRC effects in elderly. fMRI Results show that both age groups recruited similar regions [caudate nucleus, cingulate gyrus and middle occipital gyrus (MOG)] during Flanker conflict processing. Furthermore, elderly show an additional activation pattern in parietal and frontal areas. In contrast, no common activation of both age groups was found in response to the SRC. These data suggest that ageing has distinctive effects on S-S and S-R conflicts.

The RNAi machinery controls distinct responses to environmental signals in the basal fungus Mucor circinelloides.

PubMed

Nicolás, Francisco E; Vila, Ana; Moxon, Simon; Cascales, María D; Torres-Martínez, Santiago; Ruiz-Vázquez, Rosa M; Garre, Victoriano

2015-03-25

RNA interference (RNAi) is a conserved mechanism of genome defence that can also have a role in the regulation of endogenous functions through endogenous small RNAs (esRNAs). In fungi, knowledge of the functions regulated by esRNAs has been hampered by lack of clear phenotypes in most mutants affected in the RNAi machinery. Mutants of Mucor circinelloides affected in RNAi genes show defects in physiological and developmental processes, thus making Mucor an outstanding fungal model for studying endogenous functions regulated by RNAi. Some classes of Mucor esRNAs map to exons (ex-siRNAs) and regulate expression of the genes from which they derive. To have a broad picture of genes regulated by the silencing machinery during vegetative growth, we have sequenced and compared the mRNA profiles of mutants in the main RNAi genes by using RNA-seq. In addition, we have achieved a more complete phenotypic characterization of silencing mutants. Deletion of any main RNAi gene provoked a deep impact in mRNA accumulation at exponential and stationary growth. Genes showing increased mRNA levels, as expected for direct ex-siRNAs targets, but also genes with decreased expression were detected, suggesting that, most probably, the initial ex-siRNA targets regulate the expression of other genes, which can be up- or down-regulated. Expression of 50% of the genes was dependent on more than one RNAi gene in agreement with the existence of several classes of ex-siRNAs produced by different combinations of RNAi proteins. These combinations of proteins have also been involved in the regulation of different cellular processes. Besides genes regulated by the canonical RNAi pathway, this analysis identified processes, such as growth at low pH and sexual interaction that are regulated by a dicer-independent non-canonical RNAi pathway. This work shows that the RNAi pathways play a relevant role in the regulation of a significant number of endogenous genes in M. circinelloides during exponential and stationary growth phases and opens up an important avenue for in-depth study of genes involved in the regulation of physiological and developmental processes in this fungal model.

Response conflict and frontocingulate dysfunction in unmedicated participants with major depression.

PubMed

Holmes, Avram J; Pizzagalli, Diego A

2008-10-01

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.

Response conflict and frontocingulate dysfunction in unmedicated participants with Major Depression

PubMed Central

Holmes, Avram J.; Pizzagalli, Diego A.

2008-01-01

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control. PMID:18577391

Expression of a bacterial 3-dehydroshikimate dehydratase reduces lignin content and improves biomass saccharification efficiency.

PubMed

Eudes, Aymerick; Sathitsuksanoh, Noppadon; Baidoo, Edward E K; George, Anthe; Liang, Yan; Yang, Fan; Singh, Seema; Keasling, Jay D; Simmons, Blake A; Loqué, Dominique

2015-12-01

Lignin confers recalcitrance to plant biomass used as feedstocks in agro-processing industries or as source of renewable sugars for the production of bioproducts. The metabolic steps for the synthesis of lignin building blocks belong to the shikimate and phenylpropanoid pathways. Genetic engineering efforts to reduce lignin content typically employ gene knockout or gene silencing techniques to constitutively repress one of these metabolic pathways. Recently, new strategies have emerged offering better spatiotemporal control of lignin deposition, including the expression of enzymes that interfere with the normal process for cell wall lignification. In this study, we report that expression of a 3-dehydroshikimate dehydratase (QsuB from Corynebacterium glutamicum) reduces lignin deposition in Arabidopsis cell walls. QsuB was targeted to the plastids to convert 3-dehydroshikimate - an intermediate of the shikimate pathway - into protocatechuate. Compared to wild-type plants, lines expressing QsuB contain higher amounts of protocatechuate, p-coumarate, p-coumaraldehyde and p-coumaryl alcohol, and lower amounts of coniferaldehyde, coniferyl alcohol, sinapaldehyde and sinapyl alcohol. 2D-NMR spectroscopy and pyrolysis-gas chromatography/mass spectrometry (pyro-GC/MS) reveal an increase of p-hydroxyphenyl units and a reduction of guaiacyl units in the lignin of QsuB lines. Size-exclusion chromatography indicates a lower degree of lignin polymerization in the transgenic lines. Therefore, our data show that the expression of QsuB primarily affects the lignin biosynthetic pathway. Finally, biomass from these lines exhibits more than a twofold improvement in saccharification efficiency. We conclude that the expression of QsuB in plants, in combination with specific promoters, is a promising gain-of-function strategy for spatiotemporal reduction of lignin in plant biomass. © 2015 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

The costs of emotional attention: affective processing inhibits subsequent lexico-semantic analysis.

PubMed

Ihssen, Niklas; Heim, Sabine; Keil, Andreas

2007-12-01

The human brain has evolved to process motivationally relevant information in an optimized manner. The perceptual benefit for emotionally arousing material, termed motivated attention, is indexed by electrocortical amplification at various levels of stimulus analysis. An outstanding issue, particularly on a neuronal level, refers to whether and how perceptual enhancement for arousing signals translates into modified processing of information presented in temporal or spatial proximity to the affective cue. The present studies aimed to examine facilitation and interference effects of task-irrelevant emotional pictures on subsequent word identification. In the context of forced-choice lexical decision tasks, pictures varying in hedonic valence and emotional arousal preceded word/ pseudoword targets. Across measures and experiments, high-arousing compared to low-arousing pictures were associated with impaired processing of word targets. Arousing pleasant and unpleasant pictures prolonged word reaction times irrespective of stimulus-onset asynchrony (80 msec, 200 msec, 440 msec) and salient semantic category differences (e.g., erotica vs. mutilation pictures). On a neuronal level, interference was reflected in reduced N1 responses (204-264 msec) to both target types. Paralleling behavioral effects, suppression of the late positivity (404-704 msec) was more pronounced for word compared to pseudoword targets. Regional source modeling indicated that early reduction effects originated from inhibited cortical activity in posterior areas of the left inferior temporal cortex associated with orthographic processing. Modeling of later reduction effects argues for interference in distributed semantic networks comprising left anterior temporal and parietal sources. Thus, affective processing interferes with subsequent lexico-semantic analysis along the ventral stream.

Piloting a Text Message-based Social Support Intervention for Patients With Chronic Pain: Establishing Feasibility and Preliminary Efficacy.

PubMed

Guillory, Jamie; Chang, Pamara; Henderson, Charles R; Shengelia, Rouzi; Lama, Sonam; Warmington, Marcus; Jowza, Maryam; Waldman, Seth; Gay, Geri; Reid, M Carrington

2015-06-01

To examine preliminarily the effectiveness of a short message service (SMS) text message-based social support intervention for reducing daily pain and pain interference levels, improving affect and perceptions of social support in patients with chronic noncancer pain, and exploring the feasibility of a novel mobile application to track perceptions of pain and pain interference. Participants (17 men, 51 women) from 2 pain clinics in New York City downloaded a pain tracking application (App) on their Smartphone and used it to record twice-daily pain, pain interference, and affect scores over the 4-week study period. Participants were randomly assigned to receive standard care (control) or standard care along with receipt of twice-daily supportive SMS text messages delivered during the second and third week of the study (intervention). Demographic and clinical data were obtained at baseline, and social support measures were administered at baseline and at 4 weeks. Statistical analysis was carried out using general linear mixed models, taking into account variances associated with time of assessments and with patients. The social support intervention reduced perceptions of pain and pain interference and improved positive affect for chronic noncancer pain patients assigned to the intervention condition in comparison with controls. Participants completed approximately 80% of the daily measurements requested. These findings establish the feasibility of collecting daily pain data using a mobile tracking App and provide significant implications and insight into a nuanced approach to reducing the daily experience of pain through mobile technology, especially because of its accessibility.

Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality

PubMed Central

van Haaften, Gijs; Vastenhouw, Nadine L.; Nollen, Ellen A. A.; Plasterk, Ronald H. A.; Tijsterman, Marcel

2004-01-01

Here, we describe a systematic search for synthetic gene interactions in a multicellular organism, the nematode Caenorhabditis elegans. We established a high-throughput method to determine synthetic gene interactions by genome-wide RNA interference and identified genes that are required to protect the germ line against DNA double-strand breaks. Besides known DNA-repair proteins such as the C. elegans orthologs of TopBP1, RPA2, and RAD51, eight genes previously unassociated with a double-strand-break response were identified. Knockdown of these genes increased sensitivity to ionizing radiation and camptothecin and resulted in increased chromosomal nondisjunction. All genes have human orthologs that may play a role in human carcinogenesis. PMID:15326288

Rapid evolution and gene expression: a rapidly evolving Mendelian trait that silences field crickets has widespread effects on mRNA and protein expression.

PubMed

Pascoal, S; Liu, X; Ly, T; Fang, Y; Rockliffe, N; Paterson, S; Shirran, S L; Botting, C H; Bailey, N W

2016-06-01

A major advance in modern evolutionary biology is the ability to start linking phenotypic evolution in the wild with genomic changes that underlie that evolution. We capitalized on a rapidly evolving Hawaiian population of crickets (Teleogryllus oceanicus) to test hypotheses about the genomic consequences of a recent Mendelian mutation of large effect which disrupts the development of sound-producing structures on male forewings. The resulting silent phenotype, flatwing, persists because of natural selection imposed by an acoustically orienting parasitoid, but it interferes with mate attraction. We examined gene expression differences in developing wing buds of wild-type and flatwing male crickets using RNA-seq and quantitative proteomics. Most differentially expressed (DE) transcripts were down-regulated in flatwing males (625 up vs. 1716 down), whereas up- and down-regulated proteins were equally represented (30 up and 34 down). Differences between morphs were clearly not restricted to a single pathway, and we recovered annotations associated with a broad array of functions that would not be predicted a priori. Using a candidate gene detection test based on homology, we identified 30% of putative Drosophila wing development genes in the cricket transcriptome, but only 10% were DE. In addition to wing-related annotations, endocrine pathways and several biological processes such as reproduction, immunity and locomotion were DE in the mutant crickets at both biological levels. Our results illuminate the breadth of genetic pathways that are potentially affected in the early stages of adaptation. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

The expression of proinflammatory genes in epidermal keratinocytes is regulated by hydration status.

PubMed

Xu, Wei; Jia, Shengxian; Xie, Ping; Zhong, Aimei; Galiano, Robert D; Mustoe, Thomas A; Hong, Seok J

2014-04-01

Mucosal wounds heal more rapidly, exhibit less inflammation, and are associated with minimal scarring when compared with equivalent cutaneous wounds. We previously demonstrated that cutaneous epithelium exhibits an exaggerated response to injury compared with mucosal epithelium. We hypothesized that treatment of injured skin with a semiocclusive dressing preserves the hydration of the skin and results in a wound healing phenotype that more closely resembles that of mucosa. Here we explored whether changes in hydration status alter epidermal gene expression patterns in rabbit partial-thickness incisional wounds. Using microarray studies on injured epidermis, we showed that global gene expression patterns in highly occluded versus non-occluded wounds are distinct. Many genes including IL-1β, IL-8, TNF-α (tumor necrosis factor-α), and COX-2 (cyclooxygenase 2) are upregulated in non-occluded wounds compared with highly occluded wounds. In addition, decreased levels of hydration resulted in an increased expression of proinflammatory genes in human ex vivo skin culture (HESC) and stratified keratinocytes. Hierarchical analysis of genes using RNA interference showed that both TNF-α and IL-1β regulate the expression of IL-8 through independent pathways in response to reduced hydration. Furthermore, both gene knockdown and pharmacological inhibition studies showed that COX-2 mediates the TNF-α/IL-8 pathway by increasing the production of prostaglandin E2 (PGE2). IL-8 in turn controls the production of matrix metalloproteinase-9 in keratinocytes. Our data show that hydration status directly affects the expression of inflammatory signaling in the epidermis. The identification of genes involved in the epithelial hydration pathway provides an opportunity to develop strategies to reduce scarring and optimize wound healing.

Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies.

PubMed

Tortora, Giampaolo; Bianco, Roberto; Daniele, Gennaro; Ciardiello, Fortunato; McCubrey, James A; Ricciardi, Maria Rosaria; Ciuffreda, Ludovica; Cognetti, Francesco; Tafuri, Agostino; Milella, Michele

2007-06-01

Accumulating evidence suggests that cancer can be envisioned as a "signaling disease", in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to "targeted" agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here, we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in haematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects.

Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies

PubMed Central

Tortora, Giampaolo; Bianco, Roberto; Daniele, Gennaro; Ciardiello, Fortunato; McCubrey, James A; Ricciardi, Maria Rosaria; Ciuffreda, Ludovica; Cognetti, Francesco; Tafuri, Agostino; Milella, Michele

2007-01-01

Accumulating evidence suggests that cancer can be envisioned as a “signaling disease”, in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to “targeted” agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in hematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects. PMID:17482503

Choline kinase-alpha by regulating cell aggressiveness and drug sensitivity is a potential druggable target for ovarian cancer.

PubMed

Granata, A; Nicoletti, R; Tinaglia, V; De Cecco, L; Pisanu, M E; Ricci, A; Podo, F; Canevari, S; Iorio, E; Bagnoli, M; Mezzanzanica, D

2014-01-21

Aberrant choline metabolism has been proposed as a novel cancer hallmark. We recently showed that epithelial ovarian cancer (EOC) possesses an altered MRS-choline profile, characterised by increased phosphocholine (PCho) content to which mainly contribute over-expression and activation of choline kinase-alpha (ChoK-alpha). To assess its biological relevance, ChoK-alpha expression was downmodulated by transient RNA interference in EOC in vitro models. Gene expression profiling by microarray analysis and functional analysis was performed to identify the pathway/functions perturbed in ChoK-alpha-silenced cells, then validated by in vitro experiments. In silenced cells, compared with control, we observed: (I) a significant reduction of both CHKA transcript and ChoK-alpha protein expression; (II) a dramatic, proportional drop in PCho content ranging from 60 to 71%, as revealed by (1)H-magnetic spectroscopy analysis; (III) a 35-36% of cell growth inhibition, with no evidences of apoptosis or modification of the main cellular survival signalling pathways; (IV) 476 differentially expressed genes, including genes related to lipid metabolism. Ingenuity pathway analysis identified cellular functions related to cell death and cellular proliferation and movement as the most perturbed. Accordingly, CHKA-silenced cells displayed a significant delay in wound repair, a reduced migration and invasion capability were also observed. Furthermore, although CHKA silencing did not directly induce cell death, a significant increase of sensitivity to platinum, paclitaxel and doxorubicin was observed even in a drug-resistant context. We showed for the first time in EOC that CHKA downregulation significantly decreased the aggressive EOC cell behaviour also affecting cells' sensitivity to drug treatment. These observations open the way to further analysis for ChoK-alpha validation as a new EOC therapeutic target to be used alone or in combination with conventional drugs.

An analysis of available data on effects of wing-fuselage-tail and wing-nacelle interference on the distribution of the air load among components of airplanes

NASA Technical Reports Server (NTRS)

Wollner, Bertram C

1949-01-01

Available information on the effects of wing-fuselage-tail and wing-nacelle interference on the distribution of the air load among components of airplanes is analyzed. The effects of wing and nacelle incidence, horizontal andvertical position of wing and nacelle, fuselage shape, wing section and filleting are considered. Where sufficient data were unavailable to determine the distribution of the air load, the change in lift caused by interference between wing and fuselage was found. This increment is affected to the greatest extent by vertical wing position.

Direction Finding in the Presence of Complex Electro-Magnetic Environment.

DTIC Science & Technology

1995-06-29

compiling adversely affects the resolution capabilities of the MUSIC algorithm. A technique utilizing the terminal impedance matrix is devised to...performance of the MUSIC algorithm is also investigated.Interference power, as little as 15dB below the signal power from the near field scatterer greatly...reduces.the resolution capabilities of the MUSIC algorithm. A new away configuration is devised to suppress the interference. Modification of the MUSIC

Do radio frequencies of medical instruments common in the operating room interfere with near-infrared spectroscopy signals?

NASA Astrophysics Data System (ADS)

Shadgan, Babak; Molavi, Behnam; Reid, W. D.; Dumont, Guy; Macnab, Andrew J.

2010-02-01

Background: Medical and diagnostic applications of near infrared spectroscopy (NIRS) are increasing, especially in operating rooms (OR). Since NIRS is an optical technique, radio frequency (RF) interference from other instruments is unlikely to affect the raw optical data, however, NIRS data processing and signal output could be affected. Methods: We investigated the potential for three common OR instruments: an electrical cautery, an orthopaedic drill and an imaging system, to generate electromagnetic interference (EMI) that could potentially influence NIRS signals. The time of onset and duration of every operation of each device was recorded during surgery. To remove the effects of slow changing physiological variables, we first used a lowpass filter and then selected 2 windows with variable lengths around the moment of device onset. For each instant, variances (energy) and means of the signals in the 2 windows were compared. Results: Twenty patients were studied during ankle surgery. Analysis shows no statistically significant difference in the means and variance of the NIRS signals (p < 0.01) during operation of any of the three devices for all surgeries. Conclusion: This method confirms the instruments evaluated caused no significant interference. NIRS can potentially be used without EMI in clinical environments such as the OR.

A model of work-family conflict and well-being among Malaysian working women.

PubMed

Aazami, Sanaz; Akmal, Syaqirah; Shamsuddin, Khadijah

2015-01-01

Work and family are the two most important domains in a person's life. Lack of balance between work and family can lead to adverse consequences such as psychological distress; however, the effect of work-family conflict on psychological distress might be mediated by job and family dissatisfaction. This study examines a model of the four dimensions of work-family conflict and their consequences on psychological distress. In particular, we test whether job and family satisfaction mediate the effect of the four dimensions of work-family conflict on psychological distress. This cross-sectional study was conducted among 567 Malaysian women who are working in the public services. Structural Equation Modeling confirmed the mediating role of family satisfaction in the effect of strain-based work interference into family and time-based family interference into work on psychological distress. In addition, our results revealed a significant path that links job to family satisfaction. Moreover, time-based work interference into family and strain-based family interference into work significantly and negatively affect job satisfaction, which in turn influence family satisfaction and eventually affect psychological distress. The results of our study show that organizations need to develop and adapt family friendly policies to mitigate level of employees' work-family conflict.

I saw where you have been--The topography of human demonstration affects dogs' search patterns and perseverative errors.

PubMed

Péter, András; Topál, József; Miklósi, Ádám; Pongrácz, Péter

2016-04-01

Performance in object search tasks is not only influenced by the subjects' object permanence ability. For example, ostensive cues of the human manipulating the target markedly affect dogs' choices. However, the interference between the target's location and the spatial cues of the human hiding the object is still unknown. In a five-location visible displacement task, the experimental groups differed in the hiding route of the experimenter. In the 'direct' condition he moved straight towards the actual location, hid the object and returned to the dog. In the 'indirect' conditions, he additionally walked behind each screen before returning. The two 'indirect' conditions differed from each other in that the human either visited the previously baited locations before (proactive interference) or after (retroactive interference) hiding the object. In the 'indirect' groups, dogs' performance was significantly lower than in the 'direct' group, demonstrating that for dogs, in an ostensive context, spatial cues of the hider are as important as the observed location of the target. Based on their incorrect choices, dogs were most attracted to the previously baited locations that the human visited after hiding the object in the actual trial. This underlines the importance of retroactive interference in multiple choice tasks. Copyright © 2016 Elsevier B.V. All rights reserved.

Down-regulation of Gab1 inhibits cell proliferation and migration in hilar cholangiocarcinoma.

PubMed

Sang, Haiquan; Li, Tingting; Li, Hangyu; Liu, Jingang

2013-01-01

Hilar cholangiocarcinoma is a highly aggressive malignancy originating from the hilar biliary duct epithelium. Due to few effective comprehensive treatments, the prognosis of hilar cholangiocarcinoma is poor. In this study, immunohistochemistry was first used to detect and analyze the expression of Gab1, VEGFR-2, and MMP-9 in hilar cholangiocarcinoma solid tumors and the relationships to the clinical pathological features. Furthermore, Gab1 and VEGFR-2 siRNA were used to interfere the hilar cholangiocarcinoma cell line ICBD-1 and then detect the PI3K/Akt signaling pathway, MMP-9 levels and malignant biological behaviors of tumor cells. The data showed that 1. Gab1, VEGFR-2, and MMP-9 were highly expressed and positively correlated with each other in hilar cholangiocarcinoma tissues, which were related to lymph node metastasis and differentiation. 2. After Gab1 or VEGFR-2 siRNA interference, PI3K/Akt pathway activity and MMP-9 levels were decreased in ICBD-1 cells. At the same time, cell proliferation decreased, cell cycle arrested in G1 phase, apoptosis increased and invasion decreased. These results suggest that the expression of Gab1, VEGFR-2, and MMP-9 are significantly related to the malignant biological behavior of hilar cholangiocarcinoma. Gab1 regulates growth, apoptosis and invasion through the VEGFR-2/Gab1/PI3K/Akt signaling pathway in hilar cholangiocarcinoma cells and influences the invasion of tumor cells via MMP-9.

Down-Regulation of Gab1 Inhibits Cell Proliferation and Migration in Hilar Cholangiocarcinoma

PubMed Central

Sang, Haiquan; Li, Tingting; Li, Hangyu; Liu, Jingang

2013-01-01

Hilar cholangiocarcinoma is a highly aggressive malignancy originating from the hilar biliary duct epithelium. Due to few effective comprehensive treatments, the prognosis of hilar cholangiocarcinoma is poor. In this study, immunohistochemistry was first used to detect and analyze the expression of Gab1, VEGFR-2, and MMP-9 in hilar cholangiocarcinoma solid tumors and the relationships to the clinical pathological features. Furthermore, Gab1 and VEGFR-2 siRNA were used to interfere the hilar cholangiocarcinoma cell line ICBD-1 and then detect the PI3K/Akt signaling pathway, MMP-9 levels and malignant biological behaviors of tumor cells. The data showed that 1. Gab1, VEGFR-2, and MMP-9 were highly expressed and positively correlated with each other in hilar cholangiocarcinoma tissues, which were related to lymph node metastasis and differentiation. 2. After Gab1 or VEGFR-2 siRNA interference, PI3K/Akt pathway activity and MMP-9 levels were decreased in ICBD-1 cells. At the same time, cell proliferation decreased, cell cycle arrested in G1 phase, apoptosis increased and invasion decreased. These results suggest that the expression of Gab1, VEGFR-2, and MMP-9 are significantly related to the malignant biological behavior of hilar cholangiocarcinoma. Gab1 regulates growth, apoptosis and invasion through the VEGFR-2/Gab1/PI3K/Akt signaling pathway in hilar cholangiocarcinoma cells and influences the invasion of tumor cells via MMP-9. PMID:24312291

Prediction of effective RNA interference targets and pathway-related genes in lepidopteran insects by RNA sequencing analysis.

PubMed

Guan, Ruo-Bing; Li, Hai-Chao; Miao, Xue-Xia

2018-06-01

When using RNA interference (RNAi) to study gene functions in Lepidoptera insects, we discovered that some genes could not be suppressed; instead, their expression levels could be up-regulated by double-stranded RNA (dsRNA). To predict which genes could be easily silenced, we treated the Asian corn borer (Ostrinia furnacalis) with dsGFP (green fluorescent protein) and dsMLP (muscle lim protein). A transcriptome sequence analysis was conducted using the cDNAs 6 h after treatment with dsRNA. The results indicated that 160 genes were up-regulated and 44 genes were down-regulated by the two dsRNAs. Then, 50 co-up-regulated, 25 co-down-regulated and 43 unaffected genes were selected to determine their RNAi responses. All the 25 down-regulated genes were knocked down by their corresponding dsRNA. However, several of the up-regulated and unaffected genes were up-regulated when treated with their corresponding dsRNAs instead of being knocked down. The genes up-regulated by the dsGFP treatment may be involved in insect immune responses or the RNAi pathway. When the immune-related genes were excluded, only seven genes were induced by dsGFP, including ago-2 and dicer-2. These results not only provide a reference for efficient RNAi target predications, but also provide some potential RNAi pathway-related genes for further study. © 2017 Institute of Zoology, Chinese Academy of Sciences.

Removal of power line interference of space bearing vibration signal based on the morphological filter and blind source separation

NASA Astrophysics Data System (ADS)

Dong, Shaojiang; Sun, Dihua; Xu, Xiangyang; Tang, Baoping

2017-06-01

Aiming at the problem that it is difficult to extract the feature information from the space bearing vibration signal because of different noise, for example the running trend information, high-frequency noise and especially the existence of lot of power line interference (50Hz) and its octave ingredients of the running space simulated equipment in the ground. This article proposed a combination method to eliminate them. Firstly, the EMD is used to remove the running trend item information of the signal, the running trend that affect the signal processing accuracy is eliminated. Then the morphological filter is used to eliminate high-frequency noise. Finally, the components and characteristics of the power line interference are researched, based on the characteristics of the interference, the revised blind source separation model is used to remove the power line interferences. Through analysis of simulation and practical application, results suggest that the proposed method can effectively eliminate those noise.

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

PubMed

Cittaro, Davide; Lampis, Valentina; Luchetti, Alessandra; Coccurello, Roberto; Guffanti, Alessandro; Felsani, Armando; Moles, Anna; Stupka, Elia; D' Amato, Francesca R; Battaglia, Marco

2016-04-28

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.

Wnt and the Wnt signaling pathway in bone development and disease

PubMed Central

Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

2014-01-01

Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

Specific Interference between a Cognitive Task and Sensory Organization for Stance Balance Control in Healthy Young Adults: Visuospatial Effects

ERIC Educational Resources Information Center

Chong, Raymond K. Y.; Mills, Bradley; Dailey, Leanna; Lane, Elizabeth; Smith, Sarah; Lee, Kyoung-Hyun

2010-01-01

We tested the hypothesis that a computational overload results when two activities, one motor and the other cognitive that draw on the same neural processing pathways, are performed concurrently. Healthy young adult subjects carried out two seemingly distinct tasks of maintaining standing balance control under conditions of low (eyes closed),…

Mechanistic aspects of fluorescent gold nanocluster internalization by live HeLa cells

NASA Astrophysics Data System (ADS)

Yang, Linxiao; Shang, Li; Nienhaus, G. Ulrich

2013-01-01

We have studied cellular uptake of ultrasmall fluorescent gold nanoclusters (AuNCs) by HeLa cells by confocal fluorescence microscopy in combination with quantitative image analysis. Water solubilized, lipoic acid-protected AuNCs, which had an overall hydrodynamic diameter of 3.3 nm and emitted fluorescence in the near-infrared region at ~700 nm, were observed to accumulate on the cell membrane prior to internalization. The internalization mechanisms were analyzed using inhibitors known to interfere with specific pathways. Cellular uptake of AuNCs is energy-dependent and involves multiple mechanisms: clathrin-mediated endocytosis and macropinocytosis appear to play a significant role, whereas the caveolin-mediated pathway contributes only to a lesser extent. Co-labeling of different cell organelles showed that intracellular trafficking of AuNCs mainly follows through endosomal pathways. The AuNCs were ultimately transferred to lysosomes; they were completely excluded from the nucleus even after 24 h.We have studied cellular uptake of ultrasmall fluorescent gold nanoclusters (AuNCs) by HeLa cells by confocal fluorescence microscopy in combination with quantitative image analysis. Water solubilized, lipoic acid-protected AuNCs, which had an overall hydrodynamic diameter of 3.3 nm and emitted fluorescence in the near-infrared region at ~700 nm, were observed to accumulate on the cell membrane prior to internalization. The internalization mechanisms were analyzed using inhibitors known to interfere with specific pathways. Cellular uptake of AuNCs is energy-dependent and involves multiple mechanisms: clathrin-mediated endocytosis and macropinocytosis appear to play a significant role, whereas the caveolin-mediated pathway contributes only to a lesser extent. Co-labeling of different cell organelles showed that intracellular trafficking of AuNCs mainly follows through endosomal pathways. The AuNCs were ultimately transferred to lysosomes; they were completely excluded from the nucleus even after 24 h. Electronic supplementary information (ESI) available: Effect of serum on the AuNC uptake by HeLa cells and colocalization result of AuNCs with the cell nucleus for 2-24 h. See DOI: 10.1039/c2nr33147k

Endocytic pathway mediates refractoriness of insect Bactrocera dorsalis to RNA interference

PubMed Central

Li, Xiaoxue; Dong, Xiaolong; Zou, Cong; Zhang, Hongyu

2015-01-01

RNA interference (RNAi) is a powerful and convenient tool for sequence-specific gene silencing, and it is triggered by double-stranded RNA (dsRNA). RNAi can be easily achieved in many eukaryotes by either injecting or feeding dsRNAs. This mechanism has demonstrated its potential in fundamental research on genetics, medicine and agriculture. However, the possibility that insects might develop refractoriness to RNAi remains unexplored. In this study, we report that the oriental fruit fly, Bactrocera dorsalis, became refractory to RNAi using orally administered dsRNA targeting endogenous genes. Furthermore, refractoriness to RNAi is not gene-specific, and its duration depends on the dsRNA concentration. RNAi blockage requires the endocytic pathway. Fluorescence microscopy indicated that in RNAi refractory flies, dsRNA uptake is blocked. Genes involved in the entry of dsRNAs into cells, including chc, cog3, light and others, are down-regulated in RNAi refractory flies. Increasing the endocytic capacity by improving F-actin polymerization disrupts RNAi refractoriness after both primary and secondary dsRNA exposures. Our results demonstrate that an insect can become refractory to RNAi by preventing the entry of dsRNA into its cells. PMID:25731667

A member of the polymerase beta nucleotidyltransferase superfamily is required for RNA interference in C. elegans.

PubMed

Chen, Chun-Chieh G; Simard, Martin J; Tabara, Hiroaki; Brownell, Daniel R; McCollough, Jennifer A; Mello, Craig C

2005-02-22

RNA interference (RNAi) is an ancient, highly conserved mechanism in which small RNA molecules (siRNAs) guide the sequence-specific silencing of gene expression . Several silencing machinery protein components have been identified, including helicases, RNase-related proteins, double- and single-stranded RNA binding proteins, and RNA-dependent RNA polymerase-related proteins . Work on these factors has led to the revelation that RNAi mechanisms intersect with cellular pathways required for development and fertility . Despite rapid progress in understanding key steps in the RNAi pathway, it is clear that many factors required for both RNAi and related developmental mechanisms have not yet been identified. Here, we report the characterization of the C. elegans gene rde-3. Genetic analysis of presumptive null alleles indicates that rde-3 is required for siRNA accumulation and for efficient RNAi in all tissues, and it is essential for fertility and viability at high temperatures. RDE-3 contains conserved domains found in the polymerase beta nucleotidyltransferase superfamily, which includes conventional poly(A) polymerases, 2'-5' oligoadenylate synthetase (OAS), and yeast Trf4p . These findings implicate a new enzymatic modality in RNAi and suggest possible models for the role of RDE-3 in the RNAi mechanism.

Endocytic pathway mediates refractoriness of insect Bactrocera dorsalis to RNA interference.

PubMed

Li, Xiaoxue; Dong, Xiaolong; Zou, Cong; Zhang, Hongyu

2015-03-03

RNA interference (RNAi) is a powerful and convenient tool for sequence-specific gene silencing, and it is triggered by double-stranded RNA (dsRNA). RNAi can be easily achieved in many eukaryotes by either injecting or feeding dsRNAs. This mechanism has demonstrated its potential in fundamental research on genetics, medicine and agriculture. However, the possibility that insects might develop refractoriness to RNAi remains unexplored. In this study, we report that the oriental fruit fly, Bactrocera dorsalis, became refractory to RNAi using orally administered dsRNA targeting endogenous genes. Furthermore, refractoriness to RNAi is not gene-specific, and its duration depends on the dsRNA concentration. RNAi blockage requires the endocytic pathway. Fluorescence microscopy indicated that in RNAi refractory flies, dsRNA uptake is blocked. Genes involved in the entry of dsRNAs into cells, including chc, cog3, light and others, are down-regulated in RNAi refractory flies. Increasing the endocytic capacity by improving F-actin polymerization disrupts RNAi refractoriness after both primary and secondary dsRNA exposures. Our results demonstrate that an insect can become refractory to RNAi by preventing the entry of dsRNA into its cells.

RNA interference-mediated silencing of genes involved in the immune responses of the soybean pod borer Leguminivora glycinivorella (Lepidoptera: Olethreutidae).

PubMed

Ran, Ruixue; Li, Tianyu; Liu, Xinxin; Ni, Hejia; Li, Wenbin; Meng, Fanli

2018-01-01

RNA interference (RNAi) technology may be useful for developing new crop protection strategies against the soybean pod borer (SPB; Leguminivora glycinivorella ), which is a critical soybean pest in northeastern Asia. Immune-related genes have been recently identified as potential RNAi targets for controlling insects. However, little is known about these genes or mechanisms underlying their expression in the SPB. In this study, we completed a transcriptome-wide analysis of SPB immune-related genes. We identified 41 genes associated with SPB microbial recognition proteins, immune-related effectors or signalling molecules in immune response pathways (e.g., Toll and immune deficiency pathways). Eleven of these genes were selected for a double-stranded RNA artificial feeding assay. The down-regulated expression levels of LgToll-5-1a and LgPGRP-LB2a resulted in relatively high larval mortality rates and abnormal development. Our data represent a comprehensive genetic resource for immune-related SPB genes, and may contribute to the elucidation of the mechanism regulating innate immunity in Lepidoptera species. Furthermore, two immune-related SPB genes were identified as potential RNAi targets, which may be used in the development of RNAi-mediated SPB control methods.

Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

PubMed Central

De Coster, Sam; van Larebeke, Nicolas

2012-01-01

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand. PMID:22991565

RNA interference-mediated silencing of genes involved in the immune responses of the soybean pod borer Leguminivora glycinivorella (Lepidoptera: Olethreutidae)

PubMed Central

Ran, Ruixue; Li, Tianyu; Liu, Xinxin; Ni, Hejia; Li, Wenbin

2018-01-01

RNA interference (RNAi) technology may be useful for developing new crop protection strategies against the soybean pod borer (SPB; Leguminivora glycinivorella), which is a critical soybean pest in northeastern Asia. Immune-related genes have been recently identified as potential RNAi targets for controlling insects. However, little is known about these genes or mechanisms underlying their expression in the SPB. In this study, we completed a transcriptome-wide analysis of SPB immune-related genes. We identified 41 genes associated with SPB microbial recognition proteins, immune-related effectors or signalling molecules in immune response pathways (e.g., Toll and immune deficiency pathways). Eleven of these genes were selected for a double-stranded RNA artificial feeding assay. The down-regulated expression levels of LgToll-5-1a and LgPGRP-LB2a resulted in relatively high larval mortality rates and abnormal development. Our data represent a comprehensive genetic resource for immune-related SPB genes, and may contribute to the elucidation of the mechanism regulating innate immunity in Lepidoptera species. Furthermore, two immune-related SPB genes were identified as potential RNAi targets, which may be used in the development of RNAi-mediated SPB control methods. PMID:29910977

Does altercentric interference rely on mentalizing?: Results from two level-1 perspective-taking tasks

PubMed Central

Gollwitzer, Anton; Santos, Laurie R.

2018-01-01

Considerable debate has focused on whether adults possess an implicit system for representing others’ mental states. Some argue that people automatically represent the perspective of others using evidence from altercentric interference—cases in which another agent’s perspective affects the speed with which one can report one’s own perspective. Others have argued that altercentric interference is not always specific to social stimuli and thus may represent a simpler process such as submentalizing. To distinguish between these positions, Study 1 developed a novel measure of altercentric interference—a “sandbox” measure—that allowed us to more sensitively assess altercentric interference across social and non-social conditions. We replicated previous findings showing that participants experience both egocentric and altercentric interference, but we found that these effects emerge equally in social and non-social conditions. To further test whether altercentric interference emerges in social perspective-taking situations, Study 2 conducted a conceptual replication of a study which used a novel “goggle” paradigm to assess whether individuals implicitly represent others’ perspectives. Although we failed to find evidence of altercentric interference in response times, participants’ accuracy reflected the possibility of interference from others’ perspectives. We argue that these findings provide support for the idea that altercentric interference in response to social stimuli (an avatar) is driven by perspective-taking mechanisms, while such interference in response to non-social stimuli (an arrow) is driven by attention-cuing mechanisms. PMID:29566019

Internal and External Dispersal of Plants by Animals: An Aquatic Perspective on Alien Interference

PubMed Central

van Leeuwen, Casper H. A.

2018-01-01

Many alien plants use animal vectors for dispersal of their diaspores (zoochory). If alien plants interact with native disperser animals, this can interfere with animal-mediated dispersal of native diaspores. Interference by alien species is known for frugivorous animals dispersing fruits of terrestrial plants by ingestion, transport and egestion (endozoochory). However, less attention has been paid to possible interference of alien plants with dispersal of diaspores via external attachment (ectozoochory, epizoochory or exozoochory), interference in aquatic ecosystems, or positive effects of alien plants on dispersal of native plants. This literature study addresses the following hypotheses: (1) alien plants may interfere with both internal and external animal-mediated dispersal of native diaspores; (2) interference also occurs in aquatic ecosystems; (3) interference of alien plants can have both negative and positive effects on native plants. The studied literature revealed that alien species can comprise large proportions of both internally and externally transported diaspores. Because animals have limited space for ingested and adhering diaspores, alien species affect both internal and external transport of native diaspores. Alien plant species also form large proportions of all dispersed diaspores in aquatic systems and interfere with dispersal of native aquatic plants. Alien interference can be either negative (e.g., through competition with native plants) or positive (e.g., increased abundance of native dispersers, changed disperser behavior or attracting additional disperser species). I propose many future research directions, because understanding whether alien plant species disrupt or facilitate animal-mediated dispersal of native plants is crucial for targeted conservation of invaded (aquatic) plant communities. PMID:29487609

Electricity resonance-induced fast transport of water through nanochannels.

PubMed

Kou, Jianlong; Lu, Hangjun; Wu, Fengmin; Fan, Jintu; Yao, Jun

2014-09-10

We performed molecular dynamics simulations to study water permeation through a single-walled carbon nanotube with electrical interference. It was found that the water net flux across the nanochannel is greatly affected by the external electrical interference, with the maximal net flux occurred at an electrical interference frequency of 16670 GHz being about nine times as high as the net flux at the low or high frequency range of (<1000 GHz or >80,000 GHz). The above phenomena can be attributed to the breakage of hydrogen bonds as the electrical interference frequency approaches to the inherent resonant frequency of hydrogen bonds. The new mechanism of regulating water flux across nanochannels revealed in this study provides an insight into the water transportation through biological water channels and has tremendous potential in the design of high-flux nanofluidic systems.

Regulators of homologous recombination repair as novel targets for cancer treatment

PubMed Central

Krajewska, Małgorzata; Fehrmann, Rudolf S. N.; de Vries, Elisabeth G. E.; van Vugt, Marcel A. T. M.

2015-01-01

To cope with DNA damage, cells possess a complex signaling network called the ‘DNA damage response’, which coordinates cell cycle control with DNA repair. The importance of this network is underscored by the cancer predisposition that frequently goes along with hereditary mutations in DNA repair genes. One especially important DNA repair pathway in this respect is homologous recombination (HR) repair. Defects in HR repair are observed in various cancers, including hereditary breast, and ovarian cancer. Intriguingly, tumor cells with defective HR repair show increased sensitivity to chemotherapeutic reagents, including platinum-containing agents. These observations suggest that HR-proficient tumor cells might be sensitized to chemotherapeutics if HR repair could be therapeutically inactivated. HR repair is an extensively regulated process, which depends strongly on the activity of various other pathways, including cell cycle pathways, protein-control pathways, and growth factor-activated receptor signaling pathways. In this review, we discuss how the mechanistic wiring of HR is controlled by cell-intrinsic or extracellular pathways. Furthermore, we have performed a meta-analysis on available genome-wide RNA interference studies to identify additional pathways that control HR repair. Finally, we discuss how these HR-regulatory pathways may provide therapeutic targets in the context of radio/chemosensitization. PMID:25852742

Antimicrobial peptide gene induction, involvement of Toll and IMD pathways and defense against bacteria in the red flour beetle, Tribolium castaneum.

PubMed

Yokoi, Kakeru; Koyama, Hiroaki; Minakuchi, Chieka; Tanaka, Toshiharu; Miura, Ken

2012-01-01

Using Tribolium castaneum, we quantitatively investigated the induction of nine antimicrobial peptide (AMP) genes by live gram-negative bacteria (Escherichia coli and Enterobacter cloacae), gram-positive bacteria (Micrococcus luteus and Bacillus subtilis) and the budding yeast (Saccharomyces cerevisiae). Then, five representative AMP genes were selected, and the involvement of the Toll and IMD pathways in their induction by E. coli, M. luteus and S. cerevisiae was examined by utilizing RNA interference of either MyD88 or IMD. Results indicated: Robust and acute induction of three genes by the two bacterial species was mediated mainly by the IMD pathway; slow and sustained induction of one gene by the two bacteria was mediated mainly by the Toll pathway; induction of the remaining one gene by the two bacteria was mediated by both pathways; induction of the five genes by the yeast was mediated by the Toll and/or IMD pathways depending on respective genes. These results suggest that more promiscuous activation and usage of the two pathways may occur in T. castaneum than in Drosophila melanogaster. In addition, the IMD pathway was revealed to dominantly contribute to defense against two bacterial species, gram-negative E. cloacae and gram-positive B. subtilis that possesses DAP-type peptidoglycan.

Neural Mechanisms of Interference Control Underlie the Relationship Between Fluid Intelligence and Working Memory Span

PubMed Central

Burgess, Gregory C.; Gray, Jeremy R.; Conway, Andrew R. A.; Braver, Todd S.

2014-01-01

Fluid intelligence (gF) and working memory (WM) span predict success in demanding cognitive situations. Recent studies show that much of the variance in gF and WM span is shared, suggesting common neural mechanisms. This study provides a direct investigation of the degree to which shared variance in gF and WM span can be explained by neural mechanisms of interference control. We measured performance and fMRI activity in 102 participants during the n-back WM task, focusing on the selective activation effects associated with high-interference lure trials. Brain activity on these trials was correlated with gF, WM span, and task performance in core brain regions linked to WM and executive control, including bilateral dorsolateral PFC (middle frontal gyrus, BA9) and parietal cortex (inferior parietal cortex; BA 40/7). Interference-related performance and interference-related activity accounted for a significant proportion of the shared variance in gF and WM span. Path analyses indicate that interference control activity may affect gF through a common set of processes that also influence WM span. These results suggest that individual differences in interference control mechanisms are important for understanding the relationship between gF and WM span. PMID:21787103

Quantum interference in laser-induced nonsequential double ionization

NASA Astrophysics Data System (ADS)

Quan, Wei; Hao, XiaoLei; Wang, YanLan; Chen, YongJu; Yu, ShaoGang; Xu, SongPo; Xiao, ZhiLei; Sun, RenPing; Lai, XuanYang; Hu, ShiLin; Liu, MingQing; Shu, Zheng; Wang, XiaoDong; Li, WeiDong; Becker, Wilhelm; Liu, XiaoJun; Chen, Jing

2017-09-01

Quantum interference plays an important role in various intense-laser-driven atomic phenomena, e.g., above-threshold ionization and high-order-harmonic generation, and provides a useful tool in ultrafast imaging of atomic and molecular structure and dynamics. However, it has eluded observation in nonsequential double ionization (NSDI), which serves as an ideal prototype to study electron-electron correlation. Thus far, NSDI usually could be well understood from a semiclassical perspective, where all quantum aspects have been ignored after the first electron has tunneled. Here we perform coincidence measurements for NSDI of xenon subject to laser pulses at 2400 nm. It is found that the intensity dependence of the asymmetry parameter between the yields in the second and fourth quadrants and those in the first and third quadrants of the electron-momentum-correlation distributions exhibits a peculiar fast oscillatory structure, which is beyond the scope of the semiclassical picture. Our theoretical analysis indicates that this oscillation can be attributed to interference between the contributions of different excited states in the recollision-excitation-with-subsequent-ionization channel. Our work demonstrates the significant role of quantum interference in NSDI and may create an additional pathway towards manipulation and imaging of the ultrafast atomic and molecular dynamics in intense laser fields.

Vitamin and co-factor biosynthesis pathways in Plasmodium and other apicomplexan parasites

PubMed Central

Müller, Sylke; Kappes, Barbara

2007-01-01

Vitamins are essential components of the human diet. By contrast, the malaria parasite Plasmodium falciparum and related apicomplexan parasites synthesise certain vitamins, de novo, either completely or in parts. The occurrence of the various biosynthesis pathways is specific to different apicomplexan parasites, emphasising their distinct requirements for nutrients and growth factors. The absence of vitamin biosynthesis from the human host implies that inhibition of the parasite pathways may be a way to interfere specifically with parasite development. However, the precise role of biosynthesis and potential uptake of vitamins for the overall regulation of vitamin homeostasis in the parasites needs to be established first. In this review Sylke Müller and Barbara Kappes focus mainly on the procurement of vitamin B1, B5 and B6 by Plasmodium and other apicomplexan parasites. PMID:17276140

Matrix precipitation: a general strategy to eliminate matrix interference for pharmaceutical toxic impurities analysis.

PubMed

Yang, Xiaojing; Xiong, Xuewu; Cao, Ji; Luan, Baolei; Liu, Yongjun; Liu, Guozhu; Zhang, Lei

2015-01-30

Matrix interference, which can lead to false positive/negative results, contamination of injector or separation column, incompatibility between sample solution and the selected analytical instrument, and response inhibition or even quenching, is commonly suffered for the analysis of trace level toxic impurities in drug substance. In this study, a simple matrix precipitation strategy is proposed to eliminate or minimize the above stated matrix interference problems. Generally, a sample of active pharmaceutical ingredients (APIs) is dissolved in an appropriate solvent to achieve the desired high concentration and then an anti-solvent is added to precipitate the matrix substance. As a result, the target analyte is extracted into the mixed solution with very less residual of APIs. This strategy has the characteristics of simple manipulation, high recovery and excellent anti-interference capability. It was found that the precipitation ratio (R, representing the ability to remove matrix substance) and the proportion of solvent (the one used to dissolve APIs) in final solution (P, affecting R and also affecting the method sensitivity) are two important factors of the precipitation process. The correlation between R and P was investigated by performing precipitation with various APIs in different solvent/anti-solvent systems. After a detailed mathematical reasoning process, P=20% was proved to be an effective and robust condition to perform the precipitation strategy. The precipitation method with P=20% can be used as a general strategy for toxic impurity analysis in APIs. Finally, several typical examples are described in this article, where the challenging matrix interference issues have been resolved successfully. Copyright © 2014 Elsevier B.V. All rights reserved.

Auditory temporal preparation induced by rhythmic cues during concurrent auditory working memory tasks.

PubMed

Cutanda, Diana; Correa, Ángel; Sanabria, Daniel

2015-06-01

The present study investigated whether participants can develop temporal preparation driven by auditory isochronous rhythms when concurrently performing an auditory working memory (WM) task. In Experiment 1, participants had to respond to an auditory target presented after a regular or an irregular sequence of auditory stimuli while concurrently performing a Sternberg-type WM task. Results showed that participants responded faster after regular compared with irregular rhythms and that this effect was not affected by WM load; however, the lack of a significant main effect of WM load made it difficult to draw any conclusion regarding the influence of the dual-task manipulation in Experiment 1. In order to enhance dual-task interference, Experiment 2 combined the auditory rhythm procedure with an auditory N-Back task, which required WM updating (monitoring and coding of the information) and was presumably more demanding than the mere rehearsal of the WM task used in Experiment 1. Results now clearly showed dual-task interference effects (slower reaction times [RTs] in the high- vs. the low-load condition). However, such interference did not affect temporal preparation induced by rhythms, with faster RTs after regular than after irregular sequences in the high-load and low-load conditions. These results revealed that secondary tasks demanding memory updating, relative to tasks just demanding rehearsal, produced larger interference effects on overall RTs in the auditory rhythm task. Nevertheless, rhythm regularity exerted a strong temporal preparation effect that survived the interference of the WM task even when both tasks competed for processing resources within the auditory modality. (c) 2015 APA, all rights reserved).

Assessment of virus interference in a test-negative study of influenza vaccine effectiveness

PubMed Central

Feng, Shuo; Fowlkes, Ashley L.; Steffens, Andrea; Finelli, Lyn; Cowling, Benjamin J.

2017-01-01

Background The observational test-negative study design is used to estimate vaccine effectiveness against influenza virus infection. An important assumption of the test-negative design is that vaccination does not affect the risk of infection with another virus. If such virus interference occurred, detection of other respiratory viruses would be more common among influenza vaccine recipients and vaccine effectiveness estimates could differ. We evaluated the potential for virus interference using data from the Influenza Incidence Surveillance Project. Methods From 2010 to 2013, outpatients presenting to clinics in 13 US jurisdictions with acute respiratory infections were tested for influenza and other respiratory viruses. We investigated whether virus interference might affect vaccine effectiveness estimates by first evaluating the sensitivity of estimates using alternative control groups that include or exclude patients with other respiratory virus detections by age group and early/middle/late stage of influenza seasons. Second, we evaluated the association between influenza vaccination receipt and other respiratory virus detection among influenza test negative patients. Results Influenza was detected in 3,743/10,650 patients (35%), and overall vaccine effectiveness was 47% (95% CI: 42%, 52%). Estimates using each control group were consistent overall or when stratified by age groups, and there were no differences among early, middle, or late phase during influenza season. We found no associations between detection of other respiratory viruses and receipt of influenza vaccination. Conclusions In this 3-year test-negative design study in an outpatient setting in the United States, we found no evidence of virus interference or impact on influenza vaccine effectiveness estimation. PMID:28362642

Utilization of coincidence criteria in absolute length measurements by optical interferometry in vacuum and air

NASA Astrophysics Data System (ADS)

Schödel, R.

2015-08-01

Traceability of length measurements to the international system of units (SI) can be realized by using optical interferometry making use of well-known frequencies of monochromatic light sources mentioned in the Mise en Pratique for the realization of the metre. At some national metrology institutes, such as Physikalisch-Technische Bundesanstalt (PTB) in Germany, the absolute length of prismatic bodies (e.g. gauge blocks) is realized by so-called gauge-block interference comparators. At PTB, a number of such imaging phase-stepping interference comparators exist, including specialized vacuum interference comparators, each equipped with three highly stabilized laser light sources. The length of a material measure is expressed as a multiple of each wavelength. The large number of integer interference orders can be extracted by the method of exact fractions in which the coincidence of the lengths resulting from the different wavelengths is utilized as a criterion. The unambiguous extraction of the integer interference orders is an essential prerequisite for correct length measurements. This paper critically discusses coincidence criteria and their validity for three modes of absolute length measurements: 1) measurements under vacuum in which the wavelengths can be identified with the vacuum wavelengths, 2) measurements under air in which the air refractive index is obtained from environmental parameters using an empirical equation, and 3) measurements under air in which the air refractive index is obtained interferometrically by utilizing a vacuum cell placed along the measurement pathway. For case 3), which corresponds to PTB’s Kösters-Comparator for long gauge blocks, the unambiguous determination of integer interference orders related to the air refractive index could be improved by about a factor of ten when an ‘overall dispersion value,’ suggested in this paper, is used as coincidence criterion.

Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer

PubMed Central

O'Grady, Michael; Raha, Debasish; Hanson, Bonnie J; Bunting, Michaeline; Hanson, George T

2005-01-01

Background The transcription factor activator protein-1 (AP-1) has been implicated in a large variety of biological processes including oncogenic transformation. The tyrosine kinases of the epidermal growth factor receptor (EGFR) constitute the beginning of one signal transduction cascade leading to AP-1 activation and are known to control cell proliferation and differentiation. Drug discovery efforts targeting this receptor and other pathway components have centred on monoclonal antibodies and small molecule inhibitors. Resistance to such inhibitors has already been observed, guiding the prediction of their use in combination therapies with other targeted agents such as RNA interference (RNAi). This study examines the use of RNAi and kinase inhibitors for qualification of components involved in the EGFR/AP-1 pathway of ME180 cells, and their inhibitory effects when evaluated individually or in tandem against multiple components of this important disease-related pathway. Methods AP-1 activation was assessed using an ME180 cell line stably transfected with a beta-lactamase reporter gene under the control of AP-1 response element following epidermal growth factor (EGF) stimulation. Immunocytochemistry allowed for further quantification of small molecule inhibition on a cellular protein level. RNAi and RT-qPCR experiments were performed to assess the amount of knockdown on an mRNA level, and immunocytochemistry was used to reveal cellular protein levels for the targeted pathway components. Results Increased potency of kinase inhibitors was shown by combining RNAi directed towards EGFR and small molecule inhibitors acting at proximal or distal points in the pathway. After cellular stimulation with EGF and analysis at the level of AP-1 activation using a β-lactamase reporter gene, a 10–12 fold shift or 2.5–3 fold shift toward greater potency in the IC50 was observed for EGFR and MEK-1 inhibitors, respectively, in the presence of RNAi targeting EGFR. Conclusion EGFR pathway components were qualified as targets for inhibition of AP-1 activation using RNAi and small molecule inhibitors. The combination of these two targeted agents was shown to increase the efficacy of EGFR and MEK-1 kinase inhibitors, leading to possible implications for overcoming or preventing drug resistance, lowering effective drug doses, and providing new strategies for interrogating cellular signalling pathways. PMID:16202132

Dexter energy transfer pathways

PubMed Central

Skourtis, Spiros S.; Liu, Chaoren; Antoniou, Panayiotis; Virshup, Aaron M.; Beratan, David N.

2016-01-01

Energy transfer with an associated spin change of the donor and acceptor, Dexter energy transfer, is critically important in solar energy harvesting assemblies, damage protection schemes of photobiology, and organometallic opto-electronic materials. Dexter transfer between chemically linked donors and acceptors is bridge mediated, presenting an enticing analogy with bridge-mediated electron and hole transfer. However, Dexter coupling pathways must convey both an electron and a hole from donor to acceptor, and this adds considerable richness to the mediation process. We dissect the bridge-mediated Dexter coupling mechanisms and formulate a theory for triplet energy transfer coupling pathways. Virtual donor–acceptor charge-transfer exciton intermediates dominate at shorter distances or higher tunneling energy gaps, whereas virtual intermediates with an electron and a hole both on the bridge (virtual bridge excitons) dominate for longer distances or lower energy gaps. The effects of virtual bridge excitons were neglected in earlier treatments. The two-particle pathway framework developed here shows how Dexter energy-transfer rates depend on donor, bridge, and acceptor energetics, as well as on orbital symmetry and quantum interference among pathways. PMID:27382185

Modulation of the Isoprenoid/Cholesterol Biosynthetic Pathway During Neuronal Differentiation In Vitro.

PubMed

Cartocci, Veronica; Segatto, Marco; Di Tunno, Ilenia; Leone, Stefano; Pfrieger, Frank W; Pallottini, Valentina

2016-09-01

During differentiation, neurons acquire their typical shape and functional properties. At present, it is unclear, whether this important developmental step involves metabolic changes. Here, we studied the contribution of the mevalonate (MVA) pathway to neuronal differentiation using the mouse neuroblastoma cell line N1E-115 as experimental model. Our results show that during differentiation, the activity of 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR), a key enzyme of MVA pathway, and the level of Low Density Lipoprotein receptor (LDLr) decrease, whereas the level of LDLr-related protein-1 (LRP1) and the dimerization of Scavanger Receptor B1 (SRB-1) rise. Pharmacologic inhibition of HMGR by simvastatin accelerated neuronal differentiation by modulating geranylated proteins. Collectively, our data suggest that during neuronal differentiation, the activity of the MVA pathway decreases and we postulate that any interference with this process impacts neuronal morphology and function. Therefore, the MVA pathway appears as an attractive pharmacological target to modulate neurological and metabolic symptoms of developmental neuropathologies. J. Cell. Biochem. 117: 2036-2044, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Dexter energy transfer pathways.

PubMed

Skourtis, Spiros S; Liu, Chaoren; Antoniou, Panayiotis; Virshup, Aaron M; Beratan, David N

2016-07-19

Energy transfer with an associated spin change of the donor and acceptor, Dexter energy transfer, is critically important in solar energy harvesting assemblies, damage protection schemes of photobiology, and organometallic opto-electronic materials. Dexter transfer between chemically linked donors and acceptors is bridge mediated, presenting an enticing analogy with bridge-mediated electron and hole transfer. However, Dexter coupling pathways must convey both an electron and a hole from donor to acceptor, and this adds considerable richness to the mediation process. We dissect the bridge-mediated Dexter coupling mechanisms and formulate a theory for triplet energy transfer coupling pathways. Virtual donor-acceptor charge-transfer exciton intermediates dominate at shorter distances or higher tunneling energy gaps, whereas virtual intermediates with an electron and a hole both on the bridge (virtual bridge excitons) dominate for longer distances or lower energy gaps. The effects of virtual bridge excitons were neglected in earlier treatments. The two-particle pathway framework developed here shows how Dexter energy-transfer rates depend on donor, bridge, and acceptor energetics, as well as on orbital symmetry and quantum interference among pathways.

Role of nitric oxide pathway in the conditioned rewarding effects of MDMA in mice.

PubMed

García-Pardo, M P; Rodríguez-Arias, M; Miñarro, J; Aguilar, M A

2017-07-14

It is estimated that 2.1 million young adults used MDMA/Ecstasy in the last year in Europe. Vulnerable subjects can develop dependence after MDMA abuse but currently there does not exist an effective treatment for this disorder. The nitric oxide (NO) pathway seems to have an important role on the rewarding effects of different drugs and has been proposed as a new pharmacological treatment for psychostimulant addiction. In the present study, we intend to evaluate whether the blockade of the NO synthesis (NOS) interferes with the rewarding effects of MDMA in the conditioned preference place (CPP) paradigm in young adult male mice. Our results indicated that mice treated with 7-nitroindazole (a NOS inhibitor) did not show CPP after conditioning with MDMA (1.25mg/kg). These results demonstrated the role of the NO pathway in the rewarding effects of MDMA and suggested that the manipulation of this pathway could be a new therapeutic option for MDMA abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

The TNF-α/NF-κB signaling pathway has a key role in methamphetamine–induced blood–brain barrier dysfunction

PubMed Central

Coelho-Santos, Vanessa; Leitão, Ricardo A; Cardoso, Filipa L; Palmela, Inês; Rito, Manuel; Barbosa, Marcos; Brito, Maria A; Fontes-Ribeiro, Carlos A; Silva, Ana P

2015-01-01

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction. PMID:25899299

Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders.

PubMed

O'Farrell, Katherine; Harkin, Andrew

2017-01-01

The kynurenine pathway (KP), which is activated in times of stress and infection has been implicated in the pathophysiology of neurodegenerative and psychiatric disorders. Activation of this tryptophan metabolising pathway results in the production of neuroactive metabolites which have the potential to interfere with normal neuronal functioning which may contribute to altered neuronal transmission and the emergence of symptoms of these brain disorders. This review investigates the involvement of the KP in a range of neurological disorders, examining recent in vitro, in vivo and clinical discoveries highlights evidence to indicate that the KP is a potential therapeutic target in both neurodegenerative and stress-related neuropsychiatric disorders. Furthermore, this review identifies gaps in our knowledge with regard to this field which are yet to be examined to lead to a more comprehensive understanding of the role of KP activation in brain health and disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Plant-specific multisubunit RNA polymerase in gene silencing.

PubMed

Lahmy, Sylvie; Bies-Etheve, Natacha; Lagrange, Thierry

2010-01-01

In recent years, a major breakthrough in the study of epigenetic silencing in eukaryotes came with the discovery that the RNA-interference pathway (RNAi) is generally implicated in heterochromatin assembly and gene silencing. An important and paradoxical feature of the RNAi-mediated heterochromatin pathways is their requirement for some form of transcription. In fission yeast, Schizosaccharomyces pombe, centromeric siRNAs have been shown to derive from chromatin-bound nascent transcripts produced by RNA polymerase II (PolII) at the site of heterochromatin formation. Likewise, chromatin-bound nascent transcripts generated by a PolII-related DNA-dependent RNA polymerase, known as PolIVb/PolV, have recently been implicated in RNA-directed DNA methylation (RdDM), the prominent RNAi-mediated chromatin pathway in plants. In this review we discuss recent work on the plant-specific PolII variant enzymes and discuss the mechanistic convergences that have been observed in the role of these enzymes in their respective siRNA-mediated heterochromatin formation pathways.

Ras-sensitive IMP modulation of the Raf/MEK/ERK cascade through KSR1.

PubMed

Matheny, Sharon A; White, Michael A

2006-01-01

The E3 ubiquitin ligase IMP (impedes mitogenic signal propagation) was isolated as a novel Ras effector that negatively regulates ERK1/2 activation. Current evidence suggests that IMP limits the functional assembly of Raf/MEK complexes by inactivation of the KSR1 adaptor/scaffold protein. Interaction with Ras-GTP stimulates IMP autoubiquitination to relieve limitations on KSR function. The elevated sensitivity of IMP-depleted cells to ERK1/2 pathway activation suggests IMP acts as a signal threshold regulator by imposing reversible restrictions on the assembly of functional Raf/MEK/ERK kinase modules. These observations challenge commonly held concepts of signal transmission by Ras to the MAPK pathway and provide evidence for the role of amplitude modulation in tuning cellular responses to ERK1/2 pathway engagement. Here we describe details of the methods, including RNA interference, ubiquitin ligase assays, and protein complex analysis, that can be used to display the Ras-sensitive contribution of IMP to KSR-dependent modulation of the Raf/MEK/ERK pathway.

Differential interference effects of negative emotional states on subsequent semantic and perceptual processing

PubMed Central

Gorlick, Marissa A.; Mather, Mara

2012-01-01

Past studies have revealed that encountering negative events interferes with cognitive processing of subsequent stimuli. The present study investigated whether negative events affect semantic and perceptual processing differently. Presentation of negative pictures produced slower reaction times than neutral or positive pictures in tasks that require semantic processing, such as natural/man-made judgments about drawings of objects, commonness judgments about objects, and categorical judgments about pairs of words. In contrast, negative picture presentation did not slow down judgments in subsequent perceptual processing (e.g., color judgments about words, and size judgments about objects). The subjective arousal level of negative pictures did not modulate the interference effects on semantic/perceptual processing. These findings indicate that encountering negative emotional events interferes with semantic processing of subsequent stimuli more strongly than perceptual processing, and that not all types of subsequent cognitive processing are impaired by negative events. PMID:22142207

Dynamic visual noise reduces confidence in short-term memory for visual information.

PubMed

Kemps, Eva; Andrade, Jackie

2012-05-01

Previous research has shown effects of the visual interference technique, dynamic visual noise (DVN), on visual imagery, but not on visual short-term memory, unless retention of precise visual detail is required. This study tested the prediction that DVN does also affect retention of gross visual information, specifically by reducing confidence. Participants performed a matrix pattern memory task with three retention interval interference conditions (DVN, static visual noise and no interference control) that varied from trial to trial. At recall, participants indicated whether or not they were sure of their responses. As in previous research, DVN did not impair recall accuracy or latency on the task, but it did reduce recall confidence relative to static visual noise and no interference. We conclude that DVN does distort visual representations in short-term memory, but standard coarse-grained recall measures are insensitive to these distortions.

Contextual interference processing during fast categorisations of facial expressions.

PubMed

Frühholz, Sascha; Trautmann-Lengsfeld, Sina A; Herrmann, Manfred

2011-09-01

We examined interference effects of emotionally associated background colours during fast valence categorisations of negative, neutral and positive expressions. According to implicitly learned colour-emotion associations, facial expressions were presented with colours that either matched the valence of these expressions or not. Experiment 1 included infrequent non-matching trials and Experiment 2 a balanced ratio of matching and non-matching trials. Besides general modulatory effects of contextual features on the processing of facial expressions, we found differential effects depending on the valance of target facial expressions. Whereas performance accuracy was mainly affected for neutral expressions, performance speed was specifically modulated by emotional expressions indicating some susceptibility of emotional expressions to contextual features. Experiment 3 used two further colour-emotion combinations, but revealed only marginal interference effects most likely due to missing colour-emotion associations. The results are discussed with respect to inherent processing demands of emotional and neutral expressions and their susceptibility to contextual interference.

Differential interference effects of negative emotional states on subsequent semantic and perceptual processing.

PubMed

Sakaki, Michiko; Gorlick, Marissa A; Mather, Mara

2011-12-01

Past studies have revealed that encountering negative events interferes with cognitive processing of subsequent stimuli. The present study investigates whether negative events affect semantic and perceptual processing differently. Presentation of negative pictures produced slower reaction times than neutral or positive pictures in tasks that require semantic processing, such as natural or man-made judgments about drawings of objects, commonness judgments about objects, and categorical judgments about pairs of words. In contrast, negative picture presentation did not slow down judgments in subsequent perceptual processing (e.g., color judgments about words, size judgments about objects). The subjective arousal level of negative pictures did not modulate the interference effects on semantic or perceptual processing. These findings indicate that encountering negative emotional events interferes with semantic processing of subsequent stimuli more strongly than perceptual processing, and that not all types of subsequent cognitive processing are impaired by negative events. (c) 2011 APA, all rights reserved.

Semiclassical description of photoionization microscopy

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

Bordas, Ch.; Lepine, F.; Nicole, C.

2003-07-01

Recently, experiments have been reported where a geometrical interference pattern was observed when photoelectrons ejected in the threshold photoionization of xenon were detected in a velocity-map imaging apparatus [C. Nicole et al., Phys. Rev. Lett. 88, 133001 (2002)]. This technique, called photoionization microscopy, relies on the existence of interferences between various trajectories by which the electron moves from the atom to the plane of observation. Unlike previous predictions relevant to the hydrogenic case, the structure of the interference pattern evolves smoothly with the excess energy above the saddle point and is only weakly affected by the presence of continuum Starkmore » resonances. In this paper, we describe a semiclassical analysis of this process and present numerical simulations in excellent agreement with the experimental results. It is shown that the background contribution dominates in the observations, as opposed to the behavior expected for hydrogenic systems where the interference pattern is qualitatively different on quasidiscrete Stark resonances.« less

On the interaction between sad mood and cognitive control: the effect of induced sadness on electrophysiological modulations underlying Stroop conflict processing.

PubMed

Nixon, Elena; Liddle, Peter F; Nixon, Neil L; Liotti, Mario

2013-03-01

The present study employed high-density ERPs to examine the effect of induced sad mood on the spatiotemporal correlates of conflict monitoring and resolution in a colour-word Stroop interference task. Neuroimaging evidence and dipole modelling implicates the involvement of the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) regions in conflict-laden interference control. On the basis that these structures have been found to mediate emotion-cognition interactions in negative mood states, it was predicted that Stroop-related cognitive control, which relies heavily on anterior neural sources, would be affected by effective sad mood provocation. Healthy participants (N=14) were induced into transient sadness via use of autobiographical sad scripts, a well-validated mood induction technique (Liotti et al., 2000a, 2002). In accord with previous research, interference effects were shown at both baseline and sad states while Stroop conflict was associated with early (N450) and late (Late Positive Component; LPC) electrophysiological modulations at both states. Sad mood induction attenuated the N450 effect in line with our expectation that it would be susceptible to modulation by mood, given its purported anterior limbic source. The LPC effect was displayed at the typical posterior lateral sites but, as predicted, was not affected by sad mood. However, frontocentral LPC activity-presumably generated from an additional anterior limbic source-was affected at sad state, hinting a role in conflict monitoring. Although the neurophysiological underpinnings of interference control are yet to be clarified, this study provided further insight into emotion-cognition interactions as indexed by Stroop conflict-laden processing. Copyright © 2012 Elsevier B.V. All rights reserved.

Sleep Shelters Verbal Memory from Different Kinds of Interference

PubMed Central

Sheth, Bhavin R.; Varghese, Reni; Truong, Thuy

2012-01-01

Study Objectives: Studies have shown that sleep shelters old verbal memories from associative interference arising from new, more recently acquired memories. Our objective is to extend the forms of interference for which sleep provides a sheltering benefit to non-associative and prospective interference, and to examine experimental conditions and memory strengths for which sleep before or after learning particularly affects verbal memory consolidation. Design: Acquiring paired word associates, retention across intervening sleep and wake, training on new, interfering word associates, and test recall of both sets. Setting: University laboratory. Participants: Healthy volunteers. Interventions: N/A. Measurements and Results: Comparing recall before and after intervening periods of sleep versus wake, we found that: (i) Sleep preferentially shields weakly encoded verbal memories from retroactive interference. (ii) Sleep immediately following learning helps shelter memory from associative and non-associative forms of retroactive interference. (iii) Sleep protects new verbal memories from prospective interference. (iv) Word associations acquired for the first time in the evening after a day spent in the wake state are encoded more strongly than word associations acquired in the morning following a night of sleep. Conclusions: The findings extend the known sleep protection from interference to non-associative as well as prospective interference, and limit the protection to weakly encoded word associations. Combined, our results suggest that sleep immediately after verbal learning isolates newly formed memory traces and renders them inaccessible, except by specific contextual cues. Memory isolation in sleep is a passive mechanism that can reasonably account for several experimental findings. Citation: Sheth BR; Varghese R; Truong T. Sleep shelters verbal memory from different kinds of interference. SLEEP 2012;35(7):985-996. PMID:22754045

A Novel Complex-Coefficient In-Band Interference Suppression Algorithm for Cognitive Ultra-Wide Band Wireless Sensors Networks.

PubMed

Xiong, Hailiang; Zhang, Wensheng; Xu, Hongji; Du, Zhengfeng; Tang, Huaibin; Li, Jing

2017-05-25

With the rapid development of wireless communication systems and electronic techniques, the limited frequency spectrum resources are shared with various wireless devices, leading to a crowded and challenging coexistence circumstance. Cognitive radio (CR) and ultra-wide band (UWB), as sophisticated wireless techniques, have been considered as significant solutions to solve the harmonious coexistence issues. UWB wireless sensors can share the spectrum with primary user (PU) systems without harmful interference. The in-band interference of UWB systems should be considered because such interference can severely affect the transmissions of UWB wireless systems. In order to solve the in-band interference issues for UWB wireless sensor networks (WSN), a novel in-band narrow band interferences (NBIs) elimination scheme is proposed in this paper. The proposed narrow band interferences suppression scheme is based on a novel complex-coefficient adaptive notch filter unit with a single constrained zero-pole pair. Moreover, in order to reduce the computation complexity of the proposed scheme, an adaptive complex-coefficient iterative method based on two-order Taylor series is designed. To cope with multiple narrow band interferences, a linear cascaded high order adaptive filter and a cyclic cascaded high order matrix adaptive filter (CCHOMAF) interference suppression algorithm based on the basic adaptive notch filter unit are also presented. The theoretical analysis and numerical simulation results indicate that the proposed CCHOMAF algorithm can achieve better performance in terms of average bit error rate for UWB WSNs. The proposed in-band NBIs elimination scheme can significantly improve the reception performance of low-cost and low-power UWB wireless systems.

Event-related potential evidence for separable automatic and controlled retrieval processes in proactive interference.

PubMed

Bergström, Zara M; O'Connor, Richard J; Li, Martin K-H; Simons, Jon S

2012-05-21

Interference between competing memories is a major source of retrieval failure, yet, surprisingly little is known about how competitive memory activation arises in the brain. One possibility is that interference during episodic retrieval might be produced by relatively automatic conceptual priming mechanisms that are independent of strategic retrieval processes. Such priming-driven interference might occur when the competing memories have strong pre-existing associations to the retrieval cue. We used ERPs to measure the neural dynamics of retrieval competition, and investigated whether the ERP correlates of interference were affected by varying task demands for selective retrieval. Participants encoded cue words that were presented either two or four times, paired either with the same or different strongly associated words across repetitions. In a subsequent test, participants either selectively recalled each cue's most recent associate, or simply judged how many times a cue had been presented, without requiring selective recall. Interference effects on test performance were only seen in the recall task. In contrast, ERPs during test revealed an early posterior positivity for high interference items that was present in both retrieval tasks. This early ERP effect likely reflects a conceptual priming-related N400 reduction when many associations to a cue were pre-activated. A later parietal positivity resembling the ERP correlate of conscious recollection was found only in the recall task. The results suggest that early effects of proactive interference are relatively automatic and independent of intentional retrieval processes, consistent with suggestions that interference can arise through conceptual priming. Copyright © 2012 Elsevier B.V. All rights reserved.

A Novel Complex-Coefficient In-Band Interference Suppression Algorithm for Cognitive Ultra-Wide Band Wireless Sensors Networks

PubMed Central

Xiong, Hailiang; Zhang, Wensheng; Xu, Hongji; Du, Zhengfeng; Tang, Huaibin; Li, Jing

2017-01-01

With the rapid development of wireless communication systems and electronic techniques, the limited frequency spectrum resources are shared with various wireless devices, leading to a crowded and challenging coexistence circumstance. Cognitive radio (CR) and ultra-wide band (UWB), as sophisticated wireless techniques, have been considered as significant solutions to solve the harmonious coexistence issues. UWB wireless sensors can share the spectrum with primary user (PU) systems without harmful interference. The in-band interference of UWB systems should be considered because such interference can severely affect the transmissions of UWB wireless systems. In order to solve the in-band interference issues for UWB wireless sensor networks (WSN), a novel in-band narrow band interferences (NBIs) elimination scheme is proposed in this paper. The proposed narrow band interferences suppression scheme is based on a novel complex-coefficient adaptive notch filter unit with a single constrained zero-pole pair. Moreover, in order to reduce the computation complexity of the proposed scheme, an adaptive complex-coefficient iterative method based on two-order Taylor series is designed. To cope with multiple narrow band interferences, a linear cascaded high order adaptive filter and a cyclic cascaded high order matrix adaptive filter (CCHOMAF) interference suppression algorithm based on the basic adaptive notch filter unit are also presented. The theoretical analysis and numerical simulation results indicate that the proposed CCHOMAF algorithm can achieve better performance in terms of average bit error rate for UWB WSNs. The proposed in-band NBIs elimination scheme can significantly improve the reception performance of low-cost and low-power UWB wireless systems. PMID:28587085

Generation of small molecules to interfere with regulated necrosis.

PubMed

Degterev, Alexei; Linkermann, Andreas

2016-06-01

Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever be able to prevent due to the unregulated nature of this form of cell death. However, given our growing understanding of the existence of regulated forms of necrosis and the roles of key enzymes of these pathways, e.g., kinases, peroxidases, etc., the possibility emerges to identify efficient and selective small molecule inhibitors of pathologic necrosis. Here, we review the published literature on small molecule inhibition of regulated necrosis and provide an outlook on how combination therapy may be most effective in treatment of necrosis-associated clinical situations like stroke, myocardial infarction, sepsis, cancer and solid organ transplantation.

The orphan receptor ERRα interferes with steroid signaling

PubMed Central

Teyssier, Catherine; Bianco, Stéphanie; Lanvin, Olivia; Vanacker, Jean-Marc

2008-01-01

The estrogen receptor-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily that has been shown to interfere with the estrogen-signaling pathway. In this report, we demonstrate that ERRα also cross-talks with signaling driven by other steroid hormones. Treatment of human prostatic cells with a specific ERRα inverse agonist reduces the expression of several androgen-responsive genes, in a manner that does not involve perturbation of androgen receptor expression or activity. Furthermore, ERRα activates the expression of androgen response elements (ARE)-containing promoters, such as that of the prostate cancer marker PSA, in an ARE-dependent manner. In addition, promoters containing a steroid response element can be activated by all members of the ERR orphan receptor subfamily, and this, even in the presence of antisteroid compounds. PMID:18697814

Drug-induced sexual dysfunction.

PubMed

Aldridge, S A

1982-01-01

Commonly used drugs that may cause sexual dysfunction are reviewed. The anatomy and physiology of the normal sexual response are reviewed. The influence of drugs on neurogenic, hormonal, and vascular mechanisms may result in diminished libido, impotence, ejaculatory and orgasmic difficulties, inhibited vaginal lubrication, menstrual irregularities, and gynecomastia in men or painful breast enlargement in women. Parasympatholytic agents, which interfere with cholinergic transmission, may affect erectile potency, while adrenergic inhibiting agents may interfere with ejaculatory control. Central nervous system depressants or sedating drugs, drugs producing hyperprolactinemia, and antiandrogenic drugs also may affect the normal sexual response. Drugs such as antihypertensive and antipsychotic agents may induce sexual dysfunction that can result in patient noncompliance. Usually, drug-induced side effects are reversible with discontinuation of the offending agent.

Domain-Specific Interference Tests on Navigational Working Memory in Military Pilots.

PubMed

Verde, Paola; Boccia, Maddalena; Colangeli, Stefano; Barbetti, Sonia; Nori, Raffaella; Ferlazzo, Fabio; Piccolo, Francesco; Vitalone, Roberto; Lucertini, Elena; Piccardi, Laura

2016-06-01

Human navigation is a very complex ability that encompasses all four stages of human information processing (sensory input, perception/cognition, selection, and execution of an action), involving both cognitive and physical requirements. During flight, the pilot uses all of these stages and one of the most critical aspect is interference. In fact, spatial tasks competing for the same cognitive resource cause greater distraction from a concurrent task than another task that uses different resource modalities. Here we compared and contrasted the performance of pilots and nonpilots of both genders performing increasingly complex navigational memory tasks while exposed to various forms of interference. We investigated the effects of four different sources of interference: motor, spatial motor, verbal, and spatial environment, focusing on gender differences. We found that flight experts perform better than controls (Pilots: 6.50 ± 1.29; Nonpilots: 5.45 ± 1.41). Furthermore, in the general population, navigational working memory is compromised only by spatial environmental interference (Nonpilots: 4.52 ± 1.50); female nonpilots were less able than male nonpilots. Also, the flight expert group showed the same interference, even if reduced (Pilots: 5.24 ± 0.92); moreover, we highlighted a complete absence of gender-related effects. Spatial environmental interference is the only interference producing a decrease in performance. Nevertheless, pilots are less affected than the general population. This is probably a consequence of the need to commit substantial cognitive resources to process spatial information during flight.

Primary Salvage Survey of the Interference of Radiowaves Emitted by Smartphones on Medical Equipment.

PubMed

Takao, Hiroyuki; Yeh, Yu Chih; Arita, Hiroyuki; Obatake, Takumi; Sakano, Teppei; Kurihara, Minoru; Matsuki, Akira; Ishibashi, Toshihiro; Murayama, Yuichi

2016-10-01

Use of mobile phones has become a standard reality of everyday living for many people worldwide, including medical professionals, as data sharing has drastically helped to improve quality of care. This increase in the use of mobile phones within hospitals and medical facilities has raised concern regarding the influence of radio waves on medical equipment. Although comprehensive studies have examined the effects of electromagnetic interference from 2G wireless communication and personal digital cellular systems on medical equipment, similar studies on more recent wireless technologies such as Long Term Evolution, wideband code division multiple access, and high-speed uplink access have yet to be published. Numerous tests targeting current wireless technologies were conducted between December 2012 and March 2013 in an anechoic chamber, shielded from external radio signals, with a dipole antenna to assess the effects of smartphone interference on several types of medical equipment. The interference produced by electromagnetic waves across five frequency bands from four telecommunication standards was assessed on 49 components from 22 pieces of medical equipment. Of the 22 pieces of medical equipment tested, 13 experienced interference at maximum transmission power. In contrast, at minimum transmission power, the maximum interference distance varied from 2 to 5 cm for different wireless devices. Four machines were affected at the minimum transmission power, and the maximum interference distance at the maximum transmission power was 38 cm. Results show that the interference from smartphones on medical equipment is very controllable.

Cross-interference of two model peroxisome proliferators in peroxisomal and estrogenic pathways in brown trout hepatocytes.

PubMed

Madureira, Tânia Vieira; Pinheiro, Ivone; Malhão, Fernanda; Lopes, Célia; Urbatzka, Ralph; Castro, L Filipe C; Rocha, Eduardo

2017-06-01

Peroxisome proliferators cause species-specific effects, which seem to be primarily transduced by peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, PPARα has a close interrelationship with estrogenic signaling, and this latter has already been promptly activated in brown trout primary hepatocytes. Thus, and further exploring this model, we assess here the reactivity of two PPARα agonists in direct peroxisomal routes and, in parallel the cross-interferences in estrogen receptor (ER) mediated paths. To achieve these goals, three independent in vitro studies were performed using single exposures to clofibrate - CLF (50, 500 and 1000μM), Wy-14,643 - Wy (50 and 150μM), GW6471 - GW (1 and 10μM), and mixtures, including PPARα agonist or antagonist plus an ER agonist or antagonist. Endpoints included gene expression analysis of peroxisome/lipidic related genes (encoding apolipoprotein AI - ApoAI, fatty acid binding protein 1 - Fabp1, catalase - Cat, 17 beta-hydroxysteroid dehydrogenase 4 - 17β-HSD4, peroxin 11 alpha - Pex11α, PPARαBb, PPARαBa and urate oxidase - Uox) and those encoding estrogenic targets (ERα, ERβ-1 and vitellogenin A - VtgA). A quantitative morphological approach by using a pre-validated catalase immunofluorescence technique allowed checking possible changes in peroxisomes. Our results show a low responsiveness of trout hepatocytes to model PPARα agonists in direct target receptor pathways. Additionally, we unveiled interferences in estrogenic signaling caused by Wy, leading to an up-regulation VtgA and ERα at 150μM; these effects seem counteracted with a co-exposure to an ER antagonist. The present data stress the potential of this in vitro model for further exploring the physiological/toxicological implications related with this nuclear receptor cross-regulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Electromagnetic interference with pacemakers caused by portable media players.

PubMed

Thaker, Jay P; Patel, Mehul B; Jongnarangsin, Krit; Liepa, Valdis V; Thakur, Ranjan K

2008-04-01

Electromagnetic fields generated by electrical devices may cause interference with permanent pacemakers. Media players are becoming a common mode of portable entertainment. The most common media players used worldwide are iPods. These devices are often carried in a shirt chest pocket, which may place the devices close to an implanted pacemaker. The purpose of this study was to determine if iPods cause interference with pacemakers. In this prospective, single-blinded study, 100 patients who had cardiac pacemakers were tested with four types of iPods to assess for interference. Patients were monitored by a single-channel ECG monitor as well as the respective pacemaker programmer via the telemetry wand. iPods were tested by placing them 2 inches anterior to the pacemaker and wand for up to 10 seconds. To simulate actual use, standard-issue headphones were plugged into the iPods. To maintain consistency, the volume was turned up maximally, and the equalizer was turned off. A subset of 25 patients underwent testing on 2 separate days to assess for reproducibility of interference. Pacemaker interference was categorized as type I or type II telemetry interference. Type I interference was associated with atrial and/or ventricular high rates on rate histograms. Type II interference did not affect pacemaker rate counters. Electromagnetic emissions from the four iPods also were evaluated in a Faraday cage to determine the mechanism of the observed interference. One hundred patients (63 men and 37 women; mean age 77.1 +/- 7.6 years) with 11 single-chamber pacemakers and 89 dual-chamber pacemakers underwent 800 tests. The incidence of any type of interference was 51% of patients and 20% of tests. Type I interference was seen in 19% of patients and type II in 32% of patients. Reproducibility testing confirmed that interference occurred regardless of pacing configuration (unipolar or bipolar), pacing mode (AAI, VVI, or DDD), and from one day to the next. Electromagnetic emissions testing from the iPods demonstrated maximum emissions in the pacemaker carrier frequency range when the iPod was turned "on" with the headphones attached. iPods placed within 2 inches of implanted pacemakers monitored via the telemetry wand can cause interference with pacemakers.

Where have we gone wrong? Perceptual load does not affect selective attention.

PubMed

Benoni, Hanna; Tsal, Yehoshua

2010-06-18

The theory of perceptual load (Lavie & Tsal, 1994) proposes that with low load in relevant processing left over resources spill over to process irrelevant distractors. Interference could only be prevented under High-Load Conditions where relevant processing exhausts attentional resources. The theory is based primarily on the finding that distractor interference obtained in low load displays, when the target appears alone, is eliminated in high load displays when it is embedded among neutral letters. However, a possible alternative interpretation of this effect is that the distractor is similarly processed in both displays, yet its interference in the large displays is diluted by the presence of the neutral letters. We separated the possible effects of load and dilution by adding dilution displays that were high in dilution and low in perceptual load. In the first experiment these displays contained as many letters as the high load displays, but their neutral letters were clearly distinguished from the target, thereby allowing for a low load processing mode. In the second experiment we presented identical multicolor displays in the Dilution and High-Load Conditions. However, in the former the target color was known in advance (thereby preserving a low load processing mode) whereas in the latter it was not. In both experiments distractor interference was completely eliminated under the Dilution Condition. Thus, it is dilution not perceptual load affecting distractor processing. 2010 Elsevier Ltd. All rights reserved.

Don’t worry, be (moderately) happy: Mothers’ anxiety and positivity during pregnancy independently predict lower mother–infant synchrony

PubMed Central

Moore, Ginger; Quigley, Kelsey M.; Voegtline, Kristin M.; DiPietro, Janet A.

2015-01-01

Maternal positivity and mother–infant synchrony have been linked, independently, to beneficial infant outcomes; however, research that has examined relations between the two has found that higher positivity is associated with lower synchrony. Methodological issues may inform this counter-intuitive association and clinical theory supports its validity. This study examined the theory that heightened positivity associated with anxiety is a way of avoiding negative emotion and contributes to lower synchrony because it interferes with appropriate responding to infant cues. We examined mothers’ (N = 75) self-reported anxiety and verbal expression of positivity during pregnancy in relation to mother–infant synchrony at 6 months post-partum. Verbal positivity was assessed using linguistic analysis of interviews about pregnancy experiences. Mother and infant affect and gaze were coded during interaction and synchrony was computed as the correlation between mother and infant behaviors. Higher verbal positivity and anxiety during pregnancy independently predicted lower mother–infant synchrony, suggesting distinct pathways to the same degree of synchrony with potentially different consequences for infant development. PMID:26705933

Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition.

PubMed

Koliopoulos, Marios G; Lethier, Mathilde; van der Veen, Annemarthe G; Haubrich, Kevin; Hennig, Janosch; Kowalinski, Eva; Stevens, Rebecca V; Martin, Stephen R; Reis E Sousa, Caetano; Cusack, Stephen; Rittinger, Katrin

2018-05-08

RIG-I is a viral RNA sensor that induces the production of type I interferon (IFN) in response to infection with a variety of viruses. Modification of RIG-I with K63-linked poly-ubiquitin chains, synthesised by TRIM25, is crucial for activation of the RIG-I/MAVS signalling pathway. TRIM25 activity is targeted by influenza A virus non-structural protein 1 (NS1) to suppress IFN production and prevent an efficient host immune response. Here we present structures of the human TRIM25 coiled-coil-PRYSPRY module and of complexes between the TRIM25 coiled-coil domain and NS1. These structures show that binding of NS1 interferes with the correct positioning of the PRYSPRY domain of TRIM25 required for substrate ubiquitination and provide a mechanistic explanation for how NS1 suppresses RIG-I ubiquitination and hence downstream signalling. In contrast, the formation of unanchored K63-linked poly-ubiquitin chains is unchanged by NS1 binding, indicating that RING dimerisation of TRIM25 is not affected by NS1.

Ambient Concentrations of Metabolic Disrupting Chemicals and Children's Academic Achievement in El Paso, Texas.

PubMed

Clark-Reyna, Stephanie E; Grineski, Sara E; Collins, Timothy W

2016-09-01

Concerns about children's weight have steadily risen alongside the manufacture and use of myriad chemicals in the US. One class of chemicals, known as metabolic disruptors, interfere with human endocrine and metabolic functioning and are of specific concern to children's health and development. This article examines the effect of residential concentrations of metabolic disrupting chemicals on children's school performance for the first time. Census tract-level ambient concentrations for known metabolic disruptors come from the US Environmental Protection Agency's National Air Toxics Assessment. Other measures were drawn from a survey of primary caretakers of 4th and 5th grade children in El Paso Independent School District (El Paso, TX, USA). A mediation model is employed to examine two hypothetical pathways through which the ambient level of metabolic disruptors at a child's home might affect grade point average. Results indicate that concentrations of metabolic disruptors are statistically significantly associated with lower grade point averages directly and indirectly through body mass index. Findings from this study have practical implications for environmental justice research and chemical policy reform in the US.

Understanding the mechanisms of cognitive impairments in developmental coordination disorder.

PubMed

Deng, Shining; Li, Wei-Guang; Ding, Jing; Wu, Jinlin; Zhang, Yuanyuan; Li, Fei; Shen, Xiaoming

2014-01-01

Developmental coordination disorder (DCD), a neurodevelopmental disability in which a child's motor coordination difficulties significantly interfere with activities of daily life or academic achievement, together with additional symptoms of diseases with childhood sensorimotor impairments, increases the risk of many cognitive problems. This exhibits the dynamic interplay between sensorimotor and cognition systems. However, the brain structures and pathways involved have remained unknown over the past decades. Here, we review developments in recent years that elucidate the neural mechanisms involved in the sensorimotor-cognitive difficulties. First, we briefly address the clinical and epidemiological discoveries in DCD as well as its comorbidities. Subsequently, we group the growing evidence including our findings that support the notion that sensorimotor manipulation indeed affects the cognition development at systematic, circuitry, cellular, and molecular levels. This corresponds to changes in diverse brain regions, synaptic plasticity, and neurotransmitter and receptor activity during development under these effects. Finally, we address the treatment potentials of task-oriented sensorimotor enhancement, as a new therapeutic strategy for cognitive rehabilitation, based on our current understanding of the neurobiology of cognitive-sensorimotor interaction.

Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage.

PubMed

Ji, Cheng

2015-06-03

Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.

The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?

PubMed

Rosenberg, G

2007-08-01

After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of gamma-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/beta-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications.

Reprogramming the phenylpropanoid metabolism in seeds of oilseed rape by suppressing the orthologs of reduced epidermal fluorescence1.

PubMed

Mittasch, Juliane; Böttcher, Christoph; Frolov, Andrej; Strack, Dieter; Milkowski, Carsten

2013-04-01

As a result of the phenylpropanoid pathway, many Brassicaceae produce considerable amounts of soluble hydroxycinnamate conjugates, mainly sinapate esters. From oilseed rape (Brassica napus), we cloned two orthologs of the Arabidopsis (Arabidopsis thaliana) gene reduced epidermal fluorescence1 (REF1) encoding a coniferaldehyde/sinapaldehyde dehydrogenase. The enzyme is involved in the formation of ferulate and sinapate from the corresponding aldehydes, thereby linking lignin and hydroxycinnamate biosynthesis as a potential branch-point enzyme. We used RNA interference to silence REF1 genes in seeds of oilseed rape. Nontargeted metabolite profiling showed that BnREF1-suppressing seeds produced a novel chemotype characterized by reduced levels of sinapate esters, the appearance of conjugated monolignols, dilignols, and trilignols, altered accumulation patterns of kaempferol glycosides, and changes in minor conjugates of caffeate, ferulate, and 5-hydroxyferulate. BnREF1 suppression affected the level of minor sinapate conjugates more severely than that of the major component sinapine. Mapping of the changed metabolites onto the phenylpropanoid metabolic network revealed partial redirection of metabolic sequences as a major impact of BnREF1 suppression.

Reprogramming the Phenylpropanoid Metabolism in Seeds of Oilseed Rape by Suppressing the Orthologs of REDUCED EPIDERMAL FLUORESCENCE11[W

PubMed Central

Mittasch, Juliane; Böttcher, Christoph; Frolov, Andrej; Strack, Dieter; Milkowski, Carsten

2013-01-01

As a result of the phenylpropanoid pathway, many Brassicaceae produce considerable amounts of soluble hydroxycinnamate conjugates, mainly sinapate esters. From oilseed rape (Brassica napus), we cloned two orthologs of the Arabidopsis (Arabidopsis thaliana) gene REDUCED EPIDERMAL FLUORESCENCE1 (REF1) encoding a coniferaldehyde/sinapaldehyde dehydrogenase. The enzyme is involved in the formation of ferulate and sinapate from the corresponding aldehydes, thereby linking lignin and hydroxycinnamate biosynthesis as a potential branch-point enzyme. We used RNA interference to silence REF1 genes in seeds of oilseed rape. Nontargeted metabolite profiling showed that BnREF1-suppressing seeds produced a novel chemotype characterized by reduced levels of sinapate esters, the appearance of conjugated monolignols, dilignols, and trilignols, altered accumulation patterns of kaempferol glycosides, and changes in minor conjugates of caffeate, ferulate, and 5-hydroxyferulate. BnREF1 suppression affected the level of minor sinapate conjugates more severely than that of the major component sinapine. Mapping of the changed metabolites onto the phenylpropanoid metabolic network revealed partial redirection of metabolic sequences as a major impact of BnREF1 suppression. PMID:23424250

RNAi Functions in Adaptive Reprogramming of the Genome | Center for Cancer Research

Cancer.gov

The regulation of transcribing DNA into RNA, including the production, processing, and degradation of RNA transcripts, affects the expression and the regulation of the genome in ways that are just beginning to be unraveled. A surprising discovery in recent years is that the vast majority of the genome is transcribed to yield an abundance of RNA transcripts. Many transcripts are regulated by the exosome, a multi-protein complex that degrades RNAs, and may also be targeted, under certain conditions, by the RNA interference (RNAi) pathway. These RNA degrading activities can recruit factors to silence certain regions of the genome by condensing the DNA into tightly-packed heterochromatin. For some chromosomal regions, such as centromeres and telomeres, which lie at the center and ends of chromosomes, respectively, silencing must be stably enforced through each cell generation. For other regions, silencing mechanisms must be easily reversible to activate gene expression in response to changing environmental or developmental conditions. Thus, the regulation of gene silencing is key to maintaining the integrity of the genome and proper cellular expression patterns, which, when disrupted can underlie many diseases, including cancer.

MicroRNAs in osteosarcoma: diagnostic and therapeutic aspects.

PubMed

Miao, Jinglei; Wu, Song; Peng, Zhi; Tania, Mousumi; Zhang, Chaoyue

2013-08-01

MicroRNAs (miRNAs) are small RNA molecules, which can interfere with the expression of several genes and act as gene regulator. miRNAs have been proved as a successful diagnostic and therapeutic tool in several cancers. In this review, the differential expression of miRNAs in osteosarcoma and their possibility to be used as diagnostic and therapeutic tools have been discussed. Osteosarcoma is the most common primary bone tumor that mainly affects children and adolescents. The current treatment of osteosarcoma remains difficult, and osteosarcoma causes many deaths because of its complex pathogenesis and resistance to conventional treatments. Several studies demonstrated that the differential expression patterns of miRNAs are a promising tool for the diagnosis and treatment of osteosarcoma. Although some aspect of the mechanism of action of miRNAs in controlling osteosarcoma has been identified (e.g., targeting the Notch signaling pathway), it is far beyond to the clear understanding of miRNA targets in osteosarcoma. Identification of the specific target of miRNAs may aid molecular targets for drug development and future relief of osteosarcoma.

Evaluation of uptake and effect on patient-reported outcomes of a clinician and patient co-led chronic musculoskeletal pain self-management programme provided by the UK National Health Service.

PubMed

Anderson, Joanna K; Wallace, Louise M

2018-05-01

In the United Kingdom, chronic pain affects approximately 28 million adults, creating significant healthcare and socio-economic costs. The aim was to establish whether a programme designed to use best evidence of content and delivery will be used by patients with significant musculoskeletal pain problems. Of 528 patients recruited, 376 participated in a 7-week-long group-based self-management programme (SMP) co-delivered by clinical and lay tutors. Of these, 308 patients (mean age, 53 years; 69% females, 94% White) completed at least five SMP sessions. Six months after pre-course assessment, participants reported significantly improved patient activation and health status, lower depression and anxiety scores, decreased pain severity and interference, and improved self-management skills. There were no improvements in health state and pain self-efficacy. Uptake rate was 71% and completion 82%. The results should be of value to commissioners of pathways of care for the large numbers of patients attending the English NHS for chronic musculoskeletal pain.

Protection of Nonself Surfaces from Complement Attack by Factor H-Binding Peptides: Implications for Therapeutic Medicine

PubMed Central

Wu, You-Qiang; Qu, Hongchang; Sfyroera, Georgia; Tzekou, Apostolia; Kay, Brian K.; Nilsson, Bo; Ekdahl, Kristina Nilsson; Ricklin, Daniel; Lambris, John D.

2011-01-01

Exposure of nonself surfaces such as those of biomaterials or transplanted cells and organs to host blood frequently triggers innate immune responses, thereby affecting both their functionality and tolerability. Activation of the alternative pathway of complement plays a decisive role in this unfavorable reaction. Whereas previous studies demonstrated that immobilization of physiological regulators of complement activation (RCA) can attenuate this foreign body-induced activation, simple and efficient approaches for coating artificial surfaces with intact RCA are still missing. The conjugation of small molecular entities that capture RCA with high affinity is an intriguing alternative, as this creates a surface with autoregulatory activity upon exposure to blood. We therefore screened two variable cysteine-constrained phage-displayed peptide libraries for factor H-binding peptides. We discovered three peptide classes that differed with respect to their main target binding areas. Peptides binding to the broad middle region of factor H (domains 5–18) were of particular interest, as they do not interfere with either regulatory or binding activities. One peptide in this group (5C6) was further characterized and showed high factor H-capturing activity while retaining its functional integrity. Most importantly, when 5C6 was coated to a model polystyrene surface and exposed to human lepirudin-anticoagulated plasma, the bound peptide captured factor H and substantially inhibited complement activation by the alternative pathway. Our study therefore provides a promising and novel approach to produce therapeutic materials with enhanced biocompatibility. PMID:21339361

Toll-like receptor 4 is involved in the cell cycle modulation and required for effective human cytomegalovirus infection in THP-1 macrophages

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

Arcangeletti, Maria-Cristina, E-mail: mariacristina.arcangeletti@unipr.it; Germini, Diego; Rodighiero, Isabella

2013-05-25

Suitable host cell metabolic conditions are fundamental for the effective development of the human cytomegalovirus (HCMV) lytic cycle. Indeed, several studies have demonstrated the ability of this virus to interfere with cell cycle regulation, mainly by blocking proliferating cells in G1 or G1/S. In the present study, we demonstrate that HCMV deregulates the cell cycle of THP-1 macrophages (a cell line irreversibly arrested in G0) by pushing them into S and G2 phases. Moreover, we show that HCMV infection of THP-1 macrophages leads to Toll-like receptor 4 (TLR4) activation. Since various studies have indicated TLR4 to be involved in promotingmore » cell proliferation, here we investigate the possible role of TLR4 in the observed HCMV-induced cell cycle perturbation. Our data strongly support TLR4 as a mediator of HCMV-triggered cell cycle activation in THP-1 macrophages favouring, in turn, the development of an efficient viral lytic cycle. - Highlights: ► We studied HCMV infection impact on THP-1 macrophage cell cycle. ► We analysed the role played by Toll-like receptor (TLR) 4 upon HCMV infection. ► HCMV pushes THP-1 macrophages (i.e. resting cells) to re-enter the cell cycle. ► TLR4 pathway inhibition strongly affects the effectiveness of HCMV replication. ► TLR4 pathway inhibition significantly decreases HCMV-induced cell cycle re-entry.« less

Intestinal Insulin Signaling Encodes Two Different Molecular Mechanisms for the Shortened Longevity Induced by Graphene Oxide in Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Zhao, Yunli; Yang, Ruilong; Rui, Qi; Wang, Dayong

2016-04-01

Graphene oxide (GO) has been shown to cause multiple toxicities in various organisms. However, the underlying molecular mechanisms for GO-induced shortened longevity are still unclear. We employed Caenorhabditis elegans to investigate the possible involvement of insulin signaling pathway in the control of GO toxicity and its underlying molecular mechanisms. Mutation of daf-2, age-1, akt-1, or akt-2 gene induced a resistant property of nematodes to GO toxicity, while mutation of daf-16 gene led to a susceptible property of nematodes to GO toxicity, suggesting that GO may dysregulate the functions of DAF-2/IGF-1 receptor, AGE-1, AKT-1 and AKT-2-mediated kinase cascade, and DAF-16/FOXO transcription factor. Genetic interaction analysis suggested the involvement of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the control of GO toxicity on longevity. Moreover, intestinal RNA interference (RNAi) analysis demonstrated that GO reduced longevity by affecting the functions of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the intestine. DAF-16 could also regulate GO toxicity on longevity by functioning upstream of SOD-3, which encodes an antioxidation system that prevents the accumulation of oxidative stress. Therefore, intestinal insulin signaling may encode two different molecular mechanisms responsible for the GO toxicity in inducing the shortened longevity. Our results highlight the key role of insulin signaling pathway in the control of GO toxicity in organisms.

Alternative oxidase impacts ganoderic acid biosynthesis by regulating intracellular ROS levels in Ganoderma lucidum.

PubMed

Shi, Deng-Ke; Zhu, Jing; Sun, Ze-Hua; Zhang, Guang; Liu, Rui; Zhang, Tian-Jun; Wang, Sheng-Li; Ren, Ang; Zhao, Ming-Wen

2017-10-01

The alternative oxidase (AOX), which forms a branch of the mitochondrial respiratory electron transport pathway, functions to sustain electron flux and alleviate reactive oxygen species (ROS) production. In this article, a homologous AOX gene was identified in Ganoderma lucidum. The coding sequence of the AOX gene in G. lucidum contains 1038 nucleotides and encodes a protein of 39.48 kDa. RNA interference (RNAi) was used to study the function of AOX in G. lucidum, and two silenced strains (AOXi6 and AOXi21) were obtained, showing significant decreases of approximately 60 and 50 %, respectively, in alternative pathway respiratory efficiency compared to WT. The content of ganoderic acid (GA) in the mutant strains AOXi6 and AOXi21 showed significant increases of approximately 42 and 44 %, respectively, compared to WT. Elevated contents of intermediate metabolites in GA biosynthesis and elevated transcription levels of corresponding genes were also observed in the mutant strains AOXi6 and AOXi21. In addition, the intracellular ROS content in strains AOXi6 and AOXi21 was significantly increased, by approximately 1.75- and 1.93-fold, respectively, compared with WT. Furthermore, adding N-acetyl-l-cysteine (NAC), a ROS scavenger, significantly depressed the intracellular ROS content and GA accumulation in AOX-silenced strains. These results indicate that AOX affects GA biosynthesis by regulating intracellular ROS levels. Our research revealed the important role of AOX in the secondary metabolism of G. lucidum.

Therapeutic effect of photodynamic therapy combined with targeted delivery of silencing vascular endothelial growth factor (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hsu, Yih-Chih

2016-03-01

Photodynamic therapy is a novel therapeutic modality to treat cancer by using a photosensitizer which is activated by a light source to produce reactive oxygen species and mediates tumours oxygen-independent hypoxic conditions. Vascular endothelial growth factor (VEGF) is one of the primary factors that affect tumor angiogenesis. Another emerging treatment to cure cancer is the use of interference RNA to silence a specific mRNA sequence. Such treatment requires a delivery system such as liposomes. The nanoparticle size measured was about 30 nm. Cellular uptake study was performed to verify that the nanoparticles have a sigma receptor mediated pathway. Non-targeted LCP NPs did not show significant difference with or without haloperidol but has a lower intensity as than targeted LCP NPs. These results confirm that LCP NPs have a receptor mediated pathway. Cell viability was found to decrease at 25 nM of transfected VEGF siRNA. Combined therapy of PDT and VEGF siRNA showed significant response as compared with PDT and gene therapy alone. In vivo toxicity assay with mice treated with targeted LCP NPs containing control siRNA or VEGF siRNA and non-targeted LCP NPs containing VEGF siRNA did not show any significant difference with the PBS injected group which suggests that there is no toxicity with the dose. It suggests that PDT combined with targeted gene therapy has a potential mean to achieve better therapeutic outcome.

Hypericum caprifoliatum and Hypericum connatum affect human trophoblast-like cells differentiation and Ca2+ influx

PubMed Central

da Conceição, Aline O.; von Poser, Gilsane Lino; Barbeau, Benoit; Lafond, Julie

2014-01-01

Objective To study the effect of crude methanol and n-hexane extracts of Hypericum connatum (H. connatum) and Hypericum caprifoliatum on trophoblast-like cells. Methods BeWo and JEG-3 trophoblast-like cells were submitted to different extract concentrations (1, 5, 10 and 15 µg/mL) and evaluated in relation to cell viability and in vitro trophoblast differentiation and function. Cell viability was evaluated using WST-1 reagent. Differentiation was measured by luciferase production, hCG production/release, and mitogen-activated protein kinase signaling pathway activation. The function of the trophoblast-like cells was measured by 45Ca2+ influx evaluation. Results The results showed a decrease in cell viability/proliferation. Both plants and different extracts induced a significant decrease in hCG production/release and luciferase production. H. connatum did not cause mitogen-activated protein kinase signaling pathway disturbance; however, Hypericum caprifoliatum n-hexane extract at 15 µg/mL inhibited extracellular signal-regulated kinase 1/2 activation. The significant increase in Ca2+ influx by JEG-3 cells was seen after short and long incubation times with H. connatum methanolic extract at 15 µg/mL. Conclusions The results indicated that these two Hypericum species extracts can interfere on trophoblast differentiation and Ca2+ influx, according to their molecular diversity. Although in vivo experiments are necessary to establish their action on placental formation and function, this study suggests that attention must be paid to the potential toxic effect of these plants. PMID:25182721

Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells

PubMed Central

2011-01-01

Background Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics. PMID:21418624

Clinical review: kinase inhibitors: adverse effects related to the endocrine system.

PubMed

Lodish, Maya B

2013-04-01

The use of kinase inhibitors (KIs) in the treatment of cancer has become increasingly common, and practitioners must be familiar with endocrine-related side effects associated with these agents. This review provides an update to the clinician regarding the management of potential endocrinological effects of KIs. PubMed was employed to identify relevant manuscripts. A review of the literature was conducted, and data were summarized and incorporated. KIs, including small molecule KIs and monoclonal antibodies directed against kinases, have emerged over the past decade as an important class of anticancer agents. KIs specifically interfere with signaling pathways that are dysregulated in certain types of cancers and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. Currently, at least 20 KIs are approved as cancer therapeutics. However, KIs may affect a broad spectrum of targets and may have additional, unidentified mechanisms of action at the cellular level due to overlap between signaling pathways in the tumor cell and endocrine system. Recent reports in the literature have identified side effects associated with KIs, including alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, adrenal function, and glucose metabolism. Clinicians need to monitor the thyroid functions of patients on KIs. In addition, bone density and vitamin D status should be assessed. Special care should be taken to follow linear growth and development in children taking these agents. Clinicians should counsel patients appropriately on the potential adverse effects of KIs on fetal development.

Temporal aspects of copper homeostasis and its crosstalk with hormones

PubMed Central

Peñarrubia, Lola; Romero, Paco; Carrió-Seguí, Angela; Andrés-Bordería, Amparo; Moreno, Joaquín; Sanz, Amparo

2015-01-01

To cope with the dual nature of copper as being essential and toxic for cells, plants temporarily adapt the expression of copper homeostasis components to assure its delivery to cuproproteins while avoiding the interference of potential oxidative damage derived from both copper uptake and photosynthetic reactions during light hours. The circadian clock participates in the temporal organization of coordination of plant nutrition adapting metabolic responses to the daily oscillations. This timely control improves plant fitness and reproduction and holds biotechnological potential to drive increased crop yields. Hormonal pathways, including those of abscisic acid, gibberellins, ethylene, auxins, and jasmonates are also under direct clock and light control, both in mono and dicotyledons. In this review, we focus on copper transport in Arabidopsis thaliana and Oryza sativa and the presumable role of hormones in metal homeostasis matching nutrient availability to growth requirements and preventing metal toxicity. The presence of putative hormone-dependent regulatory elements in the promoters of copper transporters genes suggests hormonal regulation to match special copper requirements during plant development. Spatial and temporal processes that can be affected by hormones include the regulation of copper uptake into roots, intracellular trafficking and compartmentalization, and long-distance transport to developing vegetative and reproductive tissues. In turn, hormone biosynthesis and signaling are also influenced by copper availability, which suggests reciprocal regulation subjected to temporal control by the central oscillator of the circadian clock. This transcriptional regulatory network, coordinates environmental and hormonal signaling with developmental pathways to allow enhanced micronutrient acquisition efficiency. PMID:25941529

When writing impairs reading: letter perception's susceptibility to motor interference.

PubMed

James, Karin H; Gauthier, Isabel

2009-08-01

The effect of writing on the concurrent visual perception of letters was investigated in a series of studies using an interference paradigm. Participants drew shapes and letters while simultaneously visually identifying letters and shapes embedded in noise. Experiments 1-3 demonstrated that letter perception, but not the perception of shapes, was affected by motor interference. This suggests a strong link between the perception of letters and the neural substrates engaged during writing. The overlap both in category (letter vs. shape) and in the perceptual similarity of the features (straight vs. curvy) of the seen and drawn items determined the amount of interference. Experiment 4 demonstrated that intentional production of letters is not necessary for the interference to occur, because passive movement of the hand in the shape of letters also interfered with letter perception. When passive movements were used, however, only the category of the drawn items (letters vs. shapes), but not the perceptual similarity, had an influence, suggesting that motor representations for letters may selectively influence visual perception of letters through proprioceptive feedback, with an additional influence of perceptual similarity that depends on motor programs.

Frequency-selective fading statistics of shallow-water acoustic communication channel with a few multipaths

NASA Astrophysics Data System (ADS)

Bae, Minja; Park, Jihyun; Kim, Jongju; Xue, Dandan; Park, Kyu-Chil; Yoon, Jong Rak

2016-07-01

The bit error rate of an underwater acoustic communication system is related to multipath fading statistics, which determine the signal-to-noise ratio. The amplitude and delay of each path depend on sea surface roughness, propagation medium properties, and source-to-receiver range as a function of frequency. Therefore, received signals will show frequency-dependent fading. A shallow-water acoustic communication channel generally shows a few strong multipaths that interfere with each other and the resulting interference affects the fading statistics model. In this study, frequency-selective fading statistics are modeled on the basis of the phasor representation of the complex path amplitude. The fading statistics distribution is parameterized by the frequency-dependent constructive or destructive interference of multipaths. At a 16 m depth with a muddy bottom, a wave height of 0.2 m, and source-to-receiver ranges of 100 and 400 m, fading statistics tend to show a Rayleigh distribution at a destructive interference frequency, but a Rice distribution at a constructive interference frequency. The theoretical fading statistics well matched the experimental ones.

Patterns of pain and interference in patients with painful bone metastases: a brief pain inventory validation study.

PubMed

Wu, Jackson S Y; Beaton, Dorcas; Smith, Peter M; Hagen, Neil A

2010-02-01

Bone metastases are prevalent, painful, and carry a poorer prognosis for pain control compared with other cancer pain syndromes. Standard tools to measure pain have not been validated in this patient population, and particular subgroups with more challenging symptoms have yet to be identified and studied. The objectives of this study were 1) to validate the psychometric properties of the Brief Pain Inventory (BPI) and its Pain and Interference subscales in patients with clinically significant metastatic bone pain requiring palliative radiotherapy and 2) to examine differences in BPI subscales among predefined subgroups of bone metastases patients. A total of 258 patients evaluated and treated through a rapid access radiation therapy clinic between July 2002, and November 2006, were included in the analysis. High internal consistency of the BPI subscales of Pain, Activity interference, and Affect interference was demonstrated by Cronbach's alpha between 0.81 and 0.89. Removing sleep interference improved model fit in confirmatory factor analysis. The BPI revealed an alarming pattern in patients with lower body metastases, who reported substantial interference of activity even though pain levels were mild or moderate. Such patients may require prompt clinical attention to better meet their needs. Finally, the allocation of interference from sleep within the BPI framework, in our population of pain patients, requires further study. Copyright 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

15-deoxy-Delta12,14-prostaglandin J2 inhibits INF-gamma-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells.

PubMed

Panzer, Ulf; Zahner, Gunther; Wienberg, Ulrike; Steinmetz, Oliver M; Peters, Anett; Turner, Jan-Eric; Paust, Hans-Joachim; Wolf, Gunter; Stahl, Rolf A K; Schneider, André

2008-12-01

Activators of the peroxisome proliferator-activated receptor gamma (PPARgamma), originally found to be implicated in lipid metabolism and glucose homeostasis, have been shown to modulate inflammatory responses through interference with cytokine and chemokine production. Given the central role of mesangial cell-derived chemokines in glomerular leukocyte recruitment in human and experimental glomerulonephritis, we studied the influence of natural and synthetic PPARgamma activators on INF-gamma-induced expression of the T cell-attracting chemokines IP-10/CXCL10, Mig/CXCL9 and I-TAC/CXCL11 in mouse mesangial cells. INF-gamma-treated mesangial cells were cultured in the presence or absence of either the naturally occurring PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or synthetic PPARgamma activators of the glitazone group. Chemokine mRNA and protein expression and activation of the JAK/STAT signalling pathway were analysed. The 15d-PGJ(2), but not synthetic PPARgamma ligands, dose-dependently inhibited INF-gamma-induced chemokine gene (mRNA and protein) expression. Combined results from EMSA and western blot analysis revealed the inhibitory ability of 15d-PGJ(2), but not of synthetic PPARgamma ligands, on IFN-gamma-induced tyrosine phosphorylation of JAK1, JAK2, STAT1 and nuclear STAT1 translocation and DNA binding. Our results demonstrate that 15d-PGJ(2) inhibits INF-gamma-induced chemokine expression in mesangial cells by targeting the JAK/STAT signalling pathway. This effect is independent of an interference with PPARgamma.

Pterostilbene protects against UVB-induced photo-damage through a phosphatidylinositol-3-kinase-dependent Nrf2/ARE pathway in human keratinocytes.

PubMed

Li, Huaping; Jiang, Na; Liang, Bihua; Liu, Qing; Zhang, Erting; Peng, Liqian; Deng, Huiyan; Li, Runxiang; Li, Zhenjie; Zhu, Huilan

2017-11-01

Ultraviolet B (UVB) irradiation is the initial etiological factor for various skin disorders, including erythema, sunburn, photoaging, and photocarcinogenesis. Pterostilbene (Pter) displayed remarkable antioxidant, anti-inflammatory, and anticarcinogenic activities. This study aimed to investigate the effective mechanism of Pter against UVB-induced photodamage in immortalized human keratinocytes. Human keratinocytes were pretreated with Pter (5 and 10 μM) for 24 h prior to UVB irradiation (300 mJ/cm 2 ). Harvested cells were analyzed by MTT, DCFH-DA, comet, western blotting, luciferase promoter, small interference RNA transfection, and quantitative real-time polymerase chain reaction assay. Pter significantly attenuated UVB-induced cell death and reactive oxygen species (ROS) generation, and effectively increased nuclear translocation of NF-E2-related factor-2 (Nrf2), expression of Nrf2-dependent antioxidant enzymes, and DNA repair activity. Moreover, the protective effects of Pter were abolished by small interference RNA-mediated Nrf2 silencing. Furthermore, Pter was also found to induce the phosphorylation of Nrf2 and the known phosphatidylinositol-3-kinase (PI3K) phosphorylated kinase, Akt. The specific inhibitor of PI3K, LY294002, successfully abrogated Pter-induced Nrf2 phosphorylation, activation of Nrf2-antioxidant response element pathway, ROS scavenging ability, and DNA repair activity. The present study indicated that Pter effectively protected against UVB-induced photodamage by increasing endogenous defense mechanisms, scavenging UVB-induced ROS, and aiding in damaged DNA repair through a PI3K-dependent activation of Nrf2/ARE pathway.

Intracellular Trafficking Network of Protein Nanocapsules: Endocytosis, Exocytosis and Autophagy.

PubMed

Zhang, Jinxie; Zhang, Xudong; Liu, Gan; Chang, Danfeng; Liang, Xin; Zhu, Xianbing; Tao, Wei; Mei, Lin

2016-01-01

The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis. In addition to this classic pathway: early endosome (EEs)/late endosome (LEs) to lysosome, we identified two novel transport pathways: micropinocytosis (Rab34 positive)-LEs (Rab7 positive)-lysosome pathway and EEs-liposome (Rab18 positive)-lysosome pathway. Moreover, the cells use slow endocytosis recycling pathway (Rab11 and Rab35 positive vesicles) and GLUT4 exocytosis vesicles (Rab8 and Rab10 positive) transport the protein nanocapsules out of the cells. In addition, protein nanoparticles are observed in autophagosomes, which receive protein nanocapsules through multiple endocytosis vesicles. Using autophagy inhibitor to block these transport pathways could prevent the degradation of nanoparticles through lysosomes. Using Rab proteins as vesicle markers to investigation the detail intracellular trafficking of the protein nanocapsules, will provide new targets to interfere the cellular behaver of the nanoparticles, and improve the therapeutic effect of nanomedicine.

Transcriptional Pathways Altered in Response to Vibration in a Model of Hand-Arm Vibration Syndrome.

PubMed

Waugh, Stacey; Kashon, Michael L; Li, Shengqiao; Miller, Gerome R; Johnson, Claud; Krajnak, Kristine

2016-04-01

The aim of this study was to use an established model of vibration-induced injury to assess frequency-dependent changes in transcript expression in skin, artery, and nerve tissues. Transcript expression in tissues from control and vibration-exposed rats (4 h/day for 10 days at 62.5, 125, or 250 Hz; 49 m/s, rms) was measured. Transcripts affected by vibration were used in bioinformatics analyses to identify molecular- and disease-related pathways associated with exposure to vibration. Analyses revealed that cancer-related pathways showed frequency-dependent changes in activation or inhibition. Most notably, the breast-related cancer-1 pathway was affected. Other pathways associated with breast cancer type 1 susceptibility protein related signaling, or associated with cancer and cell cycle/cell survivability were also affected. Occupational exposure to vibration may result in DNA damage and alterations in cell signaling pathways that have significant effects on cellular division.

Interference of interchromophoric energy-transfer pathways in π-conjugated macrocycles

DOE PAGES

Alfonso Hernandez, Laura; Nelson, Tammie Renee; Gelin, Maxim F.; ...

2016-11-10

The interchromophoric energy-transfer pathways between weakly coupled units in a π-conjugated phenylene–ethynylene macrocycle and its half-ring analogue have been investigated using the nonadiabatic excited-state molecular dynamics approach. To track the flow of electronic transition density between macrocycle units, we formulate a transition density flux analysis adapted from the statistical minimum flow method previously developed to investigate vibrational energy flow. Following photoexcitation, transition density is primarily delocalized on two chromophore units and the system undergoes ultrafast energy transfer, creating a localized excited state on a single unit. In the macrocycle, distinct chromophore units donate transition density to a single acceptor unitmore » but do not interchange transition density among each other. We find that energy transfer in the macrocycle is slower than in the corresponding half ring because of the presence of multiple interfering energy-transfer pathways. Finally, simulation results are validated by modeling the fluorescence anisotropy decay.« less

An ecoimmunological approach to study evolutionary and ancient links between coagulation, complement and Innate immunity

PubMed Central

Kasetty, Gopinath; Alyafei, Saud; Smeds, Emanuel; Salo-Ahen, Outi M. H.; Hansson, Stefan R.; Egesten, Arne; Herwald, Heiko

2018-01-01

ABSTRACT Coagulation, complement, and innate immunity are tightly interwoven and form an alliance that can be traced back to early eukaryotic evolution. Here we employed an ecoimmunological approach using Tissue Factor Pathway Inhibitor (TFPI)-1-derived peptides from the different classes of vertebrates (i.e. fish, reptile, bird, and mammals) and tested whether they can boost killing of various human bacterial pathogens in plasma. We found signs of species-specific conservation and diversification during evolution in these peptides that significantly impact their antibacterial activity. Though all peptides tested executed bactericidal activity in mammalian plasma (with the exception of rodents), no killing was observed in plasma from birds, reptiles, and fish, pointing to a crucial role for the classical pathway of the complement system. We also observed an interference of these peptides with the human intrinsic pathway of coagulation though, unlike complement activation, this mechanism appears not to be evolutionary conserved. PMID:29473457

Review article: mitogen-activated protein kinases in chronic intestinal inflammation - targeting ancient pathways to treat modern diseases.

PubMed

Waetzig, G H; Schreiber, S

2003-07-01

Conventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.

Implication of the host TGFβ pathway in the onset of symbiosis between larvae of the coral Fungia scutaria and the dinoflagellate Symbiodinium sp. (clade C1f)

NASA Astrophysics Data System (ADS)

Berthelier, Jérémy; Schnitzler, Christine E.; Wood-Charlson, Elisha M.; Poole, Angela Z.; Weis, Virginia M.; Detournay, Olivier

2017-12-01

Dinoflagellate-cnidarian associations form both the trophic and structural foundation of coral-reef ecosystems. Previous studies have highlighted the role of host innate immunity in regulation of these partnerships. This study reveals the presence of a transforming growth factor beta (TGFβ) in the coral Fungia scutaria that clusters with TGFβ sensu stricto (ss) from other animals. In functional studies of F. scutaria larvae, we show that (1) TGFβ ss mRNA is expressed during early stages of development prior to the onset of symbiosis; (2) apparent interference of the TGFβ pathway impairs the onset of symbiosis; and (3) this effect is associated with an increase of cytotoxic nitric oxide secretion, an immune response. This work highlights the importance of the TGFβ pathway in early life-history stages of corals by suggesting that its inhibition impacts the onset of symbiosis.

Epigenetic changes in solid and hematopoietic tumors.

PubMed

Toyota, Minoru; Issa, Jean-Pierre J

2005-10-01

There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.

Stress and brain functional changes in patients with Crohn's disease: A functional magnetic resonance imaging study.

PubMed

Agostini, A; Ballotta, D; Righi, S; Moretti, M; Bertani, A; Scarcelli, A; Sartini, A; Ercolani, M; Nichelli, P; Campieri, M; Benuzzi, F

2017-10-01

In Crohn's disease (CD) patients, stress is believed to influence symptoms generation. Stress may act via central nervous system pathways to affect visceral sensitivity and motility thus exacerbating gastrointestinal symptoms. The neural substrate underpinning these mechanisms needs to be investigated in CD. We conducted an explorative functional magnetic resonance imaging (fMRI) study in order to investigate potential differences in the brain stress response in CD patients compared to controls. 17 CD patients and 17 healthy controls underwent a fMRI scan while performing a stressful task consisting in a Stroop color-word interference task designed to induce mental stress in the fMRI environment. Compared to controls, in CD patients the stress task elicited greater blood oxygen level dependent (BOLD) signals in the midcingulate cortex (MCC). The MCC integrate "high" emotional processes with afferent sensory information ascending from the gut. In light of these integrative functions, the stress-evoked MCC hyperactivity in CD patients might represent a plausible neural substrate for the association between stress and symptomatic disease. The MCC dysfunction might be involved in mechanisms of central disinhibition of nociceptive inputs leading to amplify the visceral sensitivity. Finally, the stress-evoked MCC hyperactivity might affect the regulation of intestinal motility resulting in exacerbation of disease symptoms and the autonomic and neuroendocrine regulation of inflammation resulting in enhanced inflammatory activity. © 2017 John Wiley & Sons Ltd.

Ectopic expression of the Drosophila Cdk1 inhibitory kinases, Wee1 and Myt1, interferes with the second mitotic wave and disrupts pattern formation during eye development.

PubMed Central

Price, Donald M; Jin, Zhigang; Rabinovitch, Simon; Campbell, Shelagh D

2002-01-01

Wee1 kinases catalyze inhibitory phosphorylation of the mitotic regulator Cdk1, preventing mitosis during S phase and delaying it in response to DNA damage or developmental signals during G2. Unlike yeast, metazoans have two distinct Wee1-like kinases, a nuclear protein (Wee1) and a cytoplasmic protein (Myt1). We have isolated the genes encoding Drosophila Wee1 and Myt1 and are using genetic approaches to dissect their functions during normal development. Overexpression of Dwee1 or Dmyt1 during eye development generates a rough adult eye phenotype. The phenotype can be modified by altering the gene dosage of known regulators of the G2/M transition, suggesting that we could use these transgenic strains in modifier screens to identify potential regulators of Wee1 and Myt1. To confirm this idea, we tested a collection of deletions for loci that can modify the eye overexpression phenotypes and identified several loci as dominant modifiers. Mutations affecting the Delta/Notch signaling pathway strongly enhance a GMR-Dmyt1 eye phenotype but do not affect a GMR-Dwee1 eye phenotype, suggesting that Myt1 is potentially a downstream target for Notch activity during eye development. We also observed interactions with p53, which suggest that Wee1 and Myt1 activity can block apoptosis. PMID:12072468

Propofol and Sevoflurane Differentially Modulate Cortical Depolarization following Electric Stimulation of the Ventrobasal Thalamus.

PubMed

Kratzer, Stephan; Mattusch, Corinna; Garcia, Paul S; Schmid, Sebastian; Kochs, Eberhard; Rammes, Gerhard; Schneider, Gerhard; Kreuzer, Matthias; Haseneder, Rainer

2017-01-01

The neuronal mechanisms how anesthetics lead to loss of consciousness are unclear. Thalamocortical interactions are crucially involved in conscious perception; hence the thalamocortical network might be a promising target for anesthetic modulation of neuronal information pertaining to arousal and waking behavior. General anesthetics affect the neurophysiology of the thalamus and the cortex but the exact mechanisms of how anesthetics interfere with processing thalamocortical information remain to be elucidated. Here we investigated the effect of the anesthetic agents sevoflurane and propofol on thalamocortical network activity in vitro . We used voltage-sensitive dye imaging techniques to analyze the cortical depolarization in response to stimulation of the thalamic ventrobasal nucleus in brain slices from mice. Exposure to sevoflurane globally decreased cortical depolarization in a dose-dependent manner. Sevoflurane reduced the intensity and extent of cortical depolarization and delayed thalamocortical signal propagation. In contrast, propofol neither affected area nor amplitude of cortical depolarization. However, propofol exposure resulted in regional changes in spatial distribution of maximum fluorescence intensity in deep regions of the cortex. In summary, our experiments revealed substance-specific effects on the thalamocortical network. Functional changes of the neuronal network are known to be pivotally involved in the anesthetic-induced loss of consciousness. Our findings provide further evidence that the mechanisms of anesthetic-mediated loss of consciousness are drug- and pathway-specific.

MYBs affect the variation in the ratio of anthocyanin and flavanol in fruit peel and flesh in response to shade.

PubMed

Lu, Yanfen; Bu, Yufen; Hao, Suxiao; Wang, Yaru; Zhang, Jie; Tian, Ji; Yao, Yuncong

2017-03-01

Fruit pigment accumulation, which represents an important indicator of nutrient quality and appearance value, is often affected by low light under rain, cloud, fog and haze conditions during the veraison period. It is not known whether continuous low light interferes with the production and accumulation of secondary metabolites in veraison fruit. In this paper, we measured pigments and the transcriptional level of genes related to secondary metabolites, i.e., flavonoid biosynthesis in the peel and flesh of Malus crabapple 'Radiant' fruit in response to normal light and shade from 10th July to 30th August. The results showed crosstalk between the flavonoid biosynthetic genes and the involvement of key transcription factors such as McMYB4, McMYB7, McMYB10, and McMYB16 in the regulation of the ratio of anthocyanins and flavanols, which accounted for the different colouration of the fruit peel and flesh under shade conditions. A model is proposed for the regulation of the flavonoid pathway in the peel and flesh of 'Radiant' fruit based on our study results. Moreover, the molecular mechanism for 'Radiant' fruit colouration provides reference information for understanding the light regulatory mechanism involved in the biosynthesis of flavonoids and for designing the next generation of apple breeding. Copyright © 2017 Elsevier B.V. All rights reserved.

Influence of metallic artifact filtering on MEG signals for source localization during interictal epileptiform activity

NASA Astrophysics Data System (ADS)

Migliorelli, Carolina; Alonso, Joan F.; Romero, Sergio; Mañanas, Miguel A.; Nowak, Rafał; Russi, Antonio

2016-04-01

Objective. Medical intractable epilepsy is a common condition that affects 40% of epileptic patients that generally have to undergo resective surgery. Magnetoencephalography (MEG) has been increasingly used to identify the epileptogenic foci through equivalent current dipole (ECD) modeling, one of the most accepted methods to obtain an accurate localization of interictal epileptiform discharges (IEDs). Modeling requires that MEG signals are adequately preprocessed to reduce interferences, a task that has been greatly improved by the use of blind source separation (BSS) methods. MEG recordings are highly sensitive to metallic interferences originated inside the head by implanted intracranial electrodes, dental prosthesis, etc and also coming from external sources such as pacemakers or vagal stimulators. To reduce these artifacts, a BSS-based fully automatic procedure was recently developed and validated, showing an effective reduction of metallic artifacts in simulated and real signals (Migliorelli et al 2015 J. Neural Eng. 12 046001). The main objective of this study was to evaluate its effects in the detection of IEDs and ECD modeling of patients with focal epilepsy and metallic interference. Approach. A comparison between the resulting positions of ECDs was performed: without removing metallic interference; rejecting only channels with large metallic artifacts; and after BSS-based reduction. Measures of dispersion and distance of ECDs were defined to analyze the results. Main results. The relationship between the artifact-to-signal ratio and ECD fitting showed that higher values of metallic interference produced highly scattered dipoles. Results revealed a significant reduction on dispersion using the BSS-based reduction procedure, yielding feasible locations of ECDs in contrast to the other two approaches. Significance. The automatic BSS-based method can be applied to MEG datasets affected by metallic artifacts as a processing step to improve the localization of epileptic foci.

Distinct loci of lexical and semantic access deficits in aphasia: Evidence from voxel-based lesion-symptom mapping and diffusion tensor imaging.

PubMed

Harvey, Denise Y; Schnur, Tatiana T

2015-06-01

Naming pictures and matching words to pictures belonging to the same semantic category negatively affects language production and comprehension. By most accounts, semantic interference arises when accessing lexical representations in naming (e.g., Damian, Vigliocco, & Levelt, 2001) and semantic representations in comprehension (e.g., Forde & Humphreys, 1997). Further, damage to the left inferior frontal gyrus (LIFG), a region implicated in cognitive control, results in increasing semantic interference when items repeat across cycles in both language production and comprehension (Jefferies, Baker, Doran, & Lambon Ralph, 2007). This generates the prediction that the LIFG via white matter connections supports resolution of semantic interference arising from different loci (lexical vs semantic) in the temporal lobe. However, it remains unclear whether the cognitive and neural mechanisms that resolve semantic interference are the same across tasks. Thus, we examined which gray matter structures [using whole brain and region of interest (ROI) approaches] and white matter connections (using deterministic tractography) when damaged impact semantic interference and its increase across cycles when repeatedly producing and understanding words in 15 speakers with varying lexical-semantic deficits from left hemisphere stroke. We found that damage to distinct brain regions, the posterior versus anterior temporal lobe, was associated with semantic interference (collapsed across cycles) in naming and comprehension, respectively. Further, those with LIFG damage compared to those without exhibited marginally larger increases in semantic interference across cycles in naming but not comprehension. Lastly, the inferior fronto-occipital fasciculus, connecting the LIFG with posterior temporal lobe, related to semantic interference in naming, whereas the inferior longitudinal fasciculus (ILF), connecting posterior with anterior temporal regions related to semantic interference in comprehension. These neuroanatomical-behavioral findings have implications for models of the lexical-semantic language network by demonstrating that semantic interference in language production and comprehension involves different representations which differentially recruit a cognitive control mechanism for interference resolution. Copyright © 2015 Elsevier Ltd. All rights reserved.

Powdery mildew suppresses herbivore-induced plant volatiles and interferes with parasitoid attraction in Brassica rapa

USDA-ARS?s Scientific Manuscript database

The co-occurrence of different antagonists on a plant can greatly affect infochemicals with ecological consequences for higher trophic levels. Here we investigated how the presence of a plant pathogen, the powdery mildew Erysiphe cruciferarum, on Brassica rapa affects 1) plant volatiles emitted in r...

How the Ability to Manage Change Affects Leadership Style

ERIC Educational Resources Information Center

Pujol, Kelley

2012-01-01

This study addressed how the ability to manage change affects leadership style. The problem addressed in this project was the natural human tendency to resist change and how the inability to mange this tendency can interfere with the development of leadership skills. The purpose of this dissertation was to investigate how an individual's change…

Anorgasmia in Women

MedlinePlus

... of these areas can affect your ability to orgasm. Physical causes A wide range of illnesses, physical changes and medications can interfere with orgasm: Diseases. Serious illnesses, such as multiple sclerosis and ...

Evidence for a differential interference of noise in sub-lexical and lexical reading routes in healthy participants and dyslexics.

PubMed

Pina Rodrigues, Ana; Rebola, José; Jorge, Helena; Ribeiro, Maria José; Pereira, Marcelino; Castelo-Branco, Miguel; van Asselen, Marieke

The ineffective exclusion of surrounding noise has been proposed to underlie the reading deficits in developmental dyslexia. However, previous studies supporting this hypothesis focused on low-level visual tasks, providing only an indirect link of noise interference on reading processes. In this study, we investigated the effect of noise on regular, irregular, and pseudoword reading in 23 dyslexic children and 26 age- and IQ-matched controls, by applying the white noise displays typically used to validate this theory to a lexical decision task. Reading performance and eye movements were measured. Results showed that white noise did not consistently affect dyslexic readers more than typical readers. Noise affected more dyslexic than typical readers in terms of reading accuracy, but it affected more typical than dyslexic readers in terms of response time and eye movements (number of fixations and regressions). Furthermore, in typical readers, noise affected more the speed of reading of pseudowords than real words. These results suggest a particular impact of noise on the sub-lexical reading route where attention has to be deployed to individual letters. The use of a lexical route would reduce the effect of noise. A differential impact of noise between words and pseudowords may therefore not be evident in dyslexic children if they are not yet proficient in using the lexical route. These findings indicate that the type of reading stimuli and consequent reading strategies play an important role in determining the effects of noise interference in reading processing and should be taken into account by further studies.

Beaked Whale Anatomy, Field Studies and Habitat Modeling

DTIC Science & Technology

2007-11-01

the notion that dual sonar sources interfere constructively to form a sonar beam in front of the animal. This is consistent with how the biosonar ...long been recognized as components of a sophisticated biosonar system. This sonar system has three categorical divisions: the sound generation and... biosonar signals in deep diving animals. These newly described transmission pathways are reminiscent of the configuration that would be seen in a sperm

REPRESSOR OF ULTRAVIOLET-B PHOTOMORPHOGENESIS function allows efficient phototropin mediated ultraviolet-B phototropism in etiolated seedlings.

PubMed

Vanhaelewyn, Lucas; Schumacher, Paolo; Poelman, Dirk; Fankhauser, Christian; Van Der Straeten, Dominique; Vandenbussche, Filip

2016-11-01

Ultraviolet B (UV-B) light is a part of the solar radiation which has significant effects on plant morphology, even at low doses. In Arabidopsis, many of these morphological changes have been attributed to a specific UV-B receptor, UV resistance locus 8 (UVR8). Recent findings showed that next to phototropin regulated phototropism, UVR8 mediated signaling is able of inducing directional bending towards UV-B light in etiolated seedlings of Arabidopsis, in a phototropin independent manner. In this study, kinetic analysis of phototropic bending was used to evaluate the relative contribution of each of these pathways in UV-B mediated phototropism. Diminishing UV-B light intensity favors the importance of phototropins. Molecular and genetic analyses suggest that UV-B is capable of inducing phototropin signaling relying on phototropin kinase activity and regulation of NPH3. Moreover, enhanced UVR8 responses in the UV-B hypersensitive rup1rup2 mutants interferes with the fast phototropin mediated phototropism. Together the data suggest that phototropins are the most important receptors for UV-B induced phototropism in etiolated seedlings, and a RUP mediated negative feedback pathway prevents UVR8 signaling to interfere with the phototropin dependent response. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Quantum interference control of an isolated resonance lifetime in the weak-field limit.

PubMed

García-Vela, A

2015-11-21

Resonance states play an important role in a large variety of physical and chemical processes. Thus, controlling the resonance behavior, and particularly a key property like the resonance lifetime, opens up the possibility of controlling those resonance mediated processes. While such a resonance control is possible by applying strong-field approaches, the development of flexible weak-field control schemes that do not alter significantly the system dynamics still remains a challenge. In this work, one such control scheme within the weak-field regime is proposed for the first time in order to modify the lifetime of an isolated resonance state. The basis of the scheme suggested is quantum interference between two pathways induced by laser fields, that pump wave packet amplitude to the target resonance under control. The simulations reported here show that the scheme allows for both enhancement and quenching of the resonance survival lifetime, being particularly flexible to achieve large lifetime enhancements. Control effects on the resonance lifetime take place only while the pulse is operating. In addition, the conditions required to generate the two interfering quantum pathways are found to be rather easy to meet for general systems, which makes the experimental implementation straightforward and implies the wide applicability of the control scheme.

Wall interference assessment and corrections

NASA Technical Reports Server (NTRS)

Newman, P. A.; Kemp, W. B., Jr.; Garriz, J. A.

1989-01-01

Wind tunnel wall interference assessment and correction (WIAC) concepts, applications, and typical results are discussed in terms of several nonlinear transonic codes and one panel method code developed for and being implemented at NASA-Langley. Contrasts between 2-D and 3-D transonic testing factors which affect WIAC procedures are illustrated using airfoil data from the 0.3 m Transonic Cryogenic Tunnel and Pathfinder 1 data from the National Transonic Facility. Initial results from the 3-D WIAC codes are encouraging; research on and implementation of WIAC concepts continue.

Sedimentation Velocity Analysis of Large Oligomeric Chromatin Complexes Using Interference Detection.

PubMed

Rogge, Ryan A; Hansen, Jeffrey C

2015-01-01

Sedimentation velocity experiments measure the transport of molecules in solution under centrifugal force. Here, we describe a method for monitoring the sedimentation of very large biological molecular assemblies using the interference optical systems of the analytical ultracentrifuge. The mass, partial-specific volume, and shape of macromolecules in solution affect their sedimentation rates as reflected in the sedimentation coefficient. The sedimentation coefficient is obtained by measuring the solute concentration as a function of radial distance during centrifugation. Monitoring the concentration can be accomplished using interference optics, absorbance optics, or the fluorescence detection system, each with inherent advantages. The interference optical system captures data much faster than these other optical systems, allowing for sedimentation velocity analysis of extremely large macromolecular complexes that sediment rapidly at very low rotor speeds. Supramolecular oligomeric complexes produced by self-association of 12-mer chromatin fibers are used to illustrate the advantages of the interference optics. Using interference optics, we show that chromatin fibers self-associate at physiological divalent salt concentrations to form structures that sediment between 10,000 and 350,000S. The method for characterizing chromatin oligomers described in this chapter will be generally useful for characterization of any biological structures that are too large to be studied by the absorbance optical system. © 2015 Elsevier Inc. All rights reserved.

Work-family conflict and sleep disturbance: the Malaysian working women study.

PubMed

Aazami, Sanaz; Mozafari, Mosayeb; Shamsuddin, Khadijah; Akmal, Syaqirah

2016-01-01

This study aimed at assessing effect of the four dimensions of work-family conflicts (strain and time-based work interference into family and family interference into work) on sleep disturbance in Malaysian working women. This cross-sectional study was conducted among 325 Malaysian married working women. Multiple-stage simple random sampling method was used to recruit women from public service departments of Malaysia. Self-administrated questionnaires were used to measure the study variables and data were analyzed using SPSS version 21. We found that high level of the four dimensions of work-family conflicts significantly increase sleep disturbance. Our analyses also revealed an age-dependent effect of the work-family conflict on sleep disturbance. Women in their 20 to 30 yr old suffer from sleep disturbance due to high level of time-based and strain-based work-interference into family. However, the quality of sleep among women aged 30-39 were affected by strain-based family-interference into work. Finally, women older than 40 yr had significantly disturbed sleep due to strain-based work-interference into family as well as time-based family interference into work. Our findings showed that sleep quality of working women might be disturbed by experiencing high level of work-family conflict. However, the effects of inter-role conflicts on sleep varied among different age groups.

Shape and color naming are inherently asymmetrical: Evidence from practice-based interference.

PubMed

Protopapas, Athanassios; Markatou, Artemis; Samaras, Evangelos; Piokos, Andreas

2017-01-01

Stroop interference is characterized by strong asymmetry between word and color naming such that the former is faster and interferes with the latter but not vice versa. This asymmetry is attributed to differential experience with naming in the two dimensions, i.e., words and colors. Here we show that training on visual-verbal paired associate tasks equivalent to color and shape naming, not involving word reading, leads to strongly asymmetric interference patterns. In two experiments adults practiced naming colors and shapes, one dimension more extensively (10days) than the other (2days), depending on group assignment. One experiment used novel shapes (ideograms) and the other familiar geometric shapes, associated with nonsense syllables. In a third experiment participants practiced naming either colors or shapes using cross-category shape and color names, respectively, for 12days. Across experiments, despite equal training of the two groups in naming the two different dimensions, color naming was strongly affected by shape even after extensive practice, whereas shape naming was resistant to interference. To reconcile these findings with theoretical accounts of interference, reading may be conceptualized as involving visual-verbal associations akin to shape naming. An inherent or early-developing advantage for naming shapes may provide an evolutionary substrate for the invention and development of reading. Copyright © 2016 Elsevier B.V. All rights reserved.

Controlling the thermoelectric effect by mechanical manipulation of the electron's quantum phase in atomic junctions.

PubMed

Aiba, Akira; Demir, Firuz; Kaneko, Satoshi; Fujii, Shintaro; Nishino, Tomoaki; Tsukagoshi, Kazuhito; Saffarzadeh, Alireza; Kirczenow, George; Kiguchi, Manabu

2017-08-11

The thermoelectric voltage developed across an atomic metal junction (i.e., a nanostructure in which one or a few atoms connect two metal electrodes) in response to a temperature difference between the electrodes, results from the quantum interference of electrons that pass through the junction multiple times after being scattered by the surrounding defects. Here we report successfully tuning this quantum interference and thus controlling the magnitude and sign of the thermoelectric voltage by applying a mechanical force that deforms the junction. The observed switching of the thermoelectric voltage is reversible and can be cycled many times. Our ab initio and semi-empirical calculations elucidate the detailed mechanism by which the quantum interference is tuned. We show that the applied strain alters the quantum phases of electrons passing through the narrowest part of the junction and hence modifies the electronic quantum interference in the device. Tuning the quantum interference causes the energies of electronic transport resonances to shift, which affects the thermoelectric voltage. These experimental and theoretical studies reveal that Au atomic junctions can be made to exhibit both positive and negative thermoelectric voltages on demand, and demonstrate the importance and tunability of the quantum interference effect in the atomic-scale metal nanostructures.

An Active Immune Defense with a Minimal CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) RNA and without the Cas6 Protein*

PubMed Central

Maier, Lisa-Katharina; Stachler, Aris-Edda; Saunders, Sita J.; Backofen, Rolf; Marchfelder, Anita

2015-01-01

The prokaryotic immune system CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) is a defense system that protects prokaryotes against foreign DNA. The short CRISPR RNAs (crRNAs) are central components of this immune system. In CRISPR-Cas systems type I and III, crRNAs are generated by the endonuclease Cas6. We developed a Cas6b-independent crRNA maturation pathway for the Haloferax type I-B system in vivo that expresses a functional crRNA, which we termed independently generated crRNA (icrRNA). The icrRNA is effective in triggering degradation of an invader plasmid carrying the matching protospacer sequence. The Cas6b-independent maturation of the icrRNA allowed mutation of the repeat sequence without interfering with signals important for Cas6b processing. We generated 23 variants of the icrRNA and analyzed them for activity in the interference reaction. icrRNAs with deletions or mutations of the 3′ handle are still active in triggering an interference reaction. The complete 3′ handle could be removed without loss of activity. However, manipulations of the 5′ handle mostly led to loss of interference activity. Furthermore, we could show that in the presence of an icrRNA a strain without Cas6b (Δcas6b) is still active in interference. PMID:25512373

Glyphosate has limited short-term effects on commensal bacterial community composition in the gut environment due to sufficient aromatic amino acid levels.

PubMed

Nielsen, Lene Nørby; Roager, Henrik M; Casas, Mònica Escolà; Frandsen, Henrik L; Gosewinkel, Ulrich; Bester, Kai; Licht, Tine Rask; Hendriksen, Niels Bohse; Bahl, Martin Iain

2018-02-01

Recently, concerns have been raised that residues of glyphosate-based herbicides may interfere with the homeostasis of the intestinal bacterial community and thereby affect the health of humans or animals. The biochemical pathway for aromatic amino acid synthesis (Shikimate pathway), which is specifically inhibited by glyphosate, is shared by plants and numerous bacterial species. Several in vitro studies have shown that various groups of intestinal bacteria may be differently affected by glyphosate. Here, we present results from an animal exposure trial combining deep 16S rRNA gene sequencing of the bacterial community with liquid chromatography mass spectrometry (LC-MS) based metabolic profiling of aromatic amino acids and their downstream metabolites. We found that glyphosate as well as the commercial formulation Glyfonova ® 450 PLUS administered at up to fifty times the established European Acceptable Daily Intake (ADI = 0.5 mg/kg body weight) had very limited effects on bacterial community composition in Sprague Dawley rats during a two-week exposure trial. The effect of glyphosate on prototrophic bacterial growth was highly dependent on the availability of aromatic amino acids, suggesting that the observed limited effect on bacterial composition was due to the presence of sufficient amounts of aromatic amino acids in the intestinal environment. A strong correlation was observed between intestinal concentrations of glyphosate and intestinal pH, which may partly be explained by an observed reduction in acetic acid produced by the gut bacteria. We conclude that sufficient intestinal levels of aromatic amino acids provided by the diet alleviates the need for bacterial synthesis of aromatic amino acids and thus prevents an antimicrobial effect of glyphosate in vivo. It is however possible that the situation is different in cases of human malnutrition or in production animals. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Comprehensive analysis of pathway or functionally related gene expression in the National Cancer Institute's anticancer screen.

PubMed

Huang, Ruili; Wallqvist, Anders; Covell, David G

2006-03-01

We have analyzed the level of gene coregulation, using gene expression patterns measured across the National Cancer Institute's 60 tumor cell panels (NCI(60)), in the context of predefined pathways or functional categories annotated by KEGG (Kyoto Encyclopedia of Genes and Genomes), BioCarta, and GO (Gene Ontology). Statistical methods were used to evaluate the level of gene expression coherence (coordinated expression) by comparing intra- and interpathway gene-gene correlations. Our results show that gene expression in pathways, or groups of functionally related genes, has a significantly higher level of coherence than that of a randomly selected set of genes. Transcriptional-level gene regulation appears to be on a "need to be" basis, such that pathways comprising genes encoding closely interacting proteins and pathways responsible for vital cellular processes or processes that are related to growth or proliferation, specifically in cancer cells, such as those engaged in genetic information processing, cell cycle, energy metabolism, and nucleotide metabolism, tend to be more modular (lower degree of gene sharing) and to have genes significantly more coherently expressed than most signaling and regular metabolic pathways. Hierarchical clustering of pathways based on their differential gene expression in the NCI(60) further revealed interesting interpathway communications or interactions indicative of a higher level of pathway regulation. The knowledge of the nature of gene expression regulation and biological pathways can be applied to understanding the mechanism by which small drug molecules interfere with biological systems.

31 CFR 0.201 - Political activity.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... (b) Employees may not use their official authority or influence to interfere with or affect election... Bureau of Alcohol, Tobacco and Firearms, Office of Law Enforcement, remain subject to significant...