Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy.

PubMed

Zhu, Bo; Tang, Liming; Chen, Shuyang; Yin, Chengqian; Peng, Shiguang; Li, Xin; Liu, Tongzheng; Liu, Wei; Han, Changpeng; Stawski, Lukasz; Xu, Zhi-Xiang; Zhou, Guangbiao; Chen, Xiang; Gao, Xiumei; Goding, Colin R; Xu, Nan; Cui, Rutao; Cao, Peng

2018-05-22

Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8 + and CD4 + T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.

Nitric Oxide Inhibits Al-Induced Programmed Cell Death in Root Tips of Peanut (Arachis hypogaea L.) by Affecting Physiological Properties of Antioxidants Systems and Cell Wall

PubMed Central

Pan, Chun-Liu; Yao, Shao-Chang; Xiong, Wei-Jiao; Luo, Shu-Zhen; Wang, Ya-Lun; Wang, Ai-Qin; Xiao, Dong; Zhan, Jie; He, Long-Fei

2017-01-01

It has been reported that nitric oxide (NO) is a negative regulator of aluminum (Al)-induced programmed cell death (PCD) in peanut root tips. However, the inhibiting mechanism of NO on Al-induced PCD is unclear. In order to investigate the mechanism by which NO inhibits Al-induced PCD, the effects of co-treatment Al with the exogenous NO donor or the NO-specific scavenger on peanut root tips, the physiological properties of antioxidants systems and cell wall (CW) in root tip cells of NO inhibiting Al-induced PCD were studied with two peanut cultivars. The results showed that Al exposure induced endogenous NO accumulation, and endogenous NO burst increased antioxidant enzyme activity in response to Al stress. The addition of NO donor sodium nitroprusside (SNP) relieved Al-induced root elongation inhibition, cell death and Al adsorption in CW, as well as oxidative damage and ROS accumulation. Furthermore, co-treatment with the exogenous NO donor decreased MDA content, LOX activity and pectin methylesterase (PME) activity, increased xyloglucan endotransglucosylase (XET) activity and relative expression of the xyloglucan endotransglucosylase/hydrolase (XTH-32) gene. Taken together, exogenous NO alleviated Al-induced PCD by inhibiting Al adsorption in CW, enhancing antioxidant defense and reducing peroxidation of membrane lipids, alleviating the inhibition of Al on root elongation by maintaining the extensibility of CW, decreasing PME activity, and increasing XET activity and relative XTH-32 expression of CW. PMID:29311970

Nitric Oxide Inhibits Al-Induced Programmed Cell Death in Root Tips of Peanut (Arachis hypogaea L.) by Affecting Physiological Properties of Antioxidants Systems and Cell Wall.

PubMed

Pan, Chun-Liu; Yao, Shao-Chang; Xiong, Wei-Jiao; Luo, Shu-Zhen; Wang, Ya-Lun; Wang, Ai-Qin; Xiao, Dong; Zhan, Jie; He, Long-Fei

2017-01-01

It has been reported that nitric oxide (NO) is a negative regulator of aluminum (Al)-induced programmed cell death (PCD) in peanut root tips. However, the inhibiting mechanism of NO on Al-induced PCD is unclear. In order to investigate the mechanism by which NO inhibits Al-induced PCD, the effects of co-treatment Al with the exogenous NO donor or the NO-specific scavenger on peanut root tips, the physiological properties of antioxidants systems and cell wall (CW) in root tip cells of NO inhibiting Al-induced PCD were studied with two peanut cultivars. The results showed that Al exposure induced endogenous NO accumulation, and endogenous NO burst increased antioxidant enzyme activity in response to Al stress. The addition of NO donor sodium nitroprusside (SNP) relieved Al-induced root elongation inhibition, cell death and Al adsorption in CW, as well as oxidative damage and ROS accumulation. Furthermore, co-treatment with the exogenous NO donor decreased MDA content, LOX activity and pectin methylesterase (PME) activity, increased xyloglucan endotransglucosylase (XET) activity and relative expression of the xyloglucan endotransglucosylase/hydrolase ( XTH-32 ) gene. Taken together, exogenous NO alleviated Al-induced PCD by inhibiting Al adsorption in CW, enhancing antioxidant defense and reducing peroxidation of membrane lipids, alleviating the inhibition of Al on root elongation by maintaining the extensibility of CW, decreasing PME activity, and increasing XET activity and relative XTH-32 expression of CW.

N2 and P3 modulation during partial inhibition in a modified go/nogo task.

PubMed

Nguyen, An T; Moyle, Jonson J; Fox, Allison M

2016-09-01

The neural response following the partial inhibition of responses can provide insight into the processes underlying response inhibition. We examined the N2 and P3 on trials where participants correctly responded to go stimuli, successfully inhibited their response to nogo stimuli, and nogo trials where they initiated but did not complete their response (partial inhibitions) in an adult sample (N=24, M(age)=21.17, SD(age)=3.52). An enhanced and delayed N2 was observed on partially inhibited compared to successfully inhibited nogo trials. Further analysis showed that this modulation was error-related. An enhanced central P3 was observed following successful inhibitions compared to correct go trials, but not following partial inhibitions. The results suggest that the central P3 enhancement is specific to the complete and successful inhibition of responses. Therefore, the absence of a central P3 on partial inhibitions could reflect insufficient inhibition or a monitored failure in inhibiting the response. Although, our findings provide support for the role of P3 in response inhibition, it raises questions about the processes involved in the subsequent inhibition or correction of the erroneous response. Further research examining the neural response following both partial and unsuccessful inhibitions could provide insight regarding these processes. Copyright © 2016 Elsevier B.V. All rights reserved.

Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells.

PubMed

Chen, Guokai; Hou, Zhonggang; Gulbranson, Daniel R; Thomson, James A

2010-08-06

Human ESCs are the pluripotent precursor of the three embryonic germ layers. Human ESCs exhibit basal-apical polarity, junctional complexes, integrin-dependent matrix adhesion, and E-cadherin-dependent cell-cell adhesion, all characteristics shared by the epiblast epithelium of the intact mammalian embryo. After disruption of epithelial structures, programmed cell death is commonly observed. If individualized human ESCs are prevented from reattaching and forming colonies, their viability is significantly reduced. Here, we show that actin-myosin contraction is a critical effector of the cell death response to human ESC dissociation. Inhibition of myosin heavy chain ATPase, downregulation of myosin heavy chain, and downregulation of myosin light chain all increase survival and cloning efficiency of individualized human ESCs. ROCK inhibition decreases phosphorylation of myosin light chain, suggesting that inhibition of actin-myosin contraction is also the mechanism through which ROCK inhibitors increase cloning efficiency of human ESCs. Copyright 2010 Elsevier Inc. All rights reserved.

Semantic processing and response inhibition.

PubMed

Chiang, Hsueh-Sheng; Motes, Michael A; Mudar, Raksha A; Rao, Neena K; Mansinghani, Sethesh; Brier, Matthew R; Maguire, Mandy J; Kraut, Michael A; Hart, John

2013-11-13

The present study examined functional MRI (fMRI) BOLD signal changes in response to object categorization during response selection and inhibition. Young adults (N=16) completed a Go/NoGo task with varying object categorization requirements while fMRI data were recorded. Response inhibition elicited increased signal change in various brain regions, including medial frontal areas, compared with response selection. BOLD signal in an area within the right angular gyrus was increased when higher-order categorization was mandated. In addition, signal change during response inhibition varied with categorization requirements in the left inferior temporal gyrus (lIT). lIT-mediated response inhibition when inhibiting the response only required lower-order categorization, but lIT mediated both response selection and inhibition when selecting and inhibiting the response required higher-order categorization. The findings characterized mechanisms mediating response inhibition associated with semantic object categorization in the 'what' visual object memory system.

Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence

PubMed Central

Cunningham, Cameron R.; Champhekar, Ameya; Tullius, Michael V.; Dillon, Barbara Jane; Zhen, Anjie; de la Fuente, Justin Rafael; Herskovitz, Jonathan; Elsaesser, Heidi; Snell, Laura M.; Wilson, Elizabeth B.; de la Torre, Juan Carlos; Kitchen, Scott G.; Horwitz, Marcus A.; Bensinger, Steven J.; Smale, Stephen T.; Brooks, David G.

2016-01-01

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections. PMID:26808628

Inhibition of Transforming Growth Factor-Beta1 SignalingAttenuates Ataxia Telangiectasia Mutated Activity in Response toGenotoxic Stress

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

Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose

2006-01-01

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor {beta} (TGF{beta})-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}I null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced H2AX radiation-induced foci; and increased radiosensitivity compared with TGF{beta} competent cells.more » We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf{beta}I, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF{beta} may be used to advantage in cancer therapy.« less

BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Prevents Experimental Autoimmune Encephalomyelitis Disease Progression

PubMed Central

Timilshina, Maheshwor; Kang, Youra; Dahal, Ishmit; You, Zhiwei; Nam, Tae-gyu; Kim, Keuk-Jun

2017-01-01

CD4+ T cells are essential in inflammation and autoimmune diseases. Interferon-γ (IFN-γ) secreting T helper (Th1) and IL-17 secreting T helper (Th17) cells are critical for several autoimmune diseases. To assess the inhibitory effect of a given compound on autoimmune disease, we screened many compounds with an in vitro Th differentiation assay. BJ-3105, a 6-alkoxypyridin-3-ol analog, inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells which were activated by T cell receptor (TCR) engagement. BJ-3105 ameliorated the experimental autoimmune encephalomyelitis (EAE) model by reducing Th1 and Th17 generation. Notably, Th cell differentiation was significantly suppressed by BJ-3105 treatment without inhibiting in vitro proliferation of T cells or inducing programmed cell death. Mechanistically, BJ-3105 inhibited the phosphorylation of JAK and its downstream signal transducer and activator of transcription (STAT) that is critical for Th differentiation. These results demonstrated that BJ-3105 inhibits the phosphorylation of STAT in response to cytokine signals and subsequently suppressed the differentiation of Th cell responses. PMID:28095433

Effects of aging on action-intentional programming.

PubMed

Shoraka, Ali R; Otzel, Dana M; M Zilli, Eduardo; Finney, Glen R; Doty, Leilani; Falchook, Adam D; Heilman, Kenneth M

2018-03-01

Action-intentional programs control "when" we initiate, inhibit, continue, and stop motor actions. The purpose of this study was to learn if there are changes in the action-intentional system with healthy aging, and if these changes are asymmetrical (right versus left upper limb) or related to impaired interhemispheric communication. We administered tests of action-intention to 41 middle-aged and older adults (61.9 ± 12.3 years). Regression analyses revealed that older age predicted a decrement in performance for tests of crossed motor response inhibition as well as slower motor initiation with the left hand. Changes in action-intention with aging appear to be related to alterations of interhemispheric communication and/or age-related right hemisphere dysfunction; however, further research is needed to identify the mechanisms for age-related changes in the brain networks that mediate action-intention.

Reinforcement and Stimulant Medication Ameliorate Deficient Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Rosch, Keri S; Fosco, Whitney D; Pelham, William E; Waxmonsky, James G; Bubnik, Michelle G; Hawk, Larry W

2016-02-01

This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions.

Reinforcement and stimulant medication ameliorate deficient response inhibition in children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Rosch, Keri S.; Fosco, Whitney D.; Pelham, William E.; Waxmonsky, James G.; Bubnik, Michelle G.; Hawk, Larry W.

2015-01-01

This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n=111, 25 girls) and typically-developing (TD) controls (n=33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

[Programmed necrosis mediated by receptor-interacting protein 3: a new target for liver disease research].

PubMed

Zhang, J; Jing, Y; Li, Y N; Zhou, L; Wang, B M

2016-09-20

Hepatocyte death mainly includes apoptosis and necrosis and is a critical process in the pathophysiological mechanism of liver injury caused by various reasons. Recent studies have shown that key regulatory molecules in the inhibition of apoptosis such as caspase cannot be used as targets for inhibiting disease progression in clinical practice. In recent years, programmed necrosis mediated by receptor-interacting protein 3(RIP3)becomes a new hot research topic. It not only plays an important role in inducing inflammatory response, but also is closely regulated by intracellular signal factors, and it is a type of active cell death which can be interfered with. Compared with apoptosis, programmed necrosis is accompanied by the release of various inflammatory factors, which significantly affects local immune microenvironment. RIP3-mediated programmed necrosis has been taken seriously in many diseases. Although its mechanism of action in liver disease remains unclear, the results of recent studies confirmed its important role in the development of liver disease. This article reviews the research advances in the role of RIP3-mediated programmed necrosis signaling pathway in liver disease of various causes and investigates the possibility of RIP3-mediated programmed necrosis as a new target in the treatment of liver disease.

ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis.

PubMed

Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi; Phillips, Naomi G; Sonntag, Tim; Hao, Ergeng; Lee, Soon; Hai, Tsonwin; Montminy, Marc

2015-03-03

Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross-coupling between stress and hormone-sensitive pathways.

Nonspecific Inhibition of the Motor System during Response Preparation

PubMed Central

Sias, Ana; Labruna, Ludovica; Ivry, Richard B.

2015-01-01

Motor system excitability is transiently inhibited during the preparation of responses. Previous studies have attributed this inhibition to the operation of two mechanisms, one hypothesized to help resolve competition between alternative response options, and the other to prevent premature response initiation. By this view, inhibition should be restricted to task-relevant muscles. Although this prediction is supported in one previous study (Duque et al., 2010), studies of stopping ongoing actions suggest that some forms of motor inhibition may be widespread (Badry et al., 2009). This motivated us to conduct a series of transcranial magnetic stimulation (TMS) experiments to examine in detail the specificity of preparatory inhibition in humans. Motor-evoked potentials were inhibited in task-irrelevant muscles during response preparation, even when the muscles were contralateral and not homologous to the responding effector. Inhibition was also observed in both choice and simple response task conditions, with and without a preparatory interval. Control experiments ruled out that this inhibition is due to expectancy of TMS or a possible need to cancel the prepared response. These findings suggest that motor inhibition during response preparation broadly influences the motor system and likely reflects a process that occurs whenever a response is selected. We propose a reinterpretation of the functional significance of preparatory inhibition, one by which inhibition reduces noise to enhance signal processing and modulates the gain of a selected response. SIGNIFICANCE STATEMENT Motor preparation entails the recruitment of excitatory and inhibitory neural mechanisms. The current experiments address the specificity of inhibitory mechanisms, asking whether preparatory inhibition affects task-irrelevant muscles. Participants prepared a finger movement to be executed at the end of a short delay period. Transcranial magnetic stimulation over primary motor cortex provided an assay of corticospinal excitability. Consistent with earlier work, the agonist muscle for the forthcoming response was inhibited during the preparatory period. Moreover, this inhibition was evident in task-irrelevant muscles, although the magnitude of inhibition depended on whether the response was fixed or involved a choice. These results implicate a broadly tuned inhibitory mechanism that facilitates response preparation, perhaps by lowering background activity before response initiation. PMID:26224853

Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells.

PubMed

Coombs, Melanie R Power; Harrison, Megan E; Hoskin, David W

2016-10-01

Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells. IFN-β-induced expression of PD-L1 by MDA-MB-468 cells was also inhibited by apigenin. In addition, luteolin, the major metabolite of apigenin, inhibited IFN-γ-induced PD-L1 expression by MDA-MB-468 cells. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 and 4T1 cells was associated with reduced phosphorylation of STAT1, which was early and transient at Tyr701 and sustained at Ser727. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 cells also increased proliferation and interleukin-2 synthesis by PD-1-expressing Jurkat T cells that were co-cultured with MDA-MB-468 cells. Apigenin therefore has the potential to increase the vulnerability of BC cells to T cell-mediated anti-tumor immune responses. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates.

PubMed

Quetscher, Clara; Yildiz, Ali; Dharmadhikari, Shalmali; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Dydak, Ulrike; Beste, Christian

2015-11-01

Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans.

Heavy drinking is associated with deficient response inhibition in women but not in men.

PubMed

Nederkoorn, Chantal; Baltus, Marcus; Guerrieri, Ramona; Wiers, Reinout W

2009-09-01

Poor response inhibition has been associated with a wide range of problem behaviours, including addictive behaviours, and could represent a general vulnerability factor. Standard tests of response inhibition have used neutral stimuli. Here we tested whether a deficit in response inhibition in heavy drinkers would be stronger for stimuli related to their problem (alcohol) or not. Response inhibition was assessed with a stop signal task, using four classes of pictures: alcohol-related, soft drinks, erotic (control appetitive categories) and neutral pictures. Participants were 32 heavy and 32 light drinkers. An equal amount of men and women were tested in both drinking groups, in view of recent studies reporting that response disinhibition may be most pronounced in heavy drinking women. Main results were first that no domain-specific differences in response inhibition were found in both groups. Second, heavy drinking females showed stronger response inhibition deficits than other groups. Results are discussed in light of a possible gender difference in response inhibition as a risk factor for addictive behaviours.

Intelligent Therapeutics and Metabolic Programming Through Tailormade, Ligand-Controlled RNA Switches

DTIC Science & Technology

2007-02-05

lines. Three regulatory mechanisms have been examined in our laboratory: antisense inhibition, ribozyme cleavage, and RNA interference (RNAi...cell lines. However, the latter two regulatory mechanisms, ribozyme -based inactivation and RNAi-mediated silencing, demonstrated significant activity...in these cell lines as is briefly described below. Microswitches responsive to the small molecule theophylline and targeting GFP based on a ribozyme

Inhibited Shaped Charge Launcher Testing of Spacecraft Shield Designs

NASA Technical Reports Server (NTRS)

Grosch, Donald J.

1996-01-01

This report describes a test program in which several orbital debris shield designs were impact tested using the inhibited shaped charge launcher facility at Southwest Research Institute. This facility enables researchers to study the impact of one-gram aluminum projectiles on various shielding designs at velocities above 11 km/s. A total of twenty tests were conducted on targets provided by NASA-MSFC. This report discusses in detail the shield design, the projectile parameters and the test configuration used for each test. A brief discussion of the target damage is provided, as the detailed analysis of the target response will be done by NASA-MSFC.

Genetic separation of phototropism from blue light inhibition of hypocotyl elongation on Arabidopsis

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

Liscum, E.; Young, J.C.; Hangarter, R.P.

1991-05-01

Phototropism and inhibition of stem elongation occur in response to blue light-induced inhibition of cell elongation. However, phototropism is a low fluence response and inhibition of hypocotyl elongation is a high irradiance response. The authors have isolated several mutant lines of Arabidopsis which lack blue light-induced inhibition of hypocotyl elongation but retain normal phototropic functions. In addition, a mutant line which completely lacks the phototropic response retains normal blue light-induced inhibition of hypocotyl elongation. F1 progeny of crosses between these two mutant classes exhibited wild-type phototropism and inhibition of hypocotyl elongation in response to blue light stimuli. In the F2more » generation, one in sixteen seedlings were double mutants lacking both phototropism and blue light-induced hypocotyl growth inhibition. These studies conclusively show that blue light-induced phototropism and hypocotyl growth inhibition function through genetically distinct signal transduction or response systems.« less

Concurrent information affects response inhibition processes via the modulation of theta oscillations in cognitive control networks.

PubMed

Chmielewski, Witold X; Mückschel, Moritz; Dippel, Gabriel; Beste, Christian

2016-11-01

Inhibiting responses is a challenge, where the outcome (partly) depends on the situational context. In everyday situations, response inhibition performance might be altered when irrelevant input is presented simultaneously with the information relevant for response inhibition. More specifically, irrelevant concurrent information may either brace or interfere with response-relevant information, depending on whether these inputs are redundant or conflicting. The aim of this study is to investigate neurophysiological mechanisms and the network underlying such modulations using EEG beamforming as method. The results show that in comparison to a baseline condition without concurrent information, response inhibition performance can be aggravated or facilitated by manipulating the extent of conflict via concurrent input. This depends on whether the requirement for cognitive control is high, as in conflicting trials, or whether it is low, as in redundant trials. In line with this, the total theta frequency power decreases in a right hemispheric orbitofrontal response inhibition network including the SFG, MFG, and SMA, when concurrent redundant information facilitates response inhibition processes. Vice versa, theta activity in a left-hemispheric response inhibition network (i.e., SFG, MFG, and IFG) increases, when conflicting concurrent information compromises response inhibition processes. We conclude that concurrent information bi-directionally shifts response inhibition performance and modulates the network architecture underlying theta oscillations which are signaling different levels of the need for cognitive control.

Contingent involuntary motoric inhibition: the involuntary inhibition of a motor response contingent on top-down goals.

PubMed

Anderson, Brian A; Folk, Charles L

2012-12-01

Effective motor control involves both the execution of appropriate responses and the inhibition of inappropriate responses that are evoked by response-associated stimuli. The inhibition of a motor response has traditionally been characterized as either a voluntary act of cognitive control or a low-level perceptual bias arising from processes such as inhibition of return and priming. Involuntary effects of top-down goals on motoric inhibition have been reported, but involve the perseveration of an inhibitory strategy. It is unknown whether the inhibition of a motor response can be selectively triggered by a goal-relevant stimulus, reflecting the automatic activation of a top-down inhibitory strategy. Here we show that irrelevant flankers that share the color of a no-go target elicit the inhibition of their associated motor response while other-colored flankers do not, even when participants have sufficient time to prepare for the upcoming target while ignoring the flankers. Our results demonstrate contingent involuntary motoric inhibition: motoric inhibition can be automatically triggered by a stimulus based on top-down goals.

ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis

PubMed Central

Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi; Phillips, Naomi G.; Sonntag, Tim; Hao, Ergeng; Lee, Soon; Hai, Tsonwin; Montminy, Marc

2015-01-01

Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross-coupling between stress and hormone-sensitive pathways. PMID:25730876

The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression.

PubMed

Chen, Miao-Fen; Chen, Ping-Tsung; Chen, Wen-Cheng; Lu, Ming-Shian; Lin, Paul-Yang; Lee, Kuan Der

2016-02-16

The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival.As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.

Development of a therapeutic vaccine for the treatment of cocaine addiction.

PubMed

Fox, B S

1997-12-15

No pharmacotherapies have yet been approved for the treatment of cocaine addiction. One new approach is to block the effects of cocaine with anti-cocaine antibodies induced by a therapeutic cocaine vaccine. A cocaine vaccine has been developed which induces a cocaine-specific antibody response in rodents. The antibody binds to cocaine in the circulation and can be shown to inhibit the ability of cocaine to enter the brain. Furthermore, anti-cocaine antibody can inhibit cocaine self-administration in rats. These data suggest that a cocaine vaccine may be a powerful therapeutic tool. The intent is to immunized motivated patients with the vaccine as part of a comprehensive treatment program. If the patient uses cocaine after being vaccinated, the antibody will inhibit the reinforcing activity of cocaine and decrease the likelihood of relapse.

Inhibition in Autism: Children with Autism Have Difficulty Inhibiting Irrelevant Distractors but Not Prepotent Responses

ERIC Educational Resources Information Center

Adams, Nena C.; Jarrold, Christopher

2012-01-01

Resistance to distractor inhibition tasks have previously revealed impairments in children with autism. However, on the classic Stroop task and other prepotent response tasks, children with autism show intact inhibition. These data may reflect a distinction between prepotent response and resistance to distractor inhibition. The current study…

Influence of supraliminal reward information on unconsciously triggered response inhibition.

PubMed

Diao, Liuting; Ding, Cody; Qi, Senqing; Zeng, Qinghong; Huang, Bo; Xu, Mengsi; Fan, Lingxia; Yang, Dong

2014-01-01

Although executive functions (e.g., response inhibition) are often thought to interact consciously with reward, recent studies have demonstrated that they can also be triggered by unconscious stimuli. Further research has suggested a close relationship between consciously and unconsciously triggered response inhibition. To date, however, the effect of reward on unconsciously triggered response inhibition has not been explored. To address this issue, participants in this study performed runs of a modified Go/No-Go task during which they were exposed to both high and low value monetary rewards presented both supraliminally and subliminally. Participants were informed that they would earn the reward displayed if they responded correctly to each trial of the run. According to the results, when rewards were presented supraliminally, a greater unconsciously triggered response inhibition was observed for high-value rewards than for low-value rewards. In contrast, when rewards were presented subliminally, no enhanced unconsciously triggered response inhibition was observed. Results revealed that supraliminal and subliminal rewards have distinct effects on unconsciously triggered response inhibition. These findings have important implications for extending our understanding of the relationship between reward and response inhibition.

Influence of Supraliminal Reward Information on Unconsciously Triggered Response Inhibition

PubMed Central

Diao, Liuting; Ding, Cody; Qi, Senqing; Zeng, Qinghong; Huang, Bo; Xu, Mengsi; Fan, Lingxia; Yang, Dong

2014-01-01

Although executive functions (e.g., response inhibition) are often thought to interact consciously with reward, recent studies have demonstrated that they can also be triggered by unconscious stimuli. Further research has suggested a close relationship between consciously and unconsciously triggered response inhibition. To date, however, the effect of reward on unconsciously triggered response inhibition has not been explored. To address this issue, participants in this study performed runs of a modified Go/No-Go task during which they were exposed to both high and low value monetary rewards presented both supraliminally and subliminally. Participants were informed that they would earn the reward displayed if they responded correctly to each trial of the run. According to the results, when rewards were presented supraliminally, a greater unconsciously triggered response inhibition was observed for high-value rewards than for low-value rewards. In contrast, when rewards were presented subliminally, no enhanced unconsciously triggered response inhibition was observed. Results revealed that supraliminal and subliminal rewards have distinct effects on unconsciously triggered response inhibition. These findings have important implications for extending our understanding of the relationship between reward and response inhibition. PMID:25268227

Global Precipitation Measurement (GPM) Safety Inhibit Timeline Tool

NASA Technical Reports Server (NTRS)

Dion, Shirley

2012-01-01

The Global Precipitation Measurement (GPM) Observatory is a joint mission under the partnership by National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA), Japan. The NASA Goddard Space Flight Center (GSFC) has the lead management responsibility for NASA on GPM. The GPM program will measure precipitation on a global basis with sufficient quality, Earth coverage, and sampling to improve prediction of the Earth's climate, weather, and specific components of the global water cycle. As part of the development process, NASA built the spacecraft (built in-house at GSFC) and provided one instrument (GPM Microwave Imager (GMI) developed by Ball Aerospace) JAXA provided the launch vehicle (H2-A by MHI) and provided one instrument (Dual-Frequency Precipitation Radar (DPR) developed by NTSpace). Each instrument developer provided a safety assessment which was incorporated into the NASA GPM Safety Hazard Assessment. Inhibit design was reviewed for hazardous subsystems which included the High Gain Antenna System (HGAS) deployment, solar array deployment, transmitter turn on, propulsion system release, GMI deployment, and DPR radar turn on. The safety inhibits for these listed hazards are controlled by software. GPM developed a "pathfinder" approach for reviewing software that controls the electrical inhibits. This is one of the first GSFC in-house programs that extensively used software controls. The GPM safety team developed a methodology to document software safety as part of the standard hazard report. As part of this process a new tool "safety inhibit time line" was created for management of inhibits and their controls during spacecraft buildup and testing during 1& Tat GSFC and at the Range in Japan. In addition to understanding inhibits and controls during 1& T the tool allows the safety analyst to better communicate with others the changes in inhibit states with each phase of hardware and software testing. The tool was very useful for communicating compliance with safety requirements especially when working with a foreign partner.

Dissociating interference-control processes between memory and response.

PubMed

Bissett, Patrick G; Nee, Derek Evan; Jonides, John

2009-09-01

The ability to mitigate interference is of central importance to cognition. Previous research has provided conflicting accounts about whether operations that resolve interference are singular in character or form a family of functions. Here, the authors examined the relationship between interference-resolution processes acting on working memory representations versus responses. The authors combined multiple forms of interference into a single paradigm by merging a directed-forgetting task, which induces proactive interference, with a stop-signal task, which taps response inhibition processes. The results demonstrated that proactive interference and response inhibition produced distinct behavioral signatures that did not interact. By contrast, combining two different measures of response inhibition by merging a go/no-go task variant and a stop signal produced overadditive behavioral interference, demonstrating that different forms of response inhibition tap the same processes. However, not all forms of response conflict interacted, suggesting that inhibition-related functions acting on response selection are dissociable from those acting on response inhibition. These results suggest that inhibition-related functions for memory and responses are dissociable. (c) 2009 APA, all rights reserved.

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

PubMed

Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping; Urban, Daniel J; White, Kate L; Giguere, Patrick M; Doak, Allison K; Bernstein, Alison I; Stout, Kristen A; Park, Su Mi; Rodriguiz, Ramona M; Gray, Bradley W; Hyatt, William S; Norwood, Andrew P; Webster, Kevin A; Gannon, Brenda M; Miller, Gary W; Porter, Joseph H; Shoichet, Brian K; Fantegrossi, William E; Wetsel, William C; Roth, Bryan L

2016-01-01

The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

Immune mediated colitis caused by lung cancer treatment with atezolizumab.

PubMed

González Vázquez, Santiago; de la Riva Onandía, Susana; Echeveste, José Ignacio; Muñoz Navas, Miguel

2017-12-01

Atezolizumab is an IgG1 isotype monoclonal antibody against the protein programmed cell death-ligand 1 (PD- L1). PD-L1 may be highly expressed in some tumors and is believed to inhibit immune cells that recognize and attack tumor cells. Inhibition of PD-L1 can remove its inhibitory effect and provoke an anti-tumor response. In October 2016, the Food and Drugs Administration (FDA) approved atezolizumab for the treatment of patients with metastatic non-small cell lung cancer after disease progression during or following platinum based chemotherapy. We present the case of a 43-year-old male with stage IV lung adenocarcinoma in progression, despite standard chemotherapy.

Inhibition by Agrobacterium tumefaciens and Pseudomonas savastanoi of development of the hypersensitive response elicited by Pseudomonas syringae pv. phaseolicola.

PubMed Central

Robinette, D; Matthysse, A G

1990-01-01

Injection into tobacco leaves of biotype 1 Agrobacterium tumefaciens or of Pseudomonas savastanoi inhibited the development of a visible hypersensitive response to the subsequent injection at the same site of Pseudomonas syringae pv. phaseolicola. This interference with the hypersensitive response was not seen with injection of bacterial growth medium or Escherichia coli cells. Live A. tumefaciens cells were required for the inhibitory effect. Various mutants and strains of A. tumefaciens were examined to determine the genes involved. Known chromosomal mutations generally had no effect on the ability of A. tumefaciens to inhibit the hypersensitive response, except for chvB mutants which showed a reduced (but still significant) inhibition of the hypersensitive response. Ti plasmid genes appeared to be required for the inhibition of the hypersensitive response. The bacteria did not need to be virulent in order to inhibit the hypersensitive response. Deletion of the vir region from pTi had no effect on the inhibition. However, the T region of the Ti plasmid was required for inhibition. Studies of transposon mutants suggested that the tms but not tmr or ocs genes were required. These genes were not acting after transfer to plant cells since they were effective in strains lacking vir genes and thus unable to transfer DNA to plant cells. The results suggest that the expression of the tms genes in the bacteria may inhibit the development of the hypersensitive response by the plant. An examination of the genes required in P. savastanoi for the inhibition of the hypersensitive response suggested that bacterial production of auxin was also required for the inhibition of the hypersensitive response by these bacteria. Images PMID:2211508

On the dependence of response inhibition processes on sensory modality.

PubMed

Bodmer, Benjamin; Beste, Christian

2017-04-01

The ability to inhibit responses is a central sensorimotor function but only recently the importance of sensory processes for motor inhibition mechanisms went more into the research focus. In this regard it is elusive, whether there are differences between sensory modalities to trigger response inhibition processes. Due to functional neuroanatomical considerations strong differences may exist, for example, between the visual and the tactile modality. In the current study we examine what neurophysiological mechanisms as well as functional neuroanatomical networks are modulated during response inhibition. Therefore, a Go/NoGo-paradigm employing a novel combination of visual, tactile, and visuotactile stimuli was used. The data show that the tactile modality is more powerful than the visual modality to trigger response inhibition processes. However, the tactile modality loses its efficacy to trigger response inhibition processes when being combined with the visual modality. This may be due to competitive mechanisms leading to a suppression of certain sensory stimuli and the response selection level. Variations in sensory modalities specifically affected conflict monitoring processes during response inhibition by modulating activity in a frontal parietal network including the right inferior frontal gyrus, anterior cingulate cortex and the temporoparietal junction. Attentional selection processes are not modulated. The results suggest that the functional neuroanatomical networks involved in response inhibition critically depends on the nature of the sensory input. Hum Brain Mapp 38:1941-1951, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

STIR: Assessing and Training Response Inhibition Abilities

DTIC Science & Technology

2014-07-30

Oct-2013 30-Jun-2014 Approved for Public Release; Distribution Unlimited Final Report: STIR: Assessing and Training Response Inhibition Abilities The...Office P.O. Box 12211 Research Triangle Park, NC 27709-2211 Civilian casualties, response inhibition, cognitive training REPORT DOCUMENTATION PAGE...Assessing and Training Response Inhibition Abilities Report Title Shooting a firearm involves a complex series of actions, and each action depends on a

Withholding and canceling a response in ADHD adolescents

PubMed Central

Bhaijiwala, Mehereen; Chevrier, Andre; Schachar, Russell

2014-01-01

Background Deficient response inhibition in situations involving a trade-off between response execution and response stopping is a hallmark of attention deficit hyperactive disorder (ADHD). There are two key components of response inhibition; reactive inhibition where one attempts to cancel an ongoing response and prospective inhibition is when one withholds a response pending a signal to stop. Prospective inhibition comes into play prior to the presentation of the stop signal and reactive inhibition follows the presentation of a signal to stop a particular action. The aim of this study is to investigate the neural activity evoked by prospective and reactive inhibition in adolescents with and without ADHD. Methods Twelve adolescents with ADHD and 12 age-matched healthy controls (age range 9–18) were imaged while performing the stop signal task (SST). Results Reactive inhibition activated right inferior frontal gyrus (IFG) in both groups. ADHD subjects activated IFG bilaterally. In controls, prospective inhibition invoked preactivation of the same part of right IFG that activated during reactive inhibition. In ADHD subjects, prospective inhibition was associated with deactivation in this region. Controls also deactivated the medial prefrontal cortex (MPFC) during prospective inhibition, whereas ADHD subjects activated the same area. Discussion This pattern of activity changes in the same structures, but in opposite directions, was also evident across all phases of the task in various task-specific areas like the superior and middle temporal gyrus and other frontal areas. Conclusion Differences between ADHD and control participants in task-specific and default mode structures (IFG and MPFC) were evident during prospective, but not during reactive inhibition. PMID:25328838

Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors

PubMed Central

Zhong, Bo; Chennamaneni, Snigdha; Lama, Rati; Yi, Xin; Geldenhuys, Werner J.; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

2013-01-01

Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development. PMID:23767669

Response inhibition predicts poor antidepressant treatment response in very old depressed patients.

PubMed

Sneed, Joel R; Roose, Steven P; Keilp, John G; Krishnan, K Ranga Rama; Alexopoulos, George S; Sackeim, Harold A

2007-07-01

There have been mixed findings regarding the prognostic significance of age of onset, executive dysfunction, and hyperintensity burden on treatment outcome in late-life depression. Growth curve models were fit to data from the only 8-week, double-blind, placebo controlled trial of citalopram (20-40 mg/day) in patients aged 75 years and older with unipolar depression. Baseline assessment included Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (to determine age at onset), Stroop Color-Word Test (to assess the response inhibition component of execution dysfunction), and structural magnetic resonance imaging (to determine hyperintensity burden). In the citalopram condition, patients with response inhibition (most impaired quartile) scored higher at endpoint than those without response inhibition. There were no effects for age of onset or hyperintensity load on response in the citalopram condition. In the placebo condition, patients with early-onset depression had higher depression scores at endpoint than patients with late-onset depression. Only response inhibition, a fundamental executive function, predicted poor treatment response to antidepressant medication. Although patients with response inhibition also showed deficits in reaction time, adjusting for reaction time in our final response inhibition model did not substantively change the findings.

Response mode-dependent differences in neurofunctional networks during response inhibition: an EEG-beamforming study.

PubMed

Dippel, Gabriel; Chmielewski, Witold; Mückschel, Moritz; Beste, Christian

2016-11-01

Response inhibition processes are one of the most important executive control functions and have been subject to intense research in cognitive neuroscience. However, knowledge on the neurophysiology and functional neuroanatomy on response inhibition is biased because studies usually employ experimental paradigms (e.g., sustained attention to response task, SART) in which behavior is susceptible to impulsive errors. Here, we investigate whether there are differences in neurophysiological mechanisms and networks depending on the response mode that predominates behavior in a response inhibition task. We do so comparing a SART with a traditionally formatted task paradigm. We use EEG-beamforming in two tasks inducing opposite response modes during action selection. We focus on theta frequency modulations, since these are implicated in cognitive control processes. The results show that a response mode that is susceptible to impulsive errors (response mode used in the SART) is associated with stronger theta band activity in the left temporo-parietal junction. The results suggest that the response modes applied during response inhibition differ in the encoding of surprise signals, or related processes of attentional sampling. Response modes during response inhibition seem to differ in processes necessary to update task representations relevant to behavioral control.

Impairment of manual but not saccadic response inhibition following acute alcohol intoxication.

PubMed

Campbell, Anne Eileen; Chambers, Christopher D; Allen, Christopher P G; Hedge, Craig; Sumner, Petroc

2017-12-01

Alcohol impairs response inhibition; however, it remains contested whether such impairments affect a general inhibition system, or whether affected inhibition systems are embedded in, and specific to, each response modality. Further, alcohol-induced impairments have not been disambiguated between proactive and reactive inhibition mechanisms, and nor have the contributions of action-updating impairments to behavioural 'inhibition' deficits been investigated. Forty Participants (25 female) completed both a manual and a saccadic stop-signal reaction time (SSRT) task before and after a 0.8g/kg dose of alcohol and, on a separate day, before and after a placebo. Blocks in which participants were required to ignore the signal to stop or make an additional 'dual' response were included to obtain measures of proactive inhibition as well as updating of attention and action. Alcohol increased manual but not saccadic SSRT. Proactive inhibition was weakly reduced by alcohol, but increases in the reaction times used to baseline this contrast prevent clear conclusions regarding response caution. Finally, alcohol also increased secondary dual response times of the dual task uniformly as a function of the delay between tasks, indicating an effect of alcohol on action-updating or execution. The modality-specific effects of alcohol favour the theory that response inhibition systems are embedded within response modalities, rather than there existing a general inhibition system. Concerning alcohol, saccadic control appears relatively more immune to disruption than manual control, even though alcohol affects saccadic latency and velocity. Within the manual domain, alcohol affects multiple types of action updating, not just inhibition. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Brief report: Response inhibition and processing speed in children with motor difficulties and developmental coordination disorder.

PubMed

Bernardi, Marialivia; Leonard, Hayley C; Hill, Elisabeth L; Henry, Lucy A

2016-01-01

A previous study reported that children with poor motor skills, classified as having motor difficulties (MD) or Developmental Coordination Disorder (DCD), produced more errors in a motor response inhibition task compared to typically developing (TD) children but did not differ in verbal inhibition errors. The present study investigated whether these groups differed in the length of time they took to respond in order to achieve these levels of accuracy, and whether any differences in response speed could be explained by generally slow information processing in children with poor motor skills. Timing data from the Verbal Inhibition Motor Inhibition test were analyzed to identify differences in performance between the groups on verbal and motor inhibition, as well as on processing speed measures from standardized batteries. Although children with MD and DCD produced more errors in the motor inhibition task than TD children, the current analyses found that they did not take longer to complete the task. Children with DCD were slower at inhibiting verbal responses than TD children, while the MD group seemed to perform at an intermediate level between the other groups in terms of verbal inhibition speed. Slow processing speed did not account for these group differences. Results extended previous research into response inhibition in children with poor motor skills by explicitly comparing motor and verbal responses, and suggesting that slow performance, even when accurate, may be attributable to an inefficient way of inhibiting responses, rather than slow information processing speed per se.

On the relationship between response selection and response inhibition: An individual differences approach.

PubMed

Bender, Angela D; Filmer, Hannah L; Garner, K G; Naughtin, Claire K; Dux, Paul E

2016-11-01

The abilities to select appropriate responses and suppress unwanted actions are key executive functions that enable flexible and goal-directed behavior. However, to date it has been unclear whether these two cognitive operations tap a common action control resource or reflect two distinct processes. In the present study, we used an individual differences approach to examine the underlying relationships across seven paradigms that varied in their response selection and response inhibition requirements: stop-signal, go-no-go, Stroop, flanker, single-response selection, psychological refractory period, and attentional blink tasks. A confirmatory factor analysis suggested that response inhibition and response selection are separable, with stop-signal and go-no-go task performance being related to response inhibition, and performance in the psychological refractory period, Stroop, single-response selection, and attentional blink tasks being related to response selection. These findings provide evidence in support of the hypothesis that response selection and response inhibition reflect two distinct cognitive operations.

Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel cell carcinoma.

PubMed

Schadendorf, Dirk; Nghiem, Paul; Bhatia, Shailender; Hauschild, Axel; Saiag, Philippe; Mahnke, Lisa; Hariharan, Subramanian; Kaufman, Howard L

2017-01-01

Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance. Unlike chemotherapy, treatment with anti-PD-L1 (avelumab) or anti-PD-1 (pembrolizumab) antibodies leads to durable responses in MCC, in both virus-positive and virus-negative tumors. As many tumors are established through the evasion of infiltrating immune-cell clearance, the lessons learned in MCC may be broadly relevant to many cancers.

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents

PubMed Central

Simon, Nicholas W.; Moghaddam, Bita

2016-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3 mg/kg) improving inhibition, and high dose (3 mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. PMID:27431940

Automatic and Controlled Response Inhibition: Associative Learning in the Go/No-Go and Stop-Signal Paradigms

PubMed Central

Verbruggen, Frederick; Logan, Gordon D.

2008-01-01

In five experiments, the authors examined the development of automatic response inhibition in the go/no-go paradigm and a modified version of the stop-signal paradigm. They hypothesized that automatic response inhibition may develop over practice when stimuli are consistently associated with stopping. All five experiments consisted of a training phase and a test phase in which the stimulus mapping was reversed for a subset of the stimuli. Consistent with the automatic-inhibition hypothesis, the authors found that responding in the test phase was slowed when the stimulus had been consistently associated with stopping in the training phase. In addition, they found that response inhibition benefited from consistent stimulus-stop associations. These findings suggest that response inhibition may rely on the retrieval of stimulus-stop associations after practice with consistent stimulus-stop mappings. Stimulus-stop mapping is typically consistent in the go/no-go paradigm, so automatic inhibition is likely to occur. However, stimulus-stop mapping is typically inconsistent in the stop-signal paradigm, so automatic inhibition is unlikely to occur. Thus, the results suggest that the two paradigms are not equivalent because they allow different kinds of response inhibition. PMID:18999358

Response inhibition, preattentive processing, and sex difference in young children: an event-related potential study.

PubMed

Liu, Tongran; Xiao, Tong; Shi, Jiannong

2013-02-13

Response inhibition and preattentive processing are two important cognitive abilities for child development, and the current study adopted both behavioral and electrophysiological protocols to examine whether young children's response inhibition correlated with their preattentive processing. A Go/Nogo task was used to explore young children's response inhibition performances and an Oddball task with event-related potential recordings was used to measure their preattentive processing. The behavioral results showed that girls committed significantly fewer commission error rates, which showed that girls had stronger inhibition control abilities than boys. Girls also achieved higher d' scores in the Go/Nogo task, which indicated that they were more sensitive to the stimulus signals than boys. Although the electrophysiological results of preattentive processing did not show any sex differences, the correlation patterns between children's response inhibition and preattentive processing were different between these two groups: the neural response speed of preattentive processing (mismatch negativity peak latency) negatively correlated with girls' commission error rates and positively correlated with boys' correct hit rates. The current findings supported that the preattentive processing correlated with human inhibition control performances, and further showed that girls' better inhibition responses might be because of the influence of their preattentive processing.

The Ability To Activate and Inhibit Speeded Responses: Separate Developmental Trends.

ERIC Educational Resources Information Center

Band, Guido P. H.; van der Molen, Maurits W.; Overtoom, Carin C. E.; Verbaten, Marinus N.

2000-01-01

Compared 5-, 8-, and 11-year-olds and young adults on 6 speeded performance tasks, 4 requiring an inhibition of response activation. Analyzed reaction and inhibition times; found support for hypothesis of generalized developmental changes in response activation, but revealed less pronounced development of inhibition. Concluded that a nonselective…

A Statewide Evaluation of the California Medical Supervision Program Using Cholinesterase Electronic Laboratory Reporting Data

PubMed Central

Laribi, Ouahiba; Malig, Brian; Sutherland-Ashley, Katherine; Broadwin, Rachel; Wieland, Walker; Salocks, Charles

2017-01-01

The California Medical Supervision program is designed to protect workers who regularly mix, load, or apply the highly toxic Category I and II organophosphates and carbamates from overexposure by monitoring cholinesterase (ChE) inhibition in plasma and red blood cells. Since January 2011, testing laboratories are required to report test results electronically to the California Department of Pesticide Regulation who shares it with the Office of Environmental Health Hazard Assessment for evaluation. The purpose of this study is to assess the utility of this reporting in evaluating the effectiveness of the Program for illness surveillance and prevention. From 2011 to 2013, we received more than 90 000 test results. Despite data gaps and data quality issues, we were able to perform spatial and temporal analyses and developed a screening tool to identify individuals potentially at risk of overexposure. The data analysis provided some evidence that the Program is effective in protecting agricultural workers handling the most toxic ChE-inhibiting pesticides even though it also identified some areas of potential concerns with individuals that appeared lacking corrective actions in the workplace in response to excessive ChE depressions and parts of the state with disproportionately at-risk individuals. However, changes to the electronic reporting are needed to more accurately identify tests related to the Program and therefore improve the utility of the data received. Moreover, data analysis also revealed that electronic reporting has its limitation in evaluating the Program.

Optimal Fermentation Conditions of Hyaluronidase Inhibition Activity on Asparagus cochinchinensis Merrill by Weissella cibaria.

PubMed

Kim, Minji; Kim, Won-Baek; Koo, Kyoung Yoon; Kim, Bo Ram; Kim, Doohyun; Lee, Seoyoun; Son, Hong Joo; Hwang, Dae Youn; Kim, Dong Seob; Lee, Chung Yeoul; Lee, Heeseob

2017-04-28

This study was conducted to evaluate the hyaluronidase (HAase) inhibition activity of Asparagus cochinchinesis (AC) extracts following fermentation by Weissella cibaria through response surface methodology. To optimize the HAase inhibition activity, a central composite design was introduced based on four variables: the concentration of AC extract ( X 1 : 1-5%), amount of starter culture ( X 2 : 1-5%), pH ( X 3 : 4-8), and fermentation time ( X 4 : 0-10 days). The experimental data were fitted to quadratic regression equations, the accuracy of the equations was analyzed by ANOVA, and the regression coefficients for the surface quadratic model of HAase inhibition activity in the fermented AC extract were estimated by the F test and the corresponding p values. The HAase inhibition activity indicated that fermentation time was most significant among the parameters within the conditions tested. To validate the model, two different conditions among those generated by the Design Expert program were selected. Under both conditions, predicted and experimental data agreed well. Moreover, the content of protodioscin (a well-known compound related to anti-inflammation activity) was elevated after fermentation of the AC extract at the optimized fermentation condition.

Explicit and Implicit Verbal Response Inhibition in Preschool-Age Children Who Stutter.

PubMed

Anderson, Julie D; Wagovich, Stacy A

2017-04-14

The purpose of this study was to examine (a) explicit and implicit verbal response inhibition in preschool children who do stutter (CWS) and do not stutter (CWNS) and (b) the relationship between response inhibition and language skills. Participants were 41 CWS and 41 CWNS between the ages of 3;1 and 6;1 (years;months). Explicit verbal response inhibition was measured using a computerized version of the grass-snow task (Carlson & Moses, 2001), and implicit verbal response inhibition was measured using the baa-meow task. Main dependent variables were reaction time and accuracy. The CWS were significantly less accurate than the CWNS on the implicit task, but not the explicit task. The CWS also exhibited slower reaction times than the CWNS on both tasks. Between-group differences in performance could not be attributed to working memory demands. Overall, children's performance on the inhibition tasks corresponded with parents' perceptions of their children's inhibition skills in daily life. CWS are less effective and efficient than CWNS in suppressing a dominant response while executing a conflicting response in the verbal domain.

Explicit and Implicit Verbal Response Inhibition in Preschool-Age Children Who Stutter

PubMed Central

Wagovich, Stacy A.

2017-01-01

Purpose The purpose of this study was to examine (a) explicit and implicit verbal response inhibition in preschool children who do stutter (CWS) and do not stutter (CWNS) and (b) the relationship between response inhibition and language skills. Method Participants were 41 CWS and 41 CWNS between the ages of 3;1 and 6;1 (years;months). Explicit verbal response inhibition was measured using a computerized version of the grass–snow task (Carlson & Moses, 2001), and implicit verbal response inhibition was measured using the baa–meow task. Main dependent variables were reaction time and accuracy. Results The CWS were significantly less accurate than the CWNS on the implicit task, but not the explicit task. The CWS also exhibited slower reaction times than the CWNS on both tasks. Between-group differences in performance could not be attributed to working memory demands. Overall, children's performance on the inhibition tasks corresponded with parents' perceptions of their children's inhibition skills in daily life. Conclusions CWS are less effective and efficient than CWNS in suppressing a dominant response while executing a conflicting response in the verbal domain. PMID:28384673

Testing interactive effects of automatic and conflict control processes during response inhibition - A system neurophysiological study.

PubMed

Chmielewski, Witold X; Beste, Christian

2017-02-01

In everyday life successful acting often requires to inhibit automatic responses that might not be appropriate in the current situation. These response inhibition processes have been shown to become aggravated with increasing automaticity of pre-potent response tendencies. Likewise, it has been shown that inhibitory processes are complicated by a concurrent engagement in additional cognitive control processes (e.g. conflicting monitoring). Therefore, opposing processes (i.e. automaticity and cognitive control) seem to strongly impact response inhibition. However, possible interactive effects of automaticity and cognitive control for the modulation of response inhibition processes have yet not been examined. In the current study we examine this question using a novel experimental paradigm combining a Go/NoGo with a Simon task in a system neurophysiological approach combining EEG recordings with source localization analyses. The results show that response inhibition is less accurate in non-conflicting than in conflicting stimulus-response mappings. Thus it seems that conflicts and the resulting engagement in conflict monitoring processes, as reflected in the N2 amplitude, may foster response inhibition processes. This engagement in conflict monitoring processes leads to an increase in cognitive control, as reflected by an increased activity in the anterior and posterior cingulate areas, while simultaneously the automaticity of response tendencies is decreased. Most importantly, this study suggests that the quality of conflict processes in anterior cingulate areas and especially the resulting interaction of cognitive control and automaticity of pre-potent response tendencies are important factors to consider, when it comes to the modulation of response inhibition processes. Copyright © 2016 Elsevier Inc. All rights reserved.

Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings

PubMed Central

van Rooij, Daan; Hartman, Catharina A.; Mennes, Maarten; Oosterlaan, Jaap; Franke, Barbara; Rommelse, Nanda; Heslenfeld, Dirk; Faraone, Stephen V.; Buitelaar, Jan K.; Hoekstra, Pieter J.

2015-01-01

Introduction Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls. Methods Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125). Results Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls. Discussion Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD. PMID:25610797

Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings.

PubMed

van Rooij, Daan; Hartman, Catharina A; Mennes, Maarten; Oosterlaan, Jaap; Franke, Barbara; Rommelse, Nanda; Heslenfeld, Dirk; Faraone, Stephen V; Buitelaar, Jan K; Hoekstra, Pieter J

2015-01-01

Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls. Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125). Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls. Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.

Defining the baseline for inhibition concentration calculations for hormetic hazards.

PubMed

Bailer, A J; Oris, J T

2000-01-01

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

Inhibition during response preparation is sensitive to response complexity

PubMed Central

Saks, Dylan; Hoang, Timothy; Ivry, Richard B.

2015-01-01

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors. PMID:25717168

Inhibition by somatostatin (growth-hormone release-inhibiting hormone, GH-RIH) of gastric acid and pepsin and G-cell release of gastrin.

PubMed Central

Barros D'sa, A A; Bloom, S R; Baron, J H

1978-01-01

Somatostatin (cyclic growth-hormone release-inhibiting hormone--GH-RIH) was infused into dogs with gastric fistulae. Somatostatin inhibited gastric acid response to four gastric stimulants--insulin, food, histamine, and pentagastrin. Histamine- and pentagastrin-stimulated pepsins were inhibited similarly to inhibition of acid. Somatostatin inhibited the gastrin response to insulin and food. PMID:348581

Can Arousal Modulate Response Inhibition?

ERIC Educational Resources Information Center

Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

2015-01-01

The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

Alpha cyano-4-hydroxy-3-methoxycinnamic acid inhibits proliferation and induces apoptosis in human breast cancer cells.

PubMed

Hamdan, Lamia; Arrar, Zoheir; Al Muataz, Yacoub; Suleiman, Lutfi; Négrier, Claude; Mulengi, Joseph Kajima; Boukerche, Habib

2013-01-01

This study investigated the underlying mechanism of 4-hydroxy-3-methoxycinnamic acid (ACCA), on the growth of breast cancer cells and normal immortal epithelial cells, and compared their cytotoxic effects responses. Treatment of breast cancer cells (MCF-7, T47D, and MDA-231) with ACCA resulted in dose- and time-dependent decrease of cell proliferation, viability in colony formation assay, and programmed cell death (apoptosis) with minimal effects on non-tumoral cells. The ability of ACCA to suppress growth in cancer cells not expressing or containing defects in p53 gene indicates a lack of involvement of this critical tumor suppressor element in mediating ACCA-induced growth inhibition. Induction of apoptosis correlated with an increase in Bax protein, an established inducer of programmed cell death, and the ratio of Bax to Bcl-2, an established inhibitor of apoptosis. We also documented the ability of ACCA to inhibit the migration and invasion of MDA-231 cells with ACCA in vitro. Additionally, tumor growth of MDA-231 breast cancer cells in vivo was dramatically affected with ACCA. On the basis of its selective anticancer inhibitory activity on tumor cells, ACCA may represent a promising therapeutic drug that should be further evaluated as a chemotherapeutic agent for human breast cancer.

Alpha Cyano-4-Hydroxy-3-Methoxycinnamic Acid Inhibits Proliferation and Induces Apoptosis in Human Breast Cancer Cells

PubMed Central

Hamdan, Lamia; Arrar, Zoheir; Al Muataz, Yacoub; Suleiman, Lutfi; Négrier, Claude; Mulengi, Joseph Kajima; Boukerche, Habib

2013-01-01

This study investigated the underlying mechanism of 4-hydroxy-3-methoxycinnamic acid (ACCA), on the growth of breast cancer cells and normal immortal epithelial cells, and compared their cytotoxic effects responses. Treatment of breast cancer cells (MCF-7, T47D, and MDA-231) with ACCA resulted in dose- and time-dependent decrease of cell proliferation, viability in colony formation assay, and programmed cell death (apoptosis) with minimal effects on non-tumoral cells. The ability of ACCA to suppress growth in cancer cells not expressing or containing defects in p53 gene indicates a lack of involvement of this critical tumor suppressor element in mediating ACCA-induced growth inhibition. Induction of apoptosis correlated with an increase in Bax protein, an established inducer of programmed cell death, and the ratio of Bax to Bcl-2, an established inhibitor of apoptosis. We also documented the ability of ACCA to inhibit the migration and invasion of MDA-231 cells with ACCA in vitro. Additionally, tumor growth of MDA-231 breast cancer cells in vivo was dramatically affected with ACCA. On the basis of its selective anticancer inhibitory activity on tumor cells, ACCA may represent a promising therapeutic drug that should be further evaluated as a chemotherapeutic agent for human breast cancer. PMID:24039831

No Effects of Bilateral tDCS over Inferior Frontal Gyrus on Response Inhibition and Aggression

PubMed Central

Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T.

2015-01-01

Response inhibition is defined as the capacity to adequately withdraw pre-planned responses. It has been shown that individuals with deficits in inhibiting pre-planned responses tend to display more aggressive behaviour. The prefrontal cortex is involved in both, response inhibition and aggression. While response inhibition is mostly associated with predominantly right prefrontal activity, the neural components underlying aggression seem to be left-lateralized. These differences in hemispheric dominance are conceptualized in cortical asymmetry theories on motivational direction, which assign avoidance motivation (relevant to inhibit responses) to the right and approach motivation (relevant for aggressive actions) to the left prefrontal cortex. The current study aimed to directly address the inverse relationship between response inhibition and aggression by assessing them within one experiment. Sixty-nine healthy participants underwent bilateral transcranial Direct Current Stimulation (tDCS) to the inferior frontal cortex. In one group we induced right-hemispheric fronto-cortical dominance by means of a combined right prefrontal anodal and left prefrontal cathodal tDCS montage. In a second group we induced left-hemispheric fronto-cortical dominance by means of a combined left prefrontal anodal and right prefrontal cathodal tDCS montage. A control group received sham stimulation. Response inhibition was assessed with a go/no-go task (GNGT) and aggression with the Taylor Aggression Paradigm (TAP). We revealed that participants with poorer performance in the GNGT displayed more aggression during the TAP. No effects of bilateral prefrontal tDCS on either response inhibition or aggression were observed. This is at odds with previous brain stimulation studies applying unilateral protocols. Our results failed to provide evidence in support of the prefrontal cortical asymmetry model in the domain of response inhibition and aggression. The absence of tDCS effects might also indicate that the methodological approach of shifting cortical asymmetry by means of bilateral tDCS protocols has failed. PMID:26161664

Qualitative process evaluation of an Australian alcohol media literacy study: recommendations for designing culturally responsive school-based programs.

PubMed

Gordon, Chloe S; Kervin, Lisa K; Jones, Sandra C; Howard, Steven J

2017-02-02

Alcohol media literacy programs seek to mitigate the potentially harmful effects of alcohol advertising on children's drinking intentions and behaviours through equipping them with skills to challenge media messages. In order for such programs to be effective, the teaching and learning experiences must be tailored to their specific cultural context. Media in the Spotlight is an alcohol media literacy program aimed at 9 to 12 year old Australian children. This study evaluates the process and implementation of the program, outlining the factors that facilitated and inhibited implementation. From this evaluation, a pedagogical framework has been developed for health professionals implementing culturally responsive programs in school settings. Process measures included: semi-structured interviews with teachers before and after the program was implemented (n = 11 interviews), program evaluation questionnaires completed by children (n = 166), lesson observations completed by teachers (n = 35 observations), and reflective journal entries completed by the researcher (n = 44 entries). A thematic analysis approach was used to analyse all of the data sets using NVivo. Inductive coding was used, whereby the findings were derived from the research objectives and multiple readings and interpretations of the data. Five key pedagogical considerations were identified that facilitated implementation. These were: connecting to the students' life worlds to achieve cultural significance; empowering students with real-world skills to ensure relevance; ensuring programs are well structured with strong connections to the school curriculum; creating developmentally appropriate activities while providing a range of assessment opportunities; and including hands-on and interactive activities to promote student engagement. Three potential inhibitors to implementing the alcohol media literacy program in upper-elementary school classrooms were identified. These included topic sensitivities, classroom management challenges, and fitting new programs into already busy school schedules. Overall, the program content and individual lessons were well received by the teachers and students. The lessons learned from the development, implementation and evaluation of this program can provide health professionals with key pedagogical strategies for designing culturally responsive educational programs. Culturally responsive programs are critical for ensuring interventions are effective for their specific context.

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents.

PubMed

Simon, Nicholas W; Moghaddam, Bita

2017-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3mg/kg) improving inhibition, and high dose (3mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

PubMed

Bunnell, Bryan E; Escobar, Jillian F; Bair, Kirsten L; Sutton, Mark D; Crane, John K

2017-01-01

Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

BH3-only protein Bim inhibits activity of antiapoptotic members of Bcl-2 family when expressed in yeast.

PubMed

Juhásová, Barbora; Mentel, Marek; Bhatia-Kiššová, Ingrid; Zeman, Igor; Kolarov, Jordan; Forte, Michael; Polčic, Peter

2011-09-02

Proteins of the Bcl-2 family regulate programmed cell death in mammals by promoting the release of cytochrome c from mitochondria in response to various proapoptotic stimuli. The mechanism by which BH3-only members of the family activate multidomain proapoptotic proteins Bax and Bak to form a pore in mitochondrial membranes remains under dispute. We report that cell death promoting activity of BH3-only protein Bim can be reconstituted in yeast when both Bax and antiapoptotic protein Bcl-X(L) are present, suggesting that Bim likely activates Bax indirectly by inhibiting antiapoptotic proteins. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Behavioural and computational varieties of response inhibition in eye movements.

PubMed

Cutsuridis, Vassilis

2017-04-19

Response inhibition is the ability to override a planned or an already initiated response. It is the hallmark of executive control as its deficits favour impulsive behaviours, which may be detrimental to an individual's life. This article reviews behavioural and computational guises of response inhibition. It focuses only on inhibition of oculomotor responses. It first reviews behavioural paradigms of response inhibition in eye movement research, namely the countermanding and antisaccade paradigms, both proven to be useful tools for the study of response inhibition in cognitive neuroscience and psychopathology. Then, it briefly reviews the neural mechanisms of response inhibition in these two behavioural paradigms. Computational models that embody a hypothesis and/or a theory of mechanisms underlying performance in both behavioural paradigms as well as provide a critical analysis of strengths and weaknesses of these models are discussed. All models assume the race of decision processes. The decision process in each paradigm that wins the race depends on different mechanisms. It has been shown that response latency is a stochastic process and has been proven to be an important measure of the cognitive control processes involved in response stopping in healthy and patient groups. Then, the inhibitory deficits in different brain diseases are reviewed, including schizophrenia and obsessive-compulsive disorder. Finally, new directions are suggested to improve the performance of models of response inhibition by drawing inspiration from successes of models in other domains.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'. © 2017 The Author(s).

STOP-IT: Windows executable software for the stop-signal paradigm.

PubMed

Verbruggen, Frederick; Logan, Gordon D; Stevens, Michaël A

2008-05-01

The stop-signal paradigm is a useful tool for the investigation of response inhibition. In this paradigm, subjects are instructed to respond as fast as possible to a stimulus unless a stop signal is presented after a variable delay. However, programming the stop-signal task is typically considered to be difficult. To overcome this issue, we present software called STOP-IT, for running the stop-signal task, as well as an additional analyzing program called ANALYZE-IT. The main advantage of both programs is that they are a precompiled executable, and for basic use there is no need for additional programming. STOP-IT and ANALYZE-IT are completely based on free software, are distributed under the GNU General Public License, and are available at the personal Web sites of the first two authors or at expsy.ugent.be/tscope/stop.html.

Cognitive Control Reflects Context Monitoring, Not Motoric Stopping, in Response Inhibition

PubMed Central

Chatham, Christopher H.; Claus, Eric D.; Kim, Albert; Curran, Tim; Banich, Marie T.; Munakata, Yuko

2012-01-01

The inhibition of unwanted behaviors is considered an effortful and controlled ability. However, inhibition also requires the detection of contexts indicating that old behaviors may be inappropriate – in other words, inhibition requires the ability to monitor context in the service of goals, which we refer to as context-monitoring. Using behavioral, neuroimaging, electrophysiological and computational approaches, we tested whether motoric stopping per se is the cognitively-controlled process supporting response inhibition, or whether context-monitoring may fill this role. Our results demonstrate that inhibition does not require control mechanisms beyond those involved in context-monitoring, and that such control mechanisms are the same regardless of stopping demands. These results challenge dominant accounts of inhibitory control, which posit that motoric stopping is the cognitively-controlled process of response inhibition, and clarify emerging debates on the frontal substrates of response inhibition by replacing the centrality of controlled mechanisms for motoric stopping with context-monitoring. PMID:22384038

Acute effects of cocaine and cannabis on response inhibition in humans: an ERP investigation.

PubMed

Spronk, Desirée B; De Bruijn, Ellen R A; van Wel, Janelle H P; Ramaekers, Johannes G; Verkes, Robbert J

2016-11-01

Substance abuse has often been associated with alterations in response inhibition in humans. Not much research has examined how the acute effects of drugs modify the neurophysiological correlates of response inhibition, or how these effects interact with individual variation in trait levels of impulsivity and novelty seeking. This study investigated the effects of cocaine and cannabis on behavioural and event-related potential (ERP) correlates of response inhibition in 38 healthy drug using volunteers. A double-blind placebo-controlled randomized three-way crossover design was used. All subjects completed a standard Go/NoGo task after administration of the drugs. Compared with a placebo, cocaine yielded improved accuracy, quicker reaction times and an increased prefrontal NoGo-P3 ERP. Cannabis produced opposing results; slower reaction times, impaired accuracy and a reduction in the amplitude of the prefrontal NoGo-P3. Cannabis in addition decreased the amplitude of the parietally recorded P3, while cocaine did not affect this. Neither drugs specifically affected the N2 component, suggesting that pre-motor response inhibitory processes remain unaffected. Neither trait impulsivity nor novelty seeking interacted with drug-induced effects on measures of response inhibition. We conclude that acute drug effects on response inhibition seem to be specific to the later, evaluative stages of response inhibition. The acute effects of cannabis appeared less specific to response inhibition than those of cocaine. Together, the results show that the behavioural effects on response inhibition are reflected in electrophysiological correlates. This study did not support a substantial role of vulnerability personality traits in the acute intoxication stage. © 2015 Society for the Study of Addiction.

Enhancing response inhibition by incentive: Comparison of adolescents with and without substance use disorder

PubMed Central

Chung, Tammy; Geier, Charles; Luna, Beatriz; Pajtek, Stefan; Terwilliger, Robert; Thatcher, Dawn; Clark, Duncan

2010-01-01

Effective response inhibition is a key component of recovery from addiction. Some research suggests that response inhibition can be enhanced through reward contingencies. We examined the effect of monetary incentive on response inhibition among adolescents with and without substance use disorder (SUD) using a fast event-related fMRI antisaccade reward task. The fMRI task permits investigation of how reward (monetary incentive) might modulate inhibitory control during three task phases: cue presentation (reward or neutral trial), response preparation, and response execution. Adolescents with lifetime SUD (n=12; 100% marijuana use disorder) were gender and age-matched to healthy controls (n=12). Monetary incentive facilitated inhibitory control for SUD adolescents; for healthy controls, the difference in error rate for neutral and reward trials was not significant. There were no significant differences in behavioral performance between groups across reward and neutral trials, however, group differences in regional brain activation were identified. During the response preparation phase of reward trials, SUD adolescents, compared to controls, showed increased activation of prefrontal and oculomotor control (e.g., frontal eye field) areas, brain regions that have been associated with effective response inhibition. Results indicate differences in brain activation between SUD and control youth when preparing to inhibit a prepotent response in the context of reward, and support a possible role for incentives in enhancing response inhibition among youth with SUD. PMID:21115229

Exogenously triggered response inhibition in developmental stuttering.

PubMed

Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

2018-06-01

The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

Striatal D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects.

PubMed

Robertson, Chelsea L; Ishibashi, Kenji; Mandelkern, Mark A; Brown, Amira K; Ghahremani, Dara G; Sabb, Fred; Bilder, Robert; Cannon, Tyrone; Borg, Jacqueline; London, Edythe D

2015-04-15

Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [(11)C]NNC-112 and [(18)F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition. Copyright © 2015 the authors 0270-6474/15/355990-08$15.00/0.

Cortical Activity during Manual Response Inhibition Guided by Color and Orientation Cues

PubMed Central

Cai, Weidong; Leung, Hoi-Chung

2009-01-01

It has been suggested that the right inferior frontal gyrus (IFG) plays a critical role in manual response inhibition, although neuroimaging studies of healthy adults have also reported widespread activations in other cortical regions during a variety of response inhibition tasks. We conducted a functional magnetic resonance imaging (fMRI) experiment to examine whether the activation of the IFG is dependent on the type of visuo-motor associations during response inhibition by varying the feature of the stop signal (color vs. orientation) in the stop-signal task. Results from 12 subjects showed that the bilateral ventral posterior IFG, anterior insula, inferior frontal junction (IFJ), middle temporal gyrus (MTG) and fusiform gyrus (FG) are active during response inhibition cued by both color and orientation stop signals. While only the MTG showed differential activity to the two stop signals, both MTG and FG showed significantly stronger activity during successful than unsuccessful stopping of unwanted responses cued by orientation and color, respectively. Our findings suggest that the right ventral posterior IFG may play a more general role in response inhibition regardless of the feature of the visual signal, while successful inhibition may depend on efficient processing of the signal. PMID:19401178

Women with borderline personality disorder do not show altered BOLD responses during response inhibition.

PubMed

van Eijk, Julia; Sebastian, Alexandra; Krause-Utz, Annegret; Cackowski, Sylvia; Demirakca, Traute; Biedermann, Sarah V; Lieb, Klaus; Bohus, Martin; Schmahl, Christian; Ende, Gabriele; Tüscher, Oliver

2015-12-30

Impulsivity is central to borderline personality disorder (BPD). Response inhibition, addressing the ability to suppress or stop actions, is one aspect of behavioral impulse control which is frequently used to assess impulsivity. BPD patients display deficits in response inhibition under stress condition or negative emotions. We assessed whether response inhibition and its neural underpinnings are impaired in BPD when tested in an emotionally neutral setting and when co-morbid attention-deficit/hyperactivity disorder (ADHD) is excluded. To this end, we studied response inhibition in unmedicated BPD patients and healthy controls (HC) in two independent samples using functional magnetic resonance imaging during Simon-, Go/nogo-, and Stopsignal tasks. BPD patients and HC did not differ significantly in their performance in the Go/nogo and the Stopsignal tasks. Response interference in the Simon task was increased in BPD patients in one sample, but this could not be replicated in the second sample. In both samples, no significant differences in brain activation patterns during any of the tasks were present while the neural impulse control network was robustly activated during the inhibition tasks in both groups. Our results provide evidence that under emotionally neutral conditions response inhibition is not impaired in patients with BPD without co-occurring ADHD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Perceptual conflict during sensorimotor integration processes - a neurophysiological study in response inhibition.

PubMed

Chmielewski, Witold X; Beste, Christian

2016-05-25

A multitude of sensory inputs needs to be processed during sensorimotor integration. A crucial factor for detecting relevant information is its complexity, since information content can be conflicting at a perceptual level. This may be central to executive control processes, such as response inhibition. This EEG study aims to investigate the system neurophysiological mechanisms behind effects of perceptual conflict on response inhibition. We systematically modulated perceptual conflict by integrating a Global-local task with a Go/Nogo paradigm. The results show that conflicting perceptual information, in comparison to non-conflicting perceptual information, impairs response inhibition performance. This effect was evident regardless of whether the relevant information for response inhibition is displayed on the global, or local perceptual level. The neurophysiological data suggests that early perceptual/ attentional processing stages do not underlie these modulations. Rather, processes at the response selection level (P3), play a role in changed response inhibition performance. This conflict-related impairment of inhibitory processes is associated with activation differences in (inferior) parietal areas (BA7 and BA40) and not as commonly found in the medial prefrontal areas. This suggests that various functional neuroanatomical structures may mediate response inhibition and that the functional neuroanatomical structures involved depend on the complexity of sensory integration processes.

Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls.

PubMed

van Rooij, D; Hoekstra, P J; Bralten, J; Hakobjan, M; Oosterlaan, J; Franke, B; Rommelse, N; Buitelaar, J K; Hartman, C A

2015-11-01

Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

Response inhibition predicts painful task duration and performance in healthy individuals performing a cold pressor task in a motivational context.

PubMed

Karsdorp, P A; Geenen, R; Vlaeyen, J W S

2014-01-01

Long-term avoidance of painful activities has shown to be dysfunctional in chronic pain. Pain may elicit escape or avoidance responses automatically, particularly when pain-related fear is high. A conflict may arise between opposing short-term escape/avoidance goals to reduce pain and long-term approach goals to receive a reward. An inhibitory control system may resolve this conflict. It was hypothesized that reduced response inhibition would be associated with greater escape/avoidance during pain, particularly among subjects with higher pain-related fear. Response inhibition was measured with the stop-signal task, and pain-related fear with the Fear of Pain Questionnaire. Participants completed a tone-detection task (TDT) in which they could earn money while being exposed to cold pressor pain. Escape/avoidance was operationalized as the hand immersion time during a cold pressor task (CPT) and the performance on the TDT. Poorer response inhibition was associated with shorter CPT immersion duration and with worse TDT performance. Pain after the CPT was associated with pain-related fear, but not with response inhibition. No supportive evidence was found for the hypothesis that the relation between inhibition and escape/avoidance would be most pronounced for those with higher pain-related fear. In contrast, the relation between response inhibition and number of hits on the TDT was most pronounced for those with lower pain-related fear. The findings suggest that individuals with a stronger ability to inhibit responses in a stop-signal task are better able to inhibit escape/avoidance responses elicited by pain, in the service of a conflicting approach goal. © 2013 European Pain Federation - EFIC®

Emotional content modulates response inhibition and perceptual processing.

PubMed

Yang, Suyong; Luo, Wenbo; Zhu, Xiangru; Broster, Lucas S; Chen, Taolin; Li, Jinzhen; Luo, Yuejia

2014-11-01

In this study, event-related potentials were used to investigate the effect of emotion on response inhibition. Participants performed an emotional go/no-go task that required responses to human faces associated with a "go" valence (i.e., emotional, neutral) and response inhibition to human faces associated with a "no-go" valence. Emotional content impaired response inhibition, as evidenced by decreased response accuracy and N2 amplitudes in no-go trials. More importantly, emotional expressions elicited larger N170 amplitudes than neutral expressions, and this effect was larger in no-go than in go trials, indicating that the perceptual processing of emotional expression had priority in inhibitory trials. In no-go trials, correlation analysis showed that increased N170 amplitudes were associated with decreased N2 amplitudes. Taken together, our findings suggest that emotional content impairs response inhibition due to the prioritization of emotional content processing. Copyright © 2014 Society for Psychophysiological Research.

Myocardial NF-κB activation is essential for zebrafish heart regeneration

PubMed Central

Karra, Ravi; Knecht, Anne K.; Kikuchi, Kazu; Poss, Kenneth D.

2015-01-01

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration. PMID:26472034

Myocardial NF-κB activation is essential for zebrafish heart regeneration.

PubMed

Karra, Ravi; Knecht, Anne K; Kikuchi, Kazu; Poss, Kenneth D

2015-10-27

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.

ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila.

PubMed

Petersen, Andrew J; Rimkus, Stacey A; Wassarman, David A

2012-03-13

To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.

Prepotent response inhibition and interference control in autism spectrum disorders: two meta-analyses.

PubMed

Geurts, Hilde M; van den Bergh, Sanne F W M; Ruzzano, Laura

2014-08-01

There is a substantial amount of data providing evidence for, but also against the hypothesis that individuals with autism spectrum disorders (ASD) encounter inhibitory control deficits. ASD is often associated with interference control deficits rather than prepotent response inhibition. Moreover, the developmental trajectory for these inhibitory control processes is hypothesized to differ in ASD as compared to typical development. In efforts to gain a more comprehensive perspective of inhibition in ASD, separate quantitative analysis for prepotent response inhibition studies and interference control studies were conducted. Together, these two meta-analyses included 41 studies with a combined sample size of 1,091 people with ASD (M age 14.8 years), and 1,306 typically developing (TD) controls (M age 13.8 years).The meta-analyses indicated that individuals with ASD show increased difficulties in prepotent response inhibition (effect size 0.55) and in interference control (effect size 0.31). In addition, age was a relevant moderator for prepotent response inhibition but not for interference control. Exploratory analyses revealed that when IQ was taken into account, heterogeneity considerably decreased among interference control studies but not among prepotent response inhibition. In contrast to the general belief, both prepotent response inhibition and interference control problems were observed in individuals with ASD. However, a large variation between studies was also found. Therefore, there remain factors beyond inhibition type, age, or IQ that significantly influence inhibitory control performance among individuals with ASD. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

Wnt signaling inhibits CTL memory programming

PubMed Central

Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra; Li, Lei

2013-01-01

Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers. PMID:23911398

Response inhibition rapidly increases single-neuron responses in the subthalamic nucleus of patients with Parkinson's disease.

PubMed

Benis, Damien; David, Olivier; Piallat, Brigitte; Kibleur, Astrid; Goetz, Laurent; Bhattacharjee, Manik; Fraix, Valérie; Seigneuret, Eric; Krack, Paul; Chabardès, Stéphan; Bastin, Julien

2016-11-01

The subthalamic nucleus (STN) plays a critical role during action inhibition, perhaps by acting like a fast brake on the motor system when inappropriate responses have to be rapidly suppressed. However, the mechanisms involving the STN during motor inhibition are still unclear, particularly because of a relative lack of single-cell responses reported in this structure in humans. In this study, we used extracellular microelectrode recordings during deep brain stimulation surgery in patients with Parkinson's disease (PD) to study STN neurophysiological correlates of inhibitory control during a stop signal task. We found two neuronal subpopulations responding either during motor execution (GO units) or during motor inhibition (STOP units). GO units fired selectively before patients' motor responses whereas STOP units fired selectively when patients successfully withheld their move at a latency preceding the duration of the inhibition process. These results provide electrophysiological evidence for the hypothesized role of the STN in current models of response inhibition. Copyright © 2016. Published by Elsevier Ltd.

A dual but asymmetric role of the dorsal anterior cingulate cortex in response inhibition and switching from a non-salient to salient action

PubMed Central

Manza, Peter; Hu, Sien; Chao, Herta H.; Zhang, Sheng; Leung, Hoi-Chung; Li, Chiang-shan R.

2016-01-01

Response inhibition and salience detection are among the most studied psychological constructs of cognitive control. Despite a growing body of work, how inhibition and salience processing interact and engage regional brain activations remains unclear. Here, we examined this issue in a stop signal task (SST), where a prepotent response needs to be inhibited to allow an alternative, less dominant response. Sixteen adult individuals performed two versions of the SST each with 25% (SST25) and 75% (SST75) of stop trials. We posited that greater regional activations to the infrequent trial type in each condition (i.e., to stop as compared to go trials in SST25 and to go as compared to stop trials in SST75) support salience detection. Further, successful inhibition in stop trials requires attention to the stop signal to trigger motor inhibition, and the stop signal reaction time (SSRT) has been used to index the efficiency of motor response inhibition. Therefore, greater regional activations to stop as compared to go success trials in association with the stop signal reaction time (SSRT) serves to expedite response inhibition. In support of an interactive role, the dorsal anterior cingulate cortex (dACC) increases activation to salience detection in both SST25 and SST75, but only mediates response inhibition in SST75. Thus, infrequency response in the dACC supports motor inhibition only when stopping has become a routine. In contrast, although the evidence is less robust, the pre-supplementary motor area (pre-SMA) increases activity to the infrequent stimulus and supports inhibition in both SST25 and SST75. These findings clarify a unique role of the dACC and add to the literature that distinguishes dACC and pre-SMA functions in cognitive control. PMID:27126003

A dual but asymmetric role of the dorsal anterior cingulate cortex in response inhibition and switching from a non-salient to salient action.

PubMed

Manza, Peter; Hu, Sien; Chao, Herta H; Zhang, Sheng; Leung, Hoi-Chung; Li, Chiang-Shan R

2016-07-01

Response inhibition and salience detection are among the most studied psychological constructs of cognitive control. Despite a growing body of work, how inhibition and salience processing interact and engage regional brain activations remains unclear. Here, we examined this issue in a stop signal task (SST), where a prepotent response needs to be inhibited to allow an alternative, less dominant response. Sixteen adult individuals performed two versions of the SST each with 25% (SST25) and 75% (SST75) of stop trials. We posited that greater regional activations to the infrequent trial type in each condition (i.e., to stop as compared to go trials in SST25 and to go as compared to stop trials in SST75) support salience detection. Further, successful inhibition in stop trials requires attention to the stop signal to trigger motor inhibition, and the stop signal reaction time (SSRT) has been used to index the efficiency of motor response inhibition. Therefore, greater regional activations to stop as compared to go success trials in association with the stop signal reaction time (SSRT) serve to expedite response inhibition. In support of an interactive role, the dorsal anterior cingulate cortex (dACC) increases activation to salience detection in both SST25 and SST75, but only mediates response inhibition in SST75. Thus, infrequency response in the dACC supports motor inhibition only when stopping has become a routine. In contrast, although the evidence is less robust, the pre-supplementary motor area (pre-SMA) increases activity to the infrequent stimulus and supports inhibition in both SST25 and SST75. These findings clarify a unique role of the dACC and add to the literature that distinguishes dACC and pre-SMA functions in cognitive control. Copyright © 2016 Elsevier Inc. All rights reserved.

FRONTO-STRIATAL FUNCTIONAL CONNECTIVITY DURING RESPONSE INHIBITION IN ALCOHOL DEPENDENCE

PubMed Central

Courtney, Kelly E.; Ghahremani, Dara G.; Ray, Lara A.

2013-01-01

Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the µ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing a Stop Signal Task (SST). The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction (PPI) analyses. Analyses revealed greater alcohol dependence severity associated with weaker functional connectivity between the putamen and prefrontal regions (e.g., the anterior insula, anterior cingulate, and medial prefrontal cortex) during response inhibition. Further, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses. PMID:23240858

Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation.

PubMed

Münch, Christian; Harper, J Wade

2016-06-30

The mitochondrial matrix is unique in that it must integrate the folding and assembly of proteins derived from the nuclear and mitochondrial genomes. In Caenorhabditis elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial-matrix-localized ornithine transcarbamylase induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 (ref. 8) or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response encompasses widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing caused by transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3 (ref. 10). This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt.

Training and transfer effects of interference control training in children and young adults.

PubMed

Zhao, Xin; Jia, Lina

2018-04-24

Many studies have examined transfer of working memory (WM) training improvements to non-trained cognitive tasks, with largely disappointing results. Interference control has been suggested to be a central feature of WM. However, studies examining transfer effects of a training program exclusively and directly targeting interference control are lacking. Forty-one 10‒12 year-old children and 47 19‒24 year-old adults were assigned to an adaptive interference control training or active control condition. Transfer of training effects to tasks measuring interference control, response inhibition, WM updating, task-switching, and non-verbal fluid intelligence were assessed during a 3-month follow-up session and/or an immediate post-training session. Substantial evidence of training improvements and a positive transfer effect to a non-trained interference control task were observed for both age groups. Marginal evidence for beneficial transfer of training effects for the trained compared to non-trained participants was found for a WM task for both age groups, and for the children for another interference control task and a response inhibition task. However, these transfer effects were absent during the 3-month follow-up measurement. These results suggest some potential for interference control training programs to enhance aspects of cognitive functioning, with some evidence for a more wide-spread, but short-lived, transfer for children compared to adults.

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition.

PubMed

van Rooij, Sanne J H; Rademaker, Arthur R; Kennis, Mitzy; Vink, Matthijs; Kahn, René S; Geuze, Elbert

2014-09-01

Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit.

Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.

PubMed

Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

2018-04-01

Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

A comparative study of ethylene growth response kinetics in eudicots and monocots reveals a role for gibberellin in growth inhibition and recovery.

PubMed

Kim, Joonyup; Wilson, Rebecca L; Case, J Brett; Binder, Brad M

2012-11-01

Time-lapse imaging of dark-grown Arabidopsis (Arabidopsis thaliana) hypocotyls has revealed new aspects about ethylene signaling. This study expands upon these results by examining ethylene growth response kinetics of seedlings of several plant species. Although the response kinetics varied between the eudicots studied, all had prolonged growth inhibition for as long as ethylene was present. In contrast, with continued application of ethylene, white millet (Panicum miliaceum) seedlings had a rapid and transient growth inhibition response, rice (Oryza sativa 'Nipponbare') seedlings had a slow onset of growth stimulation, and barley (Hordeum vulgare) had a transient growth inhibition response followed, after a delay, by a prolonged inhibition response. Growth stimulation in rice correlated with a decrease in the levels of rice ETHYLENE INSENSTIVE3-LIKE2 (OsEIL2) and an increase in rice F-BOX DOMAIN AND LRR CONTAINING PROTEIN7 transcripts. The gibberellin (GA) biosynthesis inhibitor paclobutrazol caused millet seedlings to have a prolonged growth inhibition response when ethylene was applied. A transient ethylene growth inhibition response has previously been reported for Arabidopsis ethylene insensitive3-1 (ein3-1) eil1-1 double mutants. Paclobutrazol caused these mutants to have a prolonged response to ethylene, whereas constitutive GA signaling in this background eliminated ethylene responses. Sensitivity to paclobutrazol inversely correlated with the levels of EIN3 in Arabidopsis. Wild-type Arabidopsis seedlings treated with paclobutrazol and mutants deficient in GA levels or signaling had a delayed growth recovery after ethylene removal. It is interesting to note that ethylene caused alterations in gene expression that are predicted to increase GA levels in the ein3-1 eil1-1 seedlings. These results indicate that ethylene affects GA levels leading to modulation of ethylene growth inhibition kinetics.

Go or No-Go? Developmental Improvements in the Efficiency of Response Inhibition in Mid-Childhood

ERIC Educational Resources Information Center

Cragg, Lucy; Nation, Kate

2008-01-01

This experiment used a modified go/no-go paradigm to investigate the processes by which response inhibition becomes more efficient during mid-childhood. The novel task, which measured trials on which a response was initiated but not completed, was sensitive to developmental changes in response inhibition. The effect of inducing time pressure by…

The Role of Inhibition in Age-related Off-Topic Verbosity: Not Access but Deletion and Restraint Functions.

PubMed

Yin, Shufei; Peng, Huamao

2016-01-01

The speech of older adults is commonly described as verbose and off-topic, which is thought to influence their social communication. This study investigated the role of inhibition in age-related off-topic verbosity (OTV). Inhibition consists of three functions: access, deletion, and restraint. The access function is responsible for preventing irrelevant information from accessing the attention center (pre-mechanism of inhibition); The deletion function is responsible for deleting previously relevant but currently irrelevant information from working memory, and the restraint function is responsible for restraining strong but inappropriate responses (post-mechanisms of inhibition). A referential communication task was used to determine whether OTV was influenced by the pre-mechanism of inhibition. A self-involved event interview task was used to investigate the effect of the post-mechanisms of inhibition on OTV. Results showed that the OTV of the elderly participants was associated with an age-related decline in the post-mechanisms of inhibition, while the OTV exhibited by young adults was most likely due to deficits in the pre-mechanism function of inhibition. This research contributed to fill gaps in the existing knowledge about the potential relationship between specific functions of inhibition and age-related OTV.

Contrasting neural effects of aging on proactive and reactive response inhibition.

PubMed

Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; van de Rest, Ondine; Cools, Roshan; Aarts, Esther

2016-10-01

Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition (anticipatory response slowing), which might be particularly evident with high information load. We used functional magnetic resonance imaging in young (n = 25, age range 18-32) and older adults (n = 23, 61-74) with a stop-signal task. Relative to young adults, older adults exhibited impaired reactive inhibition (i.e., longer stop-signal reaction time) and increased blood oxygen level-dependent (BOLD) signal for successful versus unsuccessful inhibition in the left frontal cortex and cerebellum. Furthermore, older adults also exhibited impaired proactive slowing, but only as a function of information load. This load-dependent behavioral deficit was accompanied by a failure to increase blood oxygen level-dependent (BOLD) signal under high information load in lateral frontal cortex, presupplementary motor area and striatum. Our findings suggest that inhibitory deficits in older adults are caused both by reduced stopping abilities and by diminished preparation capacity during information overload. Copyright © 2016 Elsevier Inc. All rights reserved.

Changes in cerebro-cerebellar interaction during response inhibition after performance improvement.

PubMed

Hirose, Satoshi; Jimura, Koji; Kunimatsu, Akira; Abe, Osamu; Ohtomo, Kuni; Miyashita, Yasushi; Konishi, Seiki

2014-10-01

It has been demonstrated that motor learning is supported by the cerebellum and the cerebro-cerebellar interaction. Response inhibition involves motor responses and the higher-order inhibition that controls the motor responses. In this functional MRI study, we measured the cerebro-cerebellar interaction during response inhibition in two separate days of task performance, and detected the changes in the interaction following performance improvement. Behaviorally, performance improved in the second day, compared to the first day. The psycho-physiological interaction (PPI) analysis revealed the interaction decrease from the right inferior frontal cortex (rIFC) to the cerebellum (lobule VII or VI). It was also revealed that the interaction increased from the same cerebellar region to the primary motor area. These results suggest the involvement of the cerebellum in response inhibition, and raise the possibility that the performance improvement was supported by the changes in the cerebro-cerebellar interaction. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibition-Induced Forgetting Results from Resource Competition between Response Inhibition and Memory Encoding Processes.

PubMed

Chiu, Yu-Chin; Egner, Tobias

2015-08-26

Response inhibition is a key component of executive control, but its relation to other cognitive processes is not well understood. We recently documented the "inhibition-induced forgetting effect": no-go cues are remembered more poorly than go cues. We attributed this effect to central-resource competition, whereby response inhibition saps attention away from memory encoding. However, this proposal is difficult to test with behavioral means alone. We therefore used fMRI in humans to test two neural predictions of the "common resource hypothesis": (1) brain regions associated with response inhibition should exhibit greater resource demands during encoding of subsequently forgotten than remembered no-go cues; and (2) this higher inhibitory resource demand should lead to memory encoding regions having less resources available during encoding of subsequently forgotten no-go cues. Participants categorized face stimuli by gender in a go/no-go task and, following a delay, performed a surprise recognition memory test for those faces. Replicating previous findings, memory was worse for no-go than for go stimuli. Crucially, forgetting of no-go cues was predicted by high inhibitory resource demand, as quantified by the trial-by-trial ratio of activity in neural "no-go" versus "go" networks. Moreover, this index of inhibitory demand exhibited an inverse trial-by-trial relationship with activity in brain regions responsible for the encoding of no-go cues into memory, notably the ventrolateral prefrontal cortex. This seesaw pattern between the neural resource demand of response inhibition and activity related to memory encoding directly supports the hypothesis that response inhibition temporarily saps attentional resources away from stimulus processing. Recent behavioral experiments showed that inhibiting a motor response to a stimulus (a "no-go cue") impairs subsequent memory for that cue. Here, we used fMRI to test whether this "inhibition-induced forgetting effect" is caused by competition for neural resources between the processes of response inhibition and memory encoding. We found that trial-by-trial variations in neural inhibitory resource demand predicted subsequent forgetting of no-go cues and that higher inhibitory demand was furthermore associated with lower concurrent activation in brain regions responsible for successful memory encoding of no-go cues. Thus, motor inhibition and stimulus encoding appear to compete with each other: when more resources have to be devoted to inhibiting action, less are available for encoding sensory stimuli. Copyright © 2015 the authors 0270-6474/15/3511936-10$15.00/0.

Frontal white matter damage impairs response inhibition in children following traumatic brain injury.

PubMed

Lipszyc, Jonathan; Levin, Harvey; Hanten, Gerri; Hunter, Jill; Dennis, Maureen; Schachar, Russell

2014-05-01

Inhibition, the ability to suppress inappropriate cognitions or behaviors, can be measured using computer tasks and questionnaires. Inhibition depends on the frontal cortex, but the role of the underlying white matter (WM) is unclear. We assessed the specific impact of frontal WM damage on inhibition in 29 children with moderate-to-severe traumatic brain injury (15 with and 14 without frontal WM damage), 21 children with orthopedic injury, and 29 population controls. We used the Stop Signal Task to measure response inhibition, the Behavior Rating Inventory of Executive Function to assess everyday inhibition, and T2 fluid-attenuated inversion recovery magnetic resonance imaging to identify lesions. Children with frontal WM damage had impaired response inhibition compared with all other groups and poorer everyday inhibition than the orthopedic injury group. Frontal WM lesions most often affected the superior frontal gyrus. These results provide evidence for the critical role of frontal WM in inhibition.

PI3K pathway inhibitors: potential prospects as adjuncts to vaccine immunotherapy for glioblastoma.

PubMed

Oh, Taemin; Ivan, Michael E; Sun, Matthew Z; Safaee, Michael; Fakurnejad, Shayan; Clark, Aaron J; Sayegh, Eli T; Bloch, Orin; Parsa, Andrew T

2014-01-01

Constitutive activation of the PI3K pathway has been implicated in glioblastoma (GBM) pathogenesis. Pharmacologic inhibition can both inhibit tumor survival and downregulate expression of programmed death ligand-1, a protein highly expressed on glioma cells that strongly contributes to cancer immunosuppression. In that manner, PI3K pathway inhibitors can help optimize GBM vaccine immunotherapy. In this review, we describe and assess the potential integration of various classes of PI3K pathway inhibitors into GBM immunotherapy. While early-generation inhibitors have a wide range of immunosuppressive effects that could negate their antitumor potency, further work should better characterize how contemporary inhibitors affect the immune response. This will help determine if these inhibitors are truly a therapeutic avenue with a strong future in GBM immunotherapy.

Is saccade preparation required for inhibition of return (IOR)?

PubMed

Michalczyk, Łukasz; Paszulewicz, Jakub; Bielas, Jacek; Wolski, Piotr

2018-02-05

The effect of slower responses to validly than invalidly cued targets is known as inhibition of return (IOR). Opposing accounts of IOR have been proposed: one postulates a singular phenomenon explained by oculomotor mechanisms alone, while the other, more diverse account postulates both perceptual-cognitive and motor factors. In our research we considered the relation between motor programming and IOR. In an extended replication of an earlier study, using an eye abduction technique we restricted eye movement in the temporal half-space; this resulted in IOR attenuation in that area, compared to the unrestricted, nasal part of the visual field. Our results contradict the earlier result and demonstrate that IOR does depend on preparation of eye movement, as predicted by the oculomotor priming hypothesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Attentional impulsivity in binge eating disorder modulates response inhibition performance and frontal brain networks.

PubMed

Hege, M A; Stingl, K T; Kullmann, S; Schag, K; Giel, K E; Zipfel, S; Preissl, H

2015-02-01

A subgroup of overweight and obese people is characterized by binge eating disorder (BED). Increased impulsivity has been suggested to cause binge eating and subsequent weight gain. In the current study, neuronal correlates of increased impulsivity in binge eating disorder during behavioral response inhibition were investigated. Magnetic brain activity and behavioral responses of 37 overweight and obese individuals with and without diagnosed BED were recorded while performing a food-related visual go-nogo task. Trait impulsivity was assessed with the Barratt Impulsiveness Scale (BIS-11). Specifically, increased attentional impulsiveness (a subscale of the BIS-11) in BED was related to decreased response inhibition performance and hypoactivity in the prefrontal control network, which was activated when response inhibition was required. Furthermore, participants with BED showed a trend for a food-specific inhibition performance decline. This was possibly related to the absence of a food-specific activity increase in the prefrontal control network in BED, as observed in the control group. In addition, an increase in activity related to the actual button press during prepotent responses and alterations in visual processing were observed. Our results suggest an attentional impulsiveness-related attenuation in response inhibition performance in individuals with BED. This might have been related to increased reward responsiveness and limited resources to activate the prefrontal control network involved in response inhibition. Our results substantiate the importance of neuronal markers for investigating prevention and treatment of obesity, especially in specific subgroups at risk such as BED.

The Effectiveness of Reward and Punishment Contingencies on Response Inhibition

ERIC Educational Resources Information Center

Costantini, Arthur F.; Hoving, Kenneth L.

1973-01-01

The relative effectiveness of reward and punishment on the development of response inhibition was evaluated developmentally with kindergarteners and second graders. Removal of positive reinforcers was apparently more effective than reward in producing inhibiting at both age levels. Transfer of inhibition training was also evaluated. (DP)

The Yin and Yang aspects of IL-27 in induction of cancer-specific T-cell responses and immunotherapy.

PubMed

Li, Ming-Song; Liu, Zhenzhen; Liu, Jin-Qing; Zhu, Xiaotong; Liu, Zhihao; Bai, Xue-Feng

2015-01-01

Accumulating evidences from animal studies have indicated that both endogenous and exogenous IL-27, an IL-12 family of cytokine, can increase antitumor T-cell activities and inhibit tumor growth. IL-27 can modulate Treg responses, and program effector T cells into a unique T-effector stem cell (TSEC) phenotype, which enhances T-cell survival in the tumor microenvironment. However, animal studies also suggest that IL-27 induces molecular pathways such as IL-10, PD-L1 and CD39, which may downregulate tumor-specific T-cell responses. In this review paper, we will discuss the Yin and Yang aspects of IL-27 in the induction of tumor-specific T-cell responses, and the potential impacts of these functions of IL-27 in the design of cancer immunotherapy.

Emotional Response Inhibition in Bipolar Disorder: A Functional Magnetic Resonance Imaging Study of Trait- and State-Related Abnormalities

PubMed Central

Hummer, Tom A.; Hulvershorn, Leslie A.; Karne, Harish S.; Gunn, Abigail D.; Wang, Yang; Anand, Amit

2018-01-01

Background Impaired response inhibition and poor impulse control are hallmarks of the manic phase of bipolar disorder but are also present during depressive and, to a lesser degree, euthymic periods. The neural mechanisms underlying these impairments are poorly understood, including how mechanisms are related to bipolar trait or state effects. Methods One-hundred four unmedicated participants with bipolar mania (BM) (n = 30), bipolar depression (BD) (n = 30), bipolar euthymia (BE) (n = 14), and healthy control subjects (n = 30) underwent functional magnetic resonance imaging during emotional and nonemotional go/no-go tasks. The go/no-go task requires participants to press a button for go stimuli, while inhibiting the response to no-go trials. In separate blocks, participants inhibited the response to happy faces, sad faces, or letters. Results The BE group had higher insula activity during happy face inhibition and greater activity in left inferior frontal gyrus during sad face inhibition, demonstrating bipolar trait effects. Relative to the BE group, BD and BM groups demonstrated lower insula activity during inhibition of happy faces, though the depressed sample had lower activity than manic patients. The BD and BM groups had a greater response to inhibiting sad faces in emotion processing and regulation regions, including putamen, insula, and lateral prefrontal cortex. The manic group also had higher activity in insula and putamen during neutral letter inhibition. Conclusions These results suggest distinct trait- and state-related neural abnormalities during response inhibition in bipolar disorder, with implications for future research and treatment. PMID:22871393

IL-3 induces apoptosis in a ras-transformed myeloid cell line.

PubMed

Ahmed, N; Anderson, S M; Berridge, M V

1999-04-01

Growth factors promote cell survival and proliferation. Homeostasis is maintained by programmed cell death which occurs when the growth stimulus is withdrawn, in response to negative growth regulators such as interferons, TNF-alpha and CD95 ligand, or following differentiation. Although acutely-transforming oncogenes often overcome the need for growth factors, growth regulatory cytokines can influence proliferative responses of transformed cells. In this study we investigated the effects of IL-3 on the proliferative responses of parental bone marrow-derived 32D cells and cells transformed with ras and abl oncogenes. We show that treatment of ras-transformed 32D cells with IL-3 reduced proliferative responses and decreased colony-forming ability. These effects were exacerbated in the absence of serum and associated with inhibition of tyrosine kinase activity, down-regulation of RAS and MYC expression, and induction of apoptosis as indicated by DNA fragmentation. In contrast, treatment of parental 32D cells with IL-3, which is obligatory for cell survival and proliferation, increased tyrosine kinase activity, upregulated MYC and RAS expression and maintained DNA integrity. With abl-transformed cells, proliferation and colony-forming ability were also inhibited by IL-3. Tyrosine kinase activity and MYC expression were reduced, but early apoptosis was not evident. Calcium uptake however, was stimulated by IL-3 in both parental and oncogene-transformed cells. These results suggest that threshold levels of tyrosine kinase activity are necessary for cell survival and proliferation and that with ras-transformed cells, IL-3 treatment may result in this threshold being breached. We conclude that in some situations, growth-promoting cytokines can inhibit proliferation of transformed cells and induce cell death by apoptosis.

Differential modulation of the N2 and P3 event-related potentials by response conflict and inhibition.

PubMed

Groom, Madeleine J; Cragg, Lucy

2015-07-01

Developing reliable and specific neural markers of cognitive processes is essential to improve understanding of healthy and atypical brain function. Despite extensive research there remains uncertainty as to whether two electrophysiological markers of cognitive control, the N2 and P3, are better conceptualised as markers of response inhibition or response conflict. The present study aimed to directly compare the effects of response inhibition and response conflict on the N2 and P3 event-related potentials, within-subjects. A novel hybrid go/no-go flanker task was performed by 19 healthy adults aged 18-25 years while EEG data were collected. The response congruence of a central target stimulus and 4 flanking stimuli was manipulated between trials to vary the degree of response conflict. Response inhibition was required on a proportion of trials. N2 amplitude was measured at two frontal electrode sites; P3 amplitude was measured at 4 midline electrode sites. N2 amplitude was greater on incongruent than congruent trials but was not enhanced by response inhibition when the stimulus array was congruent. P3 amplitude was greater on trials requiring response inhibition; this effect was more pronounced at frontal electrodes. P3 amplitude was also enhanced on incongruent compared with congruent trials. The findings support a role for N2 amplitude as a marker of response conflict and for the frontal shift of the P3 as a marker of response inhibition. This paradigm could be applied to clinical groups to help clarify the precise nature of impaired action control in disorders such as attention deficit/hyperactivity disorders (ADHD). Copyright © 2015 Elsevier Inc. All rights reserved.

Distinguishing Adolescents With ADHD From Their Unaffected Siblings and Healthy Comparison Subjects by Neural Activation Patterns During Response Inhibition.

PubMed

van Rooij, Daan; Hoekstra, Pieter J; Mennes, Maarten; von Rhein, Daniel; Thissen, Andrieke J A M; Heslenfeld, Dirk; Zwiers, Marcel P; Faraone, Stephen V; Oosterlaan, Jaap; Franke, Barbara; Rommelse, Nanda; Buitelaar, Jan K; Hartman, Catharina A

2015-07-01

Dysfunctional response inhibition is a key executive function impairment in attention deficit hyperactivity disorder (ADHD). Still, behavioral response inhibition measures do not consistently differentiate affected from unaffected individuals. The authors therefore investigated neural correlates of response inhibition and the familial nature of these neural correlates. Functional MRI measurements of neural activation during the stop-signal task and behavioral measures of response inhibition were obtained in adolescents and young adults with ADHD (N=185), their unaffected siblings (N=111), and healthy comparison subjects (N=124). Stop-signal task reaction times were longer and error rates were higher in participants with ADHD, but not in their unaffected siblings, while reaction time variability was higher in both groups than in comparison subjects. Relative to comparison subjects, participants with ADHD and unaffected siblings had neural hypoactivation in frontal-striatal and frontal-parietal networks, whereby activation in inferior frontal and temporal/parietal nodes in unaffected siblings was intermediate between levels of participants with ADHD and comparison subjects. Furthermore, neural activation in inferior frontal nodes correlated with stop-signal reaction times, and activation in both inferior frontal and temporal/parietal nodes correlated with ADHD severity. Neural activation alterations in ADHD are more robust than behavioral response inhibition deficits and explain variance in response inhibition and ADHD severity. Although only affected participants with ADHD have deficient response inhibition, hypoactivation in inferior frontal and temporal-parietal nodes in unaffected siblings supports the familial nature of the underlying neural process. Activation deficits in these nodes may be useful as endophenotypes that extend beyond the affected individuals in the family.

Neuroscience of inhibition for addiction medicine: From prediction of initiation to prediction of relapse

PubMed Central

Moeller, Scott J.; Bederson, Lucia; Alia-Klein, Nelly; Goldstein, Rita Z.

2017-01-01

A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior. Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differences from healthy non-addicted controls during tasks of response inhibition accompanied by brain activation abnormalities as revealed by functional neuroimaging. However, it is less clear whether inhibition-related deficits predate the transition to problematic use, and, in turn, whether these deficits predict the transition out of problematic substance use. Here, we review longitudinal studies of response inhibition in children/adolescents with little substance experience and longitudinal studies of already-addicted individuals attempting to sustain abstinence. Results show that response inhibition, and its underlying neural correlates, predict both substance use outcomes (onset and abstinence). Neurally, key roles were observed for multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex). In general, less activation of these regions during response inhibition predicted not only the onset of substance use, but interestingly, also better abstinence-related outcomes among individuals already addicted. The role of subcortical areas, although potentially important, is less clear because of inconsistent results and because these regions are less classically reported in studies of healthy response inhibition. Overall, this review indicates that response inhibition is not simply a manifestation of current drug addiction, but rather a core neurocognitive dimension that predicts key substance use outcomes. Early intervention in inhibitory deficits could have high clinical and public health relevance. PMID:26806776

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.

PubMed

Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj; Hermann, Thomas; Køber, Lars; Torp-Pedersen, Christian

2003-10-14

Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. These results support the concept that TNF-alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition

PubMed Central

van Rooij, Sanne J.H.; Rademaker, Arthur R.; Kennis, Mitzy; Vink, Matthijs; Kahn, René S.; Geuze, Elbert

2014-01-01

Background Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. Methods Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). Results We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. Limitations Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. Conclusion Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit. PMID:24886789

Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

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

Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov

Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional programmore » encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.« less

Individual differences in inhibitory control--relationship between baseline activation in lateral PFC and an electrophysiological index of response inhibition.

PubMed

Schiller, Bastian; Gianotti, Lorena R R; Nash, Kyle; Knoch, Daria

2014-09-01

The capacity to inhibit inappropriate responses is crucial for goal-directed behavior. Inhibiting such responses seems to come more easily to some of us than others, however. From where do these individual differences originate? Here, we measured 263 participants' neural baseline activation using resting electroencephalogram. Then, we used this stable neural marker to predict a reliable electrophysiological index of response inhibition capacity in the cued Continuous Performance Test, the NoGo-Anteriorization (NGA). Using a source-localization technique, we found that resting delta, theta, and alpha1 activity in the left middle frontal gyrus and resting alpha1 activity in the right inferior frontal gyrus were negatively correlated with the NGA. As a larger NGA is thought to represent better response inhibition capacity, our findings demonstrate that lower levels of resting slow-wave oscillations in the lateral prefrontal cortex, bilaterally, are associated with a better response inhibition capacity. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans

PubMed Central

Crockett, Molly J.; Clark, Luke; Robbins, Trevor W.

2009-01-01

The neuromodulator serotonin has been implicated in a large number of affective and executive functions, but its precise contribution to motivation remains unclear. One influential hypothesis has implicated serotonin in aversive processing; another has proposed a more general role for serotonin in behavioral inhibition. Since behavioral inhibition is a pre-potent reaction to aversive outcomes, it has been a challenge to reconcile these two accounts. Here, we show that serotonin is critical for punishment-induced inhibition, but not overall motor response inhibition or reporting aversive outcomes. We used acute tryptophan depletion to temporarily lower brain serotonin in healthy human volunteers as they completed a novel task designed to obtain separate measures of motor response inhibition, punishment-induced inhibition, and sensitivity to aversive outcomes. Following a placebo treatment, participants were slower to respond under punishment conditions, compared to reward conditions. Tryptophan depletion abolished this punishment-induced inhibition, without affecting overall motor response inhibition or the ability to adjust response bias in line with punishment contingencies. The magnitude of reduction in punishment-induced inhibition depended on the degree to which tryptophan depletion reduced plasma tryptophan levels. These findings extend and clarify previous research on the role of serotonin in aversive processing and behavioral inhibition, and fit with current theorizing on serotonin's involvement in predicting aversive outcomes. PMID:19776285

Genetic separation of phototropism and blue light inhibition of stem elongation

NASA Technical Reports Server (NTRS)

Liscum, E.; Young, J. C.; Poff, K. L.; Hangarter, R. P.

1992-01-01

Blue light-induced regulation of cell elongation is a component of the signal response pathway for both phototropic curvature and inhibition of stem elongation in higher plants. To determine if blue light regulates cell elongation in these responses through shared or discrete pathways, phototropism and hypocotyl elongation were investigated in several blue light response mutants in Arabidopsis thaliana. Specifically, the blu mutants that lack blue light-dependent inhibition of hypocotyl elongation were found to exhibit a normal phototropic response. In contrast, a phototropic null mutant (JK218) and a mutant that has a 20- to 30-fold shift in the fluence dependence for first positive phototropism (JK224) showed normal inhibition of hypocotyl elongation in blue light. F1 progeny of crosses between the blu mutants and JK218 showed normal phototropism and inhibition of hypocotyl elongation, and approximately 1 in 16 F2 progeny were double mutants lacking both responses. Thus, blue light-dependent inhibition of hypocotyl elongation and phototropism operate through at least some genetically distinct components.

Influence of Response Prepotency Strength, General Working Memory Resources, and Specific Working Memory Load on the Ability to Inhibit Predominant Responses: A Comparison of Young and Elderly Participants

ERIC Educational Resources Information Center

Grandjean, Julien; Collette, Fabienne

2011-01-01

One conception of inhibitory functioning suggests that the ability to successfully inhibit a predominant response depends mainly on the strength of that response, the general functioning of working memory processes, and the working memory demand of the task (Roberts, Hager, & Heron, 1994). The proposal that inhibition and functional working memory…

5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Inhibits RIPK1/RIPK3-Dependent Necroptosis in THP-1-Derived Foam Cells

PubMed Central

Tian, Fang; Yao, Jianting; Yan, Meng; Sun, Xin; Wang, Wei; Gao, Weiwei; Tian, Zhen; Guo, Shuyuan; Dong, Zengxiang; Li, Bicheng; Gao, Tielei; Shan, Peng; Liu, Bing; Wang, Haiyang; Cheng, Jiali; Gao, Qianping; Zhang, Zhiguo; Cao, Wenwu; Tian, Ye

2016-01-01

Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived foam cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in foam cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis. PMID:26911899

Role of Body Esteem in the Sexual Excitation and Inhibition Responses of Women With and Without a History of Childhood Sexual Abuse

PubMed Central

Kiminik, Chelsea D.; Meston, Cindy M.

2016-01-01

Introduction Women’s sexuality is influenced by their perceptions of their bodies. Negative body appraisals have been implicated in the development and maintenance of sexual concerns in women with a history of childhood sexual abuse (CSA). The sexuality of these women is often expressed in extremes of approach and avoidant sexual tendencies, which have been related to the sexual inhibition and sexual excitation pathways of the dual control model. Aim To test the influence of body esteem on the sexual excitation and inhibition responses of women with and without a history of CSA. Methods One hundred thirty-nine women with CSA and 83 non-abused women reported on their abuse history, depressive symptomology, sexual response, and affective appraisals of their body. Main Outcome Measures Validated self-report measurements of sexual excitation and inhibition responses (Sexual Excitation/Sexual Inhibition Inventory for Women) and body esteem (Body Esteem Scale) were administered. Results Body esteem was significantly associated with sexual inhibition responses of women regardless of CSA history status but was significantly related only to the sexual excitation responses of women with a CSA history. Perceived sexual attractiveness was a unique predictor of sexual excitation in women with a history of CSA. Conclusion Women with a history of CSA have lower body esteem than non-abused women, particularly in self-perceived sexual attractiveness, and these perceptions appear to influence their sexual responses by acting on the sexual excitation and inhibition response pathways. PMID:27692843

Neural and behavioral mechanisms of proactive and reactive inhibition

PubMed Central

Meyer, Heidi C.

2016-01-01

Response inhibition is an important component of adaptive behavior. Substantial prior research has focused on reactive inhibition, which refers to the cessation of a motor response that is already in progress. More recently, a growing number of studies have begun to examine mechanisms underlying proactive inhibition, whereby preparatory processes result in a response being withheld before it is initiated. It has become apparent that proactive inhibition is an essential component of the overall ability to regulate behavior and has implications for the success of reactive inhibition. Moreover, successful inhibition relies on learning the meaning of specific environmental cues that signal when a behavioral response should be withheld. Proactive inhibitory control is mediated by stopping goals, which reflect the desired outcome of inhibition and include information about how and when inhibition should be implemented. However, little is known about the circuits and cellular processes that encode and represent features in the environment that indicate the necessity for proactive inhibition or how these representations are implemented in response inhibition. In this article, we will review the brain circuits and systems involved in implementing inhibitory control through both reactive and proactive mechanisms. We also comment on possible cellular mechanisms that may contribute to inhibitory control processes, noting that substantial further research is necessary in this regard. Furthermore, we will outline a number of ways in which the temporal dynamics underlying the generation of the proactive inhibitory signal may be particularly important for parsing out the neurobiological correlates that contribute to the learning processes underlying various aspects of inhibitory control. PMID:27634142

The effect of vagus nerve stimulation on response inhibition.

PubMed

Schevernels, Hanne; van Bochove, Marlies E; De Taeye, Leen; Bombeke, Klaas; Vonck, Kristl; Van Roost, Dirk; De Herdt, Veerle; Santens, Patrick; Raedt, Robrecht; Boehler, C Nico

2016-11-01

In the current study, we explored whether vagus nerve stimulation (VNS) in patients with epilepsy, which is believed to increase norepinephrine (NE) levels via activation of the locus coeruleus, would positively affect response inhibition. Moreover, we tried to identify the dynamics of the underlying neural processes by investigating event-related potentials (ERPs) and pupil size. Patients performed a stop-signal task once when stimulation was switched on and once when it was switched off. We found a correlational pattern suggesting that patients who clinically benefit more from VNS treatment also show a larger behavioral advantage, in terms of faster response inhibition, when the vagus nerve is being stimulated. Event-related potential (ERP) results suggested more pronounced reactive inhibition when stimulation was switched on, independent of the individual amount of seizure reduction. Transient go-locked pupil size was increased from go trials to successful stop trials to unsuccessful stop trials but without displaying a clear VNS effect, which however, might relate to limited sensitivity. We conclude that VNS likely has a positive effect on response inhibition, at least in patients with epilepsy that benefit clinically from the treatment, presumably relating to enhancements of response-inhibition mechanisms and, therefore, identify enhanced response inhibition as a possible cognitive benefit of VNS. Copyright © 2016 Elsevier Inc. All rights reserved.

The Role of Inhibition in Age-related Off-Topic Verbosity: Not Access but Deletion and Restraint Functions

PubMed Central

Yin, Shufei; Peng, Huamao

2016-01-01

The speech of older adults is commonly described as verbose and off-topic, which is thought to influence their social communication. This study investigated the role of inhibition in age-related off-topic verbosity (OTV). Inhibition consists of three functions: access, deletion, and restraint. The access function is responsible for preventing irrelevant information from accessing the attention center (pre-mechanism of inhibition); The deletion function is responsible for deleting previously relevant but currently irrelevant information from working memory, and the restraint function is responsible for restraining strong but inappropriate responses (post-mechanisms of inhibition). A referential communication task was used to determine whether OTV was influenced by the pre-mechanism of inhibition. A self-involved event interview task was used to investigate the effect of the post-mechanisms of inhibition on OTV. Results showed that the OTV of the elderly participants was associated with an age-related decline in the post-mechanisms of inhibition, while the OTV exhibited by young adults was most likely due to deficits in the pre-mechanism function of inhibition. This research contributed to fill gaps in the existing knowledge about the potential relationship between specific functions of inhibition and age-related OTV. PMID:27199793

An Examination of the Effects of Stimulant Medication on Response Inhibition: A Comparison between Children with and without Attention Deficit Hyperactivity Disorder

ERIC Educational Resources Information Center

Brackenridge, Rachel; McKenzie, Karen; Murray, George C.; Quigley, April

2011-01-01

This study investigated whether methylphenidate is effective in improving response inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD). Children with ADHD were compared with normally developing children on measures of response inhibition. Participants with ADHD were compared across two conditions--medicated and unmedicated.…

Dissociating Consciousness from Inhibitory Control: Evidence for Unconsciously Triggered Response Inhibition in the Stop-Signal Task

ERIC Educational Resources Information Center

van Gaal, Simon; Ridderinkhof, K. Richard; van den Wildenberg, Wery P. M.; Lamme, Victor A. F.

2009-01-01

Theories about the functional relevance of consciousness commonly posit that higher order cognitive control functions, such as response inhibition, require consciousness. To test this assertion, the authors designed a masked stop-signal paradigm to examine whether response inhibition could be triggered and initiated by masked stop signals, which…

Automaticity of Cognitive Control: Goal Priming in Response-Inhibition Paradigms

ERIC Educational Resources Information Center

Verbruggen, Frederick; Logan, Gordon D.

2009-01-01

Response inhibition is a hallmark of cognitive control. An executive system inhibits responses by activating a stop goal when a stop signal is presented. The authors asked whether the stop goal could be primed by task-irrelevant information in stop-signal and go/no-go paradigms. In Experiment 1, the task-irrelevant primes "GO," ###, or "STOP" were…

Orphan Toxin OrtT (YdcX) of Escherichia coli Reduces Growth during the Stringent Response

DTIC Science & Technology

2015-01-29

antimicrobials trimethoprim and sulfamethoxazole; these antimicrobials induce the stringent response by inhibiting tetrahydrofolate synthesis...in the presence of both antimicrobials trimethoprim and sulfamethoxazole; these antimicrobials induce the stringent response by inhibiting...level [20]. Toxins 2015, 7 301 Despite these difficulties in determining physiological roles, TA systems are clearly phage inhibition systems

Aging effects in response inhibition: general slowing without decline in inhibitory functioning.

PubMed

Yano, Madoka

2011-12-01

Previous research has examined aging effects on response inhibition using cognitive interference paradigms such as the Stroop task and the Simon task. Performance in these tasks requires participants to inhibit predominant responses. Reduced response inhibition is reflected by poorer performance in incongruent trials where prepotent responses can interfere with other correct responses, than in congruent trials without such interference (i.e., Stroop or Simon congruency effects). It is unclear whether such effects increase with normal aging. Balota et al. (2010) reported that the Stroop effect can be a useful predictor of conversion to Alzheimer's disease in a healthy control sample. Congruency effects are also subject to trial sequencing: They are smaller following an incongruent trial than following a congruent one. The present study determined whether response inhibition was affected by normal aging using the Simon task, with focus on the influence of normal aging on sequence effects. Forty-three young participants and 14 healthy elderly adults performed the Simon task individually. Results indicated that both age groups showed the same magnitude of Simon effects and sequence effects, although overall response latencies were longer in elderly participants than in young participants. Furthermore, the elderly adults tended to make fewer errors than the younger adults. These findings suggest that normal aging may produce reduced processing speed but it does not affect response inhibition itself.

Cue response dissociates inhibitory processes: task identity information is related to backward inhibition but not to competitor rule suppression.

PubMed

Regev, Shirley; Meiran, Nachshon

2017-01-01

In task switching, a conflict between competing task-sets is resolved by inhibiting the interfering task-set. Recent models have proposed a framework of the task-set as composed of two hierarchical components: abstract task identity (e.g., respond to quantity) and more concrete task rules (e.g., category-response rules mapping the categories "one" and "three" to the left and right keys, respectively). The present study explored whether task-set inhibition is the outcome of a general control process or whether it reflects multiple inhibitory processes, each targeting a different component of the competing task-set. To this end, two effects of task-set inhibition were examined: backward inhibition (BI), reflecting the suppression of a just-performed task-set that is no longer relevant; and, competitor rule suppression (CRS), reflecting the suppression of an irrelevant task-set that generates a response conflict. In two task switching experiments, each involving three tasks, we asked participants to make two responses: a cue response, indicating the identity of the relevant task (e.g., "Color"), and a target response requiring the implementation of the task rule (e.g., "Red"). The results demonstrate that BI, but not CRS, appears in cue responses, and thus, suggests that BI reflects inhibition that influences representations related to abstract task identity, rather than (just) competing responses or response rules. These results support a dissociation between inhibitory processes in task switching. The current findings also provide further evidence for a multi-component conceptualization of task-set and task-set inhibition.

An fMRI study of behavioral response inhibition in adolescents with and without histories of heavy prenatal alcohol exposure

PubMed Central

Ware, Ashley L.; Infante, M. Alejandra; O’Brien, Jessica W.; Tapert, Susan F.; Jones, Kenneth Lyons; Riley, Edward P.; Mattson, Sarah N.

2014-01-01

Heavy prenatal alcohol exposure results in a range of deficits, including both volumetric and functional changes in brain regions involved in response inhibition such as the prefrontal cortex and striatum. The current study examined blood oxygen level-dependent (BOLD) response during a stop signal task in adolescents (ages 13–16 y) with histories of heavy prenatal alcohol exposure (AE, n = 21) and controls (CON, n = 21). Task performance was measured using percent correct inhibits during three difficulty conditions: easy, medium, and hard. Group differences in BOLD response relative to baseline motor responding were examined across all inhibition trials and for each difficulty condition separately. The contrast between hard and easy trials was analyzed to determine whether increasing task difficulty affected BOLD response. Groups had similar task performance and demographic characteristics, except for full scale IQ scores (AE < CON). The AE group demonstrated greater BOLD response in frontal, sensorimotor, striatal, and cingulate regions relative to controls, especially as task difficulty increased. When contrasting hard vs. easy inhibition trials, the AE group showed greater medial/superior frontal and cuneus BOLD response than controls. Results were unchanged after demographics and FAS diagnosis were statistically controlled. This was the first fMRI study to utilize a stop signal task, isolating fronto-striatal functioning, to assess response inhibition and the effects task difficulty in adolescents with prenatal alcohol exposure. Results suggest that heavy prenatal alcohol exposure disrupts neural function of this circuitry, resulting in immature cognitive processing and motor-association learning and neural compensation during response inhibition. PMID:25281280

Daily associations between emotional functioning and alcohol involvement: Moderating effects of response inhibition and gender.

PubMed

Dvorak, Robert D; Pearson, Matthew R; Sargent, Emily M; Stevenson, Brittany L; Mfon, Angel M

2016-06-01

Research has linked tonic and variable mood to problematic alcohol use, both between- and within-subjects. Indices of behavioral control have moderated these links, at least at the between-subjects level. The current study examines daily associations between indices of emotional functioning and alcohol involvement as a function of response inhibition. College student drinkers (n=74; 58.11% female) were enrolled in a study on emotion and alcohol use. Participants completed a stop-signal task as an index of response inhibition. They then carried a personal data device for 21 days, reporting daily on mood, alcohol use, and acute alcohol use disorder symptoms. Mood instability was the mean square of successive differences from daily mood assessments. There were 1309 person days (622 drinking days) available for analysis. Pre-drinking mood instability was positively associated the likelihood of drinking and drinks consumed on drinking days. The former association was diminished among women with high response inhibition. Pre-drinking positive mood was positively associated the likelihood of drinking and drinks consumed on drinking days. The latter association was diminished among women with high response inhibition. Pre-drinking negative mood was positively associated with drinks consumed on drinking days among women with low response inhibition. Finally, pre-drinking positive mood was associated with acute alcohol use disorder symptoms among those with low response inhibition. These results suggest that interventions targeting positive mood may be particularly important. Further, developing ways to improve response inhibition control may broadly influence negative drinking outcomes by affecting multiple mood-drinking associations. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Sleep Moderates the Association Between Response Inhibition and Self-Regulation in Early Childhood

PubMed Central

Schumacher, Allyson M.; Miller, Alison L.; Watamura, Sarah E.; Kurth, Salome; Lassonde, Jonathan M.; LeBourgeois, Monique K.

2017-01-01

Early childhood is a time of rapid developmental changes in sleep, cognitive control processes, and the regulation of emotion and behavior. This experimental study examined sleep-dependent effects on response inhibition and self-regulation, as well as whether acute sleep restriction moderated the association between these processes. Preschool children (N = 19; 45.6 ± 2.2 months; 11 female) followed a strict sleep schedule for at least 3 days before each of 2 morning behavior assessments: baseline (habitual nap/night sleep) and sleep restriction (missed nap/delayed bedtime). Response inhibition was evaluated via a go/no-go task. Twelve self-regulation strategies were coded from videotapes of children while attempting an unsolvable puzzle. We then created composite variables representing adaptive and maladaptive self-regulation strategies. Although we found no sleep-dependent effects on response inhibition or self-regulation measures, linear mixed-effects regression showed that acute sleep restriction moderated the relationship between these processes. At baseline, children with better response inhibition were more likely to use adaptive self-regulation strategies (e.g., self-talk, alternate strategies), and those with poorer response inhibition showed increased use of maladaptive self-regulation strategies (e.g., perseveration, fidgeting); however, response inhibition was not related to self-regulation strategies following sleep restriction. Our results showing a sleep-dependent effect on the associations between response inhibition and self-regulation strategies indicate that adequate sleep facilitates synergy between processes supporting optimal social-emotional functioning in early childhood. Although replication studies are needed, findings suggest that sleep may alter connections between maturing emotional and cognitive systems, which have important implications for understanding risk for or resilience to developmental psychopathology. PMID:27652491

Neural activation patterns during response inhibition distinguish adolescents with ADHD, their unaffected siblings, and healthy controls

PubMed Central

van Rooij, Daan; Hoekstra, Pieter J.; Mennes, Maarten; von Rhein, Daniel; Thissen, Andrieke J.A.M.; Heslenfeld, Dirk; Zwiers, Marcel P.; Faraone, Stephen V.; Oosterlaan, Jaap; Franke, Barbara; Rommelse, Nanda; Buitelaar, Jan K.; Hartman, Catharina A.

2015-01-01

Objective Impaired response inhibition is a key executive function deficit of attention-deficit/hyperactivity disorder (ADHD). Still, behavioral response inhibition measures do not consistently differentiate individuals with ADHD from unaffected individuals. We therefore investigated the neural correlates of response inhibition as well as the familial nature of these neural correlates. Methods fMRI measurements of neural activation during the stop-signal task along with behavioral measures of response inhibition were obtained in adolescents and young adults with ADHD (N=185), their unaffected siblings (N=111), and healthy controls (N=124). Results Stop-signal reaction times were longer in participants with ADHD, but not in their unaffected siblings, while reaction time variability and error rates were higher in both groups than in controls. Neural hypoactivation was observed in frontal-striatal and frontal-parietal networks of participants with ADHD and unaffected siblings compared to controls, whereby activation in inferior frontal and temporal/parietal nodes in unaffected siblings was intermediate between that of participants with ADHD and controls. Furthermore, neural activation in inferior frontal nodes correlated with stop-signal reaction times, and activation in both inferior frontal and temporal/parietal nodes correlated with ADHD severity. Conclusions Neural activation alterations in ADHD are more robust than behavioral response inhibition deficits and explain variance in response inhibition and ADHD severity. Although only affected participants with ADHD have deficient response inhibition, hypoactivation in inferior frontal and temporal-parietal nodes in unaffected siblings support the familial nature of the underlying neural process. Hypoactivation in these nodes may be useful as endophenotypes that extend beyond the affected individuals in the family. PMID:25615565

Sleep Moderates the Association Between Response Inhibition and Self-Regulation in Early Childhood.

PubMed

Schumacher, Allyson M; Miller, Alison L; Watamura, Sarah E; Kurth, Salome; Lassonde, Jonathan M; LeBourgeois, Monique K

2017-01-01

Early childhood is a time of rapid developmental changes in sleep, cognitive control processes, and the regulation of emotion and behavior. This experimental study examined sleep-dependent effects on response inhibition and self-regulation, as well as whether acute sleep restriction moderated the association between these processes. Preschool children (N = 19; 45.6 ± 2.2 months; 11 female) followed a strict sleep schedule for at least 3 days before each of 2 morning behavior assessments: baseline (habitual nap/night sleep) and sleep restriction (missed nap/delayed bedtime). Response inhibition was evaluated via a go/no-go task. Twelve self-regulation strategies were coded from videotapes of children while attempting an unsolvable puzzle. We then created composite variables representing adaptive and maladaptive self-regulation strategies. Although we found no sleep-dependent effects on response inhibition or self-regulation measures, linear mixed-effects regression showed that acute sleep restriction moderated the relationship between these processes. At baseline, children with better response inhibition were more likely to use adaptive self-regulation strategies (e.g., self-talk, alternate strategies), and those with poorer response inhibition showed increased use of maladaptive self-regulation strategies (e.g., perseveration, fidgeting); however, response inhibition was not related to self-regulation strategies following sleep restriction. Our results showing a sleep-dependent effect on the associations between response inhibition and self-regulation strategies indicate that adequate sleep facilitates synergy between processes supporting optimal social-emotional functioning in early childhood. Although replication studies are needed, findings suggest that sleep may alter connections between maturing emotional and cognitive systems, which have important implications for understanding risk for or resilience to developmental psychopathology.

p53 is a major component of the transcriptional and apoptotic program regulated by PI 3-kinase/Akt/GSK3 signaling.

PubMed

Nayak, G; Cooper, G M

2012-10-11

The phosphatidylinositol (PI) 3-kinase/Akt signaling pathway has a prominent role in cell survival and proliferation, in part, by regulating gene expression at the transcriptional level. Previous work using global expression profiling identified FOXOs and the E-box-binding transcription factors MITF and USF1 as key targets of PI 3-kinase signaling that lead to the induction of proapoptotic and cell cycle arrest genes in response to inhibition of PI 3-kinase. In this study, we investigated the role of p53 downstream of PI 3-kinase signaling by analyzing the effects of inhibition of PI 3-kinase in Rat-1 cells, which have wild-type p53, compared with Rat-1 cells expressing a dominant-negative p53 mutant. Expression of dominant-negative p53 conferred partial resistance to apoptosis induced by inhibition of PI 3-kinase. Global gene expression profiling combined with computational and experimental analysis of transcription factor binding sites demonstrated that p53, along with FOXO, MITF and USF1, contributed to gene induction in response to PI 3-kinase inhibition. Activation of p53 was mediated by phosphorylation of the histone acetyltransferase Tip60 by glycogen synthase kinase (GSK) 3, leading to activation of p53 by acetylation. Many of the genes targeted by p53 were also targeted by FOXO and E-box-binding transcription factors, indicating that p53 functions coordinately with these factors to regulate gene expression downstream of PI 3-kinase/Akt/GSK3 signaling.

Detrimental effects of proteasome inhibition activity in Drosophila melanogaster: implication of ER stress, autophagy, and apoptosis.

PubMed

Velentzas, Panagiotis D; Velentzas, Athanassios D; Mpakou, Vassiliki E; Antonelou, Marianna H; Margaritis, Lukas H; Papassideri, Issidora S; Stravopodis, Dimitrios J

2013-02-01

In eukaryotes, the ubiquitin-proteasome machinery regulates a number of fundamental cellular processes through accurate and tightly controlled protein degradation pathways. We have, herein, examined the effects of proteasome functional disruption in Dmp53 (+/+) (wild-type) and Dmp53 (-/-) Drosophila melanogaster fly strains through utilization of Bortezomib, a proteasome-specific inhibitor. We report that proteasome inhibition drastically shortens fly life-span and impairs climbing performance, while it also causes larval lethality and activates developmentally irregular cell death programs during oogenesis. Interestingly, Dmp53 gene seems to play a role in fly longevity and climbing ability. Moreover, Bortezomib proved to induce endoplasmic reticulum (ER) stress that was able to result in the engagement of unfolded protein response (UPR) signaling pathway, as respectively indicated by fly Xbp1 activation and Ref(2)P-containing protein aggregate formation. Larva salivary gland and adult brain both underwent strong ER stress in response to Bortezomib, thus underscoring the detrimental role of proteasome inhibition in larval development and brain function. We also propose that the observed upregulation of autophagy operates as a protective mechanism to "counterbalance" Bortezomib-induced systemic toxicity, which is tightly associated, besides ER stress, with activation of apoptosis, mainly mediated by functional Drice caspase and deregulated dAkt kinase. The reduced life-span of exposed to Bortezomib flies overexpressing Atg1_RNAi or Atg18_RNAi supports the protective nature of autophagy against proteasome inhibition-induced stress. Our data reveal the in vivo significance of proteasome functional integrity as a major defensive system against cellular toxicity likely occurring during critical biological processes and morphogenetic courses.

Neuroscience of inhibition for addiction medicine: from prediction of initiation to prediction of relapse.

PubMed

Moeller, Scott J; Bederson, Lucia; Alia-Klein, Nelly; Goldstein, Rita Z

2016-01-01

A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior. Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differences from healthy nonaddicted controls during tasks of response inhibition accompanied by brain activation abnormalities as revealed by functional neuroimaging. However, it is less clear whether inhibition-related deficits predate the transition to problematic use, and, in turn, whether these deficits predict the transition out of problematic substance use. Here, we review longitudinal studies of response inhibition in children/adolescents with little substance experience and longitudinal studies of already addicted individuals attempting to sustain abstinence. Results show that response inhibition and its underlying neural correlates predict both substance use outcomes (onset and abstinence). Neurally, key roles were observed for multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex). In general, less activation of these regions during response inhibition predicted not only the onset of substance use, but interestingly also better abstinence-related outcomes among individuals already addicted. The role of subcortical areas, although potentially important, is less clear because of inconsistent results and because these regions are less classically reported in studies of healthy response inhibition. Overall, this review indicates that response inhibition is not simply a manifestation of current drug addiction, but rather a core neurocognitive dimension that predicts key substance use outcomes. Early intervention in inhibitory deficits could have high clinical and public health relevance. © 2016 Elsevier B.V. All rights reserved.

Inhibition of antigen- and mitogen-induced human lymphocyte proliferation by gold compounds.

PubMed Central

Lipsky, P E; Ziff, M

1977-01-01

Gold sodium thiomalate (GST) inhibited in vitro antigen- and mitogen-triggered human lymphocyte DNA synthesis. Inhibition of responsiveness was observed with concentrations of GST equivalent to gold levels found in serum or tissues of patients receiving chrysotherapy, Inhibition was dependent upon the gold ion itself since GST and gold chloride were both inhibitory whereas thiomalic acid was not. Inhibition could not be explained by nonspecific killing of cells or by an alteration in the kinetics of the responses. GST inhibited mitogen-induced proliferation most effectively when present from the initiation of culture and could not inhibit the responsiveness of cells which previously had been activated by concanvalin A. These findings indicated that GST blocked a critical early step in lymphocyte activation. The degree of GST-induced inhibition of proliferation was increased in cultures of cells partially depleted of monocytes. Moreover, inhibition was reversed by supplementation of these cultures with purified monocytes. These observations suggested that GST blocked thymus-derived (T)-lymphocyte activation by interfering with a requisite function of the monocyte population in initiating such responses. Prolonged incubation of peripheral blood mononuclear cells with GST resulted in diminished mitogen responsiveness upon subsequent culture in the absence of gold. The addition of fresh monocytes restored responsiveness to these populations. Furthermore, preincubation of purified monocytes with GST rendered them deficient in their ability to support mitogen-induced T-lymphocyte proliferation on subsequent culture. These observations indicate that the major effect of GST results from interference with the functional capability of the monocyte population. PMID:838859

Deficits in inhibitory control and conflict resolution on cognitive and motor tasks in Parkinson's disease.

PubMed

Obeso, Ignacio; Wilkinson, Leonora; Casabona, Enrique; Bringas, Maria Luisa; Álvarez, Mario; Álvarez, Lázaro; Pavón, Nancy; Rodríguez-Oroz, Maria-Cruz; Macías, Raúl; Obeso, Jose A; Jahanshahi, Marjan

2011-07-01

Recent imaging studies in healthy controls with a conditional stop signal reaction time (RT) task have implicated the subthalamic nucleus (STN) in response inhibition and the pre-supplementary motor area (pre-SMA) in conflict resolution. Parkinson's disease (PD) is characterized by striatal dopamine deficiency and overactivity of the STN and underactivation of the pre-SMA during movement. We used the conditional stop signal RT task to investigate whether PD produced similar or dissociable effects on response initiation, response inhibition and response initiation under conflict. In addition, we also examined inhibition of prepotent responses on three cognitive tasks: the Stroop, random number generation and Hayling sentence completion. PD patients were impaired on the conditional stop signal reaction time task, with response initiation both in situations with or without conflict and response inhibition all being significantly delayed, and had significantly greater difficulty in suppressing prepotent or habitual responses on the Stroop, Hayling and random number generation tasks relative to controls. These results demonstrate the existence of a generalized inhibitory deficit in PD, which suggest that PD is a disorder of inhibition as well as activation and that in situations of conflict, executive control over responses is compromised.

A Comparative Study of Ethylene Growth Response Kinetics in Eudicots and Monocots Reveals a Role for Gibberellin in Growth Inhibition and Recovery1[W][OA

PubMed Central

Kim, Joonyup; Wilson, Rebecca L.; Case, J. Brett; Binder, Brad M.

2012-01-01

Time-lapse imaging of dark-grown Arabidopsis (Arabidopsis thaliana) hypocotyls has revealed new aspects about ethylene signaling. This study expands upon these results by examining ethylene growth response kinetics of seedlings of several plant species. Although the response kinetics varied between the eudicots studied, all had prolonged growth inhibition for as long as ethylene was present. In contrast, with continued application of ethylene, white millet (Panicum miliaceum) seedlings had a rapid and transient growth inhibition response, rice (Oryza sativa ‘Nipponbare’) seedlings had a slow onset of growth stimulation, and barley (Hordeum vulgare) had a transient growth inhibition response followed, after a delay, by a prolonged inhibition response. Growth stimulation in rice correlated with a decrease in the levels of rice ETHYLENE INSENSTIVE3-LIKE2 (OsEIL2) and an increase in rice F-BOX DOMAIN AND LRR CONTAINING PROTEIN7 transcripts. The gibberellin (GA) biosynthesis inhibitor paclobutrazol caused millet seedlings to have a prolonged growth inhibition response when ethylene was applied. A transient ethylene growth inhibition response has previously been reported for Arabidopsis ethylene insensitive3-1 (ein3-1) eil1-1 double mutants. Paclobutrazol caused these mutants to have a prolonged response to ethylene, whereas constitutive GA signaling in this background eliminated ethylene responses. Sensitivity to paclobutrazol inversely correlated with the levels of EIN3 in Arabidopsis. Wild-type Arabidopsis seedlings treated with paclobutrazol and mutants deficient in GA levels or signaling had a delayed growth recovery after ethylene removal. It is interesting to note that ethylene caused alterations in gene expression that are predicted to increase GA levels in the ein3-1 eil1-1 seedlings. These results indicate that ethylene affects GA levels leading to modulation of ethylene growth inhibition kinetics. PMID:22977279

Response inhibition under alcohol: effects of cognitive and motivational conflict.

PubMed

Fillmore, M T; Vogel-Sprott, M

2000-03-01

This experiment tested the effect of cognitive and motivational conflict on response inhibition under alcohol. Fifty-six male social drinkers were randomly assigned to one of eight groups (n = 8). Four pairs of groups received 0.62 g/kg of alcohol, or a placebo, and each pair performed a go/stop choice reaction time task under one of four conflict conditions. One condition (C) produced cognitive conflict by presenting "go" and "stop" signals in the task. Another condition (IR) added motivational conflict by administering an equal monetary reward for inhibiting responses to stop-signals, and for responding to go-signals. The remaining two conditions resolved the motivational conflict by administering the monetary reward only for inhibitions (I), or only for responses (R). Compared with placebo, alcohol reduced inhibitions (i.e., impaired inhibitory control) under cognitive conflict (C; p = .041) and under motivational conflict (IR; p = .012). No significant effect of alcohol on inhibitions was observed in conditions where conflict was resolved (i.e., I and R). The study shows that alcohol can reduce the ability to inhibit a response. However, impaired inhibitory control is not an inevitable outcome of the drug action, because it can be counteracted by the consequences of behavior in the situation.

Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum.

PubMed

Lorenz, Robert C; Gleich, Tobias; Buchert, Ralph; Schlagenhauf, Florian; Kühn, Simone; Gallinat, Jürgen

2015-10-01

Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine-glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition. © 2015 Wiley Periodicals, Inc.

A Co-Opted Hormonal Cascade Activates Dormant Adventitious Root Primordia upon Flooding in Solanum dulcamara.

PubMed

Dawood, Thikra; Yang, Xinping; Visser, Eric J W; Te Beek, Tim A H; Kensche, Philip R; Cristescu, Simona M; Lee, Sangseok; Floková, Kristýna; Nguyen, Duy; Mariani, Celestina; Rieu, Ivo

2016-04-01

Soil flooding is a common stress factor affecting plants. To sustain root function in the hypoxic environment, flooding-tolerant plants may form new, aerenchymatous adventitious roots (ARs), originating from preformed, dormant primordia on the stem. We investigated the signaling pathway behind AR primordium reactivation in the dicot species Solanum dulcamara Transcriptome analysis indicated that flooding imposes a state of quiescence on the stem tissue, while increasing cellular activity in the AR primordia. Flooding led to ethylene accumulation in the lower stem region and subsequently to a drop in abscisic acid (ABA) level in both stem and AR primordia tissue. Whereas ABA treatment prevented activation of AR primordia by flooding, inhibition of ABA synthesis was sufficient to activate them in absence of flooding. Together, this reveals that there is a highly tissue-specific response to reduced ABA levels. The central role for ABA in the response differentiates the pathway identified here from the AR emergence pathway known from rice (Oryza sativa). Flooding and ethylene treatment also induced expression of the polar auxin transporter PIN2, and silencing of this gene or chemical inhibition of auxin transport inhibited primordium activation, even though ABA levels were reduced. Auxin treatment, however, was not sufficient for AR emergence, indicating that the auxin pathway acts in parallel with the requirement for ABA reduction. In conclusion, adaptation of S. dulcamara to wet habitats involved co-option of a hormonal signaling cascade well known to regulate shoot growth responses, to direct a root developmental program upon soil flooding. © 2016 American Society of Plant Biologists. All Rights Reserved.

A Co-Opted Hormonal Cascade Activates Dormant Adventitious Root Primordia upon Flooding in Solanum dulcamara1[OPEN

PubMed Central

Dawood, Thikra; Kensche, Philip R.; Cristescu, Simona M.; Mariani, Celestina

2016-01-01

Soil flooding is a common stress factor affecting plants. To sustain root function in the hypoxic environment, flooding-tolerant plants may form new, aerenchymatous adventitious roots (ARs), originating from preformed, dormant primordia on the stem. We investigated the signaling pathway behind AR primordium reactivation in the dicot species Solanum dulcamara. Transcriptome analysis indicated that flooding imposes a state of quiescence on the stem tissue, while increasing cellular activity in the AR primordia. Flooding led to ethylene accumulation in the lower stem region and subsequently to a drop in abscisic acid (ABA) level in both stem and AR primordia tissue. Whereas ABA treatment prevented activation of AR primordia by flooding, inhibition of ABA synthesis was sufficient to activate them in absence of flooding. Together, this reveals that there is a highly tissue-specific response to reduced ABA levels. The central role for ABA in the response differentiates the pathway identified here from the AR emergence pathway known from rice (Oryza sativa). Flooding and ethylene treatment also induced expression of the polar auxin transporter PIN2, and silencing of this gene or chemical inhibition of auxin transport inhibited primordium activation, even though ABA levels were reduced. Auxin treatment, however, was not sufficient for AR emergence, indicating that the auxin pathway acts in parallel with the requirement for ABA reduction. In conclusion, adaptation of S. dulcamara to wet habitats involved co-option of a hormonal signaling cascade well known to regulate shoot growth responses, to direct a root developmental program upon soil flooding. PMID:26850278

Postural adjustment errors reveal deficits in inhibition during lateral step initiation in older adults

PubMed Central

Fuhrman, Susan I.; Redfern, Mark S.; Jennings, J. Richard; Perera, Subashan; Nebes, Robert D.; Furman, Joseph M.

2013-01-01

Postural dual-task studies have demonstrated effects of various executive function components on gait and postural control in older adults. The purpose of the study was to explore the role of inhibition during lateral step initiation. Forty older adults participated (range 70–94 yr). Subjects stepped to the left or right in response to congruous and incongruous visual cues that consisted of left and right arrows appearing on left or right sides of a monitor. The timing of postural adjustments was identified by inflection points in the vertical ground reaction forces (VGRF) measured separately under each foot. Step responses could be classified into preferred and nonpreferred step behavior based on the number of postural adjustments that were made. Delays in onset of the first postural adjustment (PA1) and liftoff (LO) of the step leg during preferred steps progressively increased among the simple, choice, congruous, and incongruous tasks, indicating interference in processing the relevant visuospatial cue. Incongruous cues induced subjects to make more postural adjustments than they typically would (i.e., nonpreferred steps), representing errors in selection of the appropriate motor program. During these nonpreferred steps, the onset of the PA1 was earlier than during the preferred steps, indicating a failure to inhibit an inappropriate initial postural adjustment. The functional consequence of the additional postural adjustments was a delay in the LO compared with steps in which they did not make an error. These results suggest that deficits in inhibitory function may detrimentally affect step decision processing, by delaying voluntary step responses. PMID:23114211

Tight Control of Trehalose Content Is Required for Efficient Heat-induced Cell Elongation in Candida albicans*

PubMed Central

Serneels, Joke; Tournu, Hélène; Van Dijck, Patrick

2012-01-01

The ability to form hyphae in the human pathogenic fungus Candida albicans is a prerequisite for virulence. It contributes to tissue infection, biofilm formation, as well as escape from phagocytes. Cell elongation triggered by human body temperature involves the essential heat shock protein Hsp90, which negatively governs a filamentation program dependent upon the Ras-protein kinase A (PKA) pathway. Tight regulation of Hsp90 function is required to ensure fast appropriate response and maintenance of a wide range of regulatory and signaling proteins. Client protein activation by Hsp90 relies on a conformational change of the chaperone, whose ATPase activity is competitively inhibited by geldanamycin. We demonstrate a novel regulatory mechanism of heat- and Hsp90-dependent induced morphogenesis, whereby the nonreducing disaccharide trehalose acts as a negative regulator of Hsp90 release. By means of a mutant strain deleted for Gpr1, the G protein-coupled receptor upstream of PKA, we demonstrate that elevated trehalose content in that strain, resulting from misregulation of enzymatic activities involved in trehalose metabolism, disrupts the filamentation program in response to heat. Addition of geldanamycin does not result in hyphal extensions at 30 °C in the gpr1Δ/gpr1Δ mutant as it does in wild type cells. In addition, validamycin, a specific inhibitor of trehalase, the trehalose-degrading enzyme, inhibits cell elongation in response to heat and geldanamycin. These results place Gpr1 as a regulator of trehalose metabolism in C. albicans and illustrate that trehalose modulates Hsp90-dependent activation of client proteins and signaling pathways leading to filamentation in the human fungal pathogen. PMID:22952228

Common and Dissociable Neural Activity After Mindfulness-Based Stress Reduction and Relaxation Response Programs.

PubMed

Sevinc, Gunes; Hölzel, Britta K; Hashmi, Javeria; Greenberg, Jonathan; McCallister, Adrienne; Treadway, Michael; Schneider, Marissa L; Dusek, Jeffery A; Carmody, James; Lazar, Sara W

2018-06-01

We investigated common and dissociable neural and psychological correlates of two widely used meditation-based stress reduction programs. Participants were randomized to the Relaxation Response (RR; n = 18; 56% female) or the Mindfulness-Based Stress Reduction (MBSR; n = 16; 56% female) programs. Both programs use a "bodyscan" meditation; however, the RR program explicitly emphasizes physical relaxation during this practice, whereas the MBSR program emphasizes mindful awareness with no explicit relaxation instructions. After the programs, neural activity during the respective meditation was investigated using functional magnetic resonance imaging. Both programs were associated with reduced stress (for RR, from 14.1 ± 6.6 to 11.3 ± 5.5 [Cohen's d = 0.50; for MBSR, from 17.7 ± 5.7 to 11.9 ± 5.0 [Cohen's d = 1.02]). Conjunction analyses revealed functional coupling between ventromedial prefrontal regions and supplementary motor areas (p < .001). The disjunction analysis indicated that the RR bodyscan was associated with stronger functional connectivity of the right inferior frontal gyrus-an important hub of intentional inhibition and control-with supplementary motor areas (p < .001, family-wise error [FWE] rate corrected). The MBSR program was uniquely associated with improvements in self-compassion and rumination, and the within-group analysis of MBSR bodyscan revealed significant functional connectivity of the right anterior insula-an important hub of sensory awareness and salience-with pregenual anterior cingulate during bodyscan meditation compared with rest (p = .03, FWE corrected). The bodyscan exercises in each program were associated with both overlapping and differential functional coupling patterns, which were consistent with each program's theoretical foundation. These results may have implications for the differential effects of these programs for the treatment of diverse conditions.

Automatic and Controlled Response Inhibition: Associative Learning in the Go/No-Go and Stop-Signal Paradigms

ERIC Educational Resources Information Center

Verbruggen, Frederick; Logan, Gordon D.

2008-01-01

In 5 experiments, the authors examined the development of automatic response inhibition in the go/no-go paradigm and a modified version of the stop-signal paradigm. They hypothesized that automatic response inhibition may develop over practice when stimuli are consistently associated with stopping. All 5 experiments consisted of a training phase…

Explicit and Implicit Verbal Response Inhibition in Preschool-Age Children Who Stutter

ERIC Educational Resources Information Center

Anderson, Julie D.; Wagovich, Stacy A.

2017-01-01

Purpose: The purpose of this study was to examine (a) explicit and implicit verbal response inhibition in preschool children who do stutter (CWS) and do not stutter (CWNS) and (b) the relationship between response inhibition and language skills. Method: Participants were 41 CWS and 41 CWNS between the ages of 3;1 and 6;1 (years;months). Explicit…

Separating intentional inhibition of prepotent responses and resistance to proactive interference in alcohol-dependent individuals.

PubMed

Noël, Xavier; Van der Linden, Martial; Brevers, Damien; Campanella, Salvatore; Verbanck, Paul; Hanak, Catherine; Kornreich, Charles; Verbruggen, Frederick

2013-03-01

Impulsivity is a hallmark of addictive behaviors. Addicts' weakened inhibition of irrelevant prepotent responses is commonly thought to explain this association. However, inhibition is not a unitary mechanism. This study investigated the efficiency of overcoming competition due to irrelevant responses (i.e., inhibition of a prepotent response) and overcoming competition in memory (i.e., resistance to proactive interference) in sober and recently detoxified alcohol-dependent individuals. Three cognitive tasks assessing the inhibition of a prepotent response (Hayling task, anti-saccade task and Stroop task) and two tasks tapping into the capacity to resist proactive interference (cued recall, Brown-Peterson variant) were administered to 30 non-amnesic recently detoxified alcohol-dependent individuals and 30 matched healthy participants without alcohol dependency. In addition, possible confounds such as verbal updating in working memory was assessed. Alcohol-dependent subjects performed worse than healthy participants on the three cognitive tasks assessing the inhibition of irrelevant prepotent responses but group performance was similar in the tasks assessing overcoming proactive interference in memory, updating of working memory and abstract reasoning. These findings suggest that alcohol-dependence is mainly associated with impaired capacity to intentionally suppress irrelevant prepotent response information. Control of proactive interference from memory is preserved. Theoretical and clinical implications are discussed. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma.

PubMed

Ahmad, Fahim; Patrick, Shruti; Sheikh, Touseef; Sharma, Vikas; Pathak, Pankaj; Malgulwar, Prit Benny; Kumar, Anupam; Joshi, Shanker Datt; Sarkar, Chitra; Sen, Ellora

2017-12-01

Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia-telangiectasia-mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT-EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non-canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma. © 2017 International Society for Neurochemistry.

Aging As An Evolvability-Increasing Program Which Can Be Switched Off By Organism To Mobilize Additional Resources For Survival.

PubMed

Skulachev, Maxim V; Severin, Fedor F; Skulachev, Vladimir P

2015-04-22

During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned [1]. Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no age-related diseases [2]. In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified [3]. In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event) [4]. Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies [5]. In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions. In this review, we consider point [5] in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e.g., geroprotective psychological factors). Similarly, dangerous individuals can be eliminated by programmed death due to operation of progeric psychological factors. The interplay of all these signals results in the final decision of the organism concerning its aging - to accelerate or to decelerate this process. Thus, paradoxically, such an originally counterproductive program as aging appears to be useful for the individual since this program can be switched off by the individual for a certain period of time, an action that thereby increases its resources in crucial periods of life.

Aging as an evolvability-increasing program which can be switched off by organism to mobilize additional resources for survival.

PubMed

Skulachev, Maxim V; Severin, Fedor F; Skulachev, Vladimir P

2015-01-01

During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned. (1) Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no agerelated diseases. (2) In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified. (3) In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event). (4) Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies. (5) In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions. In this review, we consider point (5) in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e.g., geroprotective psychological factors). Similarly, dangerous individuals can be eliminated by programmed death due to operation of progeric psychological factors. The interplay of all these signals results in the final decision of the organism concerning its aging - to accelerate or to decelerate this process. Thus, paradoxically, such an originally counterproductive program as aging appears to be useful for the individual since this program can be switched off by the individual for a certain period of time, an action that thereby increases its resources in crucial periods of life.

Variable Inhibition by Falling CO2 of Hypoxic Ventilatory Response in Man,

DTIC Science & Technology

1983-06-21

alkalosis which, in turn, inhibits the ventilatory response to hypoxia (4,5,11). Thus for the usual measurement of the acute ventilatory response to...rest for 20 minutes. All of the ventilatory response tests were performed with the subject breathing through a respiratory valve (Model 2700, Hans...increase ventilation because the inhibition by hypocapnic alkalosis is prevented by adding CO2 to the inspired air to maintain C02 and pH at their

Inhibitors of the PD-1 Pathway in Tumor Therapy

PubMed Central

LaFleur, Martin W.; Muroyama, Yuki; Drake, Charles G.; Sharpe, Arlene H.

2018-01-01

The programmed death 1 (PD-1) pathway delivers inhibitory signals that function as a brake for immune responses. This pathway limits the initiation and duration of immune responses, thereby protecting tissues from immune-mediated damage and autoimmune diseases. However, the PD-1 pathway also inhibits immune responses to tumors. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers with the hallmark of durability of response. Despite this success, most patients do not respond to PD-1 monotherapy, and some patients experience adverse events. In this review, we discuss the functions of the PD-1 pathway and its translation to cancer immunotherapy. We also consider current challenges and opportunities for PD-1 cancer immunotherapy, including mechanisms of response and resistance, identification of biomarkers of response to PD-1 therapy, characterization and treatment of PD-1 therapy–related adverse events, and development of safe and effective combination therapies. PMID:29311378

Learning in the tutorial group: a balance between individual freedom and institutional control.

PubMed

McAllister, Anita; Aanstoot, Janna; Hammarström, Inger Lundeborg; Samuelsson, Christina; Johannesson, Eva; Sandström, Karin; Berglind, Ulrika

2014-01-01

The study investigates factors in problem-based learning tutorial groups which promote or inhibit learning. The informants were tutors and students from speech-language pathology and physiotherapy programmes. Semi-structured focus-group interviews and individual interviews were used. Results revealed three themes: Responsibility. Time and Support. Under responsibility, the delicate balance between individual and institutional responsibility and control was shown. Time included short and long-term perspectives on learning. Under support, supporting documents, activities and personnel resources were mentioned. In summary, an increased control by the program and tutors decreases student's motivation to assume responsibility for learning. Support in tutorial groups needs to adapt to student progression and to be well aligned to tutorial work to have the intended effect. A lifelong learning perspective may help students develop a meta-awareness regarding learning that could make tutorial work more meaningful.

Role of Body Esteem in the Sexual Excitation and Inhibition Responses of Women With and Without a History of Childhood Sexual Abuse.

PubMed

Kilimnik, Chelsea D; Meston, Cindy M

2016-11-01

Women's sexuality is influenced by their perceptions of their bodies. Negative body appraisals have been implicated in the development and maintenance of sexual concerns in women with a history of childhood sexual abuse (CSA). The sexuality of these women is often expressed in extremes of approach and avoidant sexual tendencies, which have been related to the sexual inhibition and sexual excitation pathways of the dual control model. To test the influence of body esteem on the sexual excitation and inhibition responses of women with and without a history of CSA. One hundred thirty-nine women with CSA and 83 non-abused women reported on their abuse history, depressive symptomology, sexual response, and affective appraisals of their body. Validated self-report measurements of sexual excitation and inhibition responses (Sexual Excitation/Sexual Inhibition Inventory for Women) and body esteem (Body Esteem Scale) were administered. Body esteem was significantly associated with sexual inhibition responses of women regardless of CSA history status but was significantly related only to the sexual excitation responses of women with a CSA history. Perceived sexual attractiveness was a unique predictor of sexual excitation in women with a history of CSA. Women with a history of CSA have lower body esteem than non-abused women, particularly in self-perceived sexual attractiveness, and these perceptions appear to influence their sexual responses by acting on the sexual excitation and inhibition response pathways. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Training and Transfer Effects of Response Inhibition Training in Children and Adults

ERIC Educational Resources Information Center

Zhao, Xin; Chen, Ling; Maes, Joseph H. R.

2018-01-01

Response inhibition is crucial for mental and physical health but studies assessing the trainability of this type of inhibition are rare. Thirty-nine children aged 10-12 years and 46 adults aged 18-24 years were assigned to an adaptive go/no-go inhibition training condition or an active control condition. Transfer of training effects to…

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

PubMed Central

Duguid, Ian; Branco, Tiago; Chadderton, Paul; Arlt, Charlotte; Powell, Kate; Häusser, Michael

2015-01-01

Classical feed-forward inhibition involves an excitation–inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory-evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses. PMID:26432880

A pilot investigation of acute inhibitory control training in cocaine users.

PubMed

Alcorn, Joseph L; Pike, Erika; Stoops, William S; Lile, Joshua A; Rush, Craig R

2017-05-01

Disrupted response inhibition and presence of drug-cue attentional bias in cocaine-using individuals have predicted poor treatment outcomes. Inhibitory control training could help improve treatment outcomes by strengthening cognitive control. This pilot study assessed the effects of acute inhibitory control training to drug- and non-drug-related cues on response inhibition performance and cocaine-cue attentional bias in cocaine-using individuals. Participants who met criteria for a cocaine-use disorder underwent five sessions of inhibitory control training to either non-drug-related cues (i.e., rectangles) or cocaine cues (n=10/condition) in a single day. Response inhibition and attentional bias were assessed prior to and following training using the stop-signal task and visual-probe task with eye tracking, respectively. Training condition groups did not differ on demographics, inhibitory control training performance, response inhibition, or cocaine-cue attentional bias. Response inhibition performance improved as a function of inhibitory control training in both conditions. Cocaine-cue attentional bias was observed, but did not change as a function of inhibitory control training in either condition. Response inhibition in cocaine-using individuals was augmented by acute inhibitory control training, which may improve treatment outcomes through better behavioral inhibition. Future studies should investigate longer-term implementation of inhibitory control training, as well as combining inhibitory control training with other treatment modalities. Copyright © 2017 Elsevier B.V. All rights reserved.

Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4

PubMed Central

Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L.; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C.; Staudt, Louis M.; Niesvizky, Ruben; Moore, Malcolm A. S.

2012-01-01

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. PMID:22718837

Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.

PubMed

Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C; Staudt, Louis M; Niesvizky, Ruben; Moore, Malcolm A S; Chen-Kiang, Selina

2012-08-02

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

Hot or Not: Response Inhibition Reduces the Hedonic Value and Motivational Incentive of Sexual Stimuli

PubMed Central

Ferrey, Anne E.; Frischen, Alexandra; Fenske, Mark J.

2012-01-01

The motivational incentive of reward-related stimuli can become so salient that it drives behavior at the cost of other needs. Here we show that response inhibition applied during a Go/No-go task not only impacts hedonic evaluations but also reduces the behavioral incentive of motivationally relevant stimuli. We first examined the impact of response inhibition on the hedonic value of sex stimuli associated with strong behavioral-approach responses (Experiment 1). Sexually appealing and non-appealing images were both rated as less attractive when previously encountered as No-go (inhibited) than as Go (non-inhibited) items. We then discovered that inhibition reduces the motivational incentive of sexual appealing stimuli (Experiment 2). Prior Go/No-go status affected the number of key-presses by heterosexual males to view erotic-female (sexually appealing) but not erotic-male or scrambled-control (non-appealing) images. These findings may provide a foundation for developing inhibition-based interventions to reduce the hedonic value and motivational incentive of stimuli associated with disorders of self-control. PMID:23272002

The effects of DAT1 genotype on fMRI activation in an emotional go/no-go task.

PubMed

Brown, Brenna K; Murrell, Jill; Karne, Harish; Anand, Amit

2017-02-01

Dopaminergic brain circuits participate in emotional processing and impulsivity. The dopamine transporter (DAT) modulates dopamine reuptake. A variable number tandem repeat (VNTR) in the dopamine transporter gene (DAT1) affects DAT expression. The influence of DAT1 genotype on neural activation during emotional processing and impulse inhibition has not been examined. Forty-two healthy subjects were classified as 9DAT (n = 17) or 10DAT (n = 25) based on DAT1 genotype (9DAT = 9R/9R and 9R/10R; 10DAT = 10R/10R). Subjects underwent fMRI during non-emotional and emotional go/no-go tasks. Subjects were instructed to inhibit responses to letters, happy faces, or sad faces in separate blocks. Accuracy and reaction time did not differ between groups. Within group results showed activation in regions previously implicated in emotional processing and response inhibition. Between groups results showed increased activation in 9DAT individuals during inhibition. During letter inhibition, 9DAT individuals exhibited greater activation in right inferior parietal regions. During sad inhibition, 9DAT Individuals exhibited greater activation in frontal, posterior cingulate, precuneus, right cerebellar, left paracentral, and right occipital brain regions. The interaction between DAT genotype and response type in sad versus letter stimuli showed increased activation in 9DAT individuals during sad no-go responses in the anterior cingulate cortex, extending into frontal-orbital regions. 9DAT individuals have greater activation than 10DAT individuals during neutral and sad inhibition, showing that genotypic variation influencing basal dopamine levels can alter the neural basis of emotional processing and response inhibition. This may indicate that 9R carriers exert more effort to overcome increased basal dopamine activation when inhibiting responses in emotional contexts.

Injection drug users trained by overdose prevention programs: Responses to witnessed overdoses

PubMed Central

Lankenau, Stephen E.; Wagner, Karla D.; Silva, Karol; Kecojevic, Aleksander; Iverson, Ellen; McNeely, Miles; Kral, Alex H.

2012-01-01

In response to the growing public health problem of drug overdose, community-based organizations have initiated overdose prevention programs (OPP), which distribute naloxone, an opioid antagonist, and teach overdose response techniques. Injection drug users (IDUs) have been targeted for this intervention due to their high risk for drug overdose. Limited research attention has focused on factors that may inhibit or prevent IDUs who have been trained by OPPs to undertake recommended response techniques when responding to a drug overdose. IDUs (n=30) trained by two OPPs in Los Angeles were interviewed in 2010–11 about responses to their most recently witnessed drug overdose using an instrument containing both open and closed-ended questions. Among the 30 witnessed overdose events, the victim recovered in 29 cases while the outcome was unknown in one case. Participants responded to overdoses using a variety of techniques taught by OPP. Injecting the victim with naloxone was the most common recommended response while other recommended responses included stimulating the victim with knuckles, calling 911, and giving rescue breathing. Barriers preventing participants from employing recommended response techniques in certain circumstances included prior successes using folk remedies to revive a victim, concerns over attracting police to the scene, and issues surrounding access to or use of naloxone. Practical solutions, such as developing booster sessions to augment OPP, are encouraged to increase the likelihood that trained participants respond to a drug overdose with the full range of recommended techniques. PMID:22847602

Task Inhibition and Response Inhibition in Older vs. Younger Adults: A Diffusion Model Analysis

PubMed Central

Schuch, Stefanie

2016-01-01

Differences in inhibitory ability between older (64–79 years, N = 24) and younger adults (18–26 years, N = 24) were investigated using a diffusion model analysis. Participants performed a task-switching paradigm that allows assessing n−2 task repetition costs, reflecting inhibitory control on the level of tasks, as well as n−1 response-repetition costs, reflecting inhibitory control on the level of responses. N−2 task repetition costs were of similar size in both age groups. Diffusion model analysis revealed that for both younger and older adults, drift rate parameters were smaller in the inhibition condition relative to the control condition, consistent with the idea that persisting task inhibition slows down response selection. Moreover, there was preliminary evidence for task inhibition effects in threshold separation and non-decision time in the older, but not the younger adults, suggesting that older adults might apply different strategies when dealing with persisting task inhibition. N−1 response-repetition costs in mean RT were larger in older than younger adults, but in mean error rates tended to be larger in younger than older adults. Diffusion-model analysis revealed longer non-decision times in response repetitions than response switches in both age groups, consistent with the idea that motor processes take longer in response repetitions than response switches due to persisting response inhibition of a previously executed response. The data also revealed age-related differences in overall performance: Older adults responded more slowly and more accurately than young adults, which was reflected by a higher threshold separation parameter in diffusion model analysis. Moreover, older adults showed larger non-decision times and higher variability in non-decision time than young adults, possibly reflecting slower and more variable motor processes. In contrast, overall drift rate did not differ between older and younger adults. Taken together, diffusion model analysis revealed differences in overall performance between the age groups, as well as preliminary evidence for age differences in dealing with task inhibition, but no evidence for an inhibitory deficit in older age. PMID:27895599

The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action.

PubMed

Griveau, A; Devailly, G; Eberst, L; Navaratnam, N; Le Calvé, B; Ferrand, M; Faull, P; Augert, A; Dante, R; Vanacker, J M; Vindrieux, D; Bernard, D

2016-09-22

Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.

Influence of SLC6A3 and COMT Variation on Neural Activation During Response Inhibition

PubMed Central

Congdon, Eliza; Constable, R. Todd; Lesch, Klaus Peter; Canli, Turhan

2009-01-01

There is evidence concerning the neural and genetic correlates of inhibitory control, but there have been limited attempts to combine this information. This study tested the hypothesis that two dopaminergic polymorphisms, SLC6A3 and COMT, influence neural activation during response inhibition. Healthy adults were genotyped for these polymorphisms and performed a measure of response inhibition while undergoing functional magnetic resonance imaging (fMRI). Results support the role of key frontostriatal regions underlying response inhibition. Furthermore, results support a significant influence of SLC6A3 and COMT variants on neural activity during inhibition, with greater activation during inhibition in carriers of the SLC6A3 9-allele or the COMT met-allele as compared to carriers of the SLC6A3 10/10 genotype or the COMT val/val genotype. These results add to a growing literature suggesting that inhibitory control is sensitive to variation in dopamine function, and suggest that this variation may be detectable at the level of individuals’ genotypes. PMID:19482231

Local inhibition modulates learning-dependent song encoding in the songbird auditory cortex

PubMed Central

Thompson, Jason V.; Jeanne, James M.

2013-01-01

Changes in inhibition during development are well documented, but the role of inhibition in adult learning-related plasticity is not understood. In songbirds, vocal recognition learning alters the neural representation of songs across the auditory forebrain, including the caudomedial nidopallium (NCM), a region analogous to mammalian secondary auditory cortices. Here, we block local inhibition with the iontophoretic application of gabazine, while simultaneously measuring song-evoked spiking activity in NCM of European starlings trained to recognize sets of conspecific songs. We find that local inhibition differentially suppresses the responses to learned and unfamiliar songs and enhances spike-rate differences between learned categories of songs. These learning-dependent response patterns emerge, in part, through inhibitory modulation of selectivity for song components and the masking of responses to specific acoustic features without altering spectrotemporal tuning. The results describe a novel form of inhibitory modulation of the encoding of learned categories and demonstrate that inhibition plays a central role in shaping the responses of neurons to learned, natural signals. PMID:23155175

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

DOE PAGES

Helgren, Travis R.; Chen, Congling; Wangtrakuldee, Phumvadee; ...

2016-11-10

Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. In this study, we tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock wasmore » then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. Lastly, these data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection.« less

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

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

Helgren, Travis R.; Chen, Congling; Wangtrakuldee, Phumvadee

Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. In this study, we tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock wasmore » then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. Lastly, these data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection.« less

Cross-resistance to herbicides of five ALS-inhibiting groups and sequencing of the ALS gene in Cyperus difformis L.

PubMed

Merotto, Aldo; Jasieniuk, Marie; Osuna, Maria D; Vidotto, Francesco; Ferrero, Aldo; Fischer, Albert J

2009-02-25

Resistance to ALS-inhibiting herbicides in Cyperus difformis has evolved rapidly in many rice areas worldwide. This study identified the mechanism of resistance, assessed cross-resistance patterns to all five chemical groups of ALS-inhibiting herbicides in four C. difformis biotypes, and attempted to sequence the ALS gene. Whole-plant and ALS enzyme activity dose-response assays indicated that the WA biotype was resistant to all ALS-inhibiting herbicides evaluated. The IR biotype was resistant to bensulfuron-methyl, orthosulfamuron, imazethapyr, and propoxycarbazone-sodium and less resistant to bispyribac-sodium and halosulfuron-methyl, and susceptible to penoxsulam. ALS enzyme activity assays indicated that resistance is due to an altered target site yet mutations previously found to endow target-site resistance in weeds were not detected in the sequences obtained. The inability to detect resistance mutations in C. difformis may result from the presence of additional ALS genes, which were not amplified by the primers used. This study reports the first ALS gene sequence from Cyperus difformis. Certain ALS-inhibiting herbicides can still be used to control some resistant C. difformis biotypes. However, because cross-resistance to all five classes of ALS-inhibitors was detected in other resistant biotypes, these herbicides should only be used within an integrated weed management program designed to delay the evolution of herbicide resistance.

Neural correlates of emotional response inhibition in obsessive-compulsive disorder: A preliminary study.

PubMed

Berlin, Heather A; Schulz, Kurt P; Zhang, Sam; Turetzky, Rachel; Rosenthal, David; Goodman, Wayne

2015-11-30

Failure to inhibit recurrent anxiety-provoking thoughts is a central symptom of obsessive-compulsive disorder (OCD). Neuroimaging studies suggest inhibitory control and disgust processing abnormalities in patients with OCD. However, the emotional modulation of response inhibition deficits in OCD and their neural correlates remain to be elucidated. For this preliminary study we administered an adapted affective response inhibition paradigm, an emotional go/no-go task, during fMRI to characterize the neural systems underlying disgust-related and fear-related inhibition in nine adults with contamination-type OCD compared to ten matched healthy controls. Participants with OCD had significantly greater anterior insula cortex activation when inhibiting responses to both disgusting (bilateral), and fearful (right-sided) images, compared to healthy controls. They also had increased activation in several frontal, temporal, and parietal regions, but there was no evidence of amygdala activation in OCD or healthy participants and no significant between-group differences in performance on the emotion go/no-go task. The anterior insula appears to play a central role in the emotional modulation of response inhibition in contamination-type OCD to both fearful and disgusting images. The insula may serve as a potential treatment target for contamination-type OCD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

High-dose alcohol intoxication differentially modulates cognitive subprocesses involved in response inhibition.

PubMed

Stock, Ann-Kathrin; Schulz, Tom; Lenhardt, Martin; Blaszkewicz, Meinolf; Beste, Christian

2016-01-01

Aside from well-known physiological effects, high-dose alcohol intoxication (a.k.a. binge drinking) can lead to aversive social and legal consequences because response inhibition is usually compromised under the influence of alcohol. Although the behavioral aspects of this phenomenon were reported on extensively, the underlying neurophysiological mechanisms mediating this disinhibition are unclear. To close this gap, we used both behavioral and neurophysiological measures (event-related potentials, ERPs) to investigate which subprocesses of response inhibition are altered under the influence of high-dose alcohol intoxication. Using a within-subject design, we asked young healthy participants (n = 27) to complete a GO/NOGO task once sober and once intoxicated (approximately 1.2‰). During intoxication, high-dose alcohol effects were highest in a condition where the participants could not rely on automated stimulus-response mapping processes during response inhibition. In this context, the NOGO-P3 (ERP), that likely depends on dopaminergic signaling within mesocorticolimbic pathways and is thought to reflect motor inhibition and/or the evaluation of inhibitory processes, was altered in the intoxicated state. In contrast to this, the N2 component, which largely depends on nigrostriatal dopamine pathways and is thought to reflect inhibition on a pre-motor level, was not altered. Based on these results, we demonstrate that alcohol-induced changes of dopaminergic neurotransmission do not exert a global effect on response inhibition. Instead, changes are highly subprocess-specific and seem to mainly target mesocorticolimbic pathways that contribute to motor inhibition and the evaluation of such. © 2014 Society for the Study of Addiction.

The role of the anterior cingulate cortex in emotional response inhibition.

PubMed

Albert, Jacobo; López-Martín, Sara; Tapia, Manuel; Montoya, Daniel; Carretié, Luis

2012-09-01

Although the involvement of the anterior cingulate cortex (ACC) in emotional response inhibition is well established, there are several outstanding issues about the nature of this involvement that are not well understood. The present study aimed to examine the precise contribution of the ACC to emotion-modulated response inhibition by capitalizing on fine temporal resolution of the event-related potentials (ERPs) and the recent advances in source localization. To this end, participants (N = 30) performed an indirect affective Go/Nogo task (i.e., unrelated to the emotional content of stimulation) that required the inhibition of a motor response to three types of visual stimuli: arousing negative (A-), neutral (N), and arousing positive (A+). Behavioral data revealed that participants made more commission errors to A+ than to N and A-. Electrophysiological data showed that a specific region of the ACC at the intersection of its dorsal and rostral subdivisions was significantly involved in the interaction between emotional processing and motor inhibition. Specifically, activity reflecting this interaction was observed in the P3 (but not in the N2) time range, and was greater during the inhibition of responses to A+ than to N and A-. Additionally, regression analyses showed that inhibition-related activity within this ACC region was associated with the emotional content of the stimuli (its activity increased as stimulus valence was more positive), and also with behavioral performance (both with reaction times and commission errors). The present results provide additional data for understanding how, when, and where emotion interacts with response inhibition within the ACC. Copyright © 2011 Wiley Periodicals, Inc.

Biophysical Network Modelling of the dLGN Circuit: Different Effects of Triadic and Axonal Inhibition on Visual Responses of Relay Cells.

PubMed

Heiberg, Thomas; Hagen, Espen; Halnes, Geir; Einevoll, Gaute T

2016-05-01

Despite its prominent placement between the retina and primary visual cortex in the early visual pathway, the role of the dorsal lateral geniculate nucleus (dLGN) in molding and regulating the visual signals entering the brain is still poorly understood. A striking feature of the dLGN circuit is that relay cells (RCs) and interneurons (INs) form so-called triadic synapses, where an IN dendritic terminal can be simultaneously postsynaptic to a retinal ganglion cell (GC) input and presynaptic to an RC dendrite, allowing for so-called triadic inhibition. Taking advantage of a recently developed biophysically detailed multicompartmental model for an IN, we here investigate putative effects of these different inhibitory actions of INs, i.e., triadic inhibition and standard axonal inhibition, on the response properties of RCs. We compute and investigate so-called area-response curves, that is, trial-averaged visual spike responses vs. spot size, for circular flashing spots in a network of RCs and INs. The model parameters are grossly tuned to give results in qualitative accordance with previous in vivo data of responses to such stimuli for cat GCs and RCs. We particularly investigate how the model ingredients affect salient response properties such as the receptive-field center size of RCs and INs, maximal responses and center-surround antagonisms. For example, while triadic inhibition not involving firing of IN action potentials was found to provide only a non-linear gain control of the conversion of input spikes to output spikes by RCs, axonal inhibition was in contrast found to substantially affect the receptive-field center size: the larger the inhibition, the more the RC center size shrinks compared to the GC providing the feedforward excitation. Thus, a possible role of the different inhibitory actions from INs to RCs in the dLGN circuit is to provide separate mechanisms for overall gain control (direct triadic inhibition) and regulation of spatial resolution (axonal inhibition) of visual signals sent to cortex.

Childhood Social Functioning and Young Adult Intimate Partner Violence in Girls With and Without ADHD: Response Inhibition as a Moderator.

PubMed

Youn, Cherry; Meza, Jocelyn I; Hinshaw, Stephen P

2018-06-01

Examine the moderating effects of response inhibition on the longitudinal association between social preference/relational aggression measured in childhood, and intimate partner violence (IPV) measured in young adulthood, among women with ( n = 140) and without ( n = 88) histories of childhood ADHD. During childhood, social preference was measured through confidential peer sociometric nominations, yielding negative and positive peer regard; relational aggression was assessed via staff behavioral observations; and response inhibition was assessed using commission errors from the continuous performance task. During young adulthood, IPV was ascertained via a clinician-administered, semistructured interview. Social preference and relational aggression independently predicted IPV; this prospective link was moderated by response inhibition. In combination with low social preference or high relational aggression in childhood, poor response inhibition predicted the highest levels of young-adult IPV. Given the developmental significance of peer relationships, additional research on the causes of and treatments for poor social functioning in ADHD is warranted.

Genetic influences on phase synchrony of brain oscillations supporting response inhibition.

PubMed

Müller, Viktor; Anokhin, Andrey P; Lindenberger, Ulman

2017-05-01

Phase synchronization of neuronal oscillations is a fundamental mechanism underlying cognitive processing and behavior, including context-dependent response production and inhibition. Abnormalities in neural synchrony can lead to abnormal information processing and contribute to cognitive and behavioral deficits in neuropsychiatric disorders. However, little is known about genetic and environmental contributions to individual differences in cortical oscillatory dynamics underlying response inhibition. This study examined heritability of event-related phase synchronization of brain oscillations in 302 young female twins including 94 MZ and 57 DZ pairs performing a cued Go/No-Go version of the Continuous Performance Test (CPT). We used the Phase Locking Index (PLI) to assess inter-trial phase clustering (synchrony) in several frequency bands in two time intervals after stimulus onset (0-300 and 301-600ms). Response inhibition (i.e., successful response suppression in No-Go trials) was characterized by a transient increase in phase synchronization of delta- and theta-band oscillations in the fronto-central midline region. Genetic analysis showed significant heritability of the phase locking measures related to response inhibition, with 30 to 49% of inter-individual variability being accounted for by genetic factors. This is the first study providing evidence for heritability of task-related neural synchrony. The present results suggest that PLI can serve as an indicator of genetically transmitted individual differences in neural substrates of response inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

Segregating Top-Down Selective Attention from Response Inhibition in a Spatial Cueing Go/NoGo Task: An ERP and Source Localization Study.

PubMed

Hong, Xiangfei; Wang, Yao; Sun, Junfeng; Li, Chunbo; Tong, Shanbao

2017-08-29

Successfully inhibiting a prepotent response tendency requires the attentional detection of signals which cue response cancellation. Although neuroimaging studies have identified important roles of stimulus-driven processing in the attentional detection, the effects of top-down control were scarcely investigated. In this study, scalp EEG was recorded from thirty-two participants during a modified Go/NoGo task, in which a spatial-cueing approach was implemented to manipulate top-down selective attention. We observed classical event-related potential components, including N2 and P3, in the attended condition of response inhibition. While in the ignored condition of response inhibition, a smaller P3 was observed and N2 was absent. The correlation between P3 and CNV during the foreperiod suggested an inhibitory role of P3 in both conditions. Furthermore, source analysis suggested that P3 generation was mainly localized to the midcingulate cortex, and the attended condition showed increased activation relative to the ignored condition in several regions, including inferior frontal gyrus, middle frontal gyrus, precentral gyrus, insula and uncus, suggesting that these regions were involved in top-down attentional control rather than inhibitory processing. Taken together, by segregating electrophysiological correlates of top-down selective attention from those of response inhibition, our findings provide new insights in understanding the neural mechanisms of response inhibition.

Influence of impulsiveness on emotional modulation of response inhibition: An ERP study.

PubMed

Messerotti Benvenuti, Simone; Sarlo, Michela; Buodo, Giulia; Mento, Giovanni; Palomba, Daniela

2015-10-01

To examine how impulsiveness influences the emotional modulation of behavioral and neural correlates of response inhibition. Twenty-nine healthy individuals scoring high (HI, N=16) or low (LI, N=13) on motor impulsiveness performed an emotional Go/Nogo task, including the presentation of pleasant, neutral and unpleasant pictures. Behavioral [reaction times (RTs), accuracy to Go and Nogo trials] and neural (Nogo-N2 and Nogo-P3) correlates of response inhibition were compared between HI and LI groups. Larger Nogo-P3 was found for emotional than neutral stimuli in HI relative to LI group. Faster RTs to Go stimuli and lower accuracy to Nogo stimuli were correlated with larger Nogo-P3 in HI, but not LI, group. No significant interactions between emotion content and impulsiveness for Nogo-N2 and behavioral measures were noted. Impulsiveness influences the emotional modulation of response inhibition by potentiating the response tendencies evoked by the emotional stimuli. Accordingly, high impulsive individuals may need an increased and/or more effortful response inhibition in order to counteract the prepotent tendency to respond elicited by the combination of high trait impulsiveness and high emotional arousal. The present study suggests the importance to examine how pathological impulsiveness may interact with emotional arousal in modulating response inhibition. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming to promote memory formation and metabolic readiness.

PubMed

Pedicord, Virginia A; Cross, Justin R; Montalvo-Ortiz, Welby; Miller, Martin L; Allison, James P

2015-03-01

During primary Ag encounter, T cells receive numerous positive and negative signals that control their proliferation, function, and differentiation, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mammalian target of rapamycin inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8(+) T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8(+) T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8(+) T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mammalian target of rapamycin inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation, and an optimal metabolic program for CD8(+) T cell memory. Copyright © 2015 by The American Association of Immunologists, Inc.

Resisting distraction and response inhibition trigger similar enhancements of future performance.

PubMed

Bissett, Patrick G; Grant, Lauren D; Weissman, Daniel H

2017-10-01

Resisting distraction and response inhibition are crucial aspects of cognitive control. Interestingly, each of these abilities transiently improves just after it is utilized. Competing views differ, however, as to whether utilizing either of these abilities (e.g., resisting distraction) enhances future performance involving the other ability (e.g., response inhibition). To distinguish between these views, we combined a Stroop-like task that requires resisting distraction with a restraint variant of the stop-signal task that requires response inhibition. We observed similar sequential-trial effects (i.e., performance enhancements) following trials in which participants (a) resisted distraction (i.e., incongruent go trials) and (b) inhibited a response (i.e., congruent stop trials). First, the congruency effect in go trials, which indexes overall distractibility, was smaller after both incongruent go trials and congruent stop trials than it was after congruent go trials. Second, stop failures were less frequent after both incongruent go trials and congruent stop trials than after congruent go trials. A control experiment ruled out the possibility that perceptual conflict or surprise engendered by occasional stop signals triggers sequential-trial effects independent of stopping. Thus, our findings support a novel, integrated view in which resisting distraction and response inhibition trigger similar sequential enhancements of future performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Nicotine Inhibits Memory CTL Programming

PubMed Central

Sun, Zhifeng; Smyth, Kendra; Garcia, Karla; Mattson, Elliot; Li, Lei; Xiao, Zhengguo

2013-01-01

Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs) and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but impairs in vivo expansion after transfer and subsequent memory CTL differentiation, which reduces protection against subsequent pathogen challenges. Furthermore, nicotine abolishes the regulatory effect of rapamycin on memory CTL programming, which can be attributed to the fact that rapamycin enhances expression of nicotinic receptors. Interestingly, naïve CTLs from chronic nicotine-treated mice have normal memory programming, which is impaired by nicotine during activation in vitro. In conclusion, simultaneous exposure to nicotine and antigen during CTL activation negatively affects memory development. PMID:23844169

Inhibition, interference, and conflict in task switching.

PubMed

Costa, Russell E; Friedrich, Frances J

2012-12-01

The role of inhibition in the task-switching process has received increased empirical and theoretical attention in the literature on cognitive control. Many accounts have suggested that inhibition occurs when a conflict must be resolved-for example, when a target stimulus contains features of more than one task. In the two experiments reported here, we used variants of backward inhibition, or N - 2 repetition, designs to examine (1) whether inhibition occurs in the absence of conflict at the stimulus or response level, (2) when in the task-switching process such inhibition may occur, and (3) the potential consequences of inhibition. In Experiment 1, we demonstrate that neither stimulus- nor response-level conflict is necessary for inhibition to occur, while the results of Experiment 2 suggest that inhibition may be associated with a reduction of proactive interference (PI) from a previously performed task. Evidence of inhibition and the reduction of PI both occurred at the task-set level. However, inhibition of specific stimulus values can also occur, but this is clearly separable from task-set inhibition. Both experiments also provided evidence that task-set inhibition can be applied at the time of the new task cue, as opposed to at the onset of the target or at the response stage of the trial. Taken together, the results from these experiments provide insight into when and where in the task-switching process inhibition may occur, as well as into the potential functional benefits that inhibition of task sets may provide.

Aldosterone Inhibits the Fetal Program and Increases Hypertrophy in the Heart of Hypertensive Mice

PubMed Central

Azibani, Feriel; Devaux, Yvan; Coutance, Guillaume; Schlossarek, Saskia; Polidano, Evelyne; Fazal, Loubina; Merval, Regine; Carrier, Lucie; Solal, Alain Cohen; Chatziantoniou, Christos; Launay, Jean-Marie; Samuel, Jane-Lise; Delcayre, Claude

2012-01-01

Background Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of “fetal” gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. Methodology/Principal Findings RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (−75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. Conclusions/Significance Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of its transcriptional repressor Sox6. Thus, aldosterone inhibits the fetal program and increases cardiac hypertrophy in hypertensive mice. PMID:22666483

Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response

PubMed Central

Xu, Ruijuan; Wang, Kai; Mileva, Izolda; Hannun, Yusuf A.; Obeid, Lina M.; Mao, Cungui

2016-01-01

Human cells respond to DNA damage by elevating sphingosine, a bioactive sphingolipid that induces programmed cell death (PCD) in response to various forms of stress, but its regulation and role in the DNA damage response remain obscure. Herein we demonstrate that DNA damage increases sphingosine levels in tumor cells by upregulating alkaline ceramidase 2 (ACER2) and that the upregulation of the ACER2/sphingosine pathway induces PCD in response to DNA damage by increasing the production of reactive oxygen species (ROS). Treatment with the DNA damaging agent doxorubicin increased both ACER2 expression and sphingosine levels in HCT116 cells in a dose-dependent manner. ACER2 overexpression increased sphingosine in HeLa cells whereas knocking down ACER2 inhibited the doxorubicin-induced increase in sphingosine in HCT116 cells, suggesting that DNA damage elevates sphingosine by upregulating ACER2. Knocking down ACER2 inhibited an increase in the apoptotic and necrotic cell population and the cleavage of poly ADP ribose polymerase (PARP) in HCT116 cells in response to doxorubicin as well as doxorubicin-induced release of lactate dehydrogenase (LDH) from these cells. Similar to treatment with doxorubicin, ACER2 overexpression induced an increase in the apoptotic and necrotic cell population and PARP cleavage in HeLa cells and LDH release from cells, suggesting that ACER2 upregulation mediates PCD in response to DNA damage through sphingosine. Mechanistic studies demonstrated that the upregulation of the ACER2/sphingosine pathway induces PCD by increasing ROS levels. Taken together, these results suggest that the ACER2/sphingosine pathway mediates PCD in response to DNA damage through ROS production. PMID:26943039

Reduced neural activity of the prefrontal cognitive control circuitry during response inhibition to negative words in people with schizophrenia

PubMed Central

Vercammen, Ans; Morris, Richard; Green, Melissa J.; Lenroot, Rhoshel; Kulkarni, Jayashri; Carr, Vaughan J.; Weickert, Cynthia Shannon; Weickert, Thomas W.

2012-01-01

Background Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study assessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mechanisms and emotion attribution processes in people with schizophrenia. Methods Functional magnetic resonance imaging was performed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence. Results We enrolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal–parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during response inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex. Limitations Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confounding variables. Conclusion Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life. PMID:22617625

Prenatal tobacco exposure and response inhibition in school-aged children: an event-related potential study.

PubMed

Boucher, Olivier; Jacobson, Joseph L; Burden, Matthew J; Dewailly, Éric; Jacobson, Sandra W; Muckle, Gina

2014-01-01

Prenatal cigarette smoke exposure (PCSE) has been linked to problems in behavioral inhibition and attention deficit hyperactivity disorder in children in several epidemiological studies. We used event-related potentials (ERPs) to examine the effects of PCSE on neural correlates of inhibitory control of behavior. In a prospective longitudinal study on child development in the Canadian Arctic, we assessed 186 Inuit children (mean age=11.3years) on a visual Go/No-go response inhibition paradigm. PCSE was assessed through maternal recall. Potential confounders were documented from a maternal interview, and exposure to neurotoxic environmental contaminants was assessed from umbilical cord and child blood samples. PCSE was not related to behavioral performance on this simple response inhibition task. Nevertheless, this exposure was associated with smaller amplitudes of the N2 and P3 components elicited by No-go stimuli, suggesting an impairment in the neural processes underlying response inhibition. Amplitude of the No-go P3 component was also inversely associated with behavioral measures of externalizing problems and hyperactivity/impulsivity in the classroom. This study is the first to report neurophysiological evidence of impaired response inhibition in school-aged children exposed to tobacco smoke in utero. Effects were found on ERP components associated with conflict processing and inhibition of a prepotent response, indicating neurophysiological deficits that may play a critical role in the attention and behavior problems observed in children with PCSE. Copyright © 2014 Elsevier Inc. All rights reserved.

Increased GABA(A) inhibition of the RVLM after hindlimb unloading in rats

NASA Technical Reports Server (NTRS)

Moffitt, Julia A.; Heesch, Cheryl M.; Hasser, Eileen M.

2002-01-01

Attenuated baroreflex-mediated increases in renal sympathetic nerve activity (RSNA) in hindlimb unloaded (HU) rats apparently are due to changes within the central nervous system. We hypothesized that GABA(A) receptor-mediated inhibition of the rostral ventrolateral medulla (RVLM) is increased after hindlimb unloading. Responses to bilateral microinjection of the GABA(A) antagonist (-)-bicuculline methiodide (BIC) into the RVLM were examined before and during caudal ventrolateral medulla (CVLM) inhibition in Inactin-anesthetized control and HU rats. Increases in mean arterial pressure (MAP), heart rate (HR), and RSNA in response to BIC in the RVLM were significantly enhanced in HU rats. Responses to bilateral CVLM blockade were not different. When remaining GABA(A) inhibition in the RVLM was blocked by BIC during CVLM inhibition, the additional increases in MAP and RSNA were significantly greater in HU rats. These data indicate that GABA(A) receptor-mediated inhibition of RVLM neurons is augmented after hindlimb unloading. Effects of input from the CVLM were unaltered. Thus, after cardiovascular deconditioning in rodents, the attenuated increase in sympathetic nerve activity in response to hypotension is associated with greater GABA(A) receptor-mediated inhibition of RVLM neurons originating at least in part from sources other than the CVLM.

Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD).

PubMed

Chen, Tina H; Wu, Steve W; Welge, Jeffrey A; Dixon, Stephan G; Shahana, Nasrin; Huddleston, David A; Sarvis, Adam R; Sallee, Floyd R; Gilbert, Donald L

2014-12-01

Clinical trials in children with attention-deficit hyperactivity disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine. The objective of this study was to determine whether transcranial magnetic stimulation-evoked short interval cortical inhibition might be a biomarker predicting, or correlating with, clinical atomoxetine response. At baseline and after 4 weeks of atomoxetine treatment in 7- to 12-year-old children with ADHD, transcranial magnetic stimulation short interval cortical inhibition was measured, blinded to clinical improvement. Primary analysis was by multivariate analysis of covariance. Baseline short interval cortical inhibition did not predict clinical responses. However, paradoxically, after 4 weeks of atomoxetine, mean short interval cortical inhibition was reduced 31.9% in responders and increased 6.1% in nonresponders (analysis of covariance t 41 = 2.88; P = .0063). Percentage reductions in short interval cortical inhibition correlated with reductions in the ADHD Rating Scale (r = 0.50; P = .0005). In children ages 7 to 12 years with ADHD treated with atomoxetine, improvements in clinical symptoms are correlated with reductions in motor cortex short interval cortical inhibition. © The Author(s) 2014.

Novel leads from Heliotropium ovalifolium, 4,7,8-trimethoxy-naphthalene-2-carboxylic acid and 6-hydroxy-5,7-dimethoxy-naphthalene-2-carbaldehyde show specific IL-6 inhibitory activity in THP-1 cells and primary human monocytes.

PubMed

Kulkarni-Almeida, Asha; Suthar, Ashish; Goswami, Hitesh; Vishwakarma, Ram; Chauhan, Vijay Singh; Balakrishnan, Arun; Sharma, Somesh

2008-12-01

From our screening program, we identified the anti-inflammatory effects of the extracts of Heliotropium ovalifolium in its ability to inhibit specific cytokines. The H. ovalifolium extract was found to be moderately active with an IC(50) equaling 10 microg/ml for inhibition of interleukin-6 (IL-6) in a human monocytic cell line. Interleukin-6 is a pleiotropic cytokine with implications in the regulation of the immune response, inflammation and hematopoiesis. This prompted us to examine and identify the active molecules that are responsible for the bioactivity in THP-1 cells. Bioassay guided fractionation identified two compounds 4,7,8-trimethoxy-naphthalene-2-carboxylic acid and 6-hydroxy-5,7-dimethoxy-naphthalene-2-carbaldehyde with an IC(50) of 2.4 and 2.0 microM for IL-6 inhibition and an IC(50) of 15.6 and 7.0 microM for tumor necrosis factor-alpha (TNF-alpha) inhibition in THP-1 cells. The protein expression data were supported by the inhibitory effect on mRNA gene expression. The compounds isolated from H. ovalifolium were also non-toxic in human peripheral blood monocytes from normal donors and the activity profile was similar to that obtained on THP-1 cells. Thus, we believe that these scaffolds may be of interest to develop leads for treating rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease and other inflammatory disorders. However, more detailed investigations need to be carried out to explain the efficacy of these compounds as drugs.

Tomato yellow leaf curl virus infection of a resistant tomato line with a silenced sucrose transporter gene LeHT1 results in inhibition of growth, enhanced virus spread, and necrosis.

PubMed

Eybishtz, Assaf; Peretz, Yuval; Sade, Dagan; Gorovits, Rena; Czosnek, Henryk

2010-02-01

To identify genes involved in resistance of tomato to Tomato yellow leaf curl virus (TYLCV), cDNA libraries from lines resistant (R) and susceptible (S) to the virus were compared. The hexose transporter LeHT1 was found to be expressed preferentially in R tomato plants. The role of LeHT1 in the establishment of TYLCV resistance was studied in R plants where LeHT1 has been silenced using Tobacco rattle virus-induced gene silencing (TRV VIGS). Following TYLCV inoculation, LeHT1-silenced R plants showed inhibition of growth and enhanced virus accumulation and spread. In addition, a necrotic response was observed along the stem and petioles of infected LeHT1-silenced R plants, but not on infected not-silenced R plants. This response was specific of R plants since it was absent in infected LeHT1-silenced S plants. Necrosis had several characteristics of programmed cell death (PCD): DNA from necrotic tissues presented a PCD-characteristic ladder pattern, the amount of a JNK analogue increased, and production of reactive oxygen was identified by DAB staining. A similar necrotic reaction along stem and petioles was observed in LeHT1-silenced R plants infected with the DNA virus Bean dwarf mosaic virus and the RNA viruses Cucumber mosaic virus and Tobacco mosaic virus. These results constitute the first evidence for a necrotic response backing natural resistance to TYLCV in tomato, confirming that plant defense is organized in multiple layers. They demonstrate that the hexose transporter LeHT1 is essential for the expression of natural resistance against TYLCV and its expression correlates with inhibition of virus replication and movement.

Healthcare at the Crossroads: The Need to Shape an Organizational Culture of Humanistic Teaching and Practice.

PubMed

Rider, Elizabeth A; Gilligan, MaryAnn C; Osterberg, Lars G; Litzelman, Debra K; Plews-Ogan, Margaret; Weil, Amy B; Dunne, Dana W; Hafler, Janet P; May, Natalie B; Derse, Arthur R; Frankel, Richard M; Branch, William T

2018-05-08

Changes in the organization of medical practice have impeded humanistic practice and resulted in widespread physician burnout and dissatisfaction. To identify organizational factors that promote or inhibit humanistic practice of medicine by faculty physicians. From January 1, 2015, through December 31, 2016, faculty from eight US medical schools were asked to write reflectively on two open-ended questions regarding institutional-level motivators and impediments to humanistic practice and teaching within their organizations. Sixty eight of the 92 (74%) study participants who received the survey provided written responses. All subjects who were sent the survey had participated in a year-long small-group faculty development program to enhance humanistic practice and teaching. As humanistic leaders, subjects should have insights into motivating and inhibiting factors. Participants' responses were analyzed using the constant comparative method. Motivators included an organizational culture that enhances humanism, which we judged to be the overarching theme. Related themes included leadership supportive of humanistic practice, responsibility to role model humanism, organized activities that promote humanism, and practice structures that facilitate humanism. Impediments included top down organizational culture that inhibits humanism, along with related themes of non-supportive leadership, time and bureaucratic pressures, and non-facilitative practice structures. While healthcare has evolved rapidly, efforts to counteract the negative effects of changes in organizational and practice environments have largely focused on cultivating humanistic attributes in individuals. Our findings suggest that change at the organizational level is at least equally important. Physicians in our study described the characteristics of an organizational culture that supports and embraces humanism. We offer suggestions for organizational change that keep humanistic and compassionate patient care as its central focus.

A corollary discharge maintains auditory sensitivity during sound production

NASA Astrophysics Data System (ADS)

Poulet, James F. A.; Hedwig, Berthold

2002-08-01

Speaking and singing present the auditory system of the caller with two fundamental problems: discriminating between self-generated and external auditory signals and preventing desensitization. In humans and many other vertebrates, auditory neurons in the brain are inhibited during vocalization but little is known about the nature of the inhibition. Here we show, using intracellular recordings of auditory neurons in the singing cricket, that presynaptic inhibition of auditory afferents and postsynaptic inhibition of an identified auditory interneuron occur in phase with the song pattern. Presynaptic and postsynaptic inhibition persist in a fictively singing, isolated cricket central nervous system and are therefore the result of a corollary discharge from the singing motor network. Mimicking inhibition in the interneuron by injecting hyperpolarizing current suppresses its spiking response to a 100-dB sound pressure level (SPL) acoustic stimulus and maintains its response to subsequent, quieter stimuli. Inhibition by the corollary discharge reduces the neural response to self-generated sound and protects the cricket's auditory pathway from self-induced desensitization.

Atomoxetine restores the response inhibition network in Parkinson’s disease

PubMed Central

Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Parkinson’s disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson’s disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson’s disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson’s disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson’s disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson’s disease. PMID:27343257

Hospital response to the legalization of abortion in New York State: an analysis of program innovation.

PubMed

Miller, J

1979-12-01

The reorientation of hospital services in the state of New York to accommodate women's constitutional right to elective abortion was investigated. Market and resource constraints, the social orientations of the organization, and the values of physicians were examined in the effort to evaluate hospital response between 1971 and 1973. Analysis indicates that program innovation in obstetrical and gynecological services to include elective abortion was inhibited by economic factors that generally determined the feasibility of diverting finite resources to a new service and social orientations and values that determined the compatibility of elective abortions with the dominant values underlying hospital operations. The reform of New York abortion statutes and the subsequent ruling by the Supreme Court reiterating the right of women to terminate pregnancy failed to standardize the delivery of health care so that individual rights to service could be obtained everywhere in the state. The social changes ultimately realized through legislative and judicial action were essentially conditional upon the responsiveness of local health care providers. Legal action that failed to specifically address the administrative role of hospitals in social change qualified local access and could not be completely effective in legitimizing the redefinition of abortion in society.

Basal forebrain neuronal inhibition enables rapid behavioral stopping

PubMed Central

Mayse, Jeffrey D.; Nelson, Geoffrey M.; Avila, Irene; Gallagher, Michela; Lin, Shih-Chieh

2015-01-01

Cognitive inhibitory control, the ability to rapidly suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. While most studies on inhibitory control have focused on the fronto-basal-ganglia circuit, here we explore a novel hypothesis and show that rapid behavioral stopping is enabled by neuronal inhibition in the basal forebrain (BF). In rats performing the stop signal task, putative noncholinergic BF neurons with phasic bursting responses to the go signal were inhibited nearly completely by the stop signal. The onset of BF neuronal inhibition was tightly coupled with and temporally preceded the latency to stop, the stop signal reaction time. Artificial inhibition of BF activity in the absence of the stop signal was sufficient to reproduce rapid behavioral stopping. These results reveal a novel subcortical mechanism of rapid inhibitory control by the BF, which provides bidirectional control over the speed of response generation and inhibition. PMID:26368943

Executive Functions in Children with Communication Impairments, in Relation to Autistic Symptomatology. 2: Response Inhibition

ERIC Educational Resources Information Center

Bishop, Dorothy V. M.; Norbury, Courtenay Frazier

2005-01-01

Although impairment in executive functions has been described in autism, there has been debate as to whether response inhibition is specifically affected. We compared four groups: highfunctioning autism; pragmatic language impairment; specific language impairment; and control. Inhibition was assessed using two subtests from the Test of Everyday…

Response Inhibition in Adults and Teenagers: Spatiotemporal Differences in the Prefrontal Cortex

ERIC Educational Resources Information Center

Vidal, Julie; Mills, Travis; Pang, Elizabeth W.; Taylor, Margot J.

2012-01-01

Inhibition is a core executive function reliant on the frontal lobes that shows protracted maturation through to adulthood. We investigated the spatiotemporal characteristics of response inhibition during a visual go/no-go task in 14 teenagers and 14 adults using magnetoencephalography (MEG) and a contrast between two no-go experimental conditions…

Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8*

PubMed Central

Ireland, Robin; Wang, Rong; Alinger, Joshua B.; Small, Pamela; Bosio, Catharine M.

2013-01-01

Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity is a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. Here, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated Live Vaccine Strain (LVS), inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα independent inhibition of NF-κBp65 activation and selective inhibition of activation of Interferon Regulatory Factors (IRFs). Interference with NF-κBp65 and IRFs is also observed following infection with viable SchuS4. Together these data provide novel insight as to how highly virulent bacteria selectively modulate the host to interfere innate immune responses required for survival of infection. PMID:23817430

The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic

PubMed Central

Paul, Evan D.; Johnson, Philip L.; Shekhar, Anantha; Lowry, Christopher A.

2014-01-01

The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors, and that dysfunction of these neurons increases vulnerability to affective and anxiety disorders, including Panic Disorder. We outline evidence supporting the existence of a serotonergic system originally discussed by Deakin/Graeff that is implicated in the inhibition of panic-like behavioral and physiological responses. Evidence supporting this panic inhibition system comes from the following observations: 1) serotonergic neurons located in the ‘ventrolateral dorsal raphe nucleus (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; 2) chronic, but not acute, antidepressant treatment potentiates serotonin’s panicolytic effect; 3) contextual fear activates a central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; 4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic agents such as sodium lactate and CO2. Implications of the panic inhibition system are discussed. PMID:24661986

The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic.

PubMed

Paul, Evan D; Johnson, Philip L; Shekhar, Anantha; Lowry, Christopher A

2014-10-01

The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors, and that dysfunction of these neurons increases vulnerability to affective and anxiety disorders, including panic disorder. We outline evidence supporting the existence of a serotonergic system originally discussed by Deakin/Graeff that is implicated in the inhibition of panic-like behavioral and physiological responses. Evidence supporting this panic inhibition system comes from the following observations: (1) serotonergic neurons located in the 'ventrolateral dorsal raphe nucleus' (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; (2) chronic, but not acute, antidepressant treatment potentiates serotonin's panicolytic effect; (3) contextual fear activates a central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; (4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic agents such as sodium lactate and CO2. Implications of the panic inhibition system are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Response inhibition triggered by the briefly viewed image of a hand: Behavioural and electrophysiological evidence.

PubMed

Vainio, L; Alén, H; Hiltunen, S; Lehikoinen, K; Lindbäck, H; Patrikainen, A; Paavilainen, P

2013-02-01

Previous research has shown that subliminally presented arrows produce negative priming effect in which responses are performed slower when primes and targets are calling for the same response than different response. This phenomenon has been attributed to self-inhibitory mechanisms of response processes. Similar negative priming was recently observed when participants responded to the direction of the target arrow and the prime was a briefly displayed image of a left or right hand. Responses were made slower when the left-right identity of the viewed hand was compatible with the responding hand. This was suggested to demonstrate that the proposed motor self-inhibition is a general and basic functional principle in manual control processes. However, the behavioural evidence observed in that study was not capable of showing whether the negative priming associated with a briefly displayed hand could reflect other inhibitory processes than the motor self-inhibition. The present study uses an electrophysiological indicator of automatic response priming, the lateralized readiness potential (LRP), to investigate whether the negative priming triggered by the identity of the viewed hand does indeed reflect motor self-inhibition processes. The LRP revealed a pattern of motor activation that was in line with the motor self-inhibition hypothesis. Thus, the finding supports the view that the self-inhibition mechanisms are not restricted to arrow stimuli that are presented subliminally. Rather, they are general sensorimotor mechanisms that operate in planning and control of manual actions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Inferior Frontal Cortex Modulation with an Acute Dose of Heroin During Cognitive Control

PubMed Central

Schmidt, André; Walter, Marc; Gerber, Hana; Schmid, Otto; Smieskova, Renata; Bendfeldt, Kerstin; Wiesbeck, Gerhard A; Riecher-Rössler, Anita; Lang, Undine E; Rubia, Katya; McGuire, Philip; Borgwardt, Stefan

2013-01-01

Impairments in inhibitory control and in stimulus-driven attention are hallmarks of drug addiction and are associated with decreased activation in the right inferior frontal gyrus (IFG). Although previous studies indicate that the response inhibition function is impaired in abstinent heroin dependents, and that this is mediated by reduced IFG activity, it remains completely unknown whether and how an acute dose of heroin modulates IFG activity during cognitive control in heroin-dependent patients. This study investigates the acute effects of heroin administration on IFG activity during response inhibition and stimulus-driven attention in heroin-dependent patients. Using a cross-over, double-blind, placebo-controlled design, saline and heroin were administered to 26 heroin-dependent patients from stable heroin-assisted treatment, while performing a Go/No–Go event-related functional magnetic resonance imaging task to assess right IFG activity during motor response inhibition, as well as during oddball-driven attention allocation. Relative to saline, heroin significantly reduced right IFG activity during both successful response inhibition and oddball-driven attention allocation, whereas it did not change right IFG activity during response inhibition after correction for the effect of attention allocation. These heroin-induced effects were not related to changes in drug craving, state anxiety, behavioral performance, or co-consumption of psychostimulant drugs. This study demonstrates that heroin administration acutely impairs stimulus-driven attention allocation, as indicated by reduced IFG activity in response to infrequently presented stimuli, and does not specifically modulate IFG activity during response inhibition. PMID:23673865

Withholding response to self-face is faster than to other-face.

PubMed

Zhu, Min; Hu, Yinying; Tang, Xiaochen; Luo, Junlong; Gao, Xiangping

2015-01-01

Self-face advantage refers to adults' response to self-face is faster than that to other-face. A stop-signal task was used to explore how self-face advantage interacted with response inhibition. The results showed that reaction times of self-face were faster than that of other-face not in the go task but in the stop response trials. The novelty of the finding was that self-face has shorter stop-signal reaction time compared to other-face in the successful inhibition trials. These results indicated the processing mechanism of self-face may be characterized by a strong response tendency and a corresponding strong inhibition control.

Search Asymmetry, Sustained Attention, and Response Inhibition

ERIC Educational Resources Information Center

Stevenson, Hugh; Russell, Paul N.; Helton, William S.

2011-01-01

In the present experiment, we used search asymmetry to test whether the sustained attention to response task is a better measure of response inhibition or sustained attention. Participants performed feature present and feature absent target detection tasks using either a sustained attention to response task (SART; high Go low No-Go) or a…

Jasmonic Acid Enhances Al-Induced Root Growth Inhibition1[OPEN

PubMed Central

Yang, Zhong-Bao; Ma, Yanqi

2017-01-01

Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. PMID:27932419

Jasmonic Acid Enhances Al-Induced Root Growth Inhibition.

PubMed

Yang, Zhong-Bao; He, Chunmei; Ma, Yanqi; Herde, Marco; Ding, Zhaojun

2017-02-01

Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. © 2017 American Society of Plant Biologists. All Rights Reserved.

Vaccinia Virus Protein C6 Inhibits Type I IFN Signalling in the Nucleus and Binds to the Transactivation Domain of STAT2.

PubMed

Stuart, Jennifer H; Sumner, Rebecca P; Lu, Yongxu; Snowden, Joseph S; Smith, Geoffrey L

2016-12-01

The type I interferon (IFN) response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV) strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells. Ectopic expression of C6 inhibits the induction of interferon stimulated genes (ISGs) in response to IFNα treatment at both the mRNA and protein level. C6 inhibits the IFNα-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway at a late stage, downstream of STAT1 and STAT2 phosphorylation, nuclear translocation and binding of the interferon stimulated gene factor 3 (ISGF3) complex to the interferon stimulated response element (ISRE). Mechanistically, C6 associates with the transactivation domain of STAT2 and this might explain how C6 inhibits the type I IFN signalling very late in the pathway. During virus infection C6 reduces ISRE-dependent gene expression despite the presence of the viral protein phosphatase VH1 that dephosphorylates STAT1 and STAT2. The ability of a cytoplasmic replicating virus to dampen the immune response within the nucleus, and the ability of viral immunomodulators such as C6 to inhibit multiple stages of the innate immune response by distinct mechanisms, emphasizes the intricacies of host-pathogen interactions and viral immune evasion.

Inhibition of estrogen-responsive gene activation by the retinoid X receptor beta: evidence for multiple inhibitory pathways.

PubMed

Segars, J H; Marks, M S; Hirschfeld, S; Driggers, P H; Martinez, E; Grippo, J F; Brown, M; Wahli, W; Ozato, K

1993-04-01

The retinoid X receptor beta (RXR beta; H-2RIIBP) forms heterodimers with various nuclear hormone receptors and binds multiple hormone response elements, including the estrogen response element (ERE). In this report, we show that endogenous RXR beta contributes to ERE binding activity in nuclear extracts of the human breast cancer cell line MCF-7. To define a possible regulatory role of RXR beta regarding estrogen-responsive transcription in breast cancer cells, RXR beta and a reporter gene driven by the vitellogenin A2 ERE were transfected into estrogen-treated MCF-7 cells. RXR beta inhibited ERE-driven reporter activity in a dose-dependent and element-specific fashion. This inhibition occurred in the absence of the RXR ligand 9-cis retinoic acid. The RXR beta-induced inhibition was specific for estrogen receptor (ER)-mediated ERE activation because inhibition was observed in ER-negative MDA-MB-231 cells only following transfection of the estrogen-activated ER. No inhibition of the basal reporter activity was observed. The inhibition was not caused by simple competition of RXR beta with the ER for ERE binding, since deletion mutants retaining DNA binding activity but lacking the N-terminal or C-terminal domain failed to inhibit reporter activity. In addition, cross-linking studies indicated the presence of an auxiliary nuclear factor present in MCF-7 cells that contributed to RXR beta binding of the ERE. Studies using known heterodimerization partners of RXR beta confirmed that RXR beta/triiodothyronine receptor alpha heterodimers avidly bind the ERE but revealed the existence of another triiodothyronine-independent pathway of ERE inhibition. These results indicate that estrogen-responsive genes may be negatively regulated by RXR beta through two distinct pathways.

QUETIAPINE IMPROVES RESPONSE INHIBITION IN ALCOHOL DEPENDENT PATIENTS: A PLACEBO-CONTROLLED PILOT STUDY

PubMed Central

Moallem, Nathasha; Ray, Lara A.

2013-01-01

Rationale Quetiapine has been shown to be a promising medication for the treatment of alcoholism. As an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT1A and 5-HT2A, H1 and α1 and α2 receptors, quetiapine has been found to decrease impulsivity in other psychiatric disorders but its effects on impulsivity have not been studied in alcohol dependent patients. Objective This study seeks to test the effects of quetiapine on a specific dimension of impulsivity, namely response inhibition. This pilot study seeks to further elucidate the mechanisms of action of quetiapine for alcohol use disorders. Method A total of 20 non-treatment seeking alcohol dependent individuals were randomized to one of the following conditions in a double-blind, placebo-controlled design: (1) quetiapine (400 mg/day); or (2) matched placebo. Participants completed two counterbalanced intravenous placebo-alcohol administration sessions as well as behavioral measure of response inhibition (i.e. stop signal task) pre and post placebo-alcohol administration sessions. Results Analyses revealed a significant effect of quetiapine in improving response inhibition as measured by the stop signal task. These results provide preliminary evidence suggesting that quetiapine improves response inhibition in alcohol dependent patients, as compared to placebo. Conclusion This pilot study contributes a novel putative mechanism of action of quetiapine in alcoholism, namely an improvement in response inhibition. PMID:22037407

Anything goes? Regulation of the neural processes underlying response inhibition in TBI patients.

PubMed

Moreno-López, Laura; Manktelow, Anne E; Sahakian, Barbara J; Menon, David K; Stamatakis, Emmanuel A

2017-02-01

Despite evidence for beneficial use of methylphenidate in response inhibition, no studies so far have investigated the effects of this drug in the neurobiology of inhibitory control in traumatic brain injury (TBI), even though impulsive behaviours are frequently reported in this patient group. We investigated the neural basis of response inhibition in a group of TBI patients using functional magnetic resonance imaging and a stop-signal paradigm. In a randomised double-blinded crossover study, the patients received either a single 30mg dose of methylphenidate or placebo and performed the stop-signal task. Activation in the right inferior frontal gyrus (RIFG), an area associated with response inhibition, was significantly lower in patients compared to healthy controls. Poor response inhibition in this group was associated with greater connectivity between the RIFG and a set of regions considered to be part of the default mode network (DMN), a finding that suggests the interplay between DMN and frontal executive networks maybe compromised. A single dose of methylphenidate rendered activity and connectivity profiles of the patients RIFG near normal. The results of this study indicate that the neural circuitry involved in response inhibition in TBI patients may be partially restored with methylphenidate. Given the known mechanisms of action of methylphenidate, the effect we observed may be due to increased dopamine and noradrenaline levels. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Attention Diversion Improves Response Inhibition of Immediate Reward, But Only When it Is Beneficial: An fMRI Study

PubMed Central

Scalzo, Franco; O’Connor, David A.; Orr, Catherine; Murphy, Kevin; Hester, Robert

2016-01-01

Deficits of self-control are associated with a number of mental state disorders. The ability to direct attention away from an alluring stimulus appears to aid inhibition of an impulsive response. However, further functional imaging research is required to assess the impact of shifts in attention on self-regulating processes. We varied the level of attentional disengagement in an functional magnetic resonance imaging (fMRI)-based Go/No-go task to probe whether diversion of attention away from alluring stimuli facilitates response inhibition. We used the attention-grabbing characteristic of faces to exogenously direct attention away from stimuli and investigated the relative importance of attention and response inhibition mechanisms under different delayed reward scenarios [i.e., where forgoing an immediate reward ($1) led to a higher ($10) or no payoff in the future]. We found that diverting attention improved response inhibition performance, but only when resistance to an alluring stimulus led to delayed reward. Region of interest analyses indicated significant increased activity in posterior right inferior frontal gyrus during successful No-go trials for delayed reward trials compared to no delayed reward trials, and significant reduction in activity in the superior temporal gyri and left caudate in contexts of high attentional diversion. Our findings imply that strategies that increase the perceived benefits of response inhibition might assist individuals in abstaining from problematic impulsive behaviors. PMID:27616988

Poverty and Internalizing Symptoms: The Indirect Effect of Middle Childhood Poverty on Internalizing Symptoms via an Emotional Response Inhibition Pathway.

PubMed

Capistrano, Christian G; Bianco, Hannah; Kim, Pilyoung

2016-01-01

Childhood poverty is a pervasive problem that can alter mental health outcomes. Children from impoverished circumstances are more likely than their middle-income counterparts to develop internalizing problems such as depression and anxiety. To date, however, the emotional-cognitive control processes that link childhood poverty and internalizing symptoms remain largely unexplored. Using the Emotion Go/NoGo paradigm, we examined the association between poverty and emotional response inhibition in middle childhood. We further examined the role of emotional response inhibition in the link between middle childhood poverty and internalizing symptoms. Lower income was associated with emotional response inhibition difficulties (indexed by greater false alarm rates in the context of task irrelevant angry and sad faces). Furthermore, emotional response inhibition deficits in the context of angry and sad distracters were further associated with child-report internalizing problems. The results of the current study demonstrate the significance of understanding the emotional-cognitive control vulnerabilities of children raised in poverty and their association with mental health outcomes.

The role of sodium pump in the inhibition of smooth muscle responsiveness to agonists during potassium restoration

PubMed Central

Bose, D.; Innes, I. R.

1973-01-01

1. Isometric contractions of cat splenic capsular smooth muscle in response to noradrenaline and histamine were recorded. 2. Removal of potassium from the bathing medium did not change the resting tension or the responsiveness to noradrenaline. Restoration of potassium inhibited responses to noradrenaline or histamine only if the muscles were stimulated with an agonist while in the K-free medium. 3. This inhibition of responses to the agonists due to potassium was reversed rapidly by removing the ion or reversed slowly by prolonged exposure to the ion. The inhibition was also blocked by procedures or agents which block the sodium pump (ouabain, substitution of NaCl by LiCl), inhibit active processes (low ambient temperature) or prevent intracellular accumulation of sodium (substitution of choline for sodium). 4. It is proposed that under special circumstances such as when there is an increase in internal sodium concentration, the sodium pump is probably electrogenic and causes relaxation when activated by external potassium. In the normal muscle the pump is probably electrically neutral. PMID:4777707

Response inhibition and cognitive appraisal in clients with acute stress disorder and posttraumatic stress disorder.

PubMed

Abolghasemi, Abass; Bakhshian, Fereshteh; Narimani, Mohammad

2013-08-01

The purpose of the present study was to compare response inhibition and cognitive appraisal in clients with acute stress disorder, clients with posttraumatic stress disorder, and normal individuals. This was a comparative study. The sample consisted of 40 clients with acute stress disorder, 40 patients with posttraumatic stress disorder, and 40 normal individuals from Mazandaran province selected through convenience sampling method. Data were collected using Composite International Diagnostic Interview, Stroop Color-Word Test, Posttraumatic Cognitions Inventory, and the Impact of Event Scale. Results showed that individuals with acute stress disorder are less able to inhibit inappropriate responses and have more impaired cognitive appraisals compared to those with posttraumatic stress disorder. Moreover, results showed that response inhibition and cognitive appraisal explain 75% of the variance in posttraumatic stress disorder symptoms and 38% of the variance in posttraumatic stress disorder symptoms. The findings suggest that response inhibition and cognitive appraisal are two variables that influence the severity of posttraumatic stress disorder and acute stress disorder symptoms. Also, these results have important implications for pathology, prevention, and treatment of posttraumatic stress disorder and acute stress disorder.

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

PubMed Central

Galluzzi, L; Bravo-San Pedro, J M; Vitale, I; Aaronson, S A; Abrams, J M; Adam, D; Alnemri, E S; Altucci, L; Andrews, D; Annicchiarico-Petruzzelli, M; Baehrecke, E H; Bazan, N G; Bertrand, M J; Bianchi, K; Blagosklonny, M V; Blomgren, K; Borner, C; Bredesen, D E; Brenner, C; Campanella, M; Candi, E; Cecconi, F; Chan, F K; Chandel, N S; Cheng, E H; Chipuk, J E; Cidlowski, J A; Ciechanover, A; Dawson, T M; Dawson, V L; De Laurenzi, V; De Maria, R; Debatin, K-M; Di Daniele, N; Dixit, V M; Dynlacht, B D; El-Deiry, W S; Fimia, G M; Flavell, R A; Fulda, S; Garrido, C; Gougeon, M-L; Green, D R; Gronemeyer, H; Hajnoczky, G; Hardwick, J M; Hengartner, M O; Ichijo, H; Joseph, B; Jost, P J; Kaufmann, T; Kepp, O; Klionsky, D J; Knight, R A; Kumar, S; Lemasters, J J; Levine, B; Linkermann, A; Lipton, S A; Lockshin, R A; López-Otín, C; Lugli, E; Madeo, F; Malorni, W; Marine, J-C; Martin, S J; Martinou, J-C; Medema, J P; Meier, P; Melino, S; Mizushima, N; Moll, U; Muñoz-Pinedo, C; Nuñez, G; Oberst, A; Panaretakis, T; Penninger, J M; Peter, M E; Piacentini, M; Pinton, P; Prehn, J H; Puthalakath, H; Rabinovich, G A; Ravichandran, K S; Rizzuto, R; Rodrigues, C M; Rubinsztein, D C; Rudel, T; Shi, Y; Simon, H-U; Stockwell, B R; Szabadkai, G; Tait, S W; Tang, H L; Tavernarakis, N; Tsujimoto, Y; Vanden Berghe, T; Vandenabeele, P; Villunger, A; Wagner, E F; Walczak, H; White, E; Wood, W G; Yuan, J; Zakeri, Z; Zhivotovsky, B; Melino, G; Kroemer, G

2015-01-01

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death. PMID:25236395

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015.

PubMed

Galluzzi, L; Bravo-San Pedro, J M; Vitale, I; Aaronson, S A; Abrams, J M; Adam, D; Alnemri, E S; Altucci, L; Andrews, D; Annicchiarico-Petruzzelli, M; Baehrecke, E H; Bazan, N G; Bertrand, M J; Bianchi, K; Blagosklonny, M V; Blomgren, K; Borner, C; Bredesen, D E; Brenner, C; Campanella, M; Candi, E; Cecconi, F; Chan, F K; Chandel, N S; Cheng, E H; Chipuk, J E; Cidlowski, J A; Ciechanover, A; Dawson, T M; Dawson, V L; De Laurenzi, V; De Maria, R; Debatin, K-M; Di Daniele, N; Dixit, V M; Dynlacht, B D; El-Deiry, W S; Fimia, G M; Flavell, R A; Fulda, S; Garrido, C; Gougeon, M-L; Green, D R; Gronemeyer, H; Hajnoczky, G; Hardwick, J M; Hengartner, M O; Ichijo, H; Joseph, B; Jost, P J; Kaufmann, T; Kepp, O; Klionsky, D J; Knight, R A; Kumar, S; Lemasters, J J; Levine, B; Linkermann, A; Lipton, S A; Lockshin, R A; López-Otín, C; Lugli, E; Madeo, F; Malorni, W; Marine, J-C; Martin, S J; Martinou, J-C; Medema, J P; Meier, P; Melino, S; Mizushima, N; Moll, U; Muñoz-Pinedo, C; Nuñez, G; Oberst, A; Panaretakis, T; Penninger, J M; Peter, M E; Piacentini, M; Pinton, P; Prehn, J H; Puthalakath, H; Rabinovich, G A; Ravichandran, K S; Rizzuto, R; Rodrigues, C M; Rubinsztein, D C; Rudel, T; Shi, Y; Simon, H-U; Stockwell, B R; Szabadkai, G; Tait, S W; Tang, H L; Tavernarakis, N; Tsujimoto, Y; Vanden Berghe, T; Vandenabeele, P; Villunger, A; Wagner, E F; Walczak, H; White, E; Wood, W G; Yuan, J; Zakeri, Z; Zhivotovsky, B; Melino, G; Kroemer, G

2015-01-01

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output

PubMed Central

Shao, Zuoyi; Puche, Adam C.; Liu, Shaolin

2012-01-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABAA receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs. PMID:22592311

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output.

PubMed

Shao, Zuoyi; Puche, Adam C; Liu, Shaolin; Shipley, Michael T

2012-08-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABA(A) receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs.

Heritability of brain activity related to response inhibition: A longitudinal genetic study in adolescent twins.

PubMed

Anokhin, Andrey P; Golosheykin, Simon; Grant, Julia D; Heath, Andrew C

2017-05-01

The ability to inhibit prepotent but context- or goal-inappropriate responses is essential for adaptive self-regulation of behavior. Deficits in response inhibition, a key component of impulsivity, have been implicated as a core dysfunction in a range of neuropsychiatric disorders such as ADHD and addictions. Identification of genetically transmitted variation in the neural underpinnings of response inhibition can help to elucidate etiological pathways to these disorders and establish the links between genes, brain, and behavior. However, little is known about genetic influences on the neural mechanisms of response inhibition during adolescence, a developmental period characterized by weak self-regulation of behavior. Here we investigated heritability of ERPs elicited in a Go/No-Go task in a large sample of adolescent twins assessed longitudinally at ages 12, 14, and 16. Genetic analyses showed significant heritability of inhibition-related frontal N2 and P3 components at all three ages, with 50 to 60% of inter-individual variability being attributable to genetic factors. These genetic influences included both common genetic factors active at different ages and novel genetic influences emerging during development. Finally, individual differences in the rate of developmental changes from age 12 to age 16 were significantly influenced by genetic factors. In conclusion, the present study provides the first evidence for genetic influences on neural correlates of response inhibition during adolescence and suggests that ERPs elicited in the Go/No-Go task can serve as intermediate neurophysiological phenotypes (endophenotypes) for the study of disinhibition and impulse control disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Response properties of single units in the dorsal nucleus of the lateral lemniscus of decerebrate cats.

PubMed

Davis, Kevin A; Lomakin, Oleg; Pesavento, Michael J

2007-09-01

The dorsal nucleus of the lateral lemniscus (DNLL) receives afferent inputs from many brain stem nuclei and, in turn, is a major source of inhibitory inputs to the inferior colliculus (IC). The goal of this study was to characterize the monaural and binaural response properties of neurons in the DNLL of unanesthetized decerebrate cat. Monaural responses were classified according to the patterns of excitation and inhibition observed in contralateral and ipsilateral frequency response maps. Binaural classification was based on unit sensitivity to interaural level differences. The results show that units in the DNLL can be grouped into three distinct types. Type v units produce contralateral response maps that show a wide V-shaped excitatory area and no inhibition. These units receive ipsilateral excitation and exhibit binaural facilitation. The contralateral maps of type i units show a more restricted I-shaped region of excitation that is flanked by inhibition. Type o maps display an O-shaped island of excitation at low stimulus levels that is bounded by inhibition at higher levels. Both type i and type o units receive ipsilateral inhibition and exhibit binaural inhibition. Units that produce type v maps have a low best frequency (BF), whereas type i and type o units have high BFs. Type v and type i units give monotonic rate-level responses for both BF tones and broadband noise. Type o units are inhibited by tones at high levels, but are excited by high-level noise. These results show that the DNLL can exert strong, differential effects in the IC.

Heritability of brain activity related to response inhibition: a longitudinal genetic study in adolescent twins

PubMed Central

Anokhin, Andrey P.; Golosheykin, Simon; Grant, Julia D.; Heath, Andrew C.

2017-01-01

The ability to inhibit prepotent but context- or goal-inappropriate responses is essential for adaptive self-regulation of behavior. Deficits in response inhibition, a key component of impulsivity, have been implicated as a core dysfunction in a range of neuropsychiatric disorders such as ADHD and addictions. Identification of genetically transmitted variation in the neural underpinnings of response inhibition can help to elucidate etiological pathways to these disorders and establish the links between genes, brain, and behavior. However, little is known about genetic influences on the neural mechanisms of response inhibition during adolescence, a developmental period characterized by weak self-regulation of behavior. Here we investigated heritability of ERPs elicited in a Go/No-Go task in a large sample of adolescent twins assessed longitudinally at ages 12, 14, and 16. Genetic analyses showed significant heritability of inhibition-related frontal N2 and P3 components at all three ages, with 50 to 60% of inter-individual variability being attributable to genetic factors. These genetic influences included both common genetic factors active at different ages and novel genetic influences emerging during development. Finally, individual differences in the rate of developmental changes from age 12 to age 16 were significantly influenced by genetic factors. In conclusion, the present study provides the first evidence for genetic influences on neural correlates of response inhibition during adolescence and suggests that ERPs elicited in the Go/No-Go task can serve as intermediate neurophysiological phenotypes (endophenotypes) for the study of disinhibition and impulse control disorders. PMID:28300615

Cannabis intoxication inhibits avoidance action tendencies: a field study in the Amsterdam coffee shops.

PubMed

Cousijn, Janna; Snoek, Robin W M; Wiers, Reinout W

2013-09-01

Experimental laboratory studies suggest that the approach bias (relatively fast approach responses) toward substance-related materials plays an important role in problematic substance use. How this bias is moderated by intention to use versus recent use remains unknown. Moreover, the relationship between approach bias and other motivational processes (satiation and craving) and executive functioning remains unclear. The aim of this study was to investigate the cannabis approach bias before and after cannabis use in real-life setting (Amsterdam coffee shops) and to assess the relationship between approach bias, craving, satiation, cannabis use, and response inhibition. Cannabis, tobacco, and neutral approach and avoidance action tendencies were measured with the Approach Avoidance Task and compared between 42 heavy cannabis users with the intention to use and 45 heavy cannabis users shortly after cannabis use. The classical Stroop was used to measure response inhibition. Multiple regression analyses were conducted to investigate relationships between approach bias, satiation, craving, cannabis use, and response inhibition. In contrast to the hypotheses, heavy cannabis users with the intention to use did not show a cannabis approach bias, whereas intoxicated cannabis users did show an approach bias regardless of image category. This could be attributed to a general slowing of avoidance action tendencies. Moreover, craving was negatively associated with the approach bias, and no relationships were observed between the cannabis approach bias, satiation, prior cannabis use, and response inhibition. Cannabis intoxication in a real-life setting inhibited general avoidance. Expression of the cannabis approach bias appeared not to be modulated by satiation or response inhibition.

Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1

PubMed Central

Lu, Mingjian; Wan, Min; Leavens, Karla F.; Chu, Qingwei; Monks, Bobby R.; Fernandez, Sully; Ahima, Rexford S.; Ueki, Kohjiro; Kahn, C. Ronald; Birnbaum, Morris J.

2012-01-01

Considerable data support the idea that Foxo1 drives the liver transcriptional program during fasting and is inhibited by Akt after feeding. Mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant, and defective in the transcriptional response to feeding in liver. These defects were normalized upon concomitant liver–specific deletion of Foxo1. Surprisingly, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. Gene expression analysis revealed that deletion of Akt in liver led to constitutive activation of Foxo1–dependent gene expression, but once again concomitant ablation of Foxo1 restored postprandial regulation, preventing its inhibition of the metabolic response to nutrient intake. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for insulin’s actions. Rather they demonstrate that a major role of hepatic Akt is to restrain Foxo1 activity, and in the absence of Foxo1, Akt is largely dispensable for hepatic metabolic regulation in vivo. PMID:22344295

Bi-functional, substrate mimicking RNA inhibits MSK1-mediated cAMP-response element-binding protein phosphorylation and reveals magnesium ion-dependent conformational changes of the kinase.

PubMed

Hamm, Jorg; Alessi, Dario R; Biondi, Ricardo M

2002-11-29

The design of specific inhibitors for protein kinases is an important step toward elucidation of intracellular signal transduction pathways and to guide drug discovery programs. We devised a model approach to generate specific, competitive kinase inhibitors by isolating substrate mimics containing two independent binding sites with an anti-idiotype strategy from combinatorial RNA libraries. As a general test for the ability to generate highly specific kinase inhibitors, we selected the transcription factor cAMP-response element-binding protein (CREB) that is phosphorylated on the same serine residue by the protein kinase MSK1 as well as by RSK1. The sequences and structures of these kinases are very similar, about 60% of their amino acids are identical. Nevertheless, we can demonstrate that the selected RNA inhibitors inhibit specifically CREB phosphorylation by MSK1 but do not affect CREB phosphorylation by RSK1. The inhibitors interact preferentially with the inactive form of MSK1. Furthermore, we demonstrate that RNA ligands can be conformation-specific probes, and this feature allowed us to describe magnesium ion-dependent conformational changes of MSK1 upon activation.

GPR55 agonist lysophosphatidylinositol and lysophosphatidylcholine inhibit endothelial cell hyperpolarization via GPR-independent suppression of Na+-Ca2+ exchanger and endoplasmic reticulum Ca2+ refilling.

PubMed

Bondarenko, Alexander I; Montecucco, Fabrizio; Panasiuk, Olga; Sagach, Vadim; Sidoryak, Nataliya; Brandt, Karim J; Mach, François

2017-02-01

Lysophosphatidylinositol (LPI) and lysophosphatidylcholine (LPC) are lipid signaling molecules that induce endothelium-dependent vasodilation. In addition, LPC suppresses acetylcholine (Ach)-induced responses. We aimed to determine the influence of LPC and LPI on hyperpolarizing responses in vitro and in situ endothelial cells (EC) and identify the underlying mechanisms. Using patch-clamp method, we show that LPI and LPC inhibit EC hyperpolarization to histamine and suppress Na + /Ca 2+ exchanged (NCX) currents in a concentration-dependent manner. The inhibition is non-mode-specific and unaffected by intracellular GDPβS infusion and tempol, a superoxide dismutase mimetic. In excised mouse aorta, LPI strongly inhibits the sustained and the peak endothelial hyperpolarization induced by Ach, but not by SKA-31, an opener of Ca 2+ -dependent K + channels of intermediate and small conductance. The hyperpolarizing responses to consecutive histamine applications are strongly reduced by NCX inhibition. In a Ca 2+ -re-addition protocol, bepridil, a NCX inhibitor, and KB-R7943, a blocker of reversed NCX, inhibit the hyperpolarizing responses to Ca 2+ -re-addition following Ca 2+ stores depletion. These finding indicate that LPC and LPI inhibit endothelial hyperpolarization to Ach and histamine independently of G-protein coupled receptors and superoxide anions. Reversed NCX is critical for ER Ca 2+ refilling in EC. The inhibition of NCX by LPI and LPC underlies diminished endothelium-dependent responses and endothelial dysfunction accompanied by increased levels of these lipids in the blood. Copyright © 2017 Elsevier Inc. All rights reserved.

Response inhibition difficulties in preterm children aged 9-12 years: Relations with emotion and behavior.

PubMed

Réveillon, Morgane; Borradori Tolsa, Cristina; Monnier, Maryline; Hüppi, Petra S; Barisnikov, Koviljka

2016-01-01

Previous studies with children have demonstrated inhibition difficulties associated with prematurity, but the question of potentially catching up with a delay in inhibition processes before adolescence still remains. Moreover, preterm adolescents are more at risk than their term-born peers for presenting behavioral problems such as emotional difficulties and attention deficit/hyperactivity disorder. In addition to examining response inhibition, this study addressed, for the first time, the impact of an emotional context on response inhibition abilities and its relation to behavioral problems in late school-aged preterm children. Fifty-eight preterm children aged 9-12 years were compared with 61 controls on two versions of a stop-signal task, the Delay Frustration Task, and the Strengths and Difficulties Questionnaire. Results showed general difficulties in inhibiting a response, rather than a specific impact of emotional context in preterm children. Compared with controls, these children exhibited more and longer button presses in a delay situation, as well as faster go reaction times associated with lower probability of inhibition in the stop-signal tasks. These difficulties reflected impulsivity and were associated with higher hyperactivity/inattention and conduct problems. Additionally, intrauterine growth restriction was found to be an additional perinatal risk factor for hyperactivity/inattention symptoms. These findings suggest that remaining inhibition difficulties in the preterm population at preadolescence could reveal increasing behavioral issues.

Chronic inhibition of nitric oxide synthase augments the ACTH response to exercise

PubMed Central

Jankord, Ryan; McAllister, Richard M.; Ganjam, Venkataseshu K.; Laughlin, M. Harold

2009-01-01

Exercise can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and regular exercise training can impact how the HPA axis responds to stress. The mechanism by which acute exercise induces HPA activity is unclear. Therefore, the purpose of this study was to test the hypothesis that nitric oxide modulates the neuroendocrine component of the HPA axis during exercise. Female Yucatan miniature swine were treated with N-nitro-l-arginine methyl ester (l-NAME) to test the effect of chronic nitric oxide synthase (NOS) inhibition on the ACTH response to exercise. In addition, we tested the effect of NOS inhibition on blood flow to tissues of the HPA axis and report the effects of handling and treadmill exercise on the plasma concentrations of ACTH and cortisol. Chronic NOS inhibition decreased plasma NOx levels by 44%, increased mean arterial blood pressure by 46%, and increased expression of neuronal NOS in carotid arteries. Vascular conductance was decreased in the frontal cortex, the hypothalamus, and the adrenal gland. Chronic NOS inhibition exaggerated the ACTH response to exercise. In contrast, chronic NOS inhibition decreased the ACTH response to restraint, suggesting that the role of NO in modulating HPA activity is stressor dependent. These results demonstrate that NOS activity modulates the response of the neuroendocrine component of the HPA axis during exercise stress. PMID:19144752

Chronic inhibition of nitric oxide synthase augments the ACTH response to exercise.

PubMed

Jankord, Ryan; McAllister, Richard M; Ganjam, Venkataseshu K; Laughlin, M Harold

2009-03-01

Exercise can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and regular exercise training can impact how the HPA axis responds to stress. The mechanism by which acute exercise induces HPA activity is unclear. Therefore, the purpose of this study was to test the hypothesis that nitric oxide modulates the neuroendocrine component of the HPA axis during exercise. Female Yucatan miniature swine were treated with N-nitro-l-arginine methyl ester (l-NAME) to test the effect of chronic nitric oxide synthase (NOS) inhibition on the ACTH response to exercise. In addition, we tested the effect of NOS inhibition on blood flow to tissues of the HPA axis and report the effects of handling and treadmill exercise on the plasma concentrations of ACTH and cortisol. Chronic NOS inhibition decreased plasma NO(x) levels by 44%, increased mean arterial blood pressure by 46%, and increased expression of neuronal NOS in carotid arteries. Vascular conductance was decreased in the frontal cortex, the hypothalamus, and the adrenal gland. Chronic NOS inhibition exaggerated the ACTH response to exercise. In contrast, chronic NOS inhibition decreased the ACTH response to restraint, suggesting that the role of NO in modulating HPA activity is stressor dependent. These results demonstrate that NOS activity modulates the response of the neuroendocrine component of the HPA axis during exercise stress.

The impairing effects of mental fatigue on response inhibition: An ERP study

PubMed Central

Guo, Zizheng; Chen, Ruiya; Liu, Xian; Zheng, Yan; Gong, Mingliang; Zhang, Jun

2018-01-01

Mental fatigue is one of the main reasons for the decline of response inhibition. This study aimed to explore the impairing influence of mental fatigue on a driver’s response inhibition. The effects of mental fatigue on response inhibition were assessed by comparing brain activity and behavioral indices when performing a Go/NoGo task before and after a 90-min fatigue manipulation task. Participants in the driving group performed a simulated driving task, while individuals in the control group spent the same time watching movies. We found that participants in the driving group reported higher levels of mental fatigue and had a higher percentage of eye closure and larger lateral deviations from their lane positions, which indicated there was effective manipulation of mental fatigue through a prolonged simulated driving task. After manipulation of mental fatigue, we observed increased reaction time and miss rates, delayed NoGo-N2 latency and Go-P3 latency, and decreased NoGo-P3 amplitude, which indicated that mental fatigue may slow down the speed of the inhibition process, delay the evaluation of visual stimuli and reduce the availability of attentional resources. These findings revealed the underlying neurological mechanisms of how mental fatigue impaired response inhibition. PMID:29856827

Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia.

PubMed

Schäfer, M; Schäfer, C; Ewald, N; Piper, H M; Noll, Th

2003-05-16

Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling of this response, with a focus on the roles of redox signaling and the MEK/ERK pathway. Transient hypoxia (1 hour) stimulated proliferation by 61+/-4% (n=16; P<0.05 versus control), quantified after 24 hours normoxic postincubation. Hypoxia induced an activation of ERK2 and of NAD(P)H oxidase and a burst of reactive oxygen species (ROS), determined by DCF fluorescence. To inhibit the MEK/ERK pathway, we used PD 98059 (PD, 20 micromol/L); to downregulate NAD(P)H oxidase, we applied p22phox antisense oligonucleotides; and to inhibit mitochondrial ROS generation, we used the ubiquinone derivate mitoQ (MQ, 10 micromol/L). All three inhibitions suppressed the proliferative response: PD inhibited NAD(P)H oxidase activation; p22phox antisense transfection did not inhibit ERK2 activation, but suppressed ROS production; and MQ inhibited ERK2 activation and ROS production. The autonomous proliferative response depends on the MEK/ERK pathway and redox signaling steps upstream and downstream of ERK. Located upstream is ROS generation by mitochondria, downstream is NAD(P)H oxidase.

Decreased response inhibition to sad faces during explicit and implicit tasks in females with depression: Evidence from an event-related potential study.

PubMed

Yu, Fengqiong; Zhou, Xiaoqing; Qing, Wu; Li, Dan; Li, Jing; Chen, Xingui; Ji, Gongjun; Dong, Yi; Luo, Yuejia; Zhu, Chunyan; Wang, Kai

2017-01-30

The present study aimed to investigate neural substrates of response inhibition to sad faces across explicit and implicit tasks in depressed female patients. Event-related potentials were obtained while participants performed modified explicit and implicit emotional go/no-go tasks. Compared to controls, depressed patients showed decreased discrimination accuracy and amplitudes of original and nogo-go difference waves at the P3 interval in response inhibition to sad faces during explicit and implicit tasks. P3 difference wave were positively correlated with discrimination accuracy and were independent of clinical assessment. The activation of right dorsal prefrontal cortex was larger for the implicit than for the explicit task in sad condition in health controls, but was similar for the two tasks in depressed patients. The present study indicated that selectively impairment in response inhibition to sad faces in depressed female patients occurred at the behavior inhibition stage across implicit and explicit tasks and may be a trait-like marker of depression. Longitudinal studies are required to determine whether decreased response inhibition to sad faces increases the risk for future depressive episodes so that appropriate treatment can be administered to patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Women are More Sensitive than Men to Prior Trial Events on the Stop Signal Task

PubMed Central

Thakkar, Katharine N.; Congdon, Eliza; Poldrack, Russell A.; Sabb, Fred W.; London, Edythe D.; Cannon, Tyrone D.; Bilder, Robert M.

2013-01-01

Sexual dimorphism in the brain and cognition is a topic of widespread interest. Many studies of sex differences have focused on visuospatial and verbal abilities but few studies have investigated sex differences in executive functions. We examined two key components of executive function—response inhibition and response monitoring—in healthy men (n=285) and women (n=346) performing the Stop-signal task. In this task, participants are required to make a key press to a stimulus, unless a tone is presented at some delay following the initial stimulus presentation; on these infrequent trials, participants are instructed to inhibit their planned response. Response inhibition was assessed with an estimate of the latency needed to inhibit a response (stop-signal reaction time), and response monitoring was measured by calculating the degree to which participants adjusted their reaction times based on the immediately preceding trial (e.g. speeding following correct trials and slowing following errors). There were no sex differences in overall accuracy or response inhibition but women showed greater sensitivity to trial history. Women sped up more than men following correct “Go” trials, and slowed down more than men following errors. These small but statistically significant effects (Cohen’s d=0.25–0.3) suggest more flexible adjustments in speed-accuracy trade-offs in women and greater cognitive flexibility associated with the responsive control of action. PMID:24754812

Vitamin D protects keratinocytes from deleterious effects of ionizing radiation.

PubMed

Langberg, M; Rotem, C; Fenig, E; Koren, R; Ravid, A

2009-01-01

Radiotherapy can induce severe skin responses that may limit the clinically acceptable radiation dose. The responses include erythema, dry and moist desquamation, erosions and dermal-epidermal blister formation. These effects reflect injury to, and reproductive failure of, epidermal cells and may also be due to dysregulation of the tissue remodelling process caused by excessive proteolytic activity. Calcitriol, the hormonally active vitamin D metabolite, protects keratinocytes from programmed cell death induced by various noxious stimuli. To examine whether calcitriol protects proliferating keratinocytes from the damage inflicted by ionizing radiation under conditions similar to those employed during radiotherapy. Autonomously proliferating HaCaT keratinocytes, used as a model for basal layer keratinocytes, were irradiated using a linear accelerator. Cell death was monitored by vital staining, executioner caspase activation, lactic dehydrogenase release and colony formation assay. Induction of matrix metalloproteinase-9 was assessed by gelatinase activity assay and mRNA determination. Levels of specific proteins were determined by immunoblotting. Treatment with calcitriol inhibited both caspase-dependent and -independent programmed cell death occurring within 48 h of irradiation and increased the colony formation capacity of irradiated cells. These effects may be attributable to inhibition of the c-Jun NH(2)-terminal kinase cascade and to upregulation of the truncated antiapoptotic isoform of p63. Treatment with the hormone also attenuated radiation-induced increase in matrix metalloproteinase-9 protein and mRNA levels. The results of this study suggest that active vitamin D derivatives may attenuate cell death and excessive proteolytic activity in the epidermis due to exposure to ionizing radiation in the course of radiotherapy.

Target Predictability, Sustained Attention, and Response Inhibition

ERIC Educational Resources Information Center

Carter, Leonie; Russell, Paul N.; Helton, William S.

2013-01-01

We examined whether the sustained attention to response task is a better measure of response inhibition or sustained attention. Participants performed a number detection task for 37.3 min using either a Sustained Attention to Response Task (SART; high Go low No-Go) or a more traditionally formatted vigilance task (TFT; high No-Go low Go) response…

Neuron responses to substance P and enkephalin in rat dorso-lateral septum in vitro.

PubMed

Nayar, R; Sirett, N E; Hubbard, J I

1987-10-01

Using an in vitro brain slice technique the responses of spontaneously active neurons in the rat dorso-lateral septum to 10 nM substance P (SP) and enkephalin were determined. Fewer neurons responded to SP (41%) than to enkephalin (55%). The SP responses were 13 excitations, 14 inhibitions, the enkephalin responses were 13 excitations, 14 inhibitions and 11 responded to both, 6 of these were inhibited by both. Immunocytochemical techniques have shown there is a discrete localisation of SP and enkephalin axons and terminals in the rat septum. SP responsive neurons were associated with the SP terminal-rich region (p = 0.01) but no association was found for enkephalin responses in the enkephalin terminal-rich region (p = 0.7).

Lipids Derived from Virulent Francisella tularensis Broadly Inhibit Pulmonary Inflammation via Toll-Like Receptor 2 and Peroxisome Proliferator-Activated Receptor α

PubMed Central

Crane, Deborah D.; Ireland, Robin; Alinger, Joshua B.; Small, Pamela

2013-01-01

Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes an acute lethal respiratory disease in humans. The heightened virulence of the pathogen is linked to its unique ability to inhibit Toll-like receptor (TLR)-mediated inflammatory responses. The bacterial component and mechanism of this inhibition are unknown. Here we show that lipids isolated from virulent but not attenuated strains of F. tularensis are not detected by host cells, inhibit production of proinflammatory cytokines by primary macrophages in response to known TLR ligands, and suppress neutrophil recruitment in vivo. We further show that lipid-mediated inhibition of inflammation is dependent on TLR2, MyD88, and the nuclear hormone and fatty acid receptor peroxisome proliferator-activated receptor α (PPARα). Pathogen lipid-mediated interference with inflammatory responses through the engagement of TLR2 and PPARα represents a novel manipulation of host signaling pathways consistent with the ability of highly virulent F. tularensis to efficiently evade host immune responses. PMID:23925884

Less approach, more avoidance: Response inhibition has motivational consequences for sexual stimuli that reflect changes in affective value not a lingering global brake on behavior.

PubMed

Driscoll, Rachel L; de Launay, Keelia Quinn; Fenske, Mark J

2018-02-01

Response inhibition negatively impacts subsequent hedonic evaluations of motivationally relevant stimuli and reduces the behavioral incentive to seek and obtain such items. Here we expand the investigation of the motivational consequences of inhibition by presenting sexually appealing and nonappealing images in a go/no-go task and a subsequent image-viewing task. Each initially obscured image in the viewing task could either be made more visible or less visible by repeatedly pressing different keys. Fewer key presses were made to obtain better views of preferred-sex images when such images had previously been inhibited as no-go items than when previously encountered as noninhibited go items. This finding replicates prior results and is consistent with the possibility that motor-response suppression has lingering effects that include global reductions in all behavioral expression. However, for nonpreferred images, prior inhibition resulted in more key presses to obscure their visibility than when such images had not been inhibited. This novel finding suggests that the motivational consequences of response inhibition are not due to a global brake on action but are instead linked to negative changes in stimulus value that induce corresponding increases in avoidance and decreases in approach.

Inhibition of KSP by ARRY-520 Induces Cell Cycle Block and Cell Death via the Mitochondrial Pathway in AML Cells

PubMed Central

Carter, Bing Z.; Mak, Duncan H.; Woessner, Richard; Gross, Stefan; Schober, Wendy D.; Estrov, Zeev; Kantarjian, Hagop; Andreeff, Michael

2013-01-01

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines which express high levels of KSP. Knockdown of p53, overexpression of XIAP, and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP, and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has potential to eradicate AML progenitor cells. PMID:19458629

Acute glucocorticoid effects on response inhibition in borderline personality disorder.

PubMed

Carvalho Fernando, Silvia; Beblo, Thomas; Schlosser, Nicole; Terfehr, Kirsten; Wolf, Oliver Tobias; Otte, Christian; Löwe, Bernd; Spitzer, Carsten; Driessen, Martin; Wingenfeld, Katja

2013-11-01

Growing evidence suggests inhibition dysfunctions in borderline personality disorder (BPD). Moreover, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis functioning have also been found in BPD patients. In healthy individuals, response inhibition has been sensitive to acute stress, and previous research indicates that effects mediated by the HPA axis become particularly apparent when emotional stimuli are processed. This study aimed to explore the influence of acute hydrocortisone administration on response inhibition of emotional stimuli in BPD patients compared to healthy control participants. After a single administration of 10mg hydrocortisone or placebo, 32 female BPD patients and 32 healthy female participants performed an adapted emotional go/no-go paradigm to assess response inhibition for emotional face stimuli in a cross-over study. Acute cortisol elevations decreased the reaction times to target stimuli in both BPD patients and healthy controls. Patients and controls did not differ in task performance; however, BPD patients with comorbid posttraumatic stress disorder (PTSD) displayed longer reaction times than patients without PTSD. In contrast, the occurrence of comorbid eating disorder had no significant impact on go/no-go performance. No significant interaction effect between the treatment condition and the emotional valence of the face stimuli was found. Acute hydrocortisone administration enhances response inhibition of face stimuli in BPD patients and healthy controls, regardless of their emotional valence. Our results agree with the suggestion that moderate cortisol enhancement increases the inhibition of task-irrelevant distracters. Copyright © 2013 Elsevier Ltd. All rights reserved.

Orbitofrontal Cortical Neurons Encode Expectation-Driven Initiation of Reward-Seeking

PubMed Central

Aston-Jones, Gary

2014-01-01

Adaptive execution and inhibition of behavior are guided by the activity of neuronal populations across multiple frontal cortical areas. The rodent medial prefrontal cortex has been well studied with respect to these behaviors, influencing behavioral execution/inhibition based on context. Other frontal regions, in particular the orbitofrontal cortex (OFC), are critical in directing behavior to obtain rewards, but the relationship between OFC neuronal activity and response execution or inhibition has been poorly characterized. In particular, little is known about OFC with respect to extinction learning, an important example of context-guided response inhibition. Here, we recorded the activity of OFC neurons while rats performed a discriminative-stimulus (DS)-driven sucrose-seeking task followed by multiple days of extinction of the DS. OFC neuronal activity was maximally responsive (1) to reward-predicting stimuli (RS) that triggered a lever press (i.e., lever-response initiation) and (2) during reward-well approach in pursuit of sucrose (i.e., well-response initiation). RS presentation that was not followed by a lever press or RS presentation during extinction produced weak activation, as did nonrewarded stimulus (NS) presentation regardless of response (press or withhold) or session (DS-sucrose or extinction). Activity related to nonrewarded well entry was minor, and activity was significantly inhibited during reward consumption. Finally, OFC neuronal activity switched selectivity to track rewarded behaviors when the RS/NS contingencies were reversed. Thus, rather than signaling variables related to extinction or response inhibition, activity in OFC was strongest at the initiation of multiple components of reward-seeking behavior, most prominently when valid reward-predicting cues drove these behaviors. PMID:25080585

The long-term effects of prenatal nicotine exposure on response inhibition: an fMRI study of young adults.

PubMed

Longo, Carmelinda A; Fried, Peter A; Cameron, Ian; Smith, Andra M

2013-01-01

The long-term effects of prenatal nicotine exposure on response inhibition were investigated in young adults using functional magnetic resonance imaging (fMRI). Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana and alcohol exposure and current marijuana, nicotine and alcohol use. Twelve young adults with prenatal nicotine exposure and 13 non-exposed controls performed a Go/No-Go task while fMRI blood oxygen level-dependent responses were examined. Despite similar task performance, participants prenatally exposed to nicotine demonstrated significantly greater activity in several regions of the brain that typically subserve response inhibition including the inferior frontal gyrus, the inferior parietal lobe, the thalamus and the basal ganglia. In addition, prenatally exposed participants showed greater activity in relatively large posterior regions of the cerebellum. These results suggest that prenatal nicotine exposure leads to altered neural functioning during response inhibition that continues into adulthood. This alteration is compensated for by recruitment of greater neural resources within regions of the brain that subserve response inhibition and the recruitment of additional brain regions to successfully perform the task. Response inhibition is an important executive functioning skill and impairments can impede functioning in much of everyday life. Thus, awareness of the continued long-term neural physiological effects of prenatal nicotine exposure is critical. Copyright © 2013 Elsevier Inc. All rights reserved.

Impact of elevated nitrate on sulfate-reducing bacteria: A comparative study of Desulfovibrio vulgaris

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

He, Q.; He, Z.; Joyner, D.C.

2010-07-15

Sulfate-reducing bacteria have been extensively studied for their potential in heavy-metal bioremediation. However, the occurrence of elevated nitrate in contaminated environments has been shown to inhibit sulfate reduction activity. Although the inhibition has been suggested to result from the competition with nitrate-reducing bacteria, the possibility of direct inhibition of sulfate reducers by elevated nitrate needs to be explored. Using Desulfovibrio vulgaris as a model sulfate-reducing bacterium, functional genomics analysis reveals that osmotic stress contributed to growth inhibition by nitrate as shown by the upregulation of the glycine/betaine transporter genes and the relief of nitrate inhibition by osmoprotectants. The observation thatmore » significant growth inhibition was effected by 70 mM NaNO{sub 3} but not by 70 mM NaCl suggests the presence of inhibitory mechanisms in addition to osmotic stress. The differential expression of genes characteristic of nitrite stress responses, such as the hybrid cluster protein gene, under nitrate stress condition further indicates that nitrate stress response by D. vulgaris was linked to components of both osmotic and nitrite stress responses. The involvement of the oxidative stress response pathway, however, might be the result of a more general stress response. Given the low similarities between the response profiles to nitrate and other stresses, less-defined stress response pathways could also be important in nitrate stress, which might involve the shift in energy metabolism. The involvement of nitrite stress response upon exposure to nitrate may provide detoxification mechanisms for nitrite, which is inhibitory to sulfate-reducing bacteria, produced by microbial nitrate reduction as a metabolic intermediate and may enhance the survival of sulfate-reducing bacteria in environments with elevated nitrate level.« less

Effects of neutral endopeptidase (neprilysin) inhibition on the response to other vasoactive peptides in small human resistance arteries: studies with thiorphan and omapatrilat.

PubMed

Dalzell, Jonathan R; Seed, Alison; Berry, Colin; Whelan, Carol J; Petrie, Mark C; Padmanabhan, Neal; Clarke, Amanda; Biggerstaff, Fiona; Hillier, Christopher; McMurray, John J V

2014-02-01

New compounds with neprilysin or neutral endopeptidase (NEP) inhibiting activity are under clinical investigation in heart failure and hypertension. We investigated the effect of NEP inhibition on the functional vasomotor responses to a range of vasoactive peptides in human blood vessels. Small human resistance arteries from patients with coronary artery disease and preserved left ventricular systolic function were studied. Thiorphan (a NEP inhibitor) was compared with captopril (an ACE inhibitor) and omapatrilat (a dual NEP-ACE inhibitor) with regard to their effects on the response of human arteries to key vasoactive peptides. As expected, both captopril and omapatrilat (but not thiorphan) inhibited the vasoconstrictor effect of angiotensin I (maximal response [SEM]: 27 ± 8% vehicle, 6 ± 2% captopril, 39 ± 10% thiorphan, 8 ± 7% omapatrilat, P < 0.05). Thiorphan, captopril, and omapatrilat all enhanced the vasodilator response to bradykinin (all P < 0.01). Omapatrilat markedly augmented the vasodilator action of adrenomedullin (P < 0.05), whilst thiorphan and captopril did not. None of the three inhibitors studied affected the vasodilator action of c-type natriuretic peptide, calcitonin gene-related peptide, vasoactive intestinal polypeptide or substance P. NEP inhibition with thiorphan modestly augmented the vasodilator action of bradykinin, but did not potentiate the response to adrenomedullin; dual ACE and NEP inhibition with omapatrilat, as expected, markedly augmented the response to bradykinin and also potentiated the effect of adrenomedullin. Thiorphan weakly enhanced the vasoconstrictor response to angiotensin I. Neither omapatrilat nor thiorphan had any effect on the action of a range of other vasoactive peptides including CNP. © 2013 John Wiley & Sons Ltd.

Parenting Predictors of Delay Inhibition in Socioeconomically Disadvantaged Preschoolers

PubMed Central

Merz, Emily C.; Landry, Susan H.; Zucker, Tricia A.; Barnes, Marcia A.; Assel, Michael; Taylor, Heather B.; Lonigan, Christopher J.; Phillips, Beth M.; Clancy-Menchetti, Jeanine; Eisenberg, Nancy; Spinrad, Tracy L.; Valiente, Carlos; de Villiers, Jill; Consortium, the School Readiness Research

2016-01-01

This study examined longitudinal associations between specific parenting factors and delay inhibition in socioeconomically disadvantaged preschoolers. At Time 1, parents and 2- to 4-year-old children (mean age = 3.21 years; N = 247) participated in a videotaped parent-child free play session, and children completed delay inhibition tasks (gift delay-wrap, gift delay-bow, and snack delay tasks). Three months later, at Time 2, children completed the same set of tasks. Parental responsiveness was coded from the parent-child free play sessions, and parental directive language was coded from transcripts of a subset of 127 of these sessions. Structural equation modeling was used, and covariates included age, gender, language skills, parental education, and Time 1 delay inhibition. Results indicated that in separate models, Time 1 parental directive language was significantly negatively associated with Time 2 delay inhibition, and Time 1 parental responsiveness was significantly positively associated with Time 2 delay inhibition. When these parenting factors were entered simultaneously, Time 1 parental directive language significantly predicted Time 2 delay inhibition whereas Time 1 parental responsiveness was no longer significant. Findings suggest that parental language that modulates the amount of autonomy allotted the child may be an important predictor of early delay inhibition skills. PMID:27833461

Characteristics and Experiences Related to VTAE Programs That Encourage and/or Inhibit Entrepreneurial Competencies. Final Report.

ERIC Educational Resources Information Center

Gilbertson, Alan; And Others

A study examined the characteristics and features of vocational, technical, and adult education (VTAE) programs that encourage and/or inhibit entrepreneurship competencies. The study population included random samples of 50 students drawn from each of Wisconsin's VTAE districts, 30 occupational instructors from each district, and 30 graduates of…

Inhibition of ongoing responses in patients with Parkinson's disease

PubMed Central

Gauggel, S; Rieger, M; Feghoff, T

2004-01-01

Objectives: We investigated the involvement of the basal ganglia in inhibiting ongoing responses in patients with Parkinson's disease (PD). Methods: Thirty two patients with PD and 31 orthopaedic controls performed the stop signal task, which allows an estimation of the time it takes to inhibit an ongoing reaction (stop signal reaction time, SSRT). Results: Patients with PD showed significantly longer SSRTs than the controls. This effect seemed to be independent of global cognitive impairment and severity of PD. Furthermore, in the PD patients, there was no significant relation between general slowing and inhibitory efficiency. Conclusions: Our results provide evidence for involvement of the basal ganglia in the inhibition of ongoing responses. PMID:15026491

The Neural Basis of Cognitive Control: Response Selection and Inhibition

ERIC Educational Resources Information Center

Goghari, Vina M.; MacDonald, Angus W., III

2009-01-01

The functional neuroanatomy of tasks that recruit different forms of response selection and inhibition has to our knowledge, never been directly addressed in a single fMRI study using similar stimulus-response paradigms where differences between scanning time and sequence, stimuli, and experimenter instructions were minimized. Twelve right-handed…

CF3DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program.

PubMed

Taoka, Rikiya; Jinesh, Goodwin G; Xue, Wenrui; Safe, Stephen; Kamat, Ashish M

2017-05-01

Cancer stem cells are capable of undergoing cellular transformation after commencement of apoptosis through the blebbishield emergency program in a VEGF-VEGFR2-dependent manner. Development of therapeutics targeting the blebbishield emergency program would thus be important in cancer therapy. Specificity protein 1 (Sp1) orchestrates the transcription of both VEGF and VEGFR2; hence, Sp1 could act as a therapeutic target. Here, we demonstrate that CF 3 DODA-Me induced apoptosis, degraded Sp1, inhibited the expression of multiple drivers of the blebbishield emergency program such as VEGFR2, p70S6K, and N-Myc through activation of caspase-3, inhibited reactive oxygen species; and inhibited K-Ras activation to abolish transformation from blebbishields as well as transformation in soft agar. These findings confirm CF 3 DODA-Me as a potential therapeutic candidate that can induce apoptosis and block transformation from blebbishields.

Movement Activation and Inhibition in Parkinson’s Disease: a Functional Imaging Study

PubMed Central

Disbrow, E. A.; Sigvardt, K. A.; Franz, E. A.; Turner, R. S.; Russo, K. A.; Hinkley, L.B.; Herron, T. J.; Ventura, M. I.; Zhang, L.; Malhado-Chang, N.

2015-01-01

Background Parkinson’s disease (PD), traditionally considered a movement disorder, has been shown to affect executive function such as the ability to adapt behavior in response to new environmental situations. Objective to identify the impact of PD on neural substrates subserving two specific components of normal movement which we refer to as activation (initiating an un-cued response) and inhibition (suppressing a cued response). Methods We used fMRI to measure pre-movement processes associated with activating an un-cued response and inhibiting a cued response plan in 13 PD (ON anti-parkinsonian medications) and 13 control subjects. Subjects were shown a visual arrow cue followed by a matched or mismatched response target that instructed them to respond with a right, left, or bilateral button press. In mismatched trials, an un-cued (new) response was initiated, or the previously cued response was suppressed. Results We were able to isolate pre-movement responses in dorsolateral prefrontal cortex, specifically in the right hemisphere. During the activation of an un-cued movement, PD subjects showed decreased activity in the putamen and increased cortical activity in bilateral DLPFC, SMA, subcentral gyrus and inferior frontal operculum. During inhibition of a previously cued movement, the PD group showed increased activation in SMA, S1/M1, premotor and superior parietal areas. Conclusion Right DLPFC plays a role in pre-movement processes, and DLPFC activity is abnormal in PD. Decreased specificity of responses was observed in multiple ROI’s. The basal ganglia are involved in circuits that coordinate activation and inhibition involved in action selection as well as execution. PMID:23938347

The costs and benefits of temporal predictability: impaired inhibition of prepotent responses accompanies increased activation of task-relevant responses.

PubMed

Korolczuk, Inga; Burle, Boris; Coull, Jennifer T

2018-06-20

While the benefit of temporal predictability on sensorimotor processing is well established, it is still unknown whether this is due to efficient execution of an appropriate response and/or inhibition of an inappropriate one. To answer this question, we examined the effects of temporal predictability in tasks that required selective (Simon task) or global (Stop-signal task) inhibitory control of prepotent responses. We manipulated temporal expectation by presenting cues that either predicted (temporal cues) or not (neutral cues) when the target would appear. In the Simon task, performance was better when target location (left/right) was compatible with the hand of response and performance was improved further still if targets were temporally cued. However, Conditional Accuracy Functions revealed that temporal predictability selectively increased the number of fast, impulsive errors. Temporal cueing had no effect on selective response inhibition, as measured by the dynamics of the interference effect (delta plots) in the Simon task. By contrast, in the Stop-signal task, Stop-signal reaction time, a covert measure of a more global form of response inhibition, was significantly longer in temporally predictive trials. Therefore, when the time of target onset could be predicted in advance, it was harder to stop the impulse to respond to the target. Collectively, our results indicate that temporal cueing compounded the interfering effects of a prepotent response on task performance. We suggest that although temporal predictability enhances activation of task-relevant responses, it impairs inhibition of prepotent responses. Copyright © 2018 Elsevier B.V. All rights reserved.

Response inhibition of cigarette-related cues in male light smokers: behavioral evidence using a two-choice oddball paradigm

PubMed Central

Xin, Zhao; Ting, Liu X.; Yi, Zan X.; Li, Dai; Bao, Zhou A.

2015-01-01

Behavioral inhibitory control has been shown to play an important role in a variety of addictive behaviors. A number of studies involving the use of Go/NoGo and stop-signal paradigms have shown that smokers have reduced response inhibition for cigarette-related cues. However, it is not known whether male light smokers’ response inhibition for cigarette-related cues is lower than that of non-smokers in the two-choice oddball paradigm. The objective of the current study was to provide further behavioral evidence of male light smokers’ impaired response inhibition for cigarette-related cues, using the two-choice oddball paradigm. Sixty-two male students (31 smokers, 31 non-smokers), who were recruited via an advertisement, took part in this two-choice oddball experiment. Cigarette-related pictures (deviant stimuli) and pictures unrelated to cigarettes (standard stimuli) were used. Response inhibition for cigarette-related cues was measured by comparing accuracy (ACC) and reaction time (RT) for deviant and standard stimuli in the two groups of subjects. An analysis of variance (ANOVA) showed that in all the participants, ACC was significantly lower for deviant stimuli than for standard stimuli. For deviant stimuli, the RTs were significantly longer for male light smokers than for male non-smokers; however, there was no significant difference in RTs for standard stimuli. Compared to male non-smokers, male light smokers seem to have a reduced ability to inhibit responses to cigarette-related cues. PMID:26528200

The visceromotor responses to colorectal distension and skin pinch are inhibited by simultaneous jejunal distension.

PubMed

Shafton, Anthony D; Furness, John B; Ferens, Dorota; Bogeski, Goce; Koh, Shir Lin; Lean, Nicholas P; Kitchener, Peter D

2006-07-01

Noxious stimuli that are applied to different somatic sites interact; often one stimulus diminishes the sensation elicited from another site. By contrast, inhibitory interactions between visceral stimuli are not well documented. We investigated the interaction between the effects of noxious distension of the colorectum and noxious stimuli applied to the jejunum, in the rat. Colorectal distension elicited a visceromotor reflex, which was quantified using electromyographic (EMG) recordings from the external oblique muscle of the upper abdomen. The same motor units were activated when a strong pinch was applied to the flank skin. Distension of the jejunum did not provoke an EMG response at this site, but when it was applied during colorectal distension it blocked the EMG response. Jejunal distension also inhibited the response to noxious skin pinch. The inhibition of the visceromotor response to colorectal distension was prevented by local application of tetrodotoxin to the jejunum, and was markedly reduced when nicardipine was infused into the local jejunal circulation. Chronic sub-diaphragmatic vagotomy had no effect on the colorectal distension-induced EMG activity or its inhibition by jejunal distension. The nicotinic antagonist hexamethonium suppressed phasic contractile activity in the jejunum, had only a small effect on the inhibition of visceromotor response by jejunal distension. It is concluded that signals that arise from skin pinch and colorectal distension converge in the central nervous system with pathways that are activated by jejunal spinal afferents; the jejunal signals strongly inhibit the abdominal motor activity evoked by noxious stimuli.

Anterior cingulate serotonin 1B receptor binding is associated with emotional response inhibition.

PubMed

da Cunha-Bang, Sofi; Hjordt, Liv Vadskjær; Dam, Vibeke Høyrup; Stenbæk, Dea Siggaard; Sestoft, Dorte; Knudsen, Gitte M

2017-09-01

Serotonin has a well-established role in emotional processing and is a key neurotransmitter in impulsive aggression, presumably by facilitating response inhibition and regulating subcortical reactivity to aversive stimuli. In this study 44 men, of whom 19 were violent offenders and 25 were non-offender controls, completed an emotional Go/NoGo task requiring inhibition of prepotent motor responses to emotional facial expressions. We also measured cerebral serotonin 1B receptor (5-HT 1B R) binding with [ 11 C]AZ10419369 positron emission tomography within regions of the frontal cortex. We hypothesized that 5-HT 1B R would be positively associated with false alarms (failures to inhibit nogo responses) in the context of aversive (angry and fearful) facial expressions. Across groups, we found that frontal cortex 5-HT 1B R binding was positively correlated with false alarms when angry faces were go stimuli and neutral faces were nogo stimuli (p = 0.05, corrected alpha = 0.0125), but not with false alarms for non-emotional stimuli (failures to inhibit geometric figures). A posthoc analysis revealed the strongest association in anterior cingulate cortex (p = 0.006). In summary, 5-HT 1B Rs in the anterior cingulate are involved in withholding a prepotent response in the context of angry faces. Our findings suggest that serotonin modulates response inhibition in the context of certain emotional stimuli. Copyright © 2017. Published by Elsevier Ltd.

Initial HIV-1 Antigen-Specific CD8+ T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication

PubMed Central

Freel, Stephanie A.; Picking, Ralph A.; Ferrari, Guido; Ding, Haitao; Ochsenbauer, Christina; Kappes, John C.; Kirchherr, Jennifer L.; Soderberg, Kelly A.; Weinhold, Kent J.; Cunningham, Coleen K.; Denny, Thomas N.; Crump, John A.; Cohen, Myron S.; McMichael, Andrew J.; Haynes, Barton F.

2012-01-01

CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8+ T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8+ responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8+ T cells during AHI. Autologous and heterologous CD8+ T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8+ T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8+ antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8+-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8+ T cell-mediated inhibition of virus replication. CD8+ T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies. PMID:22514337

Examining methodological variation in response inhibition: The effects of outcome measures and task characteristics on age-related differences.

PubMed

Klenberg, Liisa; Närhi, Vesa; Korkman, Marit; Hokkanen, Laura

2015-01-01

This study addressed methodological issues common to developmental studies on response inhibition. Age-related differences were investigated using two Stroop-like tasks with different levels of complexity and comparing different outcome measures in a sample of 340 children and adolescents aged 7-15 years. First, speed and accuracy of task performance were examined; the results showing that improvement in speed continued until age 13 in both the basic naming task and the two inhibition tasks. Improvement in accuracy was less consistent and continued until age 9 or 13 years. Second, two different algorithms were employed to control for the effects of basic processes in inhibition tasks. The difference algorithm indicated age-related differences similar to those for speed. The ratio algorithm, however, suggested earlier deceleration of development of response inhibition at 9 or 11 years of age. Factors related to the cognitive requirements and presented stimuli also had an effect on the results. The present findings shed light on the inconsistencies in the developmental studies of response inhibition and demonstrated that the selection of outcome measures and task characteristics are critical because they affect the way development is depicted.

Rare sugar D-allose suppresses gibberellin signaling through hexokinase-dependent pathway in Oryza sativa L.

PubMed

Fukumoto, Takeshi; Kano, Akihito; Ohtani, Kouhei; Yamasaki-Kokudo, Yumiko; Kim, Bong-Gyu; Hosotani, Kouji; Saito, Miu; Shirakawa, Chikage; Tajima, Shigeyuki; Izumori, Ken; Ohara, Toshiaki; Shigematsu, Yoshio; Tanaka, Keiji; Ishida, Yutaka; Nishizawa, Yoko; Tada, Yasuomi; Ichimura, Kazuya; Gomi, Kenji; Akimitsu, Kazuya

2011-12-01

One of the rare sugars, D-allose, which is the epimer of D-glucose at C3, has an inhibitory effect on rice growth, but the molecular mechanisms of the growth inhibition by D-allose were unknown. The growth inhibition caused by D-allose was prevented by treatment with hexokinase inhibitors, D-mannoheptulose and N-acetyl-D-glucosamine. Furthermore, the Arabidopsis glucose-insensitive2 (gin2) mutant, which is a loss-of-function mutant of the glucose sensor AtHXK1, showed a D-allose-insensitive phenotype. D-Allose strongly inhibited the gibberellin-dependent responses such as elongation of the second leaf sheath and induction of α-amylase in embryo-less half rice seeds. The growth of the slender rice1 (slr1) mutant, which exhibits a constitutive gibberellin-responsive phenotype, was also inhibited by D-allose, and the growth inhibition of the slr1 mutant by D-allose was also prevented by D-mannoheptulose treatment. The expressions of gibberellin-responsive genes were down-regulated by D-allose treatment, and the down-regulations of gibberellin-responsive genes were also prevented by D-mannoheptulose treatment. These findings reveal that D-allose inhibits the gibberellin-signaling through a hexokinase-dependent pathway.

Effects of BRL 38227 on neurally-mediated responses in the guinea-pig isolated bronchus.

PubMed

Good, D M; Clapham, J C; Hamilton, T C

1992-04-01

1. In guinea-pig isolated bronchus treated with indomethacin (2.8 microM), electrical field stimulation (EFS; 10 Hz, 0.5 ms, 60-70 V, for 10 s) evoked a tetrodotoxin (3 microM)-sensitive, biphasic contraction comprising a rapid, atropine (1 microM)-sensitive cholinergic response succeeded by a slowly developing, capsaicin (10 microM)-sensitive, non-adrenergic, non-cholinergic excitatory (NANCe) response. 2. BRL 38227 (0.3-3 microM), salmeterol (0.003-3 microM) and ketotifen (1.0-300 microM) each produced concentration-dependent inhibition of both NANCe and cholinergic responses to EFS in guinea-pig isolated bronchus. 3. Substance P (SP; 1 microM) and neurokinin A (NKA; 0.07 microM) produced contractions equivalent in magnitude to the NANCe response to EFS, which were inhibited by salmeterol (1 microM), but not by BRL 38227 (3 microM) or ketotifen (100 microM). 4. Acetylcholine (ACh; 6 microM) was equi-effective with the electrical activation of cholinergic neurones. BRL 38227 (3 microM) slightly inhibited responses to ACh (6 microM). Salmeterol (1 microM) and ketotifen (100 microM) markedly inhibited responses to ACh (6 microM). 5. In bronchial rings pre-contracted with ACh (100 microM), BRL 38227 (0.1-30 microM), salmeterol (0.001-3 microM) and ketotifen (0.1-100 microM) each produced concentration-dependent relaxation. Unlike ketotifen, BRL 38227 and salmeterol only partially (18.8 +/- 2.1% and 51.8 +/- 3.9% respectively) reversed the ACh-induced contraction. 6. The (+)-analogue of BRL 38227, BRL 38226 (0.3-100 microM), was without effect on responses to EFS and had no effect on the inhibition caused by BRL 38227. The K+-channel activators pinacidil (3.0-30 microM) and RP 52891 (3.0-30 microM) exerted similar inhibitory actions on responses to EFS as BRL 38227, but were less potent. Glibenclamide (0.1-1.O microM) and phentolamine (3 microM) antagonized the inhibitory effects of BRL 38227 on responses to EFS.7. It is concluded that BRL 38227 and ketotifen can inhibit NANCe neuroeffector transmission at concentrations exerting little or no inhibitory effects on responses to exogenously applied tachykinins.By contrast, in addition to suppressing NANCe responses to EFS, salmeterol also markedly inhibits responses to SP and NKA. At concentrations markedly suppressing cholinergic neuroeffector transmission, BRL 38227 has only minor effects on responses to exogenously-applied ACh. Salmeterol and ketotifen both depress responses to ACh within the concentration-range over which they inhibit cholinergic responses to EFS. The inhibitory effects of BRL 38227 on responses to EFS exhibit stereo-specificity and may involve the opening of a neuronal K+-channel. This K+-channel is glibenclamide-and phentolamine-sensitive and appears similar to the smooth muscle K+-channel which is modulated by BRL 38227.

Testing the physiological plausibility of conflicting psychological models of response inhibition: A forward inference fMRI study.

PubMed

Criaud, Marion; Longcamp, Marieke; Anton, Jean-Luc; Nazarian, Bruno; Roth, Muriel; Sescousse, Guillaume; Strafella, Antonio P; Ballanger, Bénédicte; Boulinguez, Philippe

2017-08-30

The neural mechanisms underlying response inhibition and related disorders are unclear and controversial for several reasons. First, it is a major challenge to assess the psychological bases of behaviour, and ultimately brain-behaviour relationships, of a function which is precisely intended to suppress overt measurable behaviours. Second, response inhibition is difficult to disentangle from other parallel processes involved in more general aspects of cognitive control. Consequently, different psychological and anatomo-functional models coexist, which often appear in conflict with each other even though they are not necessarily mutually exclusive. The standard model of response inhibition in go/no-go tasks assumes that inhibitory processes are reactively and selectively triggered by the stimulus that participants must refrain from reacting to. Recent alternative models suggest that action restraint could instead rely on reactive but non-selective mechanisms (all automatic responses are automatically inhibited in uncertain contexts) or on proactive and non-selective mechanisms (a gating function by which reaction to any stimulus is prevented in anticipation of stimulation when the situation is unpredictable). Here, we assessed the physiological plausibility of these different models by testing their respective predictions regarding event-related BOLD modulations (forward inference using fMRI). We set up a single fMRI design which allowed for us to record simultaneously the different possible forms of inhibition while limiting confounds between response inhibition and parallel cognitive processes. We found BOLD dynamics consistent with non-selective models. These results provide new theoretical and methodological lines of inquiry for the study of basic functions involved in behavioural control and related disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Canonical TGF-β Signaling Pathway Represses Human NK Cell Metabolism.

PubMed

Zaiatz-Bittencourt, Vanessa; Finlay, David K; Gardiner, Clair M

2018-06-15

Cytokines stimulate rapid metabolic changes in human NK cells, including increases in both glycolysis and oxidative phosphorylation pathways. However, how these are subsequently regulated is not known. In this study, we demonstrate that TGF-β can inhibit many of these metabolic changes, including oxidative phosphorylation, glycolytic capacity, and respiratory capacity. TGF-β also inhibited cytokine-induced expression of the transferrin nutrient receptor CD71. In contrast to a recent report on murine NK cells, TGF-β-mediated suppression of these metabolic responses did not involve the inhibition of the metabolic regulator mTORC1. Inhibition of the canonical TGF-β signaling pathway was able to restore almost all metabolic and functional responses that were inhibited by TGF-β. These data suggest that pharmacological inhibition of TGF-β could provide a metabolic advantage to NK cells that is likely to result in improved functional responses. This has important implications for NK cell-based cancer immunotherapies. Copyright © 2018 by The American Association of Immunologists, Inc.

Response control networks are selectively modulated by attention to rare events and memory load regardless of the need for inhibition.

PubMed

Wijeakumar, Sobanawartiny; Magnotta, Vincent A; Buss, Aaron T; Ambrose, Joseph P; Wifall, Timothy A; Hazeltine, Eliot; Spencer, John P

2015-10-15

Recent evidence has sparked debate about the neural bases of response selection and inhibition. In the current study, we employed two reactive inhibition tasks, the Go/Nogo (GnG) and Simon tasks, to examine questions central to these debates. First, we investigated whether a fronto-cortical-striatal system was sensitive to the need for inhibition per se or the presentation of infrequent stimuli, by manipulating the proportion of trials that do not require inhibition (Go/Compatible trials) relative to trials that require inhibition (Nogo/Incompatible trials). A cortico-subcortical network composed of insula, putamen, and thalamus showed greater activation on salient and infrequent events, regardless of the need for inhibition. Thus, consistent with recent findings, key parts of the fronto-cortical-striatal system are engaged by salient events and do not appear to play a selective role in response inhibition. Second, we examined how the fronto-cortical-striatal system is modulated by working memory demands by varying the number of stimulus-response (SR) mappings. Right inferior parietal lobule showed decreasing activation as the number of SR mappings increased, suggesting that a form of associative memory - rather than working memory - might underlie performance in these tasks. A broad motor planning and control network showed similar trends that were also modulated by the number of motor responses required in each task. Finally, bilateral lingual gyri were more robustly engaged in the Simon task, consistent with the role of this area in shifts of visuo-spatial attention. The current study sheds light on how the fronto-cortical-striatal network is selectively engaged in reactive control tasks and how control is modulated by manipulations of attention and memory load. Copyright © 2015 Elsevier Inc. All rights reserved.

CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell-Mediated CD4 T Cell Responses.

PubMed

Wong, Kuan Y; Baron, Rebecca; Seldon, Therese A; Jones, Martina L; Rice, Alison M; Munster, David J

2018-05-15

Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83 + human dendritic cells, thereby inhibiting CD4 T cell-mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC. Also, Ag-specific Ab responses to immunization of SCID mice xenografted with human PBMC were inhibited by anti-CD83 treatment. This inhibition occurred without depletion of all human B cells because anti-CD83 lysed activated CD83 + B cells by Ab-dependent cellular cytotoxicity and spared resting (CD83 - ) B cells. In cultured human PBMC, anti-CD83 inhibited tetanus toxoid-stimulated B cell proliferation and concomitant dendritic cell-mediated CD4 T cell proliferation and expression of IFN-γ and IL-17A, with minimal losses of B cells (<20%). In contrast, the anti-CD20 mAb rituximab depleted >80% of B cells but had no effect on CD4 T cell proliferation and cytokine expression. By virtue of the ability of anti-CD83 to selectively deplete activated, but not resting, B cells and dendritic cells, with the latter reducing CD4 T cell responses, anti-CD83 may be clinically useful in autoimmunity and transplantation. Advantages might include inhibited expansion of autoantigen- or alloantigen-specific B cells and CD4 T cells, thus preventing further production of pathogenic Abs and inflammatory cytokines while preserving protective memory and regulatory cells. Copyright © 2018 by The American Association of Immunologists, Inc.

Remote control of an impact demonstration vehicle

NASA Technical Reports Server (NTRS)

Harney, P. F.; Craft, J. B., Jr.; Johnson, R. G.

1985-01-01

Uplink and downlink telemetry systems were installed in a Boeing 720 aircraft that was remotely flown from Rogers Dry Lake at Edwards Air Force Base and impacted into a designated crash site on the lake bed. The controlled impact demonstration (CID) program was a joint venture by the National Aeronautics and Space Administration (NASA) and the Federal Aviation Administration (FAA) to test passenger survivability using antimisting kerosene (AMK) to inhibit postcrash fires, improve passenger seats and restraints, and improve fire-retardent materials. The uplink telemetry system was used to remotely control the aircraft and activate onboard systems from takeoff until after impact. Aircraft systems for remote control, aircraft structural response, passenger seat and restraint systems, and anthropomorphic dummy responses were recorded and displayed by the downlink stems. The instrumentation uplink and downlink systems are described.

European corn borer sex pheromone : Inhibition and elicitation of behavioral response by analogs.

PubMed

Schwarz, M; Klun, J A; Uebel, E C

1990-05-01

The male sexual behavior-stimulating and inhibiting properties of a series of analogs of the European corn borer sex pheromone were determined in a flight tunnel. The structural requirements for inhibition of pheromonal response were far less restrictive than those for elicitation of that response. Analogs that by themselves elicited upwind flight response from males at a low dose were generally less inhibitory to male response than many of the analogs that had no pheromonal activity. These findings suggest that many pheromone analogs bind to pheromone receptors without provoking behavioral response and possibly undergo slower degradation on the antenna than pheromonally active compounds. The disparity of response to analogs by two pheromonal types of the European corn borer indicates that the pheromone receptor and pheromone catabolic systems are biochemically very different in the two types.

Cathodal tDCS improves task performance in participants high in Coldheartedness.

PubMed

Weidacker, Kathrin; Weidemann, Christoph T; Boy, Frederic; Johnston, Stephen J

2016-09-01

It is investigated whether personality-related inter-individual differences modulate tDCS effects on response inhibition. Psychopathic personality traits have been associated with a reduced ability to inhibit prepotent responses and as such it is likely that these traits may modulate the effect tDCS has on response inhibition. This study represents the first investigation into the effect of psychopathic traits on tDCS effects in the context of response inhibition, and based on previous research, the psychopathic traits Blame Externalization and Coldheartedness were elected as potential candidates for modulating tDCS effects to right dorsolateral prefrontal cortex. Eighteen healthy participants underwent tDCS stimulation (sham, anodal, cathodal) before completing a response inhibition task, the parametric Go/No-go task. This task measures response inhibition under conditions of low and high cognitive load. TDCS stimulation was applied to F4 (international 10-20 system), corresponding to right dorsolateral prefrontal cortex, for 20min with an intensity of 1.5mA. Analysis of covariance was performed to assess how changes in response inhibition performance across difficulty level and stimulation condition were related to individual differences in psychopathy scores as measured via the Psychopathic Personality Inventory-Revised questionnaire. A positive relationship was found between greater scores on the Psychopathic Personality Inventory-Revised subscale of Coldheartedness and improvement in Go/No-go task performance after application of cathodal tDCS. This effect specifically related to the high load condition of the Go/No-go task. The psychopathic personality trait Coldheartedness may represent an imbalance of excitatory and inhibitory inputs to dlPFC. Improvement in functioning on inhibitory tasks after cathodal tDCS may be a result of a shift of excitatory glutamate levels to a more optimal level. The current results demonstrate the utility of tDCS as a tool to assess how differences in cortical responsivity are associated with specific personality traits. Additionally, this study represents the first investigation into the influence of psychopathic traits on tDCS effects on dlPFC, and we observed beneficial changes in response inhibition as a result of, especially, cathodal stimulation in participants scoring high on Coldheartedness. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Triggering Descending Pain Inhibition by Observing Ourselves or a Loved-One in Pain.

PubMed

Gougeon, Véronique; Gaumond, Isabelle; Goffaux, Philippe; Potvin, Stéphane; Marchand, Serge

2016-03-01

Recent studies demonstrate that empathy-evoked brain responses include the activation of brainstem structures responsible for triggering descending pain inhibition. Unfortunately, direct evidence linking empathy for pain and descending inhibitory controls (conditioned pain modulation) is lacking. This study, therefore, aimed to determine if the observation of ourselves or a loved-one in pain could activate descending pain inhibition without exposure to a noxious stimulation; which is otherwise required. Descending pain inhibition was triggered by immersing the right arm of participants (15 heterosexual couples; mean age±SE: 28.89±2.14) in a bath of cold water. The effects of empathy on descending pain inhibition were observed by immersing the right arm of participants in a bath of lukewarm water while having them watch a video of either themselves or their spouse during a previous nociceptive immersion. Immersion of the arm in a bath of lukewarm water without empathic (video) observation was also included as a control condition. A strong inhibitory response activated by the mere observation of the video of themselves or their spouse in pain without a nociceptive conditioning stimulus. Associative statistics also showed that strong pain catastrophizing responses while watching the video resulted in stronger pain inhibition. Moreover, high levels of empathy were associated with stronger pain inhibition, but only for women. This study showed that observing someone in pain triggers descending pain inhibition. Results also demonstrate how empathy and gender are affecting pain modulation mechanisms.

Regulation of spatial selectivity by crossover inhibition.

PubMed

Cafaro, Jon; Rieke, Fred

2013-04-10

Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

Live or let die: manipulation of cellular suicide programs by murine cytomegalovirus.

PubMed

Handke, Wiebke; Krause, Eva; Brune, Wolfram

2012-11-01

Cytomegaloviruses (CMVs) are large double-stranded DNA viruses that replicate slowly and cause life-long persisting infections in their hosts. To achieve this, the CMVs had to evolve numerous countermeasures against innate and adaptive immune responses. Induction of programmed cell death is one important host defense mechanism against intracellular pathogens such as viruses. For a multicellular organism, it is advantageous to let infected cells die in order to thwart viral replication and dissemination. For a virus, by contrast, it is better to inhibit cell death and keep infected cells alive until the viral replication cycle has been completed. As a matter of fact, the CMVs encode a number of proteins devoted to interfering with different forms of programmed cell death: apoptosis and necroptosis. In this review, we summarize the known functions of the four best characterized cell death inhibitors of murine cytomegalovirus (MCMV), which are encoded by open reading frames, M36, m38.5, m41.1, and M45. The viral proteins interact with key molecules within different cell death pathways, namely caspase-8, Bax, Bak, and RIP1/RIP3. In addition, we discuss which events during MCMV infection might trigger apoptosis or necrosis and how MCMV's countermeasures compare to those of other herpesviruses. Since both, MCMV and its natural host, are amenable to genetic manipulation, the mouse model for CMV infection provides a particularly suitable system to study mechanisms of cell death induction and inhibition.

A Latent Variables Examination of Processing Speed, Response Inhibition, and Working Memory during Typical Development

PubMed Central

McAuley, Tara; White, Desirée

2010-01-01

The present study addressed three related aims: (1) to replicate and extend previous work regarding the non-unitary nature of processing speed, response inhibition, and working memory during development, (2) to quantify the rate at which processing speed, response inhibition, and working memory develop and the extent to which the development of these latter abilities reflect general changes in processing speed, and (3) to evaluate whether commonly used tasks of processing speed, response inhibition, and working memory are valid and reliable when used with a developmentally diverse group. To address these aims, a latent variables approach was used to analyze data from 147 participants 6 to 24 years of age. Results showed that processing speed, response inhibition, and working memory were separable abilities and that the extent of this separability was stable cross the age range of participants. All three constructs improved as a function of age; however, only the effect of age on working memory remained significant after processing speed was controlled. The psychometric properties of tasks used to assess the constructs were age invariant, thus validating their use in studies of executive development. PMID:20888572

Effects of a brief mindfulness-meditation intervention on neural measures of response inhibition in cigarette smokers

PubMed Central

Cosmelli, Diego; Slagter, Heleen A.; Franken, Ingmar H. A.

2018-01-01

Research suggests that mindfulness-practices may aid smoking cessation. Yet, the neural mechanisms underlying the effects of mindfulness-practices on smoking are unclear. Response inhibition is a main deficit in addiction, is associated with relapse, and could therefore be a candidate target for mindfulness-based practices. The current study hence investigated the effects of a brief mindfulness-practice on response inhibition in smokers using behavioral and electroencephalography (EEG) measures. Fifty participants (33 females, mean age 20 years old) underwent a protocol of cigarette exposure to induce craving (cue-exposure) and were then randomly assigned to a group receiving mindfulness-instructions or control-instructions (for 15 minutes approximately). Immediately after this, they performed a smoking Go/NoGo task, while their brain activity was recorded. At the behavioral level, no group differences were observed. However, EEG analyses revealed a decrease in P3 amplitude during NoGo vs. Go trials in the mindfulness versus control group. The lower P3 amplitude might indicate less-effortful response inhibition after the mindfulness-practice, and suggest that enhanced response inhibition underlies observed positive effects of mindfulness on smoking behavior. PMID:29370256

Effects of a brief mindfulness-meditation intervention on neural measures of response inhibition in cigarette smokers.

PubMed

Andreu, Catherine I; Cosmelli, Diego; Slagter, Heleen A; Franken, Ingmar H A

2018-01-01

Research suggests that mindfulness-practices may aid smoking cessation. Yet, the neural mechanisms underlying the effects of mindfulness-practices on smoking are unclear. Response inhibition is a main deficit in addiction, is associated with relapse, and could therefore be a candidate target for mindfulness-based practices. The current study hence investigated the effects of a brief mindfulness-practice on response inhibition in smokers using behavioral and electroencephalography (EEG) measures. Fifty participants (33 females, mean age 20 years old) underwent a protocol of cigarette exposure to induce craving (cue-exposure) and were then randomly assigned to a group receiving mindfulness-instructions or control-instructions (for 15 minutes approximately). Immediately after this, they performed a smoking Go/NoGo task, while their brain activity was recorded. At the behavioral level, no group differences were observed. However, EEG analyses revealed a decrease in P3 amplitude during NoGo vs. Go trials in the mindfulness versus control group. The lower P3 amplitude might indicate less-effortful response inhibition after the mindfulness-practice, and suggest that enhanced response inhibition underlies observed positive effects of mindfulness on smoking behavior.

Brain activation for response inhibition under gaming cue distraction in internet gaming disorder.

PubMed

Liu, Gin-Chung; Yen, Ju-Yu; Chen, Chiao-Yun; Yen, Cheng-Fang; Chen, Cheng-Sheng; Lin, Wei-Chen; Ko, Chih-Hung

2014-01-01

We evaluated neural substrates related to the loss of control in college students with internet gaming disorder (IGD). We hypothesized that deficit in response inhibition under gaming cue distraction was the possible mechanism for the loss of control internet use. Eleven cases of IGD and 11 controls performed Go/NoGo tasks with/without gaming distraction in the functional magnetic resonance imaging scanner. When the gaming picture was shown as background while individuals were performing Go/NoGo tasks, the IGD group committed more commission errors. The control group increased their brain activations more over the right dorsolateral prefrontal cortex (DLPFC) and superior parietal lobe under gaming cue distraction in comparison with the IGD group. Furthermore, brain activation of the right DLPFC and superior parietal lobe were negatively associated with performance of response inhibition among the IGD group. The results suggest that the function of response inhibition was impaired under gaming distraction among the IGD group, and individuals with IGD could not activate right DLPFC and superior parietal lobe to keep cognitive control and attention allocation for response inhibition under gaming cue distraction. This mechanism should be addressed in any intervention for IGD. Copyright © 2013. Published by Elsevier B.V.

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

PubMed Central

VanBlargan, Laura A.

2016-01-01

SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies. PMID:27784796

Novel Immunologic Approaches to Melanoma Treatment.

PubMed

Escandell, I; Martín, J M; Jordá, E

2017-10-01

Approaches to treating melanoma have changed radically since the introduction of immunotherapy, and survival figures are now higher than possible with earlier therapies. The immunomodulators currently available mainly block CTLA-4 (cytotoxicT lymphocyte-associated molecule-4) and PD-1 (programed cell death protein 1) translocated to the cell surface, where they inhibit the antitumor immune response. Treatments blocking these molecules are being more widely used. Research now seeks new molecular targets, the best combinations of available drugs, and biomarkers that can identify ideal candidates for each one. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

YB-1 regulates tiRNA-induced Stress Granule formation but not translational repression

PubMed Central

Lyons, Shawn M.; Achorn, Chris; Kedersha, Nancy L.; Anderson, Paul J.; Ivanov, Pavel

2016-01-01

Stress-induced angiogenin (ANG)-mediated tRNA cleavage promotes a cascade of cellular events that starts with production of tRNA-derived stress-induced RNAs (tiRNAs) and culminates with enhanced cell survival. This stress response program relies on a subset tiRNAs that inhibit translation initiation and induce the assembly of stress granules (SGs), cytoplasmic ribonucleoprotein complexes with cytoprotective and pro-survival properties. SG-promoting tiRNAs bear oligoguanine motifs at their 5′-ends, assemble G-quadruplex-like structures and interact with the translational silencer YB-1. We used CRISPR/Cas9-based genetic manipulations and biochemical approaches to examine the role of YB-1 in tiRNA-mediated translational repression and SG assembly. We found that YB-1 directly binds to tiRNAs via its cold shock domain. This interaction is required for packaging of tiRNA-repressed mRNAs into SGs but is dispensable for tiRNA-mediated translational repression. Our studies reveal the functional role of YB-1 in the ANG-mediated stress response program. PMID:27174937

Advances in immunotherapy for non-small cell lung cancer.

PubMed

Reckamp, Karen L

2015-12-01

In most patients, lung cancer presents as advanced disease with metastases to lymph nodes and/or distant organs, and survival is poor. Lung cancer is also a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T-cell activation. Advances in understanding the complex interactions of the immune system and cancer have led to novel therapies that promote T-cell activation at the tumor site, resulting in prolonged clinical benefit. Immune checkpoint inhibitors, specifically programmed death receptor 1 pathway antibodies, have demonstrated impressively durable responses and improved survival in patients with non-small cell lung cancer. This article will review the recent progress made in immunotherapy for lung cancer with data from trials evaluating programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies in addition to cancer vaccines. The review will focus on studies that have been published and the latest randomized trials exploring immune therapy in lung cancer. These results form the framework for a new direction in the treatment of lung cancer toward immunotherapy.

A bacterial cysteine protease effector protein interferes with photosynthesis to suppress plant innate immune responses.

PubMed

Rodríguez-Herva, José J; González-Melendi, Pablo; Cuartas-Lanza, Raquel; Antúnez-Lamas, María; Río-Alvarez, Isabel; Li, Ziduo; López-Torrejón, Gema; Díaz, Isabel; Del Pozo, Juan C; Chakravarthy, Suma; Collmer, Alan; Rodríguez-Palenzuela, Pablo; López-Solanilla, Emilia

2012-05-01

The bacterial pathogen Pseudomonas syringae pv tomato DC3000 suppresses plant innate immunity with effector proteins injected by a type III secretion system (T3SS). The cysteine protease effector HopN1, which reduces the ability of DC3000 to elicit programmed cell death in non-host tobacco, was found to also suppress the production of defence-associated reactive oxygen species (ROS) and callose when delivered by Pseudomonas fluorescens heterologously expressing a P. syringae T3SS. Purified His(6) -tagged HopN1 was used to identify tomato PsbQ, a member of the oxygen evolving complex of photosystem II (PSII), as an interacting protein. HopN1 localized to chloroplasts and both degraded PsbQ and inhibited PSII activity in chloroplast preparations, whereas a HopN1(D299A) non-catalytic mutant lost these abilities. Gene silencing of NtPsbQ in tobacco compromised ROS production and programmed cell death by DC3000. Our data reveal PsbQ as a contributor to plant immunity responses and a target for pathogen suppression. © 2012 Blackwell Publishing Ltd.

Response inhibition in motor conversion disorder.

PubMed

Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A; Hallett, Mark

2013-05-01

Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P < .001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society. Copyright © 2013 Movement Disorder Society.

Dissociation of Neural Substrates of Response Inhibition to Negative Information between Implicit and Explicit Facial Go/Nogo Tasks: Evidence from an Electrophysiological Study

PubMed Central

Sun, Shiyue; Carretié, Luis; Zhang, Lei; Dong, Yi; Zhu, Chunyan; Luo, Yuejia; Wang, Kai

2014-01-01

Background Although ample evidence suggests that emotion and response inhibition are interrelated at the behavioral and neural levels, neural substrates of response inhibition to negative facial information remain unclear. Thus we used event-related potential (ERP) methods to explore the effects of explicit and implicit facial expression processing in response inhibition. Methods We used implicit (gender categorization) and explicit emotional Go/Nogo tasks (emotion categorization) in which neutral and sad faces were presented. Electrophysiological markers at the scalp and the voxel level were analyzed during the two tasks. Results We detected a task, emotion and trial type interaction effect in the Nogo-P3 stage. Larger Nogo-P3 amplitudes during sad conditions versus neutral conditions were detected with explicit tasks. However, the amplitude differences between the two conditions were not significant for implicit tasks. Source analyses on P3 component revealed that right inferior frontal junction (rIFJ) was involved during this stage. The current source density (CSD) of rIFJ was higher with sad conditions compared to neutral conditions for explicit tasks, rather than for implicit tasks. Conclusions The findings indicated that response inhibition was modulated by sad facial information at the action inhibition stage when facial expressions were processed explicitly rather than implicitly. The rIFJ may be a key brain region in emotion regulation. PMID:25330212

Depletion of mitochondrial fission factor DRP1 causes increased apoptosis in human colon cancer cells

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

Inoue-Yamauchi, Akane, E-mail: ainoyama@research.twmu.ac.jp; Oda, Hideaki

2012-04-27

Highlights: Black-Right-Pointing-Pointer DRP1 is required for mitochondrial fission in colon cancer cells. Black-Right-Pointing-Pointer DRP1 participates in inhibition of colon cancer cell apoptosis. Black-Right-Pointing-Pointer DRP1 can inhibit apoptosis through the regulation of cytochrome c release. -- Abstract: Mitochondria play a critical role in regulation of apoptosis, a form of programmed cell death, by releasing apoptogenic factors including cytochrome c. Growing evidence suggests that dynamic changes in mitochondrial morphology are involved in cellular apoptotic response. However, whether DRP1-mediated mitochondrial fission is required for induction of apoptosis remains speculative. Here, we show that siRNA-mediated DRP1 knockdown promoted accumulation of elongated mitochondria in HCT116more » and SW480 human colon cancer cells. Surprisingly, DRP1 down-regulation led to decreased proliferation and increased apoptosis of these cells. A higher rate of cytochrome c release and reductions in mitochondrial membrane potential were also revealed in DRP1-depleted cells. Taken together, our present findings suggest that mitochondrial fission factor DRP1 inhibits colon cancer cell apoptosis through the regulation of cytochrome c release and mitochondrial membrane integrity.« less

Effect of acute psychological stress on response inhibition: An event-related potential study.

PubMed

Qi, Mingming; Gao, Heming; Liu, Guangyuan

2017-04-14

This study aimed to investigate the effect of acute psychological stress on response inhibition and its electrophysiological correlates using a dual-task paradigm. Acute stress was induced by a primary task (mental arithmetic task), which consisted of a stress block and a control block. Response inhibition was measured using a secondary task (Go/NoGo task). In each trial, a Go/NoGo stimulus was presented immediately after the mental arithmetic task. The results revealed increased subjective stress and negative affect for the stress relative to control block, suggesting that the mental arithmetic task triggered a reliable stress response. ERPs locked to the Go/NoGo stimuli revealed that decreased P2 and increased N2 components were evoked for the stress block compared to the control block. These results demonstrated that acute psychological stress alters the response inhibition process by reducing the early selective attention process and enhancing the cognitive control process. Copyright © 2017 Elsevier B.V. All rights reserved.

L-Asparaginase II Produced by Salmonella Typhimurium Inhibits T Cell Responses and Mediates Virulence

PubMed Central

Kullas, Amy L.; McClelland, Michael; Yang, Hee-Jeong; Tam, Jason W.; Torres, AnnMarie; Porwollik, Steffen; Mena, Patricio; McPhee, Joseph B.; Bogomolnaya, Lydia; Andrews-Polymenis, Helene; van der Velden, Adrianus W.M.

2013-01-01

SUMMARY Salmonella enterica serovar Typhimurium avoids clearance by the host immune system by suppressing T cell responses; however, the mechanisms that mediate this immunosuppression remain unknown. We show that S. Typhimurium inhibit T cell responses by producing L-Asparaginase II, which catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-Asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production, and proliferation and to downmodulate expression of the T cell receptor. Furthermore, S. Typhimurium-induced inhibition of T cells in vitro is prevented upon addition of L-asparagine. S. Typhimurium lacking the L-Asparaginase II gene (STM3106) are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-Asparaginases are used to treat acute lymphoblastic leukemia through mechanisms that likely involve amino acid starvation of leukemic cells, and these findings indicate that pathogens similarly use L-asparagine deprivation to limit T cell responses. PMID:23245323

Individual differences in experiencing intrusive memories: the role of the ability to resist proactive interference.

PubMed

Verwoerd, Johan; Wessel, Ineke; de Jong, Peter J

2009-06-01

This study explored whether a relatively poor ability to resist or inhibit interference from irrelevant information in working memory is associated with experiencing undesirable intrusive memories. Non-selected participants (N=91) completed a self-report measure of intrusive memories, and carried out experimental tasks intended to measure two different types of inhibition: resistance to proactive interference and response inhibition (i.e., the ability to prevent automatically triggered responses). The results showed a significant relationship between inhibition at the cognitive level (i.e., resistance to proactive interference) and the frequency of intrusive memories (especially in the group of female participants) whereas no such relationship with measures of response inhibition emerged. These findings are consistent with the idea that deficient inhibitory control reflects a vulnerability factor for experiencing intrusive memories. Implications for research investigating risk factors for the development of posttraumatic stress disorder (PTSD) are discussed.

Inhibition of glutathione synthesis eliminates the adaptive response of ascitic hepatoma 22 cells to nedaplatin that targets thioredoxin reductase

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

Wang, Yijun; Lu, Hongjuan; Wang, Dongxu

2012-12-15

Thioredoxin reductase (TrxR) is a target for cancer therapy and the anticancer mechanism of cisplatin involves TrxR inhibition. We hypothesize that the anticancer drug nedaplatin (NDP), an analogue of cisplatin and a second-generation platinum complex, also targets TrxR. Furthermore, we investigate whether the therapeutic efficacy of NDP can be enhanced by simultaneous modulation of 1) TrxR, via NDP, and 2) glutathione (GSH), via the GSH synthesis inhibitor buthionine sulfoximine (BSO). Mice bearing ascitic hepatoma 22 (H22) cells were treated with NDP alone or NDP plus BSO. TrxR activity of H22 cells was inhibited by NDP in a dose-dependent manner. Amore » high correlation between the inhibition of TrxR activity at 6 h and the inhibition of ascitic fluid volume at 72 h was established (r = 0.978, p < 0.01). As an adaptive response, the viable ascitic cancer cells after NDP treatment displayed an enlarged cell phenotype, assembled with several-fold more antioxidant enzymes and GSH-predominant non-protein free thiols. This adaptive response was largely eliminated when BSO was co-administered with NDP, leading to the decimation of the H22 cell population without enhancing renal toxicity, since at this dose, NDP did not inhibit renal TrxR activity. In conclusion, the pharmacological effect of NDP involves TrxR inhibition, and the adaptive response of NDP-treated ascitic H22 cells can be efficiently counteracted by BSO. Simultaneous modulation of TrxR and GSH on ascitic H22 cells using NDP plus BSO greatly enhances therapeutic efficacy as compared with the single modulation of TrxR using NDP alone. -- Highlights: ► Nedaplatin at a pharmacological dose inhibits TrxR in cancer cells but not in kidney. ► The nedaplatin-treated cancer cells exhibit adaptive response. ► Buthionine sulfoximine inhibits glutathione in both cancer cells and kidney. ► Buthionine sulfoximine counteracts the adaptive response to the nedaplatin treatment. ► Buthionine sulfoximine does not aggravate renal toxicity of the nedaplatin treatment.« less

Thiol dependent NF-κB suppression and inhibition of T-cell mediated adaptive immune responses by a naturally occurring steroidal lactone Withaferin A

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

Gambhir, Lokesh; Checker, Rahul; Sharma, Deepak

Withaferin A (WA), a steroidal lactone isolated from ayurvedic medicinal plant Withania somnifera, was shown to inhibit tumor growth by inducing oxidative stress and suppressing NF-κB pathway. However, its effect on T-cell mediated adaptive immune responses and the underlying mechanism has not been investigated. Since both T-cell responses and NF-κB pathway are known to be redox sensitive, the present study was undertaken to elucidate the effect of WA on adaptive immune responses in vitro and in vivo. WA inhibited mitogen induced T-cell and B-cell proliferation in vitro without inducing any cell death. It inhibited upregulation of T-cell (CD25, CD69, CD71more » and CD54) and B-cell (CD80, CD86 and MHC-II) activation markers and secretion of Th1 and Th2 cytokines. WA induced oxidative stress by increasing the basal ROS levels and the immunosuppressive effects of WA were abrogated only by thiol anti-oxidants. The redox modulatory effects of WA in T-cells were attributed to its ability to directly interact with free thiols. WA inhibited NF-κB nuclear translocation in lymphocytes and prevented the direct binding of nuclear NF-κB to its consensus sequence. MALDI-TOF analysis using a synthetic NF-κB-p50 peptide containing Cys-62 residue suggested that WA can modify the cysteine residue of NF-κB. The pharmacokinetic studies for WA were also carried out and in vivo efficacy of WA was studied using mouse model of Graft-versus-host disease. In conclusion, WA is a potent inhibitor of T-cell responses and acts via a novel thiol dependent mechanism and inhibition of NF-κB pathway. - Highlights:: • Withaferin A (WA) inhibited T-cell and B-cell mediated immune responses. • WA increased basal ROS levels in lymphocytes. • WA directly interacted with GSH as studied using spectrophotometry and HPLC. • WA inhibited NF-κB nuclear translocation and binding of nuclear NF-κB to DNA. • WA inhibited induction of the graft-versus-host disease in mice.« less

Testing differential susceptibility: Plasticity genes, the social environment, and their interplay in adolescent response inhibition.

PubMed

Richards, Jennifer S; Arias Vásquez, Alejandro; van Rooij, Daan; van der Meer, Dennis; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Hartman, Catharina A; Buitelaar, Jan K

2017-06-01

Impaired inhibitory control is a key feature of attention-deficit/hyperactivity disorder (ADHD). We investigated gene-environment interaction (GxE) as a possible contributing factor to response inhibition variation in context of the differential susceptibility theory. This states individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Behavioural and neural measures of response inhibition were assessed during a Stop-signal task in participants with (N = 197) and without (N = 295) ADHD, from N = 278 families (age M = 17.18, SD =3.65). We examined GxE between candidate plasticity genes (DAT1, 5-HTT, DRD4) and social environments (maternal expressed emotion, peer affiliation). A DRD4 × Positive peer affiliation interaction was found on the right fusiform gyrus (rFG) activation during successful inhibition. Further, 5-HTT short allele carriers showed increased rFG activation during failed inhibitions. Maternal warmth and positive peer affiliation were positively associated with right inferior frontal cortex activation during successful inhibition. Deviant peer affiliation was positively related to the error rate. While a pattern of differential genetic susceptibility was found, more clarity on the role of the FG during response inhibition is warranted before firm conclusions can be made. Positive and negative social environments were related to inhibitory control. This extends previous research emphasizing adverse environments.

Evaluating Inhibition of Motoneuron Firing From Electromyogram Data to Assess Vestibular Output Using Vestibular Evoked Myogenic Potentials.

PubMed

Prakash, S R; Herrmann, Barbara S; Milojcic, Rupprecht; Rauch, Steven D; Guinan, John J

2015-01-01

Vestibular evoked myogenic potentials (VEMPs) are due to vestibular responses producing brief inhibitions of muscle contractions that are detectable in electromyographic (EMG) responses. VEMP amplitudes are traditionally measured by the peak to peak amplitude of the averaged EMG response (VEMPpp) or by a normalized VEMPpp (nVEMPpp). However, a brief EMG inhibition does not satisfy the statistical assumptions for the average to be the optimal processing strategy. Here, it is postulated that the inhibition depth of motoneuron firing is the desired metric for showing the influence of the vestibular system on the muscle system. The authors present a metric called "VEMPid" that estimates this inhibition depth from the EMG data obtained in a usual VEMP data acquisition. The goal of this article was to compare how well VEMPid, VEMPpp, and nVEMPpp track inhibition depth. To find a robust method to compare VEMPid, VEMPpp, and nVEMPpp, realistic physiological models for the inhibition of VEMP EMG signals were made using VEMP data from four measurement sessions on each of the five normal subjects. Each of the resulting 20 EMG-production models was adjusted to match the EMG autocorrelation of an individual subject and session. Simulated VEMP traces produced by these models were used to compare how well VEMPid, VEMPpp, and nVEMPpp tracked model inhibition depth. Applied to simulated and real VEMP data, VEMPid showed good test-retest consistency and greater sensitivity at low stimulus levels than VEMPpp or nVEMPpp. For large-amplitude responses, nVEMPpp and VEMPid were equivalent in their consistency across subjects and sessions, but for low-amplitude responses, VEMPid was superior. Unnormalized VEMPpp was always worse than nVEMPpp or VEMPid. VEMPid provides a more reliable measurement of vestibular function at low sound levels than the traditional nVEMPpp, without requiring a change in how VEMP tests are performed. The calculation method for VEMPid should be applicable whenever an ongoing muscle contraction is briefly inhibited by an external stimulus.

Response to anti-programmed cell death protein-1 antibodies in men treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and stem cell transplantation.

PubMed

Zschäbitz, Stefanie; Lasitschka, Felix; Hadaschik, Boris; Hofheinz, Ralf-Dieter; Jentsch-Ullrich, Kathleen; Grüner, Marcus; Jäger, Dirk; Grüllich, Carsten

2017-05-01

Treatment options for patients with platinum refractory metastatic germ cell tumours (GCT) relapsing after high-dose chemotherapy and autologous stem cell transplantation are limited and survival is poor. Antibodies directed against programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are currently assessed within clinical trials. We present updated data on our experience with checkpoint inhibitors as a compassionate use off-label treatment attempt for highly-pretreated patients with GCT and provide an overview of the current literature on PD-L1 expression in this rare tumour entity. We analysed all patients with platinum refractory GCT treated with checkpoint inhibitors at our institutions between 2015 and 2017. Data were retrieved retrospectively from the patient charts. Seven patients were treated with nivolumab or pembrolizumab. Four patients received single-dose treatment and died shortly afterwards due to tumour progression; the remaining three patients received treatment for at least 6 months. No significant treatment toxicity was observed. Long-term tumour response was achieved in two of the three patients, both of them highly positive for PD-L1 staining. We consider checkpoint inhibition to be efficient in carefully selected patients with platinum refractory GCT. However, predictive markers associated with tumour response are not yet known and larger prospective clinical trials are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

A rapid assessment and response approach for socially marketed nutrition commodities in Viet Nam.

PubMed

Turk, Tahir; Quang, Nguyen Dinh; Nga, Tran Thuy; Phuong, Huynh; Tung, Le Van Anh; Trang, Vu Hoang

2017-01-01

The leading cause of death in children in developing countries is protein-energy malnutrition. In Viet Nam, 25.9% of children under 5 experience stunted growth and 6.6% are moderately wasted. Iron deficiency anaemia and vitamin A deficiency contribute to these and other malnutrition conditions. Given these factors, more evidence based approaches are required to improve understanding of current attitudes, opinions and behaviours of mothers with young children, in order to operationalise social marketing of nutrition commodities in Viet Nam. A literature review supported a rapid assessment and response method involving semi-structured interviews with 77 stakeholders and focus group discussions with 80 program beneficiaries from four geographic locations in the north and south of Viet Nam. Discussion agendas were developed to address key program issues with grounded theory utilized for data analysis. Data analysis highlighted challenges and opportunities within the six Ps of social marketing: Supply and demand side issues included: cost and the quality of products, the limited scale of interventions and promotional activities. Policy issues identified related to current policies that inhibited the broader promotion and distribution of micronutrient products, and opportunities for improved dialogue with policy partners. Partnerships further emphasized the need for public private partnerships to support the social change process. Implications for theory, policy, and practice indicates that rapid assessment and response is a cost-effective, pragmatic method of public health research, in resource constrained settings, to explore policies and behaviours amenable to change and build stakeholder engagement in the program.

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

PubMed Central

Sojka, Dorothy K.; Fowell, Deborah J.

2011-01-01

CD4+CD25+Forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) control immune responses to self and foreign antigens in secondary lymphoid organs and at tissue sites of inflammation. Tregs can modify the function of many immune cells and have been proposed to block early proliferation, differentiation, and effector function. Acute ablation of Tregs has revealed rapid cytokine production immediately after Treg removal, suggesting that Tregs may regulate effector function acutely rather than regulating the programming for immune function. We developed in vitro and in vivo models that enabled the direct test of Treg regulation of T-helper cell type 1 (Th1) differentiation. CD28 signaling is known to abrogate Treg suppression of IL-2 secretion and proliferation, but our studies show that Treg suppression of IFN-γ during Th1 priming proceeds despite enhanced CD28 signaling. Importantly, during Th1 differentiation, Tregs inhibited early IFN-γ transcription without disrupting expression of Th1-specific T-box transcription factor (Tbet) and Th1 programming. Acute shutoff of effector cytokine production by Tregs was selective for IFN-γ but not TNF-α and was independent of TGF-β and Epstein-Barr virus-induced gene 3. In vivo, Tregs potently controlled CD4 IFN-γ and CD4 effector cell expansion in the lymph node (four- to fivefold reduction) but not Th1 programming, independent of IL-10. Tregs additionally reduced CD4 IFN-γ in the inflamed dermis (twofold reduction) dependent on their production of IL-10. We propose a model for Treg inhibition of effector function based on acute cytokine regulation. Interestingly, Tregs used different regulatory mechanisms to regulate IFN-γ (IL-10–dependent or –independent) subject to the target T-cell stage of activation and its tissue location. PMID:22025707

Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic Excitation and Inhibition

PubMed Central

Migliore, Michele; Hines, Michael L.; Shepherd, Gordon M.

2014-01-01

The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral–granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID:25297097

The Influence of Positive Mood on Different Aspects of Cognitive Control

PubMed Central

Martin, Elizabeth A.; Kerns, John G.

2010-01-01

Some evidence suggests that positive mood influences cognitive control. The current research investigated whether positive mood has differential effects on two aspects of cognitive control, working memory and prepotent response inhibition. In Study 1, following either a positive or neutral mood induction, participants completed the Running Memory Span (RMS), a measure primarily of working memory storage capacity, and the Stroop task, a measure of prepotent response inhibition. Results were that the positive mood group performed worse on the RMS task but not on the Stroop task. In Study 2, participants completed the RMS and another measure of prepotent response inhibition, the Flanker task. Results were that when in a positive mood state participants performed worse on the RMS but not on the Flanker task. Overall, this research suggests that positive mood has differential effects on cognitive control, impairing working memory but having no effect on prepotent response inhibition. PMID:21399720

Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles

PubMed Central

Ingram, David G.; Newcomer, Sean C.; Price, Elmer M.; Eklund, Kevin E.; McAllister, Richard M.; Laughlin, M. Harold

2009-01-01

Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively. Treatment was continued for 1–3 mo (8.3 ± 0.6 mg · kg−1 · day−1). In vitro EDD of coronary LADs and arterioles was assessed via responses to ADP (LADs only) and bradykinin (BK), and endothelium-independent function was assessed via responses to sodium nitroprusside (SNP). Chronic NOS inhibition diminished coronary artery EDD to ADP and BK. Incubating LAD rings with L-NAME decreased relaxation responses of LADs from control pigs but not from CNI pigs such that between-group differences were abolished. Neither indomethacin (Indo) nor sulfaphenazole incubation significantly affected relaxation responses of LAD rings to ADP or BK. Coronary arteries from CNI pigs showed enhanced relaxation responses to SNP. In contrast to coronary arteries, coronary arterioles from CNI pigs demonstrated preserved EDD to BK and no increase in dilation responses to SNP. L-NAME, Indo, and L-NAME + Indo incubation did not result in significant between-group differences in arteriole dilation responses to BK. These results suggest that although chronic NOS inhibition diminishes EDD of LAD rings, most likely via a NOS-dependent mechanism, it does not affect EDD of coronary arterioles. PMID:17259441

Postjunctional inhibition of contractor responses in the mouse vas deferens by rat and human calcitonin gene-related peptides (CGRP).

PubMed Central

Al-Kazwini, S. J.; Craig, R. K.; Marshall, I.

1986-01-01

The effects of rat and human alpha-calcitonin gene-related peptide (CGRP) were compared in the mouse and rabbit isolated vas deferens preparation contracted by either field stimulation or acetylcholine. The peptides were about equipotent at inhibiting twitch responses of the mouse vas deferens to field stimulation at 0.2 Hz (IC50 12 +/- 4 nM and 15 +/- 3 nM, rat and human alpha-CGRP respectively). Rat alpha-CGRP was less potent at inhibiting responses to 10 Hz than to either 0.2 Hz or 1.0 Hz stimulation. The potency of rat alpha-CGRP at 1.0 Hz was unaltered by halving the calcium concentration of the Krebs solution. The inhibitory effect of human alpha-CGRP was not antagonized by either propranolol (300 nM) or idazoxan (300 nM), although in the same tissues these latter two drugs reduced responses to isoprenaline and clonidine respectively. Rat alpha-CGRP (100 nM) and human alpha-CGRP (1.0 microM) did not alter the uptake of [3H]-noradrenaline (30 nM) into mice isolated vasa deferentia. Rat alpha-CGRP (3-100 nM) did not alter the fractional release per pulse (1.0 Hz, 100 pulses) of tritium from vasa preloaded with [3H]-noradrenaline, although at the same time the peptide inhibited responses of the smooth muscle to field stimulation. Rat and human alpha-CGRP were equipotent at inhibiting contractions of the mouse vas deferens evoked by acetylcholine although the peptides were less potent than against twitch responses. In the rabbit vas deferens neither rat nor human alpha-CGRP (3 nM-1 microM) inhibited either twitch responses or acetylcholine contractions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3486688

The persistence of cognitive deficits in remitted and unremitted ADHD: a case for the state-independence of response inhibition

PubMed Central

McAuley, Tara; Crosbie, Jennifer; Charach, Alice; Schachar, Russell

2014-01-01

Background Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the disorder, a criterion known as state-independence. This study examined whether these aspects of cognition exhibit state-independence in ADHD. Methods One hundred and seventy-nine children diagnosed with ADHD in a rigorous baseline assessment were contacted for follow-up assessment in adolescence. Of this sample, 130 (73%) were reascertained. At follow-up, children previously diagnosed with ADHD were identified as remittent (n = 24), persistent (n = 64), or in partial remission (n = 42) based on symptoms and impairment of the disorder. Response inhibition, working memory, and response variability were assessed both in childhood (baseline) and adolescence (follow-up) and were compared with age-matched controls (40 children and 28 adolescents) seen at either time point. Results Relative to controls, ADHD children showed baseline deficits in response inhibition, working memory, and response variability. Only the group difference in response inhibition remained significant in adolescence. In general, cognitive performance among ADHD participants improved with age and did so regardless of changes in ADHD symptoms and impairment. Within the ADHD group, however, cognitive performance in childhood and in adolescence did not differ amongst those with persistent, remittent, and partially remittent forms of the disorder. Conclusions Results demonstrate that response inhibition not only distinguishes ADHD children from their unaffected peers but is also state-independent, such that deficits remain present irrespective of changes in the disease phenotype. In other words, inhibitory deficits measured in childhood persist into adolescence even when the ADHD phenotype remits. These findings provide further evidence that the ability to stop prepotent actions is an endophenotype of ADHD. PMID:24261515

Response Inhibition and Internet Gaming Disorder: A Meta-analysis.

PubMed

Argyriou, Evangelia; Davison, Christopher B; Lee, Tayla T C

2017-08-01

Previous research has demonstrated that Internet Gaming Disorder (IGD) has multiple negative effects in psychological functioning and health. This makes the identification of its underpinnings, such as response inhibition, essential for the development of relevant interventions that target these core features of the disorder resulting in more effective treatment. Several empirical studies have evaluated the relationship between response inhibition deficits and IGD using neurocognitive tasks, but provided mixed results. In this study, we conducted a meta-analysis of studies using three neurocognitive tasks, the Go/No Go, the Stroop, and the Stop-Signal tasks, to integrate existing research and estimate the magnitude of this relationship. We found a medium overall effect size (d=0.56, 95% CI [0.32, 0.80]) indicating that compared with healthy individuals, individuals with IGD are more likely to exhibit impaired response inhibition. This finding is in alignment with literature on inhibition and addictive and impulsive behaviors, as well as with neuroimaging research. Theoretical implications regarding the conceptualization of IGD as a clinical disorder, shared commonalities with externalizing psychopathology, and clinical implications for treatment are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Response Inhibition and Interference Control in Obsessive–Compulsive Spectrum Disorders

PubMed Central

van Velzen, Laura S.; Vriend, Chris; de Wit, Stella J.; van den Heuvel, Odile A.

2014-01-01

Over the past 20 years, motor response inhibition and interference control have received considerable scientific effort and attention, due to their important role in behavior and the development of neuropsychiatric disorders. Results of neuroimaging studies indicate that motor response inhibition and interference control are dependent on cortical–striatal–thalamic–cortical (CSTC) circuits. Structural and functional abnormalities within the CSTC circuits have been reported for many neuropsychiatric disorders, including obsessive–compulsive disorder (OCD) and related disorders, such as attention-deficit hyperactivity disorder, Tourette’s syndrome, and trichotillomania. These disorders also share impairments in motor response inhibition and interference control, which may underlie some of their behavioral and cognitive symptoms. Results of task-related neuroimaging studies on inhibitory functions in these disorders show that impaired task performance is related to altered recruitment of the CSTC circuits. Previous research has shown that inhibitory performance is dependent upon dopamine, noradrenaline, and serotonin signaling, neurotransmitters that have been implicated in the pathophysiology of these disorders. In this narrative review, we discuss the common and disorder-specific pathophysiological mechanisms of inhibition-related dysfunction in OCD and related disorders. PMID:24966828

Inhibition by ultraviolet and photosynthetically available radiation lowers model estimates of depth-integrated picophytoplankton photosynthesis: global predictions for Prochlorococcus and Synechococcus.

PubMed

Neale, Patrick J; Thomas, Brian C

2017-01-01

Phytoplankton photosynthesis is often inhibited by ultraviolet (UV) and intense photosynthetically available radiation (PAR), but the effects on ocean productivity have received little consideration aside from polar areas subject to periodic enhanced UV-B due to depletion of stratospheric ozone. A more comprehensive assessment is important for understanding the contribution of phytoplankton production to the global carbon budget, present and future. Here, we consider responses in the temperate and tropical mid-ocean regions typically dominated by picophytoplankton including the prokaryotic lineages, Prochlorococcus and Synechococcus. Spectral models of photosynthetic response for each lineage were constructed using model strains cultured at different growth irradiances and temperatures. In the model, inhibition becomes more severe once exposure exceeds a threshold (E max ) related to repair capacity. Model parameters are presented for Prochlorococcus adding to those previously presented for Synechococcus. The models were applied to estimate midday, water column photosynthesis based on an atmospheric model of spectral radiation, satellite-derived spectral water transparency and temperature. Based on a global survey of inhibitory exposure severity, a full-latitude section of the mid-Pacific and near-equatorial region of the east Pacific were identified as representative regions for prediction of responses over the entire water column. Comparing predictions integrated over the water column including versus excluding inhibition, production was 7-28% lower due to inhibition depending on strain and site conditions. Inhibition was consistently greater for Prochlorococcus compared to two strains of Synechococcus. Considering only the surface mixed layer, production was inhibited 7-73%. On average, including inhibition lowered estimates of midday productivity around 20% for the modeled region of the Pacific with UV accounting for two-thirds of the reduction. In contrast, most other productivity models either ignore inhibition or only include PAR inhibition. Incorporation of E max model responses into an existing spectral model of depth-integrated, daily production will enable efficient global predictions of picophytoplankton productivity including inhibition. © 2016 John Wiley & Sons Ltd.

Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.

PubMed

Aono, Jun; Ruiz-Rodriguez, Ernesto; Qing, Hua; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

2016-01-01

The present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase. Proliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated. We first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus. Inhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC, which depends on the epigenetic activation of S-phase gene promoters by TERT.

Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation

PubMed Central

Patsoukis, Nikolaos; Brown, Julia; Petkova, Victoria; Liu, Fang; Li, Lequn; Boussiotis, Vassiliki A.

2017-01-01

The receptor programmed death 1 (PD-1) inhibits T cell proliferation and plays a critical role in suppressing self-reactive T cells, and it also compromises antiviral and antitumor responses. To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4+ T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle. The ubiquitin ligase SCFSkp2 degrades p27kip1, an inhibitor of cyclin-dependent kinases (Cdks), and PD-1 blocked cell cycle progression through the G1 phase by suppressing transcription of SKP2, which encodes a component of this ubiquitin ligase. Thus, in T cells stimulated through PD-1, Cdks were not activated, and two critical Cdk substrates were not phosphorylated. Activation of PD-1 inhibited phosphorylation of the retinoblastoma gene product, which suppressed expression of E2F target genes. PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G1 phase inhibitor p15INK4 and repressing the Cdk-activating phosphatase Cdc25A. PD-1 suppressed SKP2 transcription by inhibiting phosphoinositide 3-kinase–Akt and Ras–mitogen-activated and extracellular signal–regulated kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) signaling. Exposure of cells to the proliferation-promoting cytokine interleukin-2 restored activation of MEK-ERK signaling, but not Akt signaling, and only partially restored SKP2 expression. Thus, PD-1 blocks cell cycle progression and proliferation of T lymphocytes by affecting multiple regulators of the cell cycle. PMID:22740686

T-cell diversification reflects antigen selection in the blood of patients on immune checkpoint inhibition and may be exploited as liquid biopsy biomarker.

PubMed

Akyüz, Nuray; Brandt, Anna; Stein, Alexander; Schliffke, Simon; Mährle, Thorben; Quidde, Julia; Goekkurt, Eray; Loges, Sonja; Haalck, Thomas; Ford, Christopher Thomas; Asemissen, Anne Marie; Thiele, Benjamin; Radloff, Janina; Thenhausen, Toni; Krohn-Grimberghe, Artus; Bokemeyer, Carsten; Binder, Mascha

2017-06-01

Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD-1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD-1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and next-generation T- and B-cell immunosequencing (TCRß/IGH). Findings were correlated with clinical outcomes. We found almost complete saturation of surface PD-1 on all T-cell subsets after the first dose of the antibody. Both T- and B-cell compartments quantitatively expanded during treatment. These expansions were mainly driven by an increase in the activated T-cell compartments, as well as of naïve B- and plasma cells. Deep immunosequencing revealed a clear diversification pattern of the clonal T-cell space indicative of antigenic selection in 47% of patients, while the remaining patients showed stable repertoires. 43% of the patients with a diversification pattern showed disease control in response to the PD-1 inhibitor. No disease stabilizations were observed without clonal T-cell space diversification. Our data show for the first time a clear impact of PD-1 targeting not only on circulating T-cells, but also on B-lineage cells, shedding light on the complexity of the anti-tumor immune response. Liquid biopsy T-cell next-generation immunosequencing should be prospectively evaluated as part of a composite response prediction biomarker panel in the context of clinical studies. © 2016 UICC.

Characterization of low phosphorus insensitive Mutants Reveals a Crosstalk between Low Phosphorus-Induced Determinate Root Development and the Activation of Genes Involved in the Adaptation of Arabidopsis to Phosphorus Deficiency1

PubMed Central

Sánchez-Calderón, Lenin; López-Bucio, José; Chacón-López, Alejandra; Gutiérrez-Ortega, Abel; Hernández-Abreu, Esmeralda; Herrera-Estrella, Luis

2006-01-01

Low phosphorus (P) availability is one of the most limiting factors for plant productivity in many natural and agricultural ecosystems. Plants display a wide range of adaptive responses to cope with low P stress, which generally serve to enhance P availability in the soil and to increase its uptake by roots. In Arabidopsis (Arabidopsis thaliana), primary root growth inhibition and increased lateral root formation have been reported to occur in response to P limitation. To gain knowledge of the genetic mechanisms that regulate root architectural responses to P availability, we designed a screen for identifying Arabidopsis mutants that fail to arrest primary root growth when grown under low P conditions. Eleven low phosphorus insensitive (lpi) mutants that define at least four different complementation groups involved in primary root growth responses to P availability were identified. The lpi mutants do not show the typical determinate developmental program induced by P stress in the primary root. Other root developmental aspects of the low P rescue system, including increased root hair elongation and anthocyanin accumulation, remained unaltered in lpi mutants. In addition to the insensitivity of primary root growth inhibition, when subjected to P deprivation, lpi mutants show a reduced induction in the expression of several genes involved in the P starvation rescue system (PHOSPHATE TRANSPORTER 1 and 2, PURPLE ACID PHOSPHATASE 1, ACID PHOSPHATASE 5, and INDUCED BY PHOSPHATE STARVATION 1). Our results provide genetic support for the role of P as an important signal for postembryonic root development and root meristem maintenance and show a crosstalk in developmental and biochemical responses to P deprivation. PMID:16443695

B cells and TCR avidity determine distinct functions of CD4+ T cells in retroviral infection1

PubMed Central

Ploquin, Mickaël J-Y; Eksmond, Urszula; Kassiotis, George

2011-01-01

The T-cell-dependent B-cell response relies on cognate interaction between B cells and CD4+ Th cells. However, the consequences of this interaction for CD4+ T cells are not entirely known. B cells generally promote CD4+ T-cell responses to pathogens, albeit to a variable degree. In contrast, CD4+ T-cell responses to self or tumor antigens are often suppressed by B cells. Here we demonstrated that interaction with B cells dramatically inhibited the function of virus-specific CD4+ T cells in retroviral infection. We have used Friend virus (FV) infection of mice as a model for retroviral infection, in which the behavior of virus-specific CD4+ T cells was monitored according to their TCR avidity. We report that avidity for antigen and interaction with B cells determine distinct aspects of the primary CD4+ T-cell response to FV infection. Virus-specific CD4+ T cells followed exclusive Th1 and T follicular helper (Tfh) differentiation. High avidity for antigen facilitated expansion during priming and enhanced the capacity for IFN-γ and IL-21 production. In contrast, Tfh differentiation was not affected by avidity for antigen. By reducing or preventing B-cell interaction we found that B cells promoted Tfh differentiation, induced programmed death 1 (PD-1) expression and inhibited IFN-γ production by virus-specific CD4+ T cells. Ultimately, B cells protected hosts from CD4+ T-cell-mediated immune pathology, at the detriment of CD4+ T-cell-mediated protective immunity. Our results suggest that B-cell presentation of vaccine antigens could be manipulated to direct the appropriate CD4+ T-cell response. PMID:21841129

Effect of fenspiride, a non-steroidal antiinflammatory agent, on neurogenic mucus secretion in ferret trachea in vitro.

PubMed

Khawaja, A M; Liu, Y C; Rogers, D F

1999-01-01

Neural mechanisms contribute to control of mucus secretion in the airways. Fenspiride is a non-steroidal antiinflammatory agent which has a variety of actions, including inhibition of neurogenic bronchoconstriction. The effect of fenspiride on neurally-mediated mucus secretion was investigated in vitro in electrically-stimulated ferret trachea, using(35)SO(4)as a mucus marker. Cholinergic secretory responses were isolated using adrenoceptor and tachykinin receptor antagonists. Tachykinin responses were isolated using cholinoceptor and adrenoceptor antagonists. Electrical stimulation increased cholinergic secretion by;90% and tachykininergic secretion by;40%. Fenspiride (1 microM-1 mM) tended to inhibit cholinergic secretion in a concentration-dependent manner, although only at 1 mM was inhibition (by 87%) significant. Inhibition by fenspiride of tachykininergic secretion was not concentration-dependent, and again significant inhibition (by 85%) was only at 1 mM. Inhibition was not due to loss of tissue viability, as assessed by restitution of secretory response after washout. Fenspiride also inhibited secretion induced by acetylcholine, but did not inhibit substance P-induced secretion. Histamine receptor antagonists increased basal secretion by 164%, whereas fenspiride did not affect basal secretion. We conclude that, in ferret trachea in vitro, fenspiride inhibits neurally-mediated mucus secretion, with antimuscarinic action the most plausible mechanism of action, but not necessarily the only mechanism. Copyright 1999 Academic Press.

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

Heterogeneity of the IgE response to allergenic determinants of cefaclor in serum samples from patients with cefaclor-induced anaphylaxis.

PubMed

Kim, Sang-Hoon; Choi, Jeong-Hee; Park, Hae-Sim

2005-06-01

Beta-lactam antibiotics, such as cefaclor, may cause IgE-mediated anaphylactic reactions. However, the clinically available serologic test has not been widely accepted, and the antigenic determinants of these drugs are unclear. To describe 4 cases of anaphylaxis caused by cefaclor in which a specific IgE response to cefaclor was demonstrated. Four patients with anaphylaxis to cefaclor and 35 nonatopic controls never exposed to cefaclor were studied. Skin tests and oral challenges with this drug were performed. The specific IgE response to the antigenic determinant of cefaclor-human serum albumin (HSA) conjugate was compared in each patient. The serum specific IgE to cefaclor-HSA conjugate was detected using enzyme-linked immunosorbent assay (ELISA). Also, ELISA inhibition studies using various concentrations of cefaclor-HSA, HSA alone, and free cefaclor were performed, as were hapten inhibition studies using cefaclor, cephalexin, cefadroxil, ampicillin, ceftriaxone, and cefotaxime. Three patients showed high levels of serum specific IgE to cefaclor-HSA and marked inhibition patterns to free cefaclor and cefaclor-HSA conjugate on ELISA inhibition testing. Hapten inhibition testing in 3 individual serum samples showed 2 different patterns. In patient 3, significant dose-dependent inhibitions (up to 92%) were noted with additions of free cefaclor and cefaclor-HSA conjugate, and lesser inhibitions (up to 74%) were noted with cephalexin, which shares the aminobenzyl side chain. In patients 1 and 2, marked dose-dependent inhibitions were noted only with additions of cefaclor-HSA conjugate and free cefaclor, whereas minimal inhibitions were noted with the other 5 compounds. The specific IgE response to cefaclor-HSA conjugate in patients with cefaclor anaphylaxis occurs against the hapten, in which heterogeneity of the antigenic determinant was noted to depend on the individual.

Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk.

PubMed

Ross, Randal G; Hunter, Sharon K; McCarthy, Lizbeth; Beuler, Julie; Hutchison, Amanda K; Wagner, Brandie D; Leonard, Sherry; Stevens, Karen E; Freedman, Robert

2013-03-01

Deficient cerebral inhibition is a pathophysiological brain deficit related to poor sensory gating and attention in schizophrenia and other disorders. Cerebral inhibition develops perinatally, influenced by genetic and in utero factors. Amniotic choline activates fetal α7-nicotinic acetylcholine receptors and facilitates development of cerebral inhibition. Increasing this activation may protect infants from future illness by promoting normal brain development. The authors investigated the effects of perinatal choline supplementation on the development of cerebral inhibition in human infants. A randomized placebo-controlled clinical trial of dietary phosphatidylcholine supplementation was conducted with 100 healthy pregnant women, starting in the second trimester. Supplementation to twice normal dietary levels for mother or newborn continued through the third postnatal month. All women received dietary advice regardless of treatment. Infants' electrophysiological recordings of inhibition of the P50 component of the cerebral evoked response to paired sounds were analyzed. The criterion for inhibition was suppression of the amplitude of the second P50 response by at least half, compared with the first response. No adverse effects of choline were observed in maternal health and delivery, birth, or infant development. At the fifth postnatal week, the P50 response was suppressed in more choline-treated infants (76%) compared with placebo-treated infants (43%) (effect size=0.7). There was no difference at the 13th week. A CHRNA7 genotype associated with schizophrenia was correlated with diminished P50 inhibition in the placebo-treated infants, but not in the choline-treated infants. Neonatal developmental delay in inhibition is associated with attentional problems as the child matures. Perinatal choline activates timely development of cerebral inhibition, even in the presence of gene mutations that otherwise delay it.

The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells.

PubMed

Wang, Huizhi; Brown, Jonathan; Gao, Shegan; Liang, Shuang; Jotwani, Ravi; Zhou, Huaxin; Suttles, Jill; Scott, David A; Lamont, Richard J

2013-08-01

The role of JAK-3 in TLR-mediated innate immune responses is poorly understood, although the suppressive function of JAK3 inhibition in adaptive immune response has been well studied. In this study, we found that JAK3 inhibition enhanced TLR-mediated immune responses by differentially regulating pro- and anti- inflammatory cytokine production in innate immune cells. Specifically, JAK3 inhibition by pharmacological inhibitors or specific small interfering RNA or JAK3 gene knockout resulted in an increase in TLR-mediated production of proinflammatory cytokines while concurrently decreasing the production of IL-10. Inhibition of JAK3 suppressed phosphorylation of PI3K downstream effectors including Akt, mammalian target of rapamycin complex 1, glycogen synthase kinase 3β (GSK3β), and CREB. Constitutive activation of Akt or inhibition of GSK3β abrogated the capability of JAK3 inhibition to enhance proinflammatory cytokines and suppress IL-10 production. In contrast, inhibition of PI3K enhanced this regulatory ability of JAK3 in LPS-stimulated monocytes. At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of STATs that could be attenuated by neutralization of de novo inflammatory cytokines. JAK3 inhibition exhibited a GSK3 activity-dependent ability to enhance phosphorylation levels and DNA binding of NF-κB p65. Moreover, JAK3 inhibition correlated with an increased CD4(+) T cell response. Additionally, higher neutrophil infiltration, IL-17 expression, and intestinal epithelium erosion were observed in JAK3 knockout mice. These findings demonstrate the negative regulatory function of JAK3 and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory cytokine production in innate immune cells.

Contrasting Transcriptional Programs Control Postharvest Development of Apples (Malus x domestica Borkh.) Submitted to Cold Storage and Ethylene Blockage.

PubMed

Storch, Tatiane Timm; Finatto, Taciane; Bruneau, Maryline; Orsel-Baldwin, Mathilde; Renou, Jean-Pierre; Rombaldi, Cesar Valmor; Quecini, Vera; Laurens, François; Girardi, César Luis

2017-09-06

Apple is commercially important worldwide. Favorable genomic contexts and postharvest technologies allow year-round availability. Although ripening is considered a unidirectional developmental process toward senescence, storage at low temperatures, alone or in combination with ethylene blockage, is effective in preserving apple properties. Quality traits and genome wide expression were integrated to investigate the mechanisms underlying postharvest changes. Development and conservation techniques were responsible for transcriptional reprogramming and distinct programs associated with quality traits. A large portion of the differentially regulated genes constitutes a program involved in ripening and senescence, whereas a smaller module consists of genes associated with reestablishment and maintenance of juvenile traits after harvest. Ethylene inhibition was associated with a reversal of ripening by transcriptional induction of anabolic pathways. Our results demonstrate that the blockage of ethylene perception and signaling leads to upregulation of genes in anabolic pathways. We also associated complex phenotypes to subsets of differentially regulated genes.

Neural activation during response inhibition in adult Attention-Deficit/Hyperactivity Disorder: Preliminary findings on the effects of medication and symptom severity

PubMed Central

Congdon, Eliza; Altshuler, Lori L.; Mumford, Jeanette A.; Karlsgodt, Katherine H.; Sabb, Fred W.; Ventura, Joseph; McGough, James J.; London, Edythe D.; Cannon, Tyrone D.; Bilder, Robert M.; Poldrack, Russell A.

2014-01-01

Studies of adults with attention-deficit/hyperactivity disorder (ADHD) have suggested that they have deficient response inhibition, but findings concerning the neural correlates of inhibition in this patient population are inconsistent. We used the Stop-Signal task and functional magnetic resonance imaging (fMRI) to compare neural activation associated with response inhibition between adults with ADHD (N = 35) and healthy comparison subjects (N = 62), and in follow-up tests to examine the effect of current medication use and symptom severity. There were no differences in Stop-Signal task performance or neural activation between ADHD and control participants. Among the ADHD participants, however, significant differences were associated with current medication, with individuals taking psychostimulants (N = 25) showing less stopping-related activation than those not currently receiving psychostimulant medication (N = 10). Follow-up analyses suggested that this difference in activation was independent of symptom severity. These results provide evidence that deficits in inhibition-related neural activation persist in a subset of adult ADHD individuals, namely those individuals currently taking psychostimulants. These findings help to explain some of the disparities in the literature, and advance our understanding of why deficits in response inhibition are more variable in adult, as compared with child and adolescent, ADHD patients. PMID:24581734

The role of necroptosis in the treatment of diseases.

PubMed

Cho, Young Sik

2018-04-11

Necroptosis is an emerging form of programmed cell death occurring via active and well-regulated necrosis, distinct from apoptosis morphologically, and biochemically. Necroptosis is mainly unmasked when apoptosis is compromised in response to cell stress. Unlike apoptotic cells, which are cleared by macrophages or neighboring cells, necrotic cells release danger signals, triggering inflammation, and exacerbating tissue damage. Evidence increasingly suggests that programmed necrosis is not only associated with pathophysiology of disease, but also induces innate immune response to viral infection. Therefore, necroptotic cell death plays both physiological and pathological roles. Physiologically, necroptosis induce an innate immune response as well as premature assembly of viral particles in cells infected with virus that abrogates host apoptotic machinery. On the other hand, necroptosis per se is detrimental, causing various diseases such as sepsis, neurodegenerative diseases and ischemic reperfusion injury. This review discusses the signaling pathways leading to necroptosis, associated necroptotic proteins with target-specific inhibitors and diseases involved. Several studies currently focus on protective approaches to inhibit necroptotic cell death. In cancer biology, however, anticancer drug resistance severely hampers the efficacy of chemotherapy based on apoptosis. Pharmacological switch of cell death finds therapeutic application in drug-resistant cancers. Therefore, the possible clinical role of necroptosis in cancer control will be discussed in brief.

Complex changes in the apoptotic and cell differentiation programs during initiation of the hair follicle response to chemotherapy.

PubMed

Sharova, Tatyana Y; Poterlowicz, Krzysztof; Botchkareva, Natalia V; Kondratiev, Nikita A; Aziz, Ahmar; Spiegel, Jeffrey H; Botchkarev, Vladimir A; Sharov, Andrey A

2014-12-01

Chemotherapy has severe side effects in normal rapidly proliferating organs, such as hair follicles, and causes massive apoptosis in hair matrix keratinocytes followed by hair loss. To define the molecular signature of hair follicle response to chemotherapy, human scalp hair follicles cultured ex vivo were treated with doxorubicin (DXR), and global microarray analysis was performed 3 hours after treatment. Microarray data revealed changes in expression of 504 genes in DXR-treated hair follicles versus controls. Among these genes, upregulations of several tumor necrosis factor family of apoptotic receptors (FAS, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors 1/2), as well as of a large number of keratin-associated protein genes, were seen after DXR treatment. Hair follicle apoptosis induced by DXR was significantly inhibited by either TRAIL-neutralizing antibody or caspase-8 inhibitor, thus suggesting a previously unreported role for TRAIL receptor signaling in mediating DXR-induced hair loss. These data demonstrate that the early phase of the hair follicle response to DXR includes upregulation of apoptosis-associated markers, as well as substantial reorganization of the terminal differentiation programs in hair follicle keratinocytes. These data provide an important platform for further studies toward the design of effective approaches for the management of chemotherapy-induced hair loss.

Complex changes in the apoptotic and cell differentiation programs during initiation of the hair follicle response to chemotherapy

PubMed Central

Sharova, Tatyana Y.; Poterlowicz, Krzysztof; Botchkareva, Natalia V.; Kondratiev, Nikita A.; Aziz, Ahmar; Spiegel, Jeffrey H.; Botchkarev, Vladimir A.; Sharov, Andrey A.

2014-01-01

Chemotherapy has severe side-effects for normal rapidly proliferating organs, such as hair follicle, and causes massive apoptosis in hair matrix keratinocytes followed by hair loss. To define the molecular signature of hair follicle response to chemotherapy, human scalp hair follicles cultured ex vivo were treated with doxorubicin and global microarray analysis was performed 3 hours after treatment. Microarray data revealed changes in expression of 504 genes in doxorubicin-treated hair follicles versus the controls. Among these genes, upregulations of several tumor necrosis factor family of apoptotic receptors (FAS, TRAIL receptors 1/2), as well as of a large number of the keratin-associated protein genes were seen after doxorubicin treatment. Hair follicle apoptosis induced by doxorubicin was significantly inhibited by either TRAIL neutralizing antibody or caspase 8 inhibitor, thus suggesting a novel role for TRAIL receptor signaling in mediating doxorubicin-induced hair loss. These data demonstrate that the early phase of the hair follicle response to doxorubicin includes upregulation of apoptosis-associated markers, as well as substantial re-organization of the terminal differentiation programs in hair follicle keratinocytes. These data provide an important platform for further studies towards the design of novel approaches for management of chemotherapy-induced hair loss. PMID:24999588

Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors.

PubMed

Giraudier, Stéphane; Chagraoui, Hédia; Komura, Emiko; Barnache, Stéphane; Blanchet, Benoit; LeCouedic, Jean Pierre; Smith, David F; Larbret, Frédéric; Taksin, Anne-Laure; Moreau-Gachelin, Françoise; Casadevall, Nicole; Tulliez, Michel; Hulin, Anne; Debili, Najet; Vainchenker, William

2002-10-15

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients' CD34(+) cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34(+) cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and heat shock protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that the calcineurin pathway was responsible for the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin-dependent pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program.

Atomoxetine restores the response inhibition network in Parkinson's disease.

PubMed

Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2016-08-01

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses

PubMed Central

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-01-01

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma. PMID:28775364

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses.

PubMed

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-08-04

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

Corrective response times in a coordinated eye-head-arm countermanding task.

PubMed

Tao, Gordon; Khan, Aarlenne Z; Blohm, Gunnar

2018-06-01

Inhibition of motor responses has been described as a race between two competing decision processes of motor initiation and inhibition, which manifest as the reaction time (RT) and the stop signal reaction time (SSRT); in the case where motor initiation wins out over inhibition, an erroneous movement occurs that usually needs to be corrected, leading to corrective response times (CRTs). Here we used a combined eye-head-arm movement countermanding task to investigate the mechanisms governing multiple effector coordination and the timing of corrective responses. We found a high degree of correlation between effector response times for RT, SSRT, and CRT, suggesting that decision processes are strongly dependent across effectors. To gain further insight into the mechanisms underlying CRTs, we tested multiple models to describe the distribution of RTs, SSRTs, and CRTs. The best-ranked model (according to 3 information criteria) extends the LATER race model governing RTs and SSRTs, whereby a second motor initiation process triggers the corrective response (CRT) only after the inhibition process completes in an expedited fashion. Our model suggests that the neural processing underpinning a failed decision has a residual effect on subsequent actions. NEW & NOTEWORTHY Failure to inhibit erroneous movements typically results in corrective movements. For coordinated eye-head-hand movements we show that corrective movements are only initiated after the erroneous movement cancellation signal has reached a decision threshold in an accelerated fashion.

Balance among Cognitive Control Processes: A Case Study of A Gifted Youth

ERIC Educational Resources Information Center

Urben, Sébastien; Camos, Valérie; Habersaat, Stéphanie; Constanty, Lauriane; Stéphan, Philippe

2018-01-01

This case study analyzed the cognitive strategies of Ethan, a gifted youth, when performing a Stop Signal Task assessing cognitive control processes including response inhibition as well as proactive and reactive adjustments of response. In the case of Ethan, the response inhibition score was biased, revealing that Ethan did not follow the…

Differential Effects of Social and Non-Social Reward on Response Inhibition in Children and Adolescents

ERIC Educational Resources Information Center

Kohls, Gregor; Peltzer, Judith; Herpertz-Dahlmann, Beate; Konrad, Kerstin

2009-01-01

An important issue in the field of clinical and developmental psychopathology is whether cognitive control processes, such as response inhibition, can be specifically enhanced by motivation. To determine whether non-social (i.e. monetary) and social (i.e. positive facial expressions) rewards are able to differentially improve response inhibition…

Corollary discharge inhibition of wind-sensitive cercal giant interneurons in the singing field cricket

PubMed Central

Hedwig, Berthold

2014-01-01

Crickets carry wind-sensitive mechanoreceptors on their cerci, which, in response to the airflow produced by approaching predators, triggers escape reactions via ascending giant interneurons (GIs). Males also activate their cercal system by air currents generated due to the wing movements underlying sound production. Singing males still respond to external wind stimulation, but are not startled by the self-generated airflow. To investigate how the nervous system discriminates sensory responses to self-generated and external airflow, we intracellularly recorded wind-sensitive afferents and ventral GIs of the cercal escape pathway in fictively singing crickets, a situation lacking any self-stimulation. GI spiking was reduced whenever cercal wind stimulation coincided with singing motor activity. The axonal terminals of cercal afferents showed no indication of presynaptic inhibition during singing. In two ventral GIs, however, a corollary discharge inhibition occurred strictly in phase with the singing motor pattern. Paired intracellular recordings revealed that this inhibition was not mediated by the activity of the previously identified corollary discharge interneuron (CDI) that rhythmically inhibits the auditory pathway during singing. Cercal wind stimulation, however, reduced the spike activity of this CDI by postsynaptic inhibition. Our study reveals how precisely timed corollary discharge inhibition of ventral GIs can prevent self-generated airflow from triggering inadvertent escape responses in singing crickets. The results indicate that the responsiveness of the auditory and wind-sensitive pathway is modulated by distinct CDIs in singing crickets and that the corollary discharge inhibition in the auditory pathway can be attenuated by cercal wind stimulation. PMID:25318763

Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk

PubMed Central

Ross, Randal G.; Hunter, Sharon K.; McCarthy, Lizbeth; Beuler, Julie; Hutchison, Amanda K.; Wagner, Brandie D.; Leonard, Sherry; Stevens, Karen E.; Freedman, Robert

2013-01-01

Background Deficient cerebral inhibition is a pathophysiological brain deficit related to poor sensory gating and attention in schizophrenia and other disorders. Cerebral inhibition develops perinatally, influenced by genetic and in utero factors. Amniotic choline activates fetal α7-nicotinic acetylcholine receptors and facilitates development of cerebral inhibition. Increasing this activation may protect infants from future illness by promoting normal brain development. Methods A randomized placebo-controlled clinical trial of dietary phosphatidylcholine supplementation was conducted with 100 healthy pregnant women, who consented to the study at second trimester. Supplementation to twice normal dietary levels for mother or newborn continued through the third postnatal month. All women received dietary advice regardless of treatment. Infants’ electroencephalographic recordings of inhibition of the P50 component of the cerebral evoked response to paired sounds were analyzed. Criterion for inhibition was suppression of the amplitude of the second P50 response by at least half, compared to the first response. Results No adverse effects of choline were observed in maternal health and delivery, birth, or infant development. More choline-treated infants (76%) suppressed the P50 response, compared to placebo-treated infants (43%) at the fifth postnatal week (effect size 0.7). There was no difference at the 13th week. A CHRNA7 genotype associated with schizophrenia diminished P50 inhibition in the placebo-treated infants, but not in the choline-treated infants. Conclusion Neonatal developmental delay in inhibition is associated with attentional problems as the child matures. Perinatal choline activates timely development of cerebral inhibition, even in the presence of gene mutations that otherwise delay it. PMID:23318559

Response Inhibition Is Facilitated by a Change to Red Over Green in the Stop Signal Paradigm

PubMed Central

Blizzard, Shawn; Fierro-Rojas, Adriela; Fallah, Mazyar

2017-01-01

Actions are informed by the complex interactions of response execution and inhibition networks. These networks integrate sensory information with internal states and behavioral goals to produce an appropriate action or to update an ongoing action. Recent investigations have shown that, behaviorally, attention is captured through a hierarchy of colors. These studies showed how the color hierarchy affected visual processing. To determine whether the color hierarchy can be extended to higher level executive functions such as response execution and inhibition, we conducted several experiments using the stop-signal task (SST). In the first experiment, we modified the classic paradigm so that the go signals could vary in task-irrelevant color, with an auditory stop signal. We found that the task-irrelevant color of the go signals did not differentially affect response times. In the second experiment we determined that making the color of the go signal relevant for response selection still did not affect reaction times(RTs) and, thus, execution. In the third experiment, we modified the paradigm so that the stop signal was a task relevant change in color of the go signal. The mean RT to the red stop signal was approximately 25 ms faster than to the green stop signal. In other words, red stop signals facilitated response inhibition more than green stop signals, however, there was no comparative facilitation of response execution. These findings suggest that response inhibition, but not execution, networks are sensitive to differences in color salience. They also suggest that the color hierarchy is based on attentional networks and not simply on early sensory processing. PMID:28101011

Inhibition of T cell-mediated functions by MVM(i), a parvovirus closely related to minute virus of mice.

PubMed

Engers, H D; Louis, J A; Zubler, R H; Hirt, B

1981-12-01

A purified preparation of MVM(i), a murine parvovirus closely related to minute virus of mice (MVM), was found to inhibit various functions mediated by murine T cells in vitro. Addition of MVM(i) virus to secondary allogeneic mixed leukocyte cultures resulted in the inhibition of both lymphocyte proliferation (3H-thymidine incorporation) and the generation of cytolytic T lymphocyte activity but not interferon production. MVM(i) virus also inhibited the growth and cytolytic activity of several cloned, long-term Lyt-2+ cytolytic T cell lines. Furthermore, the antigen-induced proliferative responses of parasite- (Leishmania) specific Lyt-1+ T cells in vitro was abrogated by the addition of MVM(i) virus to the culture. Finally, the suppression of an in vitro antibody response to SRBC by MVM(i) virus was the result of the inhibition of T helper cells required for the B cell response. These suppressive effects were specific for MVM(i); parallel studies in which the prototype MVM parvovirus was used showed no significant inhibition in the various systems tested.

Inhibition of polymorphonuclear leukocyte function by Legionella pneumophila exoproducts.

PubMed

Sahney, N N; Lambe, B C; Summersgill, J T; Miller, R D

1990-08-01

Total exoproducts (relative molecular mass greater than 10,000) from wild-type strains of Legionella pneumophila markedly inhibited human polymorphonuclear leukocyte (PMN) superoxide anion generation, at sub-lethal concentrations, in response to four stimuli [1.7, 0, 0.6 and 3.4% of control for zymosan activated particles (ZAP), phorbol myristate acetate (PMA), calcium ionophore (A 23187), and formyl-methionyl-leucyl-phenylalanine (fMLP), respectively]. PMN chemotaxis towards fMLP and spontaneous migration, were also dramatically inhibited (2.8 and 2.9% of buffer-treated controls, respectively). In contrast, total exoproducts from the cas-1 strain of L. pneumophila, a protease-deficient mutant generated by ethyl methane sulfonate mutagenesis, failed to inhibit PMN superoxide production in response to ZAP and PMA and only partially inhibited PMN response to A 23187 and fMLP. PMN spontaneous migration was unaffected by treatment with total exoproducts from the mutant, while directed chemotaxis was partially inhibited (51.4%). These data demonstrated that L. pneumophila total exoproducts, primarily protease had significant inhibitory effects on normal PMN function and may play an important contributory role in the pathogenesis of legionnaire's disease.

Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function.

PubMed

Thaxton, Jessica E; Wallace, Caroline; Riesenberg, Brian; Zhang, Yongliang; Paulos, Chrystal M; Beeson, Craig C; Liu, Bei; Li, Zihai

2017-08-01

The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) activation represents a form of acute cell stress and induces mobilization of ER Ca 2+ stores. The role of the ER in programming T-cell activation and metabolic fate remains largely undefined. Gp96 is an ER protein with functions as a molecular chaperone and Ca 2+ buffering protein. We hypothesized that the ER stress response may be important for CD4 + T-cell activation and that gp96 may be integral to this process. To test our hypothesis, we utilized genetic deletion of the gp96 gene Hsp90b1 in a CD4 + T cell-specific manner. We show that gp96-deficient CD4 + T cells cannot undergo activation-induced glycolysis due to defective Ca 2+ mobilization upon TCR engagement. We found that activating naïve CD4 + T cells while inhibiting ER Ca 2+ exchange, through pharmacological blockade of the ER Ca 2+ channel inositol trisphosphate receptor (IP 3 R), led to a reduction in cytosolic Ca 2+ content and generated a pool of CD62L high /CD44 low CD4 + T cells compared with wild-type (WT) matched controls. In vivo IP 3 R-inhibited CD4 + T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca 2+ plays a role in defining CD4 + T-cell phenotype and function. Factors associated with the ER stress response are suitable targets for T cell-based immunotherapies. Cancer Immunol Res; 5(8); 666-75. ©2017 AACR . ©2017 American Association for Cancer Research.

ERP indices of persisting and current inhibitory control: a study of saccadic task switching.

PubMed

Mueller, S C; Swainson, R; Jackson, G M

2009-03-01

Previous studies have found that inhibition of a biologically dominant prepotent response tendency is required during the execution of a less familiar, non-prepotent response. However, the lasting impact of this inhibition and the cognitive mechanisms to flexibly switch between prepotent and non-prepotent responses are poorly understood. We examined the neurophysiological (ERP) correlates of switching between prosaccade and antisaccade responses in 22 healthy volunteers. The behavioural data showed significant switch costs in terms of response latency for the prosaccade task only. These costs occurred exclusively in trials when preparation for the switch was limited to 300 ms, suggesting that inhibition of the prepotent prosaccade task either passively dissipated or was actively overcome during the longer 1000 ms preparation interval. In the neurophysiological data, a late frontal negativity (LFN) was visible during preparation for a switch to the prosaccade task that was absent when switching to the antisaccade task, which may reflect the overcoming of persisting inhibition. During task implementation both saccade types were associated with a late parietal positivity (LPP) for switch relative to repetition trials, possibly indicating attentional reorienting to the switched-to task, and visible only with short preparation intervals. When the prosaccade and antisaccade task were contrasted directly during task implementation, the antisaccade task exhibited increased stimulus-locked N2 and decreased P3 amplitudes indicative of active inhibition. The present findings indicate that neurophysiological markers of persisting and current inhibition can be revealed using a prosaccade/antisaccade-switching task.

The role of age, working memory, and response inhibition in deviance distraction: A cross-sectional study.

PubMed

Leiva, Alicia; Andrés, Pilar; Servera, Mateu; Verbruggen, Frederick; Parmentier, Fabrice B R

2016-09-01

Sounds deviating from an otherwise repeated or structured sequence capture attention and affect performance in an ongoing visual task negatively, testament to the balance between selective attention and change detection. Although deviance distraction has been the object of much research, its modulation across the life span has been more scarcely addressed. Recent findings suggest possible connections with working memory and response inhibition. In this study we measured the performance of children and young and older adults in a cross-modal oddball task (deviance distraction), a working memory task (working memory capacity), and a response inhibition task (ability to voluntarily inhibit an already planned action) with the aim to establish the contribution of the latter 2 to the first. Older adults exhibited significantly more deviance distraction than children and young adults (who did not differ from each other). Working memory capacity mediated deviance distraction in children and older adults (though in opposite directions) but not in young adults. Response inhibition capacities did not mediate deviance distraction in any of the age groups. Altogether the results suggest that although the increase in deviance distraction observed in old age may partly reflect the relative impairment of working memory mechanisms, there is no straightforward and stable relation between working memory capacity and deviance distraction across the life span. Furthermore, our results indicate that deviance distraction is unlikely to reflect the temporary inhibition of responses. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Neural correlates of inhibitory control in adult ADHD: Evidence from the Milwaukee longitudinal sample

PubMed Central

Mulligan, Richard C.; Knopik, Valerie S.; Sweet, Lawrence H.; Fischer, Mariellen; Seidenberg, Michael; Rao, Stephen M.

2011-01-01

Only a few studies have investigated the neural substrate of response inhibition in adult ADHD using Stop-Signal and Go/No-Go tasks. Inconsistencies and methodological limitations in the existing literature have resulted in limited conclusions regarding underlying pathophysiology. We examined the neural basis of response inhibition in a group of adults diagnosed with ADHD in childhood and who continue to meet criteria for ADHD while addressing limitations present in earlier studies. Adults with ADHD (n=12) and controls (n=12) were recruited from an ongoing longitudinal study and were matched for age, IQ, and education. Individuals with comorbid conditions were excluded. Functional MRI was used to identify and compare the brain activation patterns during correct trials of a response inhibition task (Go/No-Go). Our results showed that the control group recruited a more extensive network of brain regions than the ADHD group during correct inhibition trials. Adults with ADHD showed reduced brain activation in the right frontal eye field, pre-supplementary motor area, left precentral gyrus, and the inferior parietal lobe bilaterally. During successful inhibition of an inappropriate response, adults with ADHD display reduced activation in fronto-parietal networks previously implicated in working memory, goal-oriented attention, and response selection. This profile of brain activation may be specifically associated with ADHD in adulthood. PMID:21937201

Neural correlates of response inhibition in current and former smokers.

PubMed

Weywadt, Christina R; Kiehl, Kent A; Claus, Eric D

2017-02-15

Loss of behavioral control is a hallmark of addiction. Individual differences in basic cognitive processes such as response inhibition may be important for interrupting automatic behaviors associated with smoking and supporting prolonged abstinence. To examine how response inhibition and error monitoring processes differ as a function of smoking status, current smokers, former smokers and never smokers (N=126) completed a simple Go/No-Go task while undergoing functional magnetic resonance imaging. All groups performed similarly on the task and similarly engaged the inferior frontal gyrus and dorsal anterior cingulate cortex, regions traditionally associated with response inhibition and error monitoring, respectively. During response inhibition (i.e., Correct Rejects>Hits contrast), overall group differences emerged in the recruitment of the cerebellum, while individual group differences in error monitoring (False Alarms>Hits contrast) were seen for regions of the parietal lobe and thalamus (current smokers>former smokers), as well as regions of the bilateral cerebellum, parahippocampal gyrus and superior parietal lobe (i.e., ever smokers>never smokers). We discuss how our results replicate two previous large-sample studies that used the same Go/No-Go task and review these data in terms of network models of inhibitory and error monitoring abnormalities in addiction. Copyright © 2016 Elsevier B.V. All rights reserved.

Associations between regional brain physiology and trait impulsivity, motor inhibition, and impaired control over drinking

PubMed Central

Weafer, Jessica; Dzemidzic, Mario; Eiler, William; Oberlin, Brandon G.; Wang, Yang; Kareken, David A.

2015-01-01

Trait impulsivity and poor inhibitory control are well-established risk factors for alcohol misuse, yet little is known about the associated neurobiological endophenotypes. Here we examined correlations among brain physiology and self-reported trait impulsive behavior, impaired control over drinking, and a behavioral measure of response inhibition. A sample of healthy drinkers (n=117) completed a pulsed arterial spin labeling (PASL) scan to quantify resting regional cerebral blood flow (rCBF), and measures of self-reported impulsivity (Eysenck I7 Impulsivity scale) and impaired control over drinking. A subset of subjects (n=40) performed a stop signal task during blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to assess brain regions involved in response inhibition. Eysenck I7 scores were inversely related to blood flow in the right precentral gyrus. Significant BOLD activation during response inhibition occurred in an overlapping right frontal motor/premotor region. Moreover, impaired control over drinking was associated with reduced BOLD response in the same region. These findings suggest that impulsive personality and impaired control over drinking are associated with brain physiology in areas implicated in response inhibition. This is consistent with the idea that difficulty controlling behavior is due in part to impairment in motor restraint systems. PMID:26065376

Sleep hygiene behaviours: an application of the theory of planned behaviour and the investigation of perceived autonomy support, past behaviour and response inhibition.

PubMed

Kor, Kenny; Mullan, Barbara Ann

2011-09-01

This study investigated the sleep hygiene behaviour of university students within the framework of the Theory of Planned Behaviour (TPB [Ajzen, I. (1991). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50, 179-211.]), and examined the predictive validity of additional variables including perceived autonomy support, past behaviour and response inhibition. A total of 257 undergraduate students from an Australian university were administered two online questionnaires at two time points. At time 1, participants completed the TPB questionnaire and the Go/NoGo task as a measure of response inhibition. A week later at time 2, participants completed a questionnaire measuring the performance of sleep hygiene behaviours. Multiple and hierarchical regression analyses showed that the TPB model significantly predicted intention and behaviour. Although intention and perceived behavioural control were statistically significant in predicting behaviour, past behaviour and response inhibition accounted for more variance when added to the TPB model. Subjective norm was found to be the strongest predictor of intention implying the importance of normative influences in sleep hygiene behaviours. Response inhibition was the strongest predictor of behaviour, reinforcing the argument that the performance of health protective behaviours requires self-regulatory ability. Therefore, interventions should be targeted at enhancing self-regulatory capacity.

PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency

PubMed Central

Xu, Benjamin; Sandrini, Marco; Wang, Wen-tung; Smith, Jason F.; Sarlls, Joelle E.; Awosika, Oluwole; Butman, John A.; Horwitz, Barry; Cohen, Leonardo G.

2016-01-01

Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right pre-supplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA – rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. PMID:27144466

Effects of prenatal marijuana on response inhibition: an fMRI study of young adults.

PubMed

Smith, Andra M; Fried, Peter A; Hogan, Matthew J; Cameron, Ian

2004-01-01

The neurophysiological effects of prenatal marijuana exposure on response inhibition were assessed in 18- to 22-year-olds. Thirty-one participants from the Ottawa Prenatal Prospective Study (OPPS) performed a blocked design Go/No-Go task while neural activity was imaged with functional magnetic resonance imaging (fMRI). The OPPS is a longitudinal study that provides a unique body of information collected from each participant over 20 years, including prenatal drug history, detailed cognitive/behavioral performance from infancy to young adulthood, and current and past drug usage. The fMRI results showed that with increased prenatal marijuana exposure, there was a significant increase in neural activity in bilateral prefrontal cortex and right premotor cortex during response inhibition. There was also an attenuation of activity in left cerebellum with increased prenatal exposure to marijuana when challenging the response inhibition neural circuitry. Prenatally exposed offspring had significantly more commission errors than nonexposed participants, but all participants were able to perform the task with more than 85% accuracy. These findings were observed when controlling for present marijuana use and prenatal exposure to nicotine, alcohol and caffeine, and suggest that prenatal marijuana exposure is related to changes in neural activity during response inhibition that last into young adulthood. Copyright 2004 Elsevier Inc.

Focal hand dystonia: individualized intervention with repeated application of repetitive transcranial magnetic stimulation

PubMed Central

Kimberley, Teresa Jacobson; Borich, Michael R.; Schmidt, Rebekah; Carey, James R.; Gillick, Bernadette

2016-01-01

Objective Examine for individual factors that may predict response to inhibitory repetitive transcranial magnetic stimulation (rTMS) in focal hand dystonia (FHD); present method for determining the optimal stimulation to increase inhibition in a given patient; and examine individual responses to prolonged intervention. Design A single-subject design to determine optimal parameters to increase inhibition for a given subject and to employ the selected parameters 1/wk for 6 weeks, with 1 wk follow up, to determine response. Setting Clinical research laboratory Participants A volunteer sample of 2 subjects with FHD. One participant had TMS responses indicating impaired inhibition, the other had responses within normal limits. Interventions 1200 pulses of 1 Hz rTMS delivered using 4 different stimulation site/intensity combinations: primary motor cortex (M1) at 90% or 110% resting motor threshold (RMT); dorsal premotor cortex (PMd) at 90% or 110% of RMT. The parameters producing the greatest within-session increase in cortical silent period (CSP) duration were then used as intervention. Main outcome measures Response variables included handwriting pressure and velocity, subjective symptom rating, CSP, and short-latency intracortical inhibition and facilitation. Results The individual with baseline TMS responses indicating impaired inhibition responded favorably to the repeated intervention, with reduced handwriting force, increase in CSP and subjective report of “moderate” symptom improvement at 1-wk follow-up. The individual with normal baseline responses failed to respond to the intervention. In both subjects, 90% RMT to PMd produced greatest lengthening of CSP and was used as intervention. Conclusions An individualized understanding of neurophysiologic measures may be indicators of responsiveness to inhibitory rTMS in focal dystonia, with further work needed to determine 3 likely responders vs. non-responders. PMID:25256555

Role of N-type calcium channels in autonomic neurotransmission in guineapig isolated left atria

PubMed Central

Serone, Adrian P; Angus, James A

1999-01-01

Calcium entry via neuronal calcium channels is essential for the process of neurotransmission. We investigated the calcium channel subtypes involved in the operation of cardiac autonomic neurotransmission by examining the effects of selective calcium channel blockers on the inotropic responses to electrical field stimulation (EFS) of driven (4 Hz) guineapig isolated left atria. In this tissue, a previous report (Hong & Chang, 1995) found no evidence for N-type channels involved in the vagal negative inotropic response and only weak involvement in sympathetic responses. The effects of cumulative concentrations of the selective N-type calcium channel blocker, ω-conotoxin GVIA (GVIA; 0.1–10 nM) and the nonselective N-, P/Q-type calcium channel blocker, ω-conotoxin MVIIC (MVIIC; 0.01–10 nM) were examined on the positive (with atropine, 1 μM present) and negative (with propranolol, 1 μM and clonidine, 1 μM present) inotropic responses to EFS (eight trains, each train four pulses per punctate stimulus). GVIA caused complete inhibition of both cardiac vagal and sympathetic inotropic responses to EFS. GVIA was equipotent at inhibiting positive (pIC50 9.29±0.08) and negative (pIC50 9.13±0.17) inotropic responses. MVIIC also mediated complete inhibition of inotropic responses to EFS and was 160 and 85 fold less potent than GVIA at inhibiting positive (pIC50 7.08±0.10) and negative (pIC50 7.20±0.14) inotropic responses, respectively. MVIIC was also equipotent at inhibiting both sympathetic and vagal responses. Our data demonstrates that N-type calcium channels account for all the calcium current required for cardiac autonomic neurotransmission in the guinea-pig isolated left atrium. PMID:10433500

Response competition and response inhibition during different choice-discrimination tasks: evidence from ERP measured inside MRI scanner.

PubMed

Gonzalez-Rosa, Javier J; Inuggi, Alberto; Blasi, Valeria; Cursi, Marco; Annovazzi, Pietro; Comi, Giancarlo; Falini, Andrea; Leocani, Letizia

2013-07-01

We investigated the neural correlates underlying response inhibition and conflict detection processes using ERPs and source localization analyses simultaneously acquired during fMRI scanning. ERPs were elicited by a simple reaction time task (SRT), a Go/NoGo task, and a Stroop-like task (CST). The cognitive conflict was thus manipulated in order to probe the degree to which information processing is shared across cognitive systems. We proposed to dissociate inhibition and interference conflict effects on brain activity by using identical Stroop-like congruent/incongruent stimuli in all three task contexts and while varying the response required. NoGo-incongruent trials showed a larger N2 and enhanced activations of rostral anterior cingulate cortex (ACC) and pre-supplementary motor area, whereas Go-congruent trials showed a larger P3 and increased parietal activations. Congruent and incongruent conditions of the CST task also elicited similar N2, P3 and late negativity (LN) ERPs, though CST-incongruent trials revealed a larger LN and enhanced prefrontal and ACC activations. Considering the stimulus probability and experimental manipulation of our study, current findings suggest that NoGo N2 and frontal NoGo P3 appear to be more associated to response inhibition rather than a specific conflict monitoring, whereas occipito-parietal P3 of Go and CST conditions may be more linked to a planned response competition between the prepared and required response. LN, however, appears to be related to higher level conflict monitoring associated with response choice-discrimination but not when the presence of cognitive conflict is associated with response inhibition. Copyright © 2013. Published by Elsevier B.V.

Local Transcriptional Control of YUCCA Regulates Auxin Promoted Root-Growth Inhibition in Response to Aluminium Stress in Arabidopsis.

PubMed

Liu, Guangchao; Gao, Shan; Tian, Huiyu; Wu, Wenwen; Robert, Hélène S; Ding, Zhaojun

2016-10-01

Auxin is necessary for the inhibition of root growth induced by aluminium (Al) stress, however the molecular mechanism controlling this is largely unknown. Here, we report that YUCCA (YUC), which encodes flavin monooxygenase-like proteins, regulates local auxin biosynthesis in the root apex transition zone (TZ) in response to Al stress. Al stress up-regulates YUC3/5/7/8/9 in the root-apex TZ, which we show results in the accumulation of auxin in the root-apex TZ and root-growth inhibition during the Al stress response. These Al-dependent changes in the regulation of YUCs in the root-apex TZ and YUC-regulated root growth inhibition are dependent on ethylene signalling. Increasing or disruption of ethylene signalling caused either enhanced or reduced up-regulation, respectively, of YUCs in root-apex TZ in response to Al stress. In addition, ethylene enhanced root growth inhibition under Al stress was strongly alleviated in yuc mutants or by co-treatment with yucasin, an inhibitor of YUC activity, suggesting a downstream role of YUCs in this process. Moreover, ethylene-insensitive 3 (EIN3) is involved into the direct regulation of YUC9 transcription in this process. Furthermore, we demonstrated that PHYTOCHROME INTERACTING FACTOR4 (PIF4) functions as a transcriptional activator for YUC5/8/9. PIF4 promotes Al-inhibited primary root growth by regulating the local expression of YUCs and auxin signal in the root-apex TZ. The Al-induced expression of PIF4 in root TZ acts downstream of ethylene signalling. Taken together, our results highlight a regulatory cascade for YUCs-regulated local auxin biosynthesis in the root-apex TZ mediating root growth inhibition in response to Al stress.

Hunger modulates behavioral disinhibition and attention allocation to food-associated cues in normal-weight controls.

PubMed

Loeber, Sabine; Grosshans, Martin; Herpertz, Stephan; Kiefer, Falk; Herpertz, Sabine C

2013-12-01

Overeating, weight gain and obesity are considered as a major health problem in Western societies. At present, an impairment of response inhibition and a biased salience attribution to food-associated stimuli are considered as important factors associated with weight gain. However, recent findings suggest that the association between an impaired response inhibition and salience attribution and weight gain might be modulated by other factors. Thus, hunger might cause food-associated cues to be perceived as more salient and rewarding and might be associated with an impairment of response inhibition. However, at present, little is known how hunger interacts with these processes. Thus, the aim of the present study was to investigate whether hunger modulates response inhibition and attention allocation towards food-associated stimuli in normal-weight controls. A go-/nogo task with food-associated and control words and a visual dot-probe task with food-associated and control pictures were administered to 48 normal-weight participants (mean age 24.5 years, range 19-40; mean BMI 21.6, range 18.5-25.4). Hunger was assessed twofold using a self-reported measure of hunger and a measurement of the blood glucose level. Our results indicated that self-reported hunger affected behavioral response inhibition in the go-/nogo task. Thus, hungry participants committed significantly more commission errors when food-associated stimuli served as distractors compared to when control stimuli were the distractors. This effect was not observed in sated participants. In addition, we found that self-reported hunger was associated with a lower number of omission errors in response to food-associated stimuli indicating a higher salience of these stimuli. Low blood glucose level was not associated with an impairment of response inhibition. However, our results indicated that the blood glucose level was associated with an attentional bias towards food-associated cues in the visual dot probe task. In conclusion our results suggest that hunger induces an approach bias and is associated with an impairment of response inhibition when normal-weight participants are confronted with food-associated cues. These findings are important as these processes play a crucial role with regard to the control of food-intake and weight gain and are assumed to contribute to obesity. Thus, individualized treatment approaches taking into account the experience of hunger in everyday-life situations should be considered in addition to a training of response inhibition. Copyright © 2013 Elsevier Ltd. All rights reserved.

PIP₂ hydrolysis is responsible for voltage independent inhibition of CaV2.2 channels in sympathetic neurons.

PubMed

Vivas, Oscar; Castro, Hector; Arenas, Isabel; Elías-Viñas, David; García, David E

2013-03-08

GPCRs regulate Ca(V)2.2 channels through both voltage dependent and independent inhibition pathways. The aim of the present work was to assess the phosphatidylinositol-4,5-bisphosphate (PIP2) as the molecule underlying the voltage independent inhibition of Ca(V)2.2 channels in SCG neurons. We used a double pulse protocol to study the voltage independent inhibition and changed the PIP(2) concentration by means of blocking the enzyme PLC, filling the cell with a PIP(2) analogue and preventing the PIP(2) resynthesis with wortmannin. We found that voltage independent inhibition requires the activation of PLC and can be hampered by internal dialysis of exogenous PIP(2). In addition, the recovery from voltage independent inhibition is blocked by inhibition of the enzymes involved in the resynthesis of PIP(2). These results support that the hydrolysis of PIP(2) is responsible for the voltage independent inhibition of Ca(V)2.2 channels. Copyright © 2013 Elsevier Inc. All rights reserved.

The effect of methylphenidate and rearing environment on behavioral inhibition in adult male rats.

PubMed

Hill, Jade C; Covarrubias, Pablo; Terry, Joel; Sanabria, Federico

2012-01-01

The ability to withhold reinforced responses-behavioral inhibition-is impaired in various psychiatric conditions including Attention Deficit Hyperactivity Disorder (ADHD). Methodological and analytical limitations have constrained our understanding of the effects of pharmacological and environmental factors on behavioral inhibition. To determine the effects of acute methylphenidate (MPH) administration and rearing conditions (isolated vs. pair-housed) on behavioral inhibition in adult rats. Inhibitory capacity was evaluated using two response-withholding tasks, differential reinforcement of low rates (DRL) and fixed minimum interval (FMI) schedules of reinforcement. Both tasks made sugar pellets contingent on intervals longer than 6 s between consecutive responses. Inferences on inhibitory and timing capacities were drawn from the distribution of withholding times (interresponse times, or IRTs). MPH increased the number of intervals produced in both tasks. Estimates of behavioral inhibition increased with MPH dose in FMI and with social isolation in DRL. Nonetheless, burst responding in DRL and the divergence of DRL data relative to past studies, among other limitations, undermined the reliability of DRL data as the basis for inferences on behavioral inhibition. Inhibitory capacity was more precisely estimated from FMI than from DRL performance. Based on FMI data, MPH, but not a socially enriched environment, appears to improve inhibitory capacity. The highest dose of MPH tested, 8 mg/kg, did not reduce inhibitory capacity but reduced the responsiveness to waiting contingencies. These results support the use of the FMI schedule, complemented with appropriate analytic techniques, for the assessment of behavioral inhibition in animal models.

Sex differences in emotional contexts modulation on response inhibition.

PubMed

Ramos-Loyo, Julieta; Angulo-Chavira, Armando; Llamas-Alonso, Luis A; González-Garrido, Andrés A

2016-10-01

The aim of the present study was to explore sex differences in the effects that emotional contexts exert on the temporal course of response inhibition using event-related potentials (ERP). Participants performed a Go-NoGo response inhibition task under 3 context conditions: with 1) neutral background stimuli, and 2) pleasant, and 3) unpleasant emotional contexts. No sex differences were found in relation to accuracy. Women showed higher N2NoGo amplitudes than men in both emotional contexts; whereas during inhibition men tended to show higher P3NoGo amplitudes than women in the unpleasant context. Both groups experienced a relevant effect of the presence of the unpleasant context during inhibition processing, as shown by the enhancement of the N2NoGo amplitudes in frontal regions compared to results from the neutral and pleasant conditions. In addition, women showed differences between the pleasant and unpleasant contexts, with the latter inducing higher amplitude values. Only in men did inhibition accuracy correlate with higher N2NoGo and lower P3NoGo amplitudes in the emotional context conditions. These findings suggest that when an inhibition task is performed in an emotionally-neutral background context no sex differences are observed in either accuracy or ERP components. However, when the emotional context was introduced -especially the unpleasant one- some gender differences did become evident. The higher N2NoGo amplitude at the presence of the unpleasant context may reflect an effect on attention and conflict monitoring. In addition, results suggest that during earlier processing stages, women invested more resources to process inhibition than men. Furthermore, men who invested more neural resources during earlier stages showed better response inhibition than those who did it during later processing stages, more closely-related to cognitive and motor inhibition processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Expression differences of programmed death ligand 1 in de-novo and recurrent glioblastoma multiforme

PubMed Central

Heynckes, Sabrina; Gaebelein, Annette; Haaker, Gerrit; Grauvogel, Jürgen; Franco, Pamela; Mader, Irina; Carro, Maria Stella; Prinz, Marco; Delev, Daniel; Schnell, Oliver; Heiland, Dieter Henrik

2017-01-01

The biology of recurrent glioblastoma multiforme (GBM) is a dynamic process influenced by selection pressure induced by different antitumoural therapies. The poor clinical outcome of tumours in the recurrent stage necessitates the development of effective therapeutic strategies. Checkpoint-inhibition (PD1/PD-L1 Inhibition) is a hallmark of immunotherapy being investigated in ongoing clinical trials. The purpose of this study was to analyse the PD-L1 expression in de-novo and recurrent glioblastoma multiforme and to explore associated genetic alterations and clinical traits. We show that PD-L1 expression was reduced in recurrent GBM in comparison to de-novo GBM. Additionally, patients who received an extended dose of temozolomide (TMZ) chemotherapy showed a significantly reduced level of PD-L1 expression in the recurrence stage compared to the corresponding de-novo tumour. Our findings may provide an explanation for potentially lower response to immunotherapy in the recurrent stage due to the reduced expression of the therapeutic target PD-L1. PMID:29088776

Stem cell plasticity enables hair regeneration following Lgr5+ cell loss.

PubMed

Hoeck, Joerg D; Biehs, Brian; Kurtova, Antonina V; Kljavin, Noelyn M; de Sousa E Melo, Felipe; Alicke, Bruno; Koeppen, Hartmut; Modrusan, Zora; Piskol, Robert; de Sauvage, Frederic J

2017-06-01

Under injury conditions, dedicated stem cell populations govern tissue regeneration. However, the molecular mechanisms that induce stem cell regeneration and enable plasticity are poorly understood. Here, we investigate stem cell recovery in the context of the hair follicle to understand how two molecularly distinct stem cell populations are integrated. Utilizing diphtheria-toxin-mediated cell ablation of Lgr5 + (leucine-rich repeat-containing G-protein-coupled receptor 5) stem cells, we show that killing of Lgr5 + cells in mice abrogates hair regeneration but this is reversible. During recovery, CD34 + (CD34 antigen) stem cells activate inflammatory response programs and start dividing. Pharmacological attenuation of inflammation inhibits CD34 + cell proliferation. Subsequently, the Wnt pathway controls the recovery of Lgr5 + cells and inhibition of Wnt signalling prevents Lgr5 + cell and hair germ recovery. Thus, our study uncovers a compensatory relationship between two stem cell populations and the underlying molecular mechanisms that enable hair follicle regeneration.

CaMKII determines mitochondrial stress responses in heart

PubMed Central

Joiner, Mei-ling A.; Koval, Olha M.; Jingdong, Li; He, B. Julie; Allamargot, Chantal; Gao, Zhan; Luczak, Elizabeth D.; Hall, Duane D.; Fink, Brian D.; Chen, Biyi; Yang, Jinying; Moore, Steven A.; Scholz, Thomas D.; Strack, Stefan; Mohler, Peter J.; Sivitz, William I.; Song, Long-Sheng; Anderson, Mark E.

2012-01-01

Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm)1,2. However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3–5 are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury6, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress. PMID:23051746

The Persistence of Cognitive Deficits in Remitted and Unremitted ADHD: A Case for the State-Independence of Response Inhibition

ERIC Educational Resources Information Center

McAuley, Tara; Crosbie, Jennifer; Charach, Alice; Schachar, Russell

2014-01-01

Background: Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the…

Saccadic Eye Movement Task Identifies Cognitive Deficits in Children with Schizophrenia, but Not in Unaffected Child Relatives

ERIC Educational Resources Information Center

Ross, Randal G.; Heinlein, Shari; Zerbe, Gary O.; Radant, Allen

2005-01-01

Background: The delayed oculomotor response (DOR) task requires response inhibition followed by movement of gaze towards a known spatial location without a current stimulus. Abnormalities in response inhibition and in the spatial accuracy of the eye movement are found in individuals with schizophrenia and in many of their relatives, supporting the…

Intergenerational transmission of risk for social inhibition: the interplay between parental responsiveness and genetic influences.

PubMed

Natsuaki, Misaki N; Leve, Leslie D; Neiderhiser, Jenae M; Shaw, Daniel S; Scaramella, Laura V; Ge, Xiaojia; Reiss, David

2013-02-01

To better understand mechanisms underlying the intergenerational transmission of social anxiety, we used a prospective adoption design to examine the roles of genetic influences (inferred from birth mothers' social phobia) and rearing environment (adoptive mothers' and fathers' responsiveness) on the development of socially inhibited, anxious behaviors in children between 18 and 27 months of age. The sample consisted of 275 adoption-linked families, each including an adopted child, adoptive parents, and a birth mother. Results indicated that children whose birth mothers met criteria for the diagnosis of social phobia showed elevated levels of observed behavioral inhibition in a social situation at 27 months of age if their adoptive mothers provided less emotionally and verbally responsive rearing environments at 18 months of age. Conversely, in the context of higher levels of maternal responsiveness, children of birth mothers with a history of social phobia did not show elevated levels of behavioral inhibition. These findings on maternal responsiveness were replicated in a model predicting parent reports of child social anxiety. The findings are discussed in terms of gene-environment interactions in the intergenerational transmission of social anxiety.

Appetitive and aversive motivation in dysphoria: A time-domain and time-frequency study of response inhibition.

PubMed

Messerotti Benvenuti, Simone; Buodo, Giulia; Palomba, Daniela

2017-04-01

The study of emotional response inhibition could provide novel insight into dysphoria-related deficits in appetitive and aversive motivational systems. Therefore, dysphoric (N=21) and nondysphoric (N=21) participants completed an emotional Go/Nogo paradigm, including the presentation of pleasant, neutral and unpleasant pictures. Behavioral measures [reaction times (RTs), accuracy to Go and Nogo stimuli] and neural correlates (Go/Nogo-N2 and Go/Nogo-P3) of response inhibition were compared between the two groups. Time-frequency analysis was also used as a novel approach to disentangle the multiple processes underlying time-domain ERP data. A reduced Go/Nogo effect for P3 and oscillatory delta activity was found in response to pleasant and neutral, but not unpleasant, stimuli in dysphoric relative to nondysphoric individuals. These findings showed that dysphoric individuals need a reduced and/or less effortful response inhibition to pleasant stimuli, suggesting that dysphoria is characterized by under-engagement of appetitive rather than over-engagement of aversive motivational system. Copyright © 2017 Elsevier B.V. All rights reserved.

The negative compatibility effect with relevant masks: a case for automatic motor inhibition

PubMed Central

Ocampo, Brenda; Finkbeiner, Matthew

2013-01-01

For many years controversy has surrounded the so-called “negative compatibility effect” (NCE), a surprising phenomenon whereby responses to a target stimulus are delayed when the target is preceded by an unconscious, response-compatible prime. According to proponents of the “self-inhibition” hypothesis, the NCE occurs when a low-level self-inhibitory mechanism supresses early motor activations that are no longer supported by perceptual evidence. This account has been debated, however, by those who regard the NCE to be a stimulus-specific phenomenon that can be explained without recourse to a self-inhibitory mechanism. The present study used a novel reach-to-touch paradigm to test whether unconscious response priming would manifest as motor activation of the opposite-to-prime response (supporting mask-induced priming accounts), or motor inhibition of the primed response (supporting the notion of low-level self-inhibition). This paper presents new findings that show the emergence of positive and negative compatibility effects as they occur in stimulus processing time. In addition, evidence is provided suggesting that the NCE is not driven by the activation of the incorrect, “opposite-to-prime” response, but rather might reflect automatic motor inhibition. PMID:24265623

Neurophysiological correlates of response inhibition predict relapse in detoxified alcoholic patients: some preliminary evidence from event-related potentials

PubMed Central

Petit, Géraldine; Cimochowska, Agnieszka; Kornreich, Charles; Hanak, Catherine; Verbanck, Paul; Campanella, Salvatore

2014-01-01

Background Alcohol dependence is a chronic relapsing disease. The impairment of response inhibition and alcohol-cue reactivity are the main cognitive mechanisms that trigger relapse. Despite the interaction suggested between the two processes, they have long been investigated as two different lines of research. The present study aimed to investigate the interaction between response inhibition and alcohol-cue reactivity and their potential link with relapse. Materials and methods Event-related potentials were recorded during a variant of a “go/no-go” task. Frequent and rare stimuli (to be inhibited) were superimposed on neutral, nonalcohol-related, and alcohol-related contexts. The task was administered following a 3-week detoxification course. Relapse outcome was measured after 3 months, using self-reported abstinence. There were 27 controls (seven females) and 27 patients (seven females), among whom 13 relapsed during the 3-month follow-up period. The no-go N2, no-go P3, and the “difference” wave (P3d) were examined with the aim of linking neural correlates of response inhibition on alcohol-related contexts to the observed relapse rate. Results Results showed that 1) at the behavioral level, alcohol-dependent patients made significantly more commission errors than controls (P<0.001), independently of context; 2) through the subtraction no-go P3 minus go P3, this inhibition deficit was neurophysiologically indexed in patients with greater P3d amplitudes (P=0.034); and 3) within the patient group, increased P3d amplitude enabled us to differentiate between future relapsers and nonrelapsers (P=0.026). Conclusion Our findings suggest that recently detoxified alcoholics are characterized by poorer response-inhibition skills that demand greater neural resources. We propose that event-related potentials can be used in conjunction with behavioral data to predict relapse; this would identify patients that need a higher level of neural resources when suppressing a response is requested. PMID:24966675

Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma

PubMed Central

Balakrishnan, Ilango; Harris, Peter; Birks, Diane K; Griesinger, Andrea; Amani, Vladimir; Cristiano, Brian; Remke, Marc; Taylor, Michael D; Handler, Michael; Foreman, Nicholas K; Vibhakar, Rajeev

2014-01-01

Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo. PMID:24796395

Brain stem stimulation and the acetylcholine-evoked inhibition of neurones in the feline nucleus reticularis thalami

PubMed Central

Dingledine, Raymond; Kelly, J. S.

1977-01-01

1. In cats anaesthetized with halothane and nitrous oxide, the responses to iontophoretically applied acetylcholine (ACh) and to high-frequency stimulation of the mid-brain reticular formation (MRF) were tested on spontaneously active neurones in the nucleus reticularis thalami and underlying ventrobasal complex. 2. The initial response to MRF stimulation of 90% of the ACh-inhibited neurones found in the region of the dorsolateral nucleus reticularis was an inhibition. Conversely, the initial response of 82% of the ACh-excited neurones in the ventrobasal complex was an excitation. Neurones in the rostral pole of the nucleus reticularis were inhibited by both ACh and RMF stimulation. 3. The mean latency (and s.e. of mean) for the MRF-evoked inhibition was 13·7 ± 3·2 ms (n = 42) and that for the MRF-evoked excitation, 44.1 ± 4.2 ms (n = 35). 4. The ACh-evoked inhibitions were blocked by iontophoretic atropine, in doses that did not block amino acid-evoked inhibition. In twenty-four ACh-inhibited neurones the effect of iontophoretic atropine was tested on MRF-evoked inhibition. In all twenty-four neurones atropine had no effect on the early phase of MRF-evoked inhibition but weakly antagonized the late phase of inhibition in nine of fourteen neurones. 5. Interspike-interval histograms showed that the firing pattern of neurones in the nucleus reticularis was characterized by periods of prolonged, high-frequency bursting. Both the ACh-evoked inhibitions and the late phase of MRF-evoked inhibitions were accompanied by an increased burst activity. In contrast, iontophoretic atropine tended to suppress burst activity. 6. The possibility is discussed that electrical stimulation of the MRF activates an inhibitory cholinergic projection to the nucleus reticularis. Since neurones of the nucleus reticularis have been shown to inhibit thalamic relay cells, activation of this inhibitory pathway may play a role in MRF-evoked facilitation of thalamo-cortical relay transmission and the associated electrocortical desynchronization. PMID:915830

Facing competition: Neural mechanisms underlying parallel programming of antisaccades and prosaccades.

PubMed

Talanow, Tobias; Kasparbauer, Anna-Maria; Steffens, Maria; Meyhöfer, Inga; Weber, Bernd; Smyrnis, Nikolaos; Ettinger, Ulrich

2016-08-01

The antisaccade task is a prominent tool to investigate the response inhibition component of cognitive control. Recent theoretical accounts explain performance in terms of parallel programming of exogenous and endogenous saccades, linked to the horse race metaphor. Previous studies have tested the hypothesis of competing saccade signals at the behavioral level by selectively slowing the programming of endogenous or exogenous processes e.g. by manipulating the probability of antisaccades in an experimental block. To gain a better understanding of inhibitory control processes in parallel saccade programming, we analyzed task-related eye movements and blood oxygenation level dependent (BOLD) responses obtained using functional magnetic resonance imaging (fMRI) at 3T from 16 healthy participants in a mixed antisaccade and prosaccade task. The frequency of antisaccade trials was manipulated across blocks of high (75%) and low (25%) antisaccade frequency. In blocks with high antisaccade frequency, antisaccade latencies were shorter and error rates lower whilst prosaccade latencies were longer and error rates were higher. At the level of BOLD, activations in the task-related saccade network (left inferior parietal lobe, right inferior parietal sulcus, left precentral gyrus reaching into left middle frontal gyrus and inferior frontal junction) and deactivations in components of the default mode network (bilateral temporal cortex, ventromedial prefrontal cortex) compensated increased cognitive control demands. These findings illustrate context dependent mechanisms underlying the coordination of competing decision signals in volitional gaze control. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Astringent compounds suppress taste responses in gerbil.

PubMed

Schiffman, S S; Suggs, M S; Simon, S A

1992-11-06

Astringent tastes are generally considered those that induce long-lasting puckering and drying sensations on the tongue and membranes of the oral cavity. Electrophysiological recordings were made here from the whole chorda tympani nerve in gerbil to understand the interactive effect of astringent-tasting molecules with a broad spectrum of tastants including mono- and divalent salts, bitter compounds, acids, and sweeteners. The astringent tasting compounds were tannic acid (24 mM at pH's 2.9 and 5.5), aluminum ammonium sulfate (30 mM), aluminum potassium sulfate (10 mM) and gallic acid (30 mM). Hydrochloric acid (1 mM, pH 2.9) was also tested to control for acidity, since aqueous solutions of astringent-tasting compounds are acidic. Adaptation of the tongue to tannic acid (24 mM) at both pH 2.9 and 5.5 markedly inhibited responses elicited by salts, acids, sweeteners, and bitter-tasting compounds. The degree of the inhibition at these two pH values is about the same which suggests that tannic acid itself (as opposed to acidity) may produce this inhibition. Chorda tympani responses to sweeteners were completely suppressed by tannic acid; responses to KCl, NH4Cl, and urea were the least suppressed. The aluminum salts also inhibited the chorda tympani responses to all stimuli tested. Gallic acid, which is weakly astringent, had minimal effects on the chorda tympani responses to the test compounds. These data suggest that both tannic acid and the aluminum salts inhibit a variety of transport pathways and receptors in taste cells for a broad spectrum of tastants. The inhibition of some of these pathways may contribute to the astringent taste sensation.

ADHD and Cannabis Use in Young Adults Examined Using fMRI of a Go/NoGo Task

PubMed Central

Rasmussen, Jerod; Casey, B.J.; van Erp, Theo G.M.; Tamm, Leanne; Epstein, Jeffery N.; Buss, Claudia; Bjork, James M.; Molina, Brooke S.G.; Velanova, Katerina; Mathalon, Daniel H.; Somerville, Leah; Swanson, James M.; Wigal, Tim; Arnold, L. Eugene; Potkin, Steven G.

2015-01-01

Background Children diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for substance abuse. Response inhibition is a hallmark of ADHD, yet the combined effects of ADHD and regular substance use on neural networks associated with response inhibition are unknown. Methods Task-based functional Magnetic Resonance Imaging (fMRI) data from young adults with childhood ADHD with (n=25) and without (n=25) cannabis use ≥ monthly in the past year were compared with a local normative comparison group (LNCG) with (n=11) and without (n=12) cannabis use. Go/NoGo behavioral and fMRI data were evaluated for main and interaction effects of ADHD diagnosis and cannabis use. Results ADHD participants made significantly more commission errors on NoGo trials than controls. ADHD participants also had less frontoparietal and frontostriatal activity, independent of cannabis use. No main effects of cannabis use on response inhibition or functional brain activation were observed. An interaction of ADHD diagnosis and cannabis use was found in the right hippocampus and cerebellar vermis, with increased recruitment of these regions in cannabis-using controls during correct response inhibition. Conclusions ADHD participants had impaired response inhibition combined with less fronto-parietal/striatal activity, regardless of cannabis use history. Cannabis use did not impact behavioral response inhibition. Cannabis use was associated with hippocampal and cerebellar activation, areas rich in cannabinoid receptors, in LNCG but not ADHD participants. This may reflect recruitment of compensatory circuitry in cannabis using controls but not ADHD participants. Future studies targeting hippocampal and cerebellar-dependent function in these groups may provide further insight into how this circuitry is altered by ADHD and cannabis use. PMID:26489976

ADHD and cannabis use in young adults examined using fMRI of a Go/NoGo task.

PubMed

Rasmussen, Jerod; Casey, B J; van Erp, Theo G M; Tamm, Leanne; Epstein, Jeffery N; Buss, Claudia; Bjork, James M; Molina, Brooke S G; Velanova, Katerina; Mathalon, Daniel H; Somerville, Leah; Swanson, James M; Wigal, Tim; Arnold, L Eugene; Potkin, Steven G

2016-09-01

Children diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for substance abuse. Response inhibition is a hallmark of ADHD, yet the combined effects of ADHD and regular substance use on neural networks associated with response inhibition are unknown. Task-based functional Magnetic Resonance Imaging (fMRI) data from young adults with childhood ADHD with (n = 25) and without (n = 25) cannabis use ≥ monthly in the past year were compared with a local normative comparison group (LNCG) with (n = 11) and without (n = 12) cannabis use. Go/NoGo behavioral and fMRI data were evaluated for main and interaction effects of ADHD diagnosis and cannabis use. ADHD participants made significantly more commission errors on NoGo trials than controls. ADHD participants also had less frontoparietal and frontostriatal activity, independent of cannabis use. No main effects of cannabis use on response inhibition or functional brain activation were observed. An interaction of ADHD diagnosis and cannabis use was found in the right hippocampus and cerebellar vermis, with increased recruitment of these regions in cannabis-using controls during correct response inhibition. ADHD participants had impaired response inhibition combined with less fronto-parietal/striatal activity, regardless of cannabis use history. Cannabis use did not impact behavioral response inhibition. Cannabis use was associated with hippocampal and cerebellar activation, areas rich in cannabinoid receptors, in LNCG but not ADHD participants. This may reflect recruitment of compensatory circuitry in cannabis using controls but not ADHD participants. Future studies targeting hippocampal and cerebellar-dependent function in these groups may provide further insight into how this circuitry is altered by ADHD and cannabis use.

Complete unconscious control: Using (in)action primes to demonstrate completely unconscious activation of inhibitory control mechanisms

PubMed Central

Hepler, Justin; Albarracin, Dolores

2018-01-01

Although robust evidence indicates that action initiation can occur unconsciously and unintentionally, the literature on action inhibition suggests that inhibition requires both conscious thought and intentionality. In prior research demonstrating automatic inhibition in response to unconsciously processed stimuli, the unconscious stimuli had previously been consciously associated with an inhibitory response within the context of the experiment, and participants had consciously formed a goal to activate inhibition processes when presented with the stimuli (because task instructions required participants to engage in inhibition when the stimuli occurred). Therefore, prior work suggests that some amount of conscious thought and intentionality are required for inhibitory control. In the present research, we recorded event-related potentials during two go/no-go experiments in which participants were subliminally primed with general action/inaction concepts that had never been consciously associated with task-specific responses. We provide the first demonstration that inhibitory control processes can be modulated completely unconsciously and unintentionally. PMID:23747649

Influence of calcium on glucose biosensor response and on hydrogen peroxide detection.

PubMed

Labat-Allietta, N; Thévenot, D R

1998-01-01

Of small species capable of reaching a platinum working electrode from biological samples, calcium cations have been found to inhibit significantly glucose biosensor responses. The sensitivities to glucose of sensors immersed in carbonate buffer saline solutions decreased when 0.5 mM calcium chloride was added. The degree of inhibition was proportional to the glucose response in the absence of calcium (0-17% of the normalized current). Likewise, sensor sensitivities to hydrogen peroxide decreased, in the 5-90% range, in the presence of 0.5 mM calcium. Bare Pt-lr wires show a reversible inhibition of hydrogen peroxide sensitivity. This reversible inhibition is directly related to the decrease of hydrogen peroxide oxidation rate at the platinum anode: this has been evidenced, using rotating disk electrodes, by plotting Koutecky-Levich plots. Such inhibition has been found both for free and chelated calcium cations at levels below 1 mM. Several hypotheses for possible reactions between platinum, hydrogen peroxide and calcium are discussed.

Psychosis-proneness and neural correlates of self-inhibition in theory of mind.

PubMed

van der Meer, Lisette; Groenewold, Nynke A; Pijnenborg, Marieke; Aleman, André

2013-01-01

Impaired Theory of Mind (ToM) has been repeatedly reported as a feature of psychotic disorders. ToM is crucial in social interactions and for the development of social behavior. It has been suggested that reasoning about the belief of others, requires inhibition of the self-perspective. We investigated the neural correlates of self-inhibition in nineteen low psychosis prone (PP) and eighteen high PP subjects presenting with subclinical features. High PP subjects have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. Brain activation was measured with functional Magnetic Resonance Imaging during a ToM task differentiating between self-perspective inhibition and belief reasoning. Furthermore, to test underlying inhibitory mechanisms, we included a stop-signal task. We predicted worse behavioral performance for high compared to low PP subjects on both tasks. Moreover, based on previous neuroimaging results, different activation patterns were expected in the inferior frontal gyrus (IFG) in high versus low PP subjects in self-perspective inhibition and simple response inhibition. Results showed increased activation in left IFG during self-perspective inhibition, but not during simple response inhibition, for high PP subjects as compared to low PP subjects. High and low PP subjects showed equal behavioral performance. The results suggest that at a neural level, high PP subjects need more resources for inhibiting the self-perspective, but not for simple motor response inhibition, to equal the performance of low PP subjects. This may reflect a compensatory mechanism, which may no longer be available for patients with schizophrenia-spectrum disorders resulting in ToM impairments.

Psychosis-Proneness and Neural Correlates of Self-Inhibition in Theory of Mind

PubMed Central

van der Meer, Lisette; Groenewold, Nynke A.; Pijnenborg, Marieke; Aleman, André

2013-01-01

Impaired Theory of Mind (ToM) has been repeatedly reported as a feature of psychotic disorders. ToM is crucial in social interactions and for the development of social behavior. It has been suggested that reasoning about the belief of others, requires inhibition of the self-perspective. We investigated the neural correlates of self-inhibition in nineteen low psychosis prone (PP) and eighteen high PP subjects presenting with subclinical features. High PP subjects have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. Brain activation was measured with functional Magnetic Resonance Imaging during a ToM task differentiating between self-perspective inhibition and belief reasoning. Furthermore, to test underlying inhibitory mechanisms, we included a stop-signal task. We predicted worse behavioral performance for high compared to low PP subjects on both tasks. Moreover, based on previous neuroimaging results, different activation patterns were expected in the inferior frontal gyrus (IFG) in high versus low PP subjects in self-perspective inhibition and simple response inhibition. Results showed increased activation in left IFG during self-perspective inhibition, but not during simple response inhibition, for high PP subjects as compared to low PP subjects. High and low PP subjects showed equal behavioral performance. The results suggest that at a neural level, high PP subjects need more resources for inhibiting the self-perspective, but not for simple motor response inhibition, to equal the performance of low PP subjects. This may reflect a compensatory mechanism, which may no longer be available for patients with schizophrenia-spectrum disorders resulting in ToM impairments. PMID:23874445

Dissociations of cognitive inhibition, response inhibition, and emotional interference: Voxelwise ALE meta-analyses of fMRI studies.

PubMed

Hung, Yuwen; Gaillard, Schuyler L; Yarmak, Pavel; Arsalidou, Marie

2018-06-19

Inhibitory control is the stopping of a mental process with or without intention, conceptualized as mental suppression of competing information because of limited cognitive capacity. Inhibitory control dysfunction is a core characteristic of many major psychiatric disorders. Inhibition is generally thought to involve the prefrontal cortex; however, a single inhibitory mechanism is insufficient for interpreting the heterogeneous nature of human cognition. It remains unclear whether different dimensions of inhibitory processes-specifically cognitive inhibition, response inhibition, and emotional interference-rely on dissociated neural systems. We conducted systematic meta-analyses of fMRI studies in the BrainMap database supplemented by PubMed using whole-brain activation likelihood estimation. A total of 66 study experiments including 1,447 participants and 987 foci revealed that while the left anterior insula was concordant in all inhibitory dimensions, cognitive inhibition reliably activated specific dorsal frontal inhibitory system, engaging dorsal anterior cingulate, dorsolateral prefrontal cortex, and parietal areas, whereas emotional interference reliably implicated a ventral inhibitory system, involving the ventral surface of the inferior frontal gyrus and the amygdala. Response inhibition showed concordant clusters in the fronto-striatal system, including the dorsal anterior cingulate region and extended supplementary motor areas, the dorsal and ventral lateral prefrontal cortex, basal ganglia, midbrain regions, and parietal regions. We provide an empirically derived dimensional model of inhibition characterizing neural systems underlying different aspects of inhibitory mechanisms. This study offers a fundamental framework to advance current understanding of inhibition and provides new insights for future clinical research into disorders with different types of inhibition-related dysfunctions. © 2018 Wiley Periodicals, Inc.

Functional neural networks underlying response inhibition in adolescents and adults.

PubMed

Stevens, Michael C; Kiehl, Kent A; Pearlson, Godfrey D; Calhoun, Vince D

2007-07-19

This study provides the first description of neural network dynamics associated with response inhibition in healthy adolescents and adults. Functional and effective connectivity analyses of whole brain hemodynamic activity elicited during performance of a Go/No-Go task were used to identify functionally integrated neural networks and characterize their causal interactions. Three response inhibition circuits formed a hierarchical, inter-dependent system wherein thalamic modulation of input to premotor cortex by fronto-striatal regions led to response suppression. Adolescents differed from adults in the degree of network engagement, regional fronto-striatal-thalamic connectivity, and network dynamics. We identify and characterize several age-related differences in the function of neural circuits that are associated with behavioral performance changes across adolescent development.

Functional neural networks underlying response inhibition in adolescents and adults

PubMed Central

Stevens, Michael C.; Kiehl, Kent A.; Pearlson, Godfrey D.; Calhoun, Vince D.

2008-01-01

This study provides the first description of neural network dynamics associated with response inhibition in healthy adolescents and adults. Functional and effective connectivity analyses of whole brain hemodynamic activity elicited during performance of a Go/No-Go task were used to identify functionally-integrated neural networks and characterize their causal interactions. Three response inhibition circuits formed a hierarchical, inter-dependent system wherein thalamic modulation of input to premotor cortex by frontostriatal regions led to response suppression. Adolescents differed from adults in the degree of network engagement, regional fronto-striatal-thalamic connectivity, and network dynamics. We identify and characterize several age-related differences in the function of neural circuits that are associated with behavioral performance changes across adolescent development. PMID:17467816

Sensorimotor-Independent Prefrontal Activity During Response Inhibition

PubMed Central

Cai, Weidong; Cannistraci, Christopher J.; Gore, John C.; Leung, Hoi-Chung

2015-01-01

A network of brain regions involving the ventral inferior frontal gyrus/anterior insula (vIFG/AI), presupplementary motor area (pre-SMA) and basal ganglia has been implicated in stopping impulsive, unwanted responses. However, whether this network plays an equal role in response inhibition under different sensorimotor contexts has not been tested systematically. Here, we conducted an fMRI experiment using the stop signal task, a sensorimotor task requiring occasional withholding of the planned response upon the presentation of a stop signal. We manipulated both the sensory modality of the stop signal (visual versus auditory) and the motor response modality (hand versus eye). Results showed that the vIFG/AI and the preSMA along with the right middle frontal gyrus were commonly activated in response inhibition across the various sensorimotor conditions. Our findings provide direct evidence for a common role of these frontal areas, but not striatal areas in response inhibition independent of the sensorimotor contexts. Nevertheless, these three frontal regions exhibited different activation patterns during successful and unsuccessful stopping. Together with the existing evidence, we suggest that the vIFG/AI is involved in the early stages of stopping such as triggering the stop process while the preSMA may play a role in regulating other cortical and subcortical regions involved in stopping. PMID:23798325

Perceptual and Motor Inhibition in Adolescents/Young Adults with Childhood-Diagnosed ADHD

PubMed Central

Bedard, Anne-Claude V.; Trampush, Joey W.; Newcorn, Jeffrey H.; Halperin, Jeffrey M.

2010-01-01

Objective This study examined perceptual and motor inhibition in a longitudinal sample of adolescents/young adults who were diagnosed with ADHD in childhood, and as a function of the relative persistence of ADHD. Method Ninety-eight participants diagnosed with ADHD in childhood were re-evaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, sociodemographic background, and gender distribution served as a comparison group. Participants were administered a psychiatric interview and the Stimulus and Response Conflict Tasks (Nassauer & Halperin, 2003). Results Participants with childhood ADHD demonstrated slower and less accurate responses to both control and conflict conditions relative to the comparison group, as well as more variable responses in both conditions of the motor inhibition task; there was no specific effect of childhood ADHD on perceptual or motor inhibition. ADHD persisters and partial remitters did not differ in overall accuracy, speed or variability in responding, but relative to partial remitters, persisters demonstrated greater slowing in response to perceptual conflict. Conclusions These findings are consistent with theories positing state regulation, but not inhibitory control deficits in the etiology of ADHD, and suggest that improved perceptual inhibition may be associated with better outcome for ADHD. PMID:20604617

Fluid shear stress inhibits TNF-alpha-induced apoptosis in osteoblasts: a role for fluid shear stress-induced activation of PI3-kinase and inhibition of caspase-3

NASA Technical Reports Server (NTRS)

Pavalko, Fredrick M.; Gerard, Rita L.; Ponik, Suzanne M.; Gallagher, Patricia J.; Jin, Yijun; Norvell, Suzanne M.

2003-01-01

In bone, a large proportion of osteoblasts, the cells responsible for deposition of new bone, normally undergo programmed cell death (apoptosis). Because mechanical loading of bone increases the rate of new bone formation, we hypothesized that mechanical stimulation of osteoblasts might increase their survival. To test this hypothesis, we investigated the effects of fluid shear stress (FSS) on osteoblast apoptosis using three osteoblast cell types: primary rat calvarial osteoblasts (RCOB), MC3T3-E1 osteoblastic cells, and UMR106 osteosarcoma cells. Cells were treated with TNF-alpha in the presence of cyclohexamide (CHX) to rapidly induce apoptosis. Osteoblasts showed significant signs of apoptosis within 4-6 h of exposure to TNF-alpha and CHX, and application of FSS (12 dyne/cm(2)) significantly attenuated this TNF-alpha-induced apoptosis. FSS activated PI3-kinase signaling, induced phosphorylation of Akt, and inhibited TNF-alpha-induced activation of caspase-3. Inhibition of PI3-kinase, using LY294002, blocked the ability of FSS to rescue osteoblasts from TNF-alpha-induced apoptosis and blocked FSS-induced inhibition of caspase-3 activation in osteoblasts treated with TNF-alpha. LY294002 did not, however, prevent FSS-induced phosphorylation of Akt suggesting that activation of Akt alone is not sufficient to rescue cells from apoptosis. This result also suggests that FSS can activate Akt via a PI3-kinase-independent pathway. These studies demonstrate for the first time that application of FSS to osteoblasts in vitro results in inhibition of TNF-alpha-induced apoptosis through a mechanism involving activation of PI3-kinase signaling and inhibition of caspases. FSS-induced activation of PI3-kinase may promote cell survival through a mechanism that is distinct from the Akt-mediated survival pathway. Copyright 2002 Wiley-Liss, Inc.

Motivational Influences on Response Inhibition Measures

ERIC Educational Resources Information Center

Leotti, Lauren A.; Wager, Tor D.

2010-01-01

Psychological research has placed great emphasis on inhibitory control due to its integral role in normal cognition and clinical disorders. The stop-signal task and associated measure--stop-signal reaction time (SSRT)--provides a well-established paradigm for measuring response inhibition. However, motivational influences on stop-signal…

Altered neural activation during prepotent response inhibition in breast cancer survivors treated with chemotherapy: an fMRI study.

PubMed

Kam, Julia W Y; Boyd, Lara A; Hsu, Chun L; Liu-Ambrose, Teresa; Handy, Todd C; Lim, Howard J; Hayden, Sherri; Campbell, Kristin L

2016-09-01

While impairments in executive functions have been reported in breast cancer survivors (BCS) who have undergone adjuvant chemotherapy, only a limited number of functional neuroimaging studies have associated alterations in cerebral activity with executive functions deficits in BCS. Using fMRI, the current study assessed the neural basis underlying a specific facet of executive function, namely prepotent response inhibition. 12 BCS who self-reported cognitive problems up to 3 years following cancer treatment and 12 female healthy comparisons (HC) performed the Stroop task. We compared their neural activation between the incongruent and neutral experimental conditions. Relative to the HC group, BCS showed lower blood-oxygen level dependent signal in several frontal regions, including the anterior cingulate cortex, a region critical for response inhibition. Our data indicates reduced neural activation in BCS during a prepotent response inhibition task, providing support for the prevailing notion of neural alterations observed in BCS treated with chemotherapy.

Too little, too late or too much, too early? Differential hemodynamics of response inhibition in high and low sensation seekers

PubMed Central

Collins, Heather R.; Corbly, Christine R.; Liu, Xun; Kelly, Thomas H.; Lynam, Donald; Joseph, Jane E.

2012-01-01

High sensation seeking is associated with strong approach behaviors and weak avoidance responses. The present study used functional magnetic resonance imaging (fMRI) to further characterize the neurobiological underpinnings of this behavioral profile using a Go/No-go task. Analysis of brain activation associated with response inhibition (No-go) versus response initiation and execution (Go) revealed the commonly reported right lateral prefrontal, insula, cingulate, and supplementary motor area network. However, right lateral activation was associated with greater No-go than Go responses only in low sensation seekers. High sensation seekers showed no differential activation in these regions but a more pronounced Go compared to No-go response in several other regions that are involved in salience detection (insula), motor initiation (anterior cingulate) and attention (inferior parietal cortex). Temporal analysis of the hemodynamic response for Go and No-go conditions revealed that the stronger response to Go than No-go trials in high sensation seekers occurred in in the earliest time window in the right middle frontal gyrus, right mid-cingulate and right precuneus. In contrast, the greater No-go than Go response in low sensation seekers occurred in the later time window in these same regions. These findings indicate that high sensation seekers more strongly attend to or process Go trials and show delayed or minimal inhibitory responses on No-go trials in regions that low sensation seekers use for response inhibition. Failure to engage such regions for response inhibition may underlie some of the risky and impulsive behaviors observed in high sensation seekers. PMID:22902769

Influence of Alcohol Use on Neural Response to Go/No-Go Task in College Drinkers

PubMed Central

Ahmadi, Aral; Pearlson, Godfrey D; Meda, Shashwath A; Dager, Alecia; Potenza, Marc N; Rosen, Rivkah; Austad, Carol S; Raskin, Sarah A; Fallahi, Carolyn R; Tennen, Howard; Wood, Rebecca M; Stevens, Michael C

2013-01-01

Impaired inhibition of prepotent motor response may represent an important risk factor for alcoholism. Alcohol use may also increase impulsive behavior, including impaired response inhibition. Little is known about the brain function underlying response inhibition among college-age drinkers based on their drinking patterns, despite college-age drinkers demonstrating high rates of alcohol-use disorders. Our major objective was to compare behavior and associated brain activity measured with fMRI during a response-inhibition task in matched heavy- and light-alcohol-drinking college students. Participants were light (N=36) and heavy (N=56) drinkers, aged 18–20 years. We characterized blood oxygen level-dependent (BOLD) responses, while participants performed an fMRI Go/No-Go task to quantify inhibitory behavior and brain activity. Behaviorally, group performance differences were observed for Go correct-hit and No-Go false-alarm reaction times with increased reaction times in heavy compared with light drinkers. During fMRI No-Go correct rejections, light drinkers exhibited greater BOLD response than did heavy drinkers in left supplementary motor area (SMA), bilateral parietal lobule, right hippocampus, bilateral middle frontal gyrus, left superior temporal gyrus, and cingulate gyrus/anterior cingulate cortex (Brodmann area 24). Group differences in Go/No-Go-related regional activations correlated with alcohol- and impulsivity-related measures. These findings suggest that heavy alcohol drinkers may have dysfunction in brain regions underlying attention and response inhibition, leading to diminished abilities to suppress prepotent responding. The extent to which these tendencies relate to impulsive decision-making and behaviors in real-life settings and may guide intervention development warrants additional investigation. PMID:23670589

Overdrinking, swallowing inhibition, and regional brain responses prior to swallowing

PubMed Central

Saker, Pascal; Egan, Gary F.; McKinley, Michael J.; Denton, Derek A.

2016-01-01

In humans, drinking replenishes fluid loss and satiates the sensation of thirst that accompanies dehydration. Typically, the volume of water drunk in response to thirst matches the deficit. Exactly how this accurate metering is achieved is unknown; recent evidence implicates swallowing inhibition as a potential factor. Using fMRI, this study investigated whether swallowing inhibition is present after more water has been drunk than is necessary to restore fluid balance within the body. This proposal was tested using ratings of swallowing effort and measuring regional brain responses as participants prepared to swallow small volumes of liquid while they were thirsty and after they had overdrunk. Effort ratings provided unequivocal support for swallowing inhibition, with a threefold increase in effort after overdrinking, whereas addition of 8% (wt/vol) sucrose to water had minimal effect on effort before or after overdrinking. Regional brain responses when participants prepared to swallow showed increases in the motor cortex, prefrontal cortices, posterior parietal cortex, striatum, and thalamus after overdrinking, relative to thirst. Ratings of swallowing effort were correlated with activity in the right prefrontal cortex and pontine regions in the brainstem; no brain regions showed correlated activity with pleasantness ratings. These findings are all consistent with the presence of swallowing inhibition after excess water has been drunk. We conclude that swallowing inhibition is an important mechanism in the overall regulation of fluid intake in humans. PMID:27791015

The effect of drugs acting on cholinoceptors and mucosal chloride on luminal bicarbonate transport by rat caecum under in vitro conditions.

PubMed Central

Canfield, P.; Abdul-Ghaffar, T.

1991-01-01

1. The transport of HCO3- (Jsm) from a HCO3(-)-buffered serosal to an unbuffered mucosal saline solution has been studied in rat caecum in vitro. 2. Carbachol, bethanechol and acetylcholine (ACh) caused a concentration-dependent fall in Jsm with similar maximum effects. 1,1-Dimethyl-4-phenyl-piperazinium iodide (DMPP) also inhibited Jsm but the effect was less than with the other drugs. Maximum cholinoceptor inhibition was less than that obtained with anoxia. 3. Responses were blocked by atropine (10(-5) M) but hexamethonium (2 x 10(-4) M) significantly altered the response only to DMPP. 4. Physostigmine (10(-5) M) shifted the ACh response curve to the left but physostigmine itself caused inhibition of Jsm which was blocked by atropine. 5. Substitution of mucosal Cl- by NO3- reduced Jsm to a similar extent to maximum cholinoceptor effect and abolished responses to bethanecol. Anoxia further reduced Jsm in the presence of NO3-. 6. Mucosal SITS and DIDS (1 mM) reduced Jsm but this was less than the maximum inhibition seen with drugs acting on cholinoceptors or mucosal Cl- removal. Serosal DIDS caused a similar inhibition. 7. We conclude that cholinoceptor agonists inhibit but do not abolish luminal bicarbonate transport by an action on muscarinic receptors. PMID:1884114

Neural activation during response inhibition in adult attention-deficit/hyperactivity disorder: preliminary findings on the effects of medication and symptom severity.

PubMed

Congdon, Eliza; Altshuler, Lori L; Mumford, Jeanette A; Karlsgodt, Katherine H; Sabb, Fred W; Ventura, Joseph; McGough, James J; London, Edythe D; Cannon, Tyrone D; Bilder, Robert M; Poldrack, Russell A

2014-04-30

Studies of adults with attention-deficit/hyperactivity disorder (ADHD) have suggested that they have deficient response inhibition, but findings concerning the neural correlates of inhibition in this patient population are inconsistent. We used the Stop-Signal task and functional magnetic resonance imaging (fMRI) to compare neural activation associated with response inhibition between adults with ADHD (N=35) and healthy comparison subjects (N=62), and in follow-up tests to examine the effect of current medication use and symptom severity. There were no differences in Stop-Signal task performance or neural activation between ADHD and control participants. Among the ADHD participants, however, significant differences were associated with current medication, with individuals taking psychostimulants (N=25) showing less stopping-related activation than those not currently receiving psychostimulant medication (N=10). Follow-up analyses suggested that this difference in activation was independent of symptom severity. These results provide evidence that deficits in inhibition-related neural activation persist in a subset of adult ADHD individuals, namely those individuals currently taking psychostimulants. These findings help to explain some of the disparities in the literature, and advance our understanding of why deficits in response inhibition are more variable in adult, as compared with child and adolescent, ADHD patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The relationship between the development of response inhibition and intelligence in preschool children

PubMed Central

Lee, Hon Wah; Lo, Yu-Hui; Li, Kuan-Hui; Sung, Wen-Shin; Juan, Chi-Hung

2015-01-01

Building on the theoretical framework that intellectual behavior relies on one's ability to process both task-relevant and task-irrelevant information, this study aimed to empirically investigate the association of response inhibition with intelligence in preschool children's development. In a sample of 152 typically developing children aged between 3.6 and 6.6 years, we found evidence that suggests that inhibitory control is linked to age-related differences in intelligence. Stop-signal inhibition improved at a rate similar to the age-related changes in Verbal IQ. Components of variance analyses revealed that stop-signal reaction time predicted a larger proportion of the age-related variance in children's verbal intelligence than non-age-related variance. Results are discussed with respect to possible explanations for this intriguing relationship between response inhibition and the verbal aspects of intelligence. PMID:26113838

General and food-specific inhibitory deficits in binge eating disorder.

PubMed

Svaldi, Jennifer; Naumann, Eva; Trentowska, Monika; Schmitz, Florian

2014-07-01

To investigate behavioral inhibition in individuals with binge eating disorder (BED) compared with overweight and obese individuals without BED (No-BED). Participants with BED (n = 31) and the weight-matched No-BED group (n = 29) completed an inhibitory control task (stop-signal task, SST) with food and neutral stimuli. The BED group needed more time to stop an ongoing response, as indicated by increased stop signal reaction time (SSRT) relative to the No-BED group. Additionally, compared with the No-BED group, the BED group displayed more difficulty inhibiting responses elicited by food stimuli. The deficits in behavioral response inhibition were also found to be related to the severity of reported symptoms. There is a general deficit in late stage behavioral inhibition in BED, and this may be particularly pronounced in the context of food stimuli. © 2014 Wiley Periodicals, Inc.

Mind magic: a pilot study of preventive mind-body-based stress reduction in behaviorally inhibited and activated children.

PubMed

Jellesma, Francine C; Cornelis, Janine

2012-03-01

The aim of this pilot study was to examine a mind-body-based preventive intervention program and to determine relationships between children's behavioral inhibition system (BIS) and behavioral activation system, stress, and stress reduction after the program. Children participated in the program (n=30) or in a control condition (n=24). They filled out questionnaires before and after the program and reported their levels of stress before and after each of the five sessions. The program consisted of weekly sessions. Each session incorporated yoga postures, visualization, and social exercises. Breathing techniques were integrated. Stress reductions were only seen in the intervention group and mainly in children with high BIS--irrespective of their behavioral activation system. The results demonstrate that children with high BIS may benefit from a mind-body-based stress reduction program.

The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells.

PubMed

Huang, Bo Yuan; Zhan, Yi Ping; Zong, Wen Jing; Yu, Chun Jiang; Li, Jun Fa; Qu, Yan Ming; Han, Song

2015-01-01

Glioblastoma multiforme (GBM) is the most malignant primary type of brain tumor in adults. There has been increased focus on the immunotherapies to treat GBM patients, the therapeutic value of natural killer (NK) cells is still unknown. Programmed death-1 (PD-1) is a major immunological checkpoint that can negatively regulate the T-cell-mediated immune response. We tested the combination of the inhibiting the PD-1/B7H1 pathway with a NK-cell mediated immune response in an orthotopic mouse model of GBM. Mouse glioma stem cells (GL261GSCs) and mouse NK cells were isolated and identified. A lactate dehydrogenase (LDH) assay was perfomed to detect the cytotoxicity of NK cells against GL261GSCs. GL261GSCs were intracranially implanted into mice, and the mice were stratified into 3 treatment groups: 1) control, 2) NK cells treatment, and 3) PD-1 inhibited NK cells treatment group. Overall survival was quantified, and animal magnetic resonance imaging (MRI) was performed to determine tumor growth. The brains were harvested after the mice were euthanized, and immunohistochemistry against CD45 and PCNA was performed. The mouse NK cells were identified as 90% CD3- NK1.1+CD335+ by flow cytometric analysis. In the LDH assay, the ratios of the damaged GL261GSCs, with the E:T ratios of 2.5:1, 5:1, and 10:1, were as follows: 1) non-inhibited group: 7.42%, 11.31%, and 15.1%, 2) B7H1 inhibited group: 14.75%, 18.25% and 29.1%, 3) PD-1 inhibited group: 15.53%, 19.21% and 29.93%, 4) double inhibited group: 33.24%, 42.86% and 54.91%. In the in vivo experiments, the mice in the PD-1 inhibited NK cells treatment group and IL-2-stimulated-NK cells treatment group displayed a slowest tumor growth (F = 308.5, P<0.01) and a slower tumor growth compared with control group (F = 118.9, P<0.01), respectively. The median survival of the mice in the three groups were as follows: 1) conrol group: 29 days, 2) NK cells treatment group: 35 days (P = 0.0012), 3) PD-1 inhibited NK cells treatment group: 44 days (P = 0.0024). Immunologic data of PCNA-positive cell ratios and CD45-positive cell ratios of the tumor specimens in the three groups were as follows: 1) control group: 65.72% (PCNA) and 0.92% (CD45), 2) NK treatment group: 27.66% (PCNA) and 13.46% (CD45), and 3) PD-1 inhibited NK cells treatment group: 13.66% (PCNA) and 23.66% (CD45) (P<0.001). The results demonstrated that blockade of PD-1/B7H1 pathway could promote mouse NK cells to kill the GL261GSCs, and the PD-1-inhibited NK cells could be a feasible immune therapeutic approach against GBM.

Evaluation of Biomarkers Predictive of Benefit from the PD-1 Inhibitor MK-3475 in Patients with Non-Small Cell Lung Cancer and Brain Metastases

DTIC Science & Technology

2017-07-01

Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Immunotherapies inhibiting the Programmed Death -1 (PD-1) axis can result in dramatic responses and durable...9. Appendices……………………………………………………………14 4 1. INTRODUCTION: Lung cancer is the leading cause of cancer death in the United States, resulting in more...than 160,000 deaths each year. The majority of patients with lung cancer have non-small cell lung cancer (NSCLC) and present with disease at an

Solution of non-steady-state substrate concentration in the action of biosensor response at mixed enzyme kinetics

NASA Astrophysics Data System (ADS)

Senthamarai, R.; Jana Ranjani, R.

2018-04-01

In this paper, a mathematical model of an amperometric biosensor at mixed enzyme kinetics and diffusion limitation in the case of substrate inhibition has been developed. The model is based on time dependent reaction diffusion equation containing a non -linear term related to non -Michaelis - Menten kinetics of the enzymatic reaction. Solution for the concentration of the substrate has been derived for all values of parameters using the homotopy perturbation method. All the approximate analytic expressions of substrate concentration are compared with simulation results using Scilab/Matlab program. Finally, we have given a satisfactory agreement between them.

Developmental consequences of behavioral inhibition: a model in rhesus monkeys (Macaca mulatta).

PubMed

Chun, Katie; Capitanio, John P

2016-11-01

In children, behavioral inhibition is characterized by a disposition to withdraw in the presence of strangers and novel situations. Later in life, behavioral inhibition can result in an increased risk for anxiety and depression and a decrease in social behavior. We selected rhesus monkeys that, during infancy, showed evidence of behavioral inhibition in response to separation, and contrasted them with non-inhibited peers. To understand the development of behavioral inhibition at juvenile age, we collected behavioral data in response to relocation; in response to a human intruder challenge; and in naturalistic outdoor field corrals. At 4 years of age (young adulthood), we again collected behavioral data in the outdoor field corrals to understand the adult social consequences of behavioral inhibition. We also included sex, dominance rank, and number of available kin in our analyses. Finally, to understand the consistency in behavior in behaviorally inhibited animals, we conducted exploratory analyses contrasting behaviorally inhibited animals that showed high vs. low durations of non-social behaviors as adults. At juvenile age, behaviorally inhibited animals continued to show behavioral differences in the novel testing room and during the human intruder challenge, generally showing evidence of greater anxiety and emotionality compared to non-inhibited controls. In their outdoor corrals, behaviorally inhibited juveniles spent more time alone and less time in proximity and grooming with mother and other adult females. In young adulthood, we found that behavioral inhibition was not related to time spent alone. We did find that duration of time alone in adulthood was related to time alone exhibited as juveniles; sex, dominance rank, or the number of kin were not influential in adult non-social duration, either as main effects or as moderators. Finally, exploratory analyses revealed that behaviorally inhibited females that were more sociable (less time spent alone) as adults had spent more time grooming as juveniles, suggesting that high-quality social interaction at a young age might mitigate the social consequences of behavioral inhibition. Overall, we believe that the many similarities with the human data that we found suggest that this monkey model of naturally occurring behavioral inhibition can be valuable for understanding social development. © 2015 John Wiley & Sons Ltd.

Improving response inhibition in Parkinson's disease with atomoxetine.

PubMed

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2015-04-15

Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Improving Response Inhibition in Parkinson’s Disease with Atomoxetine

PubMed Central

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.; Rowe, James B.

2015-01-01

Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease. PMID:24655598

Neural Correlates of Inhibition and Contextual Cue Processing Related to Treatment Response in PTSD

PubMed Central

van Rooij, Sanne JH; Geuze, Elbert; Kennis, Mitzy; Rademaker, Arthur R; Vink, Matthijs

2015-01-01

Thirty to fifty percent of posttraumatic stress disorder (PTSD) patients do not respond to treatment. Understanding the neural mechanisms underlying treatment response could contribute to improve response rates. PTSD is often associated with decreased inhibition of fear responses in a safe environment. Importantly, the mechanism of effective treatment (psychotherapy) relies on inhibition and so-called contextual cue processing. Therefore, we investigate inhibition and contextual cue processing in the context of treatment. Forty-one male war veterans with PTSD and 22 healthy male war veterans (combat controls) were scanned twice with a 6- to 8-month interval, in which PTSD patients received treatment (psychotherapy). We distinguished treatment responders from nonresponders on the base of percentage symptom decrease. Inhibition and contextual cue processing were assessed with the stop-signal anticipation task. Behavioral and functional MRI measures were compared between PTSD patients and combat controls, and between responders and nonresponders using repeated measures analyses. PTSD patients showed behavioral and neural deficits in inhibition and contextual cue processing at both time points compared with combat controls. These deficits were unaffected by treatment; therefore, they likely represent vulnerability factors or scar aspects of PTSD. Second, responders showed increased pretreatment activation of the left inferior parietal lobe (IPL) during contextual cue processing compared with nonresponders. Moreover, left IPL activation predicted percentage symptom improvement. The IPL has an important role in contextual cue processing, and may therefore facilitate the effect of psychotherapy. Hence, increased left IPL activation may represent a potential predictive biomarker for PTSD treatment response. PMID:25154707

Developmental Trends in Simple and Selective Inhibition of Compatible and Incompatible Responses

ERIC Educational Resources Information Center

van den Wildenberg, Wery P. M.; van der Molen, Maurits W.

2004-01-01

This study examined age-related change in the ability to inhibit responses using two varieties of the stop signal paradigm. Three age groups (29 7-year-olds, 24 10-year-olds, and 28 young adults) performed first on a visual choice reaction task in which the spatial mapping between the go signal and response was varied between blocks. The choice…

Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

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

Kim, Sun Ae; Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr

2012-09-07

Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), amore » key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-{alpha}. Taken together, PTEN could be a possible downstream regulator of AMPK, and the AMPK-PTEN pathway might be important in the regulation of the inflammatory response in VSMCs.« less

Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model.

PubMed

Tomlinson, Anneka; Grayson, Ben; Marsh, Samuel; Hayward, Andrew; Marshall, Kay M; Neill, Joanna C

2015-04-01

Prefrontal cortical dopamine plays an important role in cognitive control, specifically in attention and response inhibition; the core deficits in ADHD. We have previously shown that methylphenidate and atomoxetine differentially improve these deficits dependent on baseline performance. The present study extends this work to investigate the effects of putative therapeutic targets in our model. A selective dopamine D4 receptor agonist (A-412997) and the catechol-O-methyl-transferase (COMT) inhibitor; tolcapone, were investigated in the combined subtype of adult ADHD (ADHD-C). Adult female rats were trained to criterion in the 5C-CPT (5-Choice Continuous Performance Task) and then separated into subgroups according to baseline levels of sustained attention, vigilance, and response disinhibition. The subgroups included: high-attentive (HA) and low-attentive with high response disinhibition (ADHD-C). The ADHD-C subgroup was selected to represent the combined subtype of adult ADHD. Effects of tolcapone (3.0, 10.0, 15.0mg/kg) and A-412997 (0.1, 0.3, 1.0µmol/kg) were tested by increasing the variable inter-trial-interval (ITI) duration in the 5C-CPT. Tolcapone (15mg/kg) significantly increased sustained attention, vigilance and response inhibition in ADHD-C animals, and impaired attention in HA animals. A-412997 (1.0µmol/kg) significantly increased vigilance and response inhibition in ADHD-C animals only, with no effect in HA animals. This is the first study to use the translational 5C-CPT to model the adult ADHD-C subtype in rats and to study new targets in this model. Both tolcapone and A-412997 increased vigilance and response inhibition in the ADHD-C subgroup. D4 and COMT are emerging as important potential therapeutic targets in adult ADHD that warrant further investigation. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Differential Recruitment of Brain Regions During Response Inhibition in Children Prenatally Exposed to Alcohol.

PubMed

Kodali, Vikas N; Jacobson, Joseph L; Lindinger, Nadine M; Dodge, Neil C; Molteno, Christopher D; Meintjes, Ernesta M; Jacobson, Sandra W

2017-02-01

Response inhibition is a distinct aspect of executive function that is frequently impaired in children with fetal alcohol spectrum disorders (FASD). We used a Go/NoGo (GNG) task in a functional MRI protocol to investigate differential activation of brain regions in the response inhibition network in children diagnosed with full or partial fetal alcohol syndrome (FAS/PFAS), compared with healthy controls. A rapid, event-related task with 120 Go and 60 NoGo trials was used to study children aged 8 to 12 years-8 with FAS/PFAS, 17 controls. Letters were projected sequentially, with Go and NoGo trials randomly interspersed across the task. BOLD signal in the whole brain was contrasted for the correct NoGo minus correct Go trials between the FAS/PFAS and control groups. Compared to the FAS/PFAS group, controls showed greater activation of the inferior frontal and anterior cingulate network linked to response inhibition in typically developing children. By contrast, the FAS/PFAS group showed greater BOLD response in dorsolateral prefrontal cortex and other middle prefrontal regions, suggesting compensation for inefficient function of pathways that normally mediate inhibitory processing. All group differences were significant after control for potential confounding variables. None of the effects of prenatal alcohol exposure on activation of the regions associated with response inhibition were attributable to the effects of this exposure on IQ. This is the first FASD GNG study in which all participants in the exposed group met criteria for a diagnosis of full FAS or PFAS. Although FASD is frequently comorbid with attention deficit hyperactivity disorder, the pattern of brain activation seen in these disorders differs, suggesting that different neural pathways mediate response inhibition in FASD and that different interventions for FASD are, therefore, warranted. Copyright © 2017 by the Research Society on Alcoholism.

PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency.

PubMed

Xu, Benjamin; Sandrini, Marco; Wang, Wen-Tung; Smith, Jason F; Sarlls, Joelle E; Awosika, Oluwole; Butman, John A; Horwitz, Barry; Cohen, Leonardo G

2016-09-01

Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right presupplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA-rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. Hum Brain Mapp 37:3236-3249, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Karrikin-KAI2 signalling provides Arabidopsis seeds with tolerance to abiotic stress and inhibits germination under conditions unfavourable to seedling establishment.

PubMed

Wang, Lu; Waters, Mark T; Smith, Steven M

2018-07-01

The control of seed germination in response to environmental conditions is important for plant success. We investigated the role of the karrikin receptor KARRIKIN INSENSITIVE2 (KAI2) in the response of Arabidopsis seeds to osmotic stress, salinity and high temperature. Germination of the kai2 mutant was examined in response to NaCl, mannitol and elevated temperature. The effect of karrikin on germination of wild-type seeds, hypocotyl elongation and the expression of karrikin-responsive genes was also examined in response to such stresses. The kai2 seeds germinated less readily than wild-type seeds and germination was more sensitive to inhibition by abiotic stress. Karrikin-induced KAI2 signalling stimulated germination of wild-type seeds under favourable conditions, but, surprisingly, inhibited germination in the presence of osmolytes or at elevated temperature. By contrast, GA stimulated germination of wild-type seeds and mutants under all conditions. Karrikin induced expression of DLK2 and KUF1 genes and inhibited hypocotyl elongation independently of osmotic stress. Under mild osmotic stress, karrikin enhanced expression of DREB2A, WRKY33 and ERF5 genes, but not ABA signalling genes. Thus, the karrikin-KAI2 signalling system can protect against abiotic stress, first by providing stress tolerance, and second by inhibiting germination under conditions unfavourable to seedling establishment. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Non-specific actions of the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, on neurotransmission.

PubMed Central

Wang, Z. Y.; Tung, S. R.; Strichartz, G. R.; Håkanson, R.

1994-01-01

1. Three non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, were found to inhibit the electrically-evoked, tachykinin-mediated contractile responses of the rabbit iris sphincter in a concentration-dependent fashion; the pIC50 values were 5.6 +/- 0.01, 5.4 +/- 0.07 and 4.8 +/- 0.03, respectively. 2. These antagonists also inhibited the electrically-evoked, parasympathetic response of the rabbit iris sphincter and the sympathetic response of the guinea-pig vas deferens in a concentration-dependent manner; the pIC50 values were 0.3-1.2 log units lower than those recorded for the tachykinin-mediated responses. 3. Two local anaesthetics, bupivacaine and oxybuprocaine, were also found to inhibit the tachykinin-mediated, cholinergic and sympathetic contractile responses in these tissues in a concentration-dependent manner; the concentration ranges for producing the inhibition were similar to those of the non-peptide tachykinin receptor antagonists. 4. On the sciatic nerves of frogs, the tachykinin receptor antagonists inhibited action potentials in a concentration-dependent manner; the potency of the three drugs was similar to that of bupivacaine. 5. Our results suggest that, in addition to blocking tachykinin receptors, the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, may exert non-specific inhibitory effects on neurotransmission. PMID:8012694

Effects of stop-signal probability in the stop-signal paradigm: the N2/P3 complex further validated.

PubMed

Ramautar, J R; Kok, A; Ridderinkhof, K R

2004-11-01

The aim of this study was to examine the effects of frequency of occurrence of stop signals in the stop-signal paradigm. Presenting stop signals less frequently resulted in faster reaction times to the go stimulus and a lower probability of inhibition. Also, go stimuli elicited larger and somewhat earlier P3 responses when stop signals occurred less frequently. Since the amplitude effect was more pronounced on trials when go signals were followed by fast than slow reactions, it probably reflected a stronger set to produce fast responses. N2 and P3 components to stop signals were observed to be larger and of longer latency when stop signals occurred less frequently. The amplitude enhancement of these N2 and P3 components were more pronounced for unsuccessful than for successful stop-signal trials. Moreover, the successfully inhibited stop trials elicited a frontocentral P3 whereas unsuccessfully inhibited stop trials elicited a more posterior P3 that resembled the classical P3b. P3 amplitude in the unsuccessfully inhibited condition also differed between waveforms synchronized with the stop signal and waveforms synchronized with response onset whereas N2 amplitude did not. Taken together these findings suggest that N2 reflected a greater significance of failed inhibitions after low probability stop signals while P3 reflected continued processing of the erroneous response after response execution.

Global inhibition and stimulus competition in the owl optic tectum

PubMed Central

Mysore, Shreesh P.; Asadollahi, Ali; Knudsen, Eric I.

2010-01-01

Stimulus selection for gaze and spatial attention involves competition among stimuli across sensory modalities and across all of space. We demonstrate that such cross-modal, global competition takes place in the intermediate and deep layers of the optic tectum, a structure known to be involved in gaze control and attention. A variety of either visual or auditory stimuli located anywhere outside of a neuron's receptive field (RF) were shown to suppress or completely eliminate responses to a visual stimulus located inside the RF in nitrous oxide sedated owls. The essential mechanism underlying this stimulus competition is global, divisive inhibition. Unlike the effect of the classical inhibitory surround, which decreases with distance from the RF center and shapes neuronal responses to individual stimuli, global inhibition acts across the entirety of space and modulates responses primarily in the context of multiple stimuli. Whereas the source of this global inhibition is as yet unknown, our data indicate that different networks mediate the classical surround and global inhibition. We hypothesize that this global, cross-modal inhibition, which acts automatically in a bottom-up fashion even in sedated animals, is critical to the creation of a map of stimulus salience in the optic tectum. PMID:20130182

Assessment of maternal antibody decay and response to canine parvovirus vaccination using a clinic-based enzyme-linked immunosorbent assay.

PubMed

Waner, T; Naveh, A; Wudovsky, I; Carmichael, L E

1996-10-01

Interference caused by maternal antibodies is considered a major cause of canine parvovirus (CPV) vaccination failure. In this study, an immunoblot clinic-based enzyme-linked immunosorbent assay (ELISA) method was used to detect CPV antibodies in sera of pregnant bitches and their offspring to study the response of pups to vaccination. With a easily accessible procedure for CPV antibody determination, the veterinarian should be able to gauge the response of pups after vaccination. The validity of the technique was tested in parallel against the standard hemagglutination inhibition (HI) test. Results of the ELISA were correlated with those of the standard HI method for quantification of CPV antibodies. With the ELISA, successfully immunized pups were identified, allowing for a more reliable and cost-effective program of vaccination. This simple clinic-based test could be used for the assessment of vaccination status of pups during the critical phase of 6 to about 16 weeks of age. This study is the first in which vaccination response to CPV in pups was followed, using a clinic-based ELISA for CPV antibody monitoring.

Cell Wall Invertase Promotes Fruit Set under Heat Stress by Suppressing ROS-Independent Cell Death1[OPEN

PubMed Central

2016-01-01

Reduced cell wall invertase (CWIN) activity has been shown to be associated with poor seed and fruit set under abiotic stress. Here, we examined whether genetically increasing native CWIN activity would sustain fruit set under long-term moderate heat stress (LMHS), an important factor limiting crop production, by using transgenic tomato (Solanum lycopersicum) with its CWIN inhibitor gene silenced and focusing on ovaries and fruits at 2 d before and after pollination, respectively. We found that the increase of CWIN activity suppressed LMHS-induced programmed cell death in fruits. Surprisingly, measurement of the contents of H2O2 and malondialdehyde and the activities of a cohort of antioxidant enzymes revealed that the CWIN-mediated inhibition on programmed cell death is exerted in a reactive oxygen species-independent manner. Elevation of CWIN activity sustained Suc import into fruits and increased activities of hexokinase and fructokinase in the ovaries in response to LMHS. Compared to the wild type, the CWIN-elevated transgenic plants exhibited higher transcript levels of heat shock protein genes Hsp90 and Hsp100 in ovaries and HspII17.6 in fruits under LMHS, which corresponded to a lower transcript level of a negative auxin responsive factor IAA9 but a higher expression of the auxin biosynthesis gene ToFZY6 in fruits at 2 d after pollination. Collectively, the data indicate that CWIN enhances fruit set under LMHS through suppression of programmed cell death in a reactive oxygen species-independent manner that could involve enhanced Suc import and catabolism, HSP expression, and auxin response and biosynthesis. PMID:27462084

Postnatal functional inactivation of the entorhinal cortex or ventral subiculum has different consequences for latent inhibition-related striatal dopaminergic responses in adult rats.

PubMed

Meyer, F; Peterschmitt, Y; Louilot, A

2009-05-01

Latent inhibition has been found to be disrupted in patients with acute schizophrenia. Striatal dopaminergic dysregulation is commonly acknowledged in schizophrenia. This disease may be consecutive to a functional disconnection between integrative regions, stemming from neurodevelopmental failures. Various anomalies suggesting early abnormal brain development have been described in the entorhinal cortex (ENT) and ventral subiculum (SUB) of patients. This study examines the consequences of a neonatal transitory blockade of the left ENT or left SUB for latent inhibition-related dopamine responses in the anterior part of the dorsal striatum using in-vivo voltammetry in freely moving adult rats. Reversible inactivation of both structures in different animals was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the functional neonatal disconnection of the ENT or SUB caused the behavioural latent inhibition expression in pre-exposed (PE)-TTX-conditioned adult rats to disappear. After postnatal inactivation of the SUB, PE-TTX-conditioned rats displayed a reversal of the latent inhibition-related striatal dopamine responses, whereas after neonatal blockade of the ENT, dopamine changes in PE-TTX-conditioned rats monitored in the anterior striatum were between those observed in PE-phosphate-buffered-saline-conditioned and non-PE-TTX-conditioned animals. These data suggest that neonatal functional inactivation of the SUB disrupts latent inhibition-related striatal dopamine responses in adult animals more than that of the ENT. They may help improve understanding of the pathophysiology of schizophrenia.

Effects of inhibition of ubiquitin-proteasome pathway on human primary leukemic cells.

PubMed

Lan, Yu; Zhang, Xuemin; Yang, Pingdi; Hu, Meiru; Yu, Ming; Yang, Yi; Shen, Beifen

2002-12-01

Though there were a lot of reports about the totally different responses to the inhibition of ubiquitin-proteasome pathway in different kinds of cell lines, much less has been known about the responses in primary human leukemic cells. In this study, the effects of inhibition of ubiquitin-proteasome pathway on human bone marrow (BM) mononuclear cells (MNCs) obtained from 10 normal persons and 8 leukemia patients were examined. The results showed that the responses obviously varied individually. Among them, BM MNCs in 3 cases of leukemic patients were extremely sensitive, demonstrated by that > 90% cells were induced to undergo apoptosis within 24 h, but MNCs in 10 cases of normal persons showed resistance to the inhibition and no apoptosis was observed. Furthermore, Western blots revealed that the Bcl-2 expression was relatively high in the sensitive primary leukemia cells, and especially the cleavage of 26 ku Bcl-2 into a 22 ku fragment occurred during the induction of apoptosis. In contrast, the Bcl-2 expression was either undetectable or detectable but no cleavage of that above was observed in the cells insensitive to the inhibition of the pathway (including BM MNCs in normal persons). Together with the observations on the leukemic cell lines, these findings suggested the correlation of the specific cleavage of Bcl-2 into a shortened fragment with the sensitivity of cells to the inhibition of ubiquitin-proteasome pathway, which provides clues to the further understanding of the mechanisms of that dramatically different responses existing in different kinds of cells to the inhibition of ubiquitin-proteasome pathway.

The effect of ethylene on root growth of Zea mays seedlings

NASA Technical Reports Server (NTRS)

Whalen, M. C.; Feldman, L. J.

1988-01-01

The control of primary root growth in Zea mays cv. Merit by ethylene was examined. At applied concentrations of ethylene equal to or greater than 0.1 microliter L-1, root elongation during 24 h was inhibited. The half-maximal response occurred at 0.6 microliter L-1 and the response saturated at 6 microliters L-1. Inhibition of elongation took place within 20 min. However, after ethylene was removed, elongation recovered to control values within 15 min. Root elongation was also inhibited by green light. The inhibition caused by a 24-h exposure to ethylene was restricted to the elongating region just behind the apex, with inhibition of cortical cell elongation being the primary contributor to the effect. Based on use of 2,5-norbornadiene, a gaseous competitive inhibitor of ethylene, it was concluded that endogenous ethylene normally inhibits root elongation.

Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs

PubMed Central

Clay, Emlyn; Patacchini, Riccardo; Trevisani, Marcello; Preti, Delia; Branà, Maria Pia; Spina, Domenico

2016-01-01

Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs. PMID:26837703

Inhibition of Glycoprotein VI Clustering by Collagen as a Mechanism of Inhibiting Collagen-Induced Platelet Responses: The Example of Losartan

PubMed Central

Jiang, Peng; Loyau, Stéphane; Tchitchinadze, Maria; Ropers, Jacques; Jondeau, Guillaume; Jandrot-Perrus, Martine

2015-01-01

Exposure of platelets to collagen triggers the formation of a platelet clot. Pharmacological agents capable of inhibiting platelet activation by collagen are thus of potential therapeutic interest. Thrombus formation is initiated by the interaction of the GPIb-V-IX complex with collagen-bound vWF, while GPVI interaction with collagen triggers platelet activation that is reinforced by ADP and thromboxane A2. Losartan is an angiotensin II (Ang II) type I receptor (AT1R) antagonist proposed to have an antiplatelet activity via the inhibition of both the thromboxane A2 (TXA2) receptor (TP) and the glycoprotein VI (GPVI). Here, we characterized in vitro the effects of losartan at different doses on platelet responses: losartan inhibited platelet aggregation and secretion induced by 1 μg.mL-1 and 10 μg.mL-1 of collagen with an IC50 of ~ 6 μM. Losartan inhibited platelet responses induced by the GPVI specific collagen related peptide but not by the α2β1 specific peptide. However, losartan did not inhibit the binding of recombinant GPVI to collagen, which is not in favor of a simple competition. Indeed, the clustering of GPVI observed in flow cytometry and using the Duolink methodology, was inhibited by losartan. The impact of a therapeutic dose of losartan (100 mg/day) on platelet responses was analyzed ex vivo in a double blind study. No statistically significant differences were observed between losartan-treated (n=25) and non-treated (n=30) patients in terms of collagen and U46619-induced platelet activation. These data indicate that in treated patients, losartan does not achieve a measurable antiplatelet effect but provide the proof of concept that inhibiting collagen-induced GPVI clustering is of pharmacological interest to obtain an antithrombotic efficacy. Trial Registration ClinicalTrials.gov NCT00763893 PMID:26052700

Pharmacological analysis of the cardiac sympatho-inhibitory actions of moxonidine and agmatine in pithed spontaneously hypertensive rats.

PubMed

Cobos-Puc, Luis E; Sánchez-López, Araceli; Centurión, David

2016-11-15

This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3μg/kgmin); (2) partially inhibited by B-HT 933 (30μg/kgmin), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100μg/kgmin), moxonidine (10μg/kgmin) or agmatine (1000 and 3000μg/kgmin) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000μg/kgmin agmatine. In SHR, 300μg/kg rauwolscine failed to block the sympatho-inhibition to 100μg/kgmin B-HT 933 or 10μg/kgmin moxonidine, but 1000μg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000μg/kg AGN 192403 or 300μg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α 2 -adrenoceptors and to a lesser extent by I 1 -imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α 2 -adrenoceptors and I 1 -imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α 2 -adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats. Copyright © 2016 Elsevier B.V. All rights reserved.

MMB-4 Inhibition of Aceylcholinesterase Is Similar across Species

DTIC Science & Technology

2014-11-01

version 5.4). An IC50 value was determined for AChE from each animal species by fitting the percent of AChE activity with respect to MMB 4 concentration...in GraphPad Prism (version 5) using a nonlinear regression dose response model for inhibition (normalized response with variable slope). Assessing the...Therefore, AChE activity and inhibition studies were carried out at 435 nm to reduce interference from MMB 4. Comparison of IC50 Values for MMB 4 with AChE

Cognitive control training for emotion-related impulsivity.

PubMed

Peckham, Andrew D; Johnson, Sheri L

2018-06-01

Many forms of psychopathology are tied to a heightened tendency to respond impulsively to strong emotions, and this tendency, in turn, is closely tied to problems with cognitive control. The goal of the present study was to test whether a two-week, six-session cognitive control training program is efficacious in reducing emotion-related impulsivity. Participants (N = 52) reporting elevated scores on an emotion-related impulsivity measure completed cognitive control training targeting working memory and response inhibition. A subset of participants were randomized to a waitlist control group. Impulsivity, emotion regulation, and performance on near and far-transfer cognitive tasks were assessed at baseline and after completion of training. Emotion-related impulsivity declined significantly from pre-training to post-training and at two-week follow-up; improvements were not observed in the waitlist control group. A decrease in brooding rumination and an increase in reappraisal were also observed. Participants showed significant improvements on trained versions of the working memory and inhibition tasks as well as improvements on an inhibition transfer task. In sum, these preliminary findings show that cognitive training appears to be well-tolerated for people with significant emotion-driven impulsivity. Results provide preliminary support for the efficacy of cognitive training interventions as a way to reduce emotion-related impulsivity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity.

PubMed

Hamilton, Gerhard; Rath, Barbara

2017-04-01

Immune checkpoint inhibition holds great promise for selected tumors. The human monoclonal antibody (mAB) avelumab is directed to programmed death ligand-1 (PD-L1) and is supposed to inhibit the immunosuppressive PD-L1/PD-1 interaction and, furthermore, effect antibody-dependent cytotoxicity (ADCC) lysis of tumor cells. Areas covered: This article presents an overview of the current means to activate the antitumor immune defense by targeting PD-1 or PD-L1 with mABs and their possible role in ADCC-mediated tumor cell elimination. Expert opinion: Avelumab contains a Fc region which can bind cognate receptors on immune effector cells and induce ADCC-mediated tumor cell lysis, in contrast to other mABs directed to PD-1/PD-L1 which lack the ability to trigger ADCC due to belonging to the IgG4 subclass or possessing a mutated Fc region. Preclinical and clinical data indicate that avelumab can be safely administered to cancer patients with a toxicity profile comparable to other mABs and without lysis of PD-L1-positive activated immune cells. This antibody yielded durable responses in a phase II trial in advanced Merkel cell carcinoma patients. Tumor cell lysis by avelumab prevents cells from resorting to alternative checkpoints as shown by targeting PD-1 and the upregulation of TIM-3.

Response Inhibition Is Associated with White Matter Microstructure in Children

ERIC Educational Resources Information Center

Madsen, Kathrine Skak; Baare, William F. C.; Vestergaard, Martin; Skimminge, Arnold; Ejersbo, Lisser Rye; Ramsoy, Thomas Z.; Gerlach, Christian; Akeson, Per; Paulson, Olaf B.; Jernigan, Terry L.

2010-01-01

Cognitive control of thoughts, actions and emotions is important for normal behaviour and the development of such control continues throughout childhood and adolescence. Several lines of evidence suggest that response inhibition is primarily mediated by a right-lateralized network involving inferior frontal gyrus (IFG), presupplementary motor…

Oily fraction of Semecarpus anacardium Linn nuts involves protein kinase C activation for its pro-inflammatory response.

PubMed

Tripathi, Yamini B; Pandey, Nidhi; Tripathi, Deepshikha; Tripathi, Pratibha

2010-12-01

The oily fraction (non polar fraction-NPF) of S. anacardium (SA) significantly increased the expression of protein kinase C-delta (PKC-delta) in macrophages in concentration dependent manner, which was similar to phorbol myristate acetate (PMA) response. Further, H-7 (1-(5-isoquinolinesulphonyl)-2-methylpiperazine), an inhibitor of PKC significantly inhibited this NPF mediated response in a concentration dependent manner. In the post treatment kinetics, H-7 showed this inhibition only up to 6 min post NPF/PMA addition, but in similar condition, quercetin, a flavone with reported antioxidant property, showed this inhibition only up to 2 min. The results clearly suggest that oily fraction of SA nuts enhances the expression of PKC protein, which may be responsible for its reported pro-inflammatory property.

From approach to inhibition: the influence of power on responses to poor performers.

PubMed

Ferguson, Amanda J; Ormiston, Margaret E; Moon, Henry

2010-03-01

This article examines how relative differences in power affect responses to poor performers in organizations. We predicted that higher power individuals would engage in approach-related behaviors, whereas lower power individuals would be inhibited when responding to poor performers. Results from a scenario study and a field study generally supported this prediction, indicating that power was positively related to training or confronting a poor performer and negatively related to compensating for or rejecting a poor performer. A second scenario study investigated the effect of the interaction of power and emotion on individual responses to poor performers. Results showed that the type of emotion expressed moderated the effect of power on inhibition-related responses. We discuss implications for managing poor performers with relative power differences. 2010 APA, all rights reserved

Cortical organization of inhibition-related functions and modulation by psychopathology

PubMed Central

Warren, Stacie L.; Crocker, Laura D.; Spielberg, Jeffery M.; Engels, Anna S.; Banich, Marie T.; Sutton, Bradley P.; Miller, Gregory A.; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology. PMID:23781192

Cortical organization of inhibition-related functions and modulation by psychopathology.

PubMed

Warren, Stacie L; Crocker, Laura D; Spielberg, Jeffery M; Engels, Anna S; Banich, Marie T; Sutton, Bradley P; Miller, Gregory A; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology.

The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia.

PubMed

Choi, Sung Hee; Severson, Eric; Pear, Warren S; Liu, Xiaole S; Aster, Jon C; Blacklow, Stephen C

2017-01-01

Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL), in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition.

The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia

PubMed Central

Pear, Warren S.; Liu, Xiaole S.; Aster, Jon C.

2017-01-01

Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL), in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition. PMID:29023469

Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells

PubMed Central

Lichtenegger, Felix S.; Rothe, Maurine; Schnorfeil, Frauke M.; Deiser, Katrin; Krupka, Christina; Augsberger, Christian; Schlüter, Miriam; Neitz, Julia; Subklewe, Marion

2018-01-01

Immune checkpoint inhibition has been shown to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, resulting in significantly prolonged overall survival in patients with various tumor entities. For malignancies with low endogenous immune responses, this approach has not shown a clear clinical benefit so far. Therapeutic vaccination, particularly dendritic cell (DC) vaccination, is a strategy to induce T cell responses. Interaction of DCs and T cells is dependent on receptor–ligand interactions of various immune checkpoints. In this study, we analyzed the influence of blocking antibodies targeting programmed cell death protein 1 (PD-1), HVEM, CD244, TIM-3, and lymphocyte activation gene 3 (LAG-3) on the proliferation and cytokine secretion of T cells after stimulation with autologous TLR-matured DCs. In this context, we found that LAG-3 blockade resulted in superior T cell activation compared to inhibition of other pathways, including PD-1/PD-L1. This result was consistent across different methods to measure T cell stimulation (proliferation, IFN-γ secretion), various stimulatory antigens (viral and bacterial peptide pool, specific viral antigen, specific tumor antigen), and seen for both CD4+ and CD8+ T cells. Only under conditions with a weak antigenic stimulus, particularly when combining antigen presentation by peripheral blood mononuclear cells with low concentrations of peptides, we observed the highest T cell stimulation with dual blockade of LAG-3 and PD-1 blockade. We conclude that priming of novel immune responses can be strongly enhanced by blockade of LAG-3 or dual blockade of LAG-3 and PD-1, depending on the strength of the antigenic stimulus. PMID:29535740

Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells.

PubMed

Lichtenegger, Felix S; Rothe, Maurine; Schnorfeil, Frauke M; Deiser, Katrin; Krupka, Christina; Augsberger, Christian; Schlüter, Miriam; Neitz, Julia; Subklewe, Marion

2018-01-01

Immune checkpoint inhibition has been shown to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, resulting in significantly prolonged overall survival in patients with various tumor entities. For malignancies with low endogenous immune responses, this approach has not shown a clear clinical benefit so far. Therapeutic vaccination, particularly dendritic cell (DC) vaccination, is a strategy to induce T cell responses. Interaction of DCs and T cells is dependent on receptor-ligand interactions of various immune checkpoints. In this study, we analyzed the influence of blocking antibodies targeting programmed cell death protein 1 (PD-1), HVEM, CD244, TIM-3, and lymphocyte activation gene 3 (LAG-3) on the proliferation and cytokine secretion of T cells after stimulation with autologous TLR-matured DCs. In this context, we found that LAG-3 blockade resulted in superior T cell activation compared to inhibition of other pathways, including PD-1/PD-L1. This result was consistent across different methods to measure T cell stimulation (proliferation, IFN-γ secretion), various stimulatory antigens (viral and bacterial peptide pool, specific viral antigen, specific tumor antigen), and seen for both CD4 + and CD8 + T cells. Only under conditions with a weak antigenic stimulus, particularly when combining antigen presentation by peripheral blood mononuclear cells with low concentrations of peptides, we observed the highest T cell stimulation with dual blockade of LAG-3 and PD-1 blockade. We conclude that priming of novel immune responses can be strongly enhanced by blockade of LAG-3 or dual blockade of LAG-3 and PD-1, depending on the strength of the antigenic stimulus.

ROCK activity affects IL-1-induced signaling possibly through MKK4 and p38 MAPK in Caco-2 cells.

PubMed

Banerjee, Sayantan; McGee, Dennis W

2016-09-01

Elevated levels of interleukin-1 (IL-1) accompany inflammatory bowel disease. IL-1-stimulated intestinal epithelial cells can secrete potent chemokines like CXCL8 to exacerbate inflammation. Previously, we found that inhibiting the Rho-associated kinase (ROCK) could inhibit IL-1- or TNF-α-induced CXCL8 secretion by the Caco-2 colonic epithelial cell line. This ROCK inhibition did not affect IκBα phosphorylation and degradation, but suppressed the phosphorylation of c-Jun N-terminal kinase (JNK). Therefore, ROCK must play an important role in epithelial cell CXCL8 responses through an effect on the JNK signaling pathway. Here, we extend these studies by showing that inhibiting ROCK suppressed the IL-1-induced phosphorylation of MKK4, a known activator of JNK, but not MKK7. Yet, ROCK inhibition had no significant effect on the IL-1-induced phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2. Inhibiting ROCK also suppressed the phosphorylation of p38 MAPK after IL-1 stimulation, but this inhibition had no significant effect on the stability of CXCL8 messenger RNA (mRNA) after IL-1 stimulation. These results suggest that ROCK may be important in IL-1-induced signaling through MKK4 to JNK and the activation of p38 MAPK. Finally, inhibiting ROCK in IL-1 and TNF-α co-stimulated Caco-2 cells also resulted in a significant suppression of CXCL8 secretion and mRNA levels suggesting that inhibiting ROCK may be a mechanism to inhibit the overall response of epithelial cells to both cytokines. These studies indicate a novel signaling event, which could provide a target for suppressing intestinal epithelial cells (IEC) chemokine responses involved in mucosal inflammation.

Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

PubMed

Marney, Annis; Kunchakarra, Siri; Byrne, Loretta; Brown, Nancy J

2010-10-01

Dipeptidyl peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that dipeptidyl peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum dipeptidyl peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of dipeptidyl peptidase-IV and ACE inhibition in humans.

A novel muscarinic receptor-independent mechanism of KCNQ2/3 potassium channel blockade by Oxotremorine-M.

PubMed

Zwart, Ruud; Reed, Hannah; Clarke, Sophie; Sher, Emanuele

2016-11-15

Inhibition of KCNQ (Kv7) potassium channels by activation of muscarinic acetylcholine receptors has been well established, and the ion currents through these channels have been long known as M-currents. We found that this cross-talk can be reconstituted in Xenopus oocytes by co-transfection of human recombinant muscarinic M1 receptors and KCNQ2/3 potassium channels. Application of the muscarinic acetylcholine receptor agonist Oxotremorine-methiodide (Oxo-M) between voltage pulses to activate KCNQ2/3 channels caused inhibition of the subsequent KCNQ2/3 responses. This effect of Oxo-M was blocked by the muscarinic acetylcholine receptor antagonist atropine. We also found that KCNQ2/3 currents were inhibited when Oxo-M was applied during an ongoing KCNQ2/3 response, an effect that was not blocked by atropine, suggesting that Oxo-M inhibits KCNQ2/3 channels directly. Indeed, also in oocytes that were transfected with only KCNQ2/3 channels, but not with muscarinic M1 receptors, Oxo-M inhibited the KCNQ2/3 response. These results show that besides the usual muscarinic acetylcholine receptor-mediated inhibition, Oxo-M also inhibits KCNQ2/3 channels by a direct mechanism. We subsequently tested xanomeline, which is a chemically distinct muscarinic acetylcholine receptor agonist, and oxotremorine, which is a close analogue of Oxo-M. Both compounds inhibited KCNQ2/3 currents via activation of M1 muscarinic acetylcholine receptors but, in contrast to Oxo-M, they did not directly inhibit KCNQ2/3 channels. Xanomeline and oxotremorine do not contain a positively charged trimethylammonium moiety that is present in Oxo-M, suggesting that such a charged moiety could be a crucial component mediating this newly described direct inhibition of KCNQ2/3 channels. Copyright © 2016 Elsevier B.V. All rights reserved.

Adeno-associated virus-RNAi of GlyRα1 and characterization of its synapse-specific inhibition in OFF alpha transient retinal ganglion cells

PubMed Central

Zhang, C.; Rompani, S. B.; Roska, B.

2014-01-01

In the central nervous system, inhibition shapes neuronal excitation. In spinal cord glycinergic inhibition predominates, whereas GABAergic inhibition predominates in the brain. The retina uses GABA and glycine in approximately equal proportions. Glycinergic crossover inhibition, initiated in the On retinal pathway, controls glutamate release from presynaptic OFF cone bipolar cells (CBCs) and directly shapes temporal response properties of OFF retinal ganglion cells (RGCs). In the retina, four glycine receptor (GlyR) α-subunit isoforms are expressed in different sublaminae and their synaptic currents differ in decay kinetics. GlyRα1, expressed in both On and Off sublaminae of the inner plexiform layer, could be the glycinergic isoform that mediates On-to-Off crossover inhibition. However, subunit-selective glycine contributions remain unknown because we lack selective antagonists or cell class-specific subunit knockouts. To examine the role of GlyRα1 in direct inhibition in mature RGCs, we used retrogradely transported adeno-associated virus (AAV) that performed RNAi and eliminated almost all glycinergic spontaneous and visually evoked responses in PV5 (OFFαTransient) RGCs. Comparisons of responses in PV5 RGCs infected with AAV-scrambled-short hairpin RNA (shRNA) or AAV-Glra1-shRNA confirm a role for GlyRα1 in crossover inhibition in cone-driven circuits. Our results also define a role for direct GlyRα1 inhibition in setting the resting membrane potential of PV5 RGCs. The absence of GlyRα1 input unmasked a serial and a direct feedforward GABAAergic modulation in PV5 RGCs, reflecting a complex interaction between glycinergic and GABAAergic inhibition. PMID:25231618

Nuclear ubiquitin proteasome degradation affects WRKY45 function in the rice defense program.

PubMed

Matsushita, Akane; Inoue, Haruhiko; Goto, Shingo; Nakayama, Akira; Sugano, Shoji; Hayashi, Nagao; Takatsuji, Hiroshi

2013-01-01

The transcriptional activator WRKY45 plays a major role in the salicylic acid/benzothiadiazole-induced defense program in rice. Here, we show that the nuclear ubiquitin-proteasome system (UPS) plays a role in regulating the function of WRKY45. Proteasome inhibitors induced accumulation of polyubiquitinated WRKY45 and transient up-regulation of WRKY45 target genes in rice cells, suggesting that WRKY45 is constantly degraded by the UPS to suppress defense responses in the absence of defense signals. Mutational analysis of the nuclear localization signal indicated that UPS-dependent WRKY45 degradation occurs in the nuclei. Interestingly, the transcriptional activity of WRKY45 after salicylic acid treatment was impaired by proteasome inhibition. The same C-terminal region in WRKY45 was essential for both transcriptional activity and UPS-dependent degradation. These results suggest that UPS regulation also plays a role in the transcriptional activity of WRKY45. It has been reported that AtNPR1, the central regulator of the salicylic acid pathway in Arabidopsis, is regulated by the UPS. We found that OsNPR1/NH1, the rice counterpart of NPR1, was not stabilized by proteasome inhibition under uninfected conditions. We discuss the differences in post-translational regulation of salicylic acid pathway components between rice and Arabidopsis. © 2012 The Authors The Plant Journal © 2012 Blackwell Publishing Ltd.

The RY/Sph element mediates transcriptional repression of maturation genes from late maturation to early seedling growth.

PubMed

Guerriero, Gea; Martin, Nathalie; Golovko, Anna; Sundström, Jens F; Rask, Lars; Ezcurra, Ines

2009-11-01

In orthodox seeds, the transcriptional activator ABI3 regulates two major stages in embryo maturation: a mid-maturation (MAT) stage leading to accumulation of storage compounds, and a late maturation (LEA) stage leading to quiescence and desiccation tolerance. Our aim was to elucidate mechanisms for transcriptional shutdown of MAT genes during late maturation, to better understand phase transition between MAT and LEA stages. Using transgenic and transient approaches in Nicotiana, we examined activities of two ABI3-dependent reporter genes driven by multimeric RY and abscisic acid response elements (ABREs) from a Brassica napus napin gene, termed RY and ABRE, where the RY reporter requires ABI3 DNA binding. Expression of RY peaks during mid-maturation and drops during late maturation, mimicking the MAT gene program, and in Arabidopsis thaliana RY elements are over-represented in MAT, but not in LEA, genes. The ABI3 transactivation of RY is inhibited by staurosporine, by a PP2C phosphatase, and by a repressor of maturation genes, VAL1/HSI2. The RY element mediates repression of MAT genes, and we propose that transcriptional shutdown of the MAT program during late maturation involves inhibition of ABI3 DNA binding by dephosphorylation. Later, during seedling growth, VAL1/HSI2 family repressors silence MAT genes by binding RY elements.

Neural activation during response inhibition is associated with adolescents’ frequency of risky sex and substance use

PubMed Central

Feldstein Ewing, Sarah W.; Houck, Jon M.; Bryan, Angela D.

2015-01-01

While many have identified the important role of the developing brain in youth risk behavior, few have examined the relationship between salient cognitive factors (response inhibition) and different types of real-world adolescent health risk behaviors (substance use and risky sex) within the same sample of youth. We therefore sought to examine these relationships with 95 high-risk youth (ages 14-18; M age = 16.29 years). We examined the relationship between blood oxygen level dependent (BOLD) response to an fMRI-based cognitive task designed to assess response inhibition (Go/NoGo) and past month risk behavior (number of substance use days; number of unprotected sex days). For this sample of youth, we found significant negative correlations between past month substance use and response inhibition within the left inferior frontal gyrus (IFG) and right insula (uncorrected p < .001; extent threshold ≥ 10 voxels). In addition, in the same contrast, we found significant positive correlations between past month risky sex and activation within the right IFG and left middle occipital gyrus (uncorrected p < .001; extent threshold ≥ 10 voxels). These results suggest the particular relevance of these regions in this compelling, albeit slightly different pattern of response for adolescent substance use and risky sex. PMID:25532443

Neural activation during response inhibition is associated with adolescents' frequency of risky sex and substance use.

PubMed

Feldstein Ewing, Sarah W; Houck, Jon M; Bryan, Angela D

2015-05-01

While many have identified the important role of the developing brain in youth risk behavior, few have examined the relationship between salient cognitive factors (response inhibition) and different types of real-world adolescent health risk behaviors such as substance use and risky sex, within the same sample of youth. We therefore sought to examine these relationships with 95 high-risk youth (ages 14-18; M age = 16.29 years). We examined blood oxygen level dependent (BOLD) response to an fMRI-based cognitive task designed to assess response inhibition (Go/NoGo) and past month risk behavior (number of substance use days; number of unprotected sex days). For this sample of youth, we found significant negative correlations between past month substance use and response inhibition within the left inferior frontal gyrus (IFG) and right insula (uncorrected p < .001; extent threshold ≥ 10 voxels). In addition, in the same contrast, we found significant positive correlations between past month risky sex and activation within the right IFG and left middle occipital gyrus (uncorrected p < .001; extent threshold ≥ 10 voxels). These results suggest the particular relevance of these regions in this compelling, albeit slightly different, pattern of response for adolescent risky behaviors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Reversible inhibition of the platelet procoagulant response through manipulation of the Gardos channel.

PubMed

Wolfs, Jef L; Wielders, Simone J; Comfurius, Paul; Lindhout, Theo; Giddings, John C; Zwaal, Robert F; Bevers, Edouard M

2006-10-01

The platelet procoagulant response requires a sustained elevation of the intracellular Ca2+ concentration, [Ca2+]i, causing exposure of phosphatidylserine (PS) at the outer surface of the plasma membrane. An increased [Ca2+]i also activates Ca2+-dependent K+ channels. Here, we investigated the contribution of the efflux of K+ ions on the platelet procoagulant response in collagen-thrombin-activated platelets using selective K+ channel blockers. The Gardos channel blockers clotrimazol, charybdotoxin, and quinine caused a similar decrease in prothrombinase activity as well as in the number of PS-exposing platelets detected by fluorescence-conjugated annexin A5. Apamin and iberiotoxin, inhibitors of other K+ channels, were without effect. Only clotrimazol showed a significant inhibition of the collagen-plus-thrombin-induced intracellular calcium response. Clotrimazol and charybdotoxin did not inhibit aggregation and release under the conditions used. Inhibition by Gardos channel blockers was reversed by valinomycin, a selective K+ ionophore. The impaired procoagulant response of platelets from a patient with Scott syndrome was partially restored by pretreatment with valinomycin, suggesting a possible defect of the Gardos channel in this syndrome. Collectively, these results provide evidence for the involvement of efflux of K+ ions through Ca2+-activated K+ channels in the procoagulant response of platelets, opening potential strategies for therapeutic interventions.

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

PubMed

Strempel, Sebastian; Schroeder, Christoph; Hemmersbach, Ruth; Boese, Andrea; Tank, Jens; Diedrich, André; Heer, Martina; Luft, Friedrich C; Jordan, Jens

2008-03-01

Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 +/- 1 yr, body mass index 24 +/- 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.

Cardiac effects produced by long-term stimulation of thoracic autonomic ganglia or nerves: implications for interneuronal interactions within the thoracic autonomic nervous system.

PubMed

Butler, C; Watson-Wright, W M; Wilkinson, M; Johnstone, D E; Armour, J A

1988-03-01

Electrical stimulation of an acutely decentralized stellate or middle cervical ganglion or cardiopulmonary nerve augments cardiac chronotropism or inotropism; as the stimulation continues there is a gradual reduction of this augmentation following the peak response, i.e., an inhibition of augmentation. The amount of this inhibition was found to be dependent upon the region of the heart investigated and the neural structure stimulated. The cardiac parameters which were augmented the most displayed the greatest inhibition. Maximum augmentation or inhibition occurred, in most instances, when 5-20 Hz stimuli were used. Inhibition of augmentation was overcome when the stimulation frequency was subsequently increased or following the administration of nicotine or tyramine, indicating that the inhibition was not primarily due to the lack of availability of noradrenaline in the nerve terminals of the efferent postganglionic sympathetic neurons. Furthermore, as infusions of isoproterenol or noradrenaline during the period of inhibition could still augment cardiac responses, whereas during the early peak responses they did not, the inhibition of augmentation does not appear to be due primarily to down regulation of cardiac myocyte beta-adrenergic receptors. The inhibition was modified by hexamethonium but not by phentolamine or atropine. Inhibition occurred when all ipsilateral cardiopulmonary nerves connected with acutely decentralized middle cervical and stellate ganglia were stimulated, whereas significant inhibition did not occur when these nerves were stimulated after they had been disconnected from the ipsilateral decentralized ganglia. Taken together these data indicate that the inhibition of cardiac augmentation which occurs during relatively long-term stimulation of intrathoracic sympathetic neural elements is due in large part to nicotinic cholinergic synaptic mechanisms that lie primarily in the major thoracic autonomic ganglia. They also indicate that long-term stimulation in intrathoracic sympathetic neural elements with frequencies as low as 2 Hz may augment the heart as much as higher stimulation frequencies, depending upon the structure stimulated and the cardiovascular parameter monitored.

Inhibition of homodimerization of toll-like receptor 4 by 6-shogaol.

PubMed

Ahn, Sang-Il; Lee, Jun-Kyung; Youn, Hyung-Sun

2009-02-28

Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the activation of downstream signaling pathways including nuclear factor-kappa B (NF-kappaB). Therefore, TLR4 dimerization may be an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here, we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced dimerization of TLR4 resulting in the inhibition of NF-kappaB activation and the expression of cyclooxygenase-2. Furthermore, we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases.

Using eye tracking to identify faking attempts during penile plethysmography assessment.

PubMed

Trottier, Dominique; Rouleau, Joanne-Lucine; Renaud, Patrice; Goyette, Mathieu

2014-01-01

Penile plethysmography (PPG) is considered the most rigorous method for sexual interest assessment. Nevertheless, it is subject to faking attempts by participants, which compromises the internal validity of the instrument. To date, various attempts have been made to limit voluntary control of sexual response during PPG assessments, without satisfactory results. This exploratory research examined eye-tracking technologies' ability to identify the presence of cognitive strategies responsible for erectile inhibition during PPG assessment. Eye movements and penile responses for 20 subjects were recorded while exploring animated human-like computer-generated stimuli in a virtual environment under three distinct viewing conditions: (a) the free visual exploration of a preferred sexual stimulus without erectile inhibition; (b) the viewing of a preferred sexual stimulus with erectile inhibition; and (c) the free visual exploration of a non-preferred sexual stimulus. Results suggest that attempts to control erectile responses generate specific eye-movement variations, characterized by a general deceleration of the exploration process and limited exploration of the erogenous zone. Findings indicate that recording eye movements can provide significant information on the presence of competing covert processes responsible for erectile inhibition. The use of eye-tracking technologies during PPG could therefore lead to improved internal validity of the plethysmographic procedure.

The Swedish Hayling task, and its relation to working memory, verbal ability, and speech-recognition-in-noise.

PubMed

Stenbäck, Victoria; Hällgren, Mathias; Lyxell, Björn; Larsby, Birgitta

2015-06-01

Cognitive functions and speech-recognition-in-noise were evaluated with a cognitive test battery, assessing response inhibition using the Hayling task, working memory capacity (WMC) and verbal information processing, and an auditory test of speech recognition. The cognitive tests were performed in silence whereas the speech recognition task was presented in noise. Thirty young normally-hearing individuals participated in the study. The aim of the study was to investigate one executive function, response inhibition, and whether it is related to individual working memory capacity (WMC), and how speech-recognition-in-noise relates to WMC and inhibitory control. The results showed a significant difference between initiation and response inhibition, suggesting that the Hayling task taps cognitive activity responsible for executive control. Our findings also suggest that high verbal ability was associated with better performance in the Hayling task. We also present findings suggesting that individuals who perform well on tasks involving response inhibition, and WMC, also perform well on a speech-in-noise task. Our findings indicate that capacity to resist semantic interference can be used to predict performance on speech-in-noise tasks. © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

Cue-type manipulation dissociates two types of task set inhibition: backward inhibition and competitor rule suppression.

PubMed

Regev, Shirley; Meiran, Nachshon

2016-07-01

Backward inhibition (BI) reflects the suppression of a recently abandoned task set to allow for smooth transition to a new task even when the rules do not generate a response conflict. Competitor rule suppression (CRS) reflects the inhibition/suppression of irrelevant task rules when these rules generate a response conflict even if they have not recently been abandoned. We assessed whether BI and CRS are differentially affected by the difficulty in retrieving category-response mappings from memory. Retrieval demands were manipulated via the information provided by the task cues, which either indicated the relevant dimension (dimension cues; "color") or the relevant dimension with its category-to-key mapping (mapping cues; "red green", indicating that "red" and "green" go with the left/right responses, respectively). CRS was larger with dimension compared to mapping cues when cue-type varied between groups and was larger after trials involving dimension cues when cue-type varied on a trial-by-trial basis. In contrast, BI was not influenced by cue-type. These results suggest that task switching involve at least two distinct inhibitory processes, with CRS being related to the ease of retrieval of category-response mappings from memory.

Intergenerational Transmission of Risk for Social Inhibition: the Interplay between Parental Responsiveness and Genetic Influences

PubMed Central

Natsuaki, Misaki N.; Leve, Leslie D.; Neiderhiser, Jenae M.; Shaw, Daniel S.; Scaramella, Laura V.; Ge, Xiaojia; Reiss, David

2013-01-01

To better understand mechanisms underlying the intergenerational transmission of social anxiety, we used a prospective adoption design to examine the roles of genetic influences (inferred from birth mothers’ social phobia) and rearing environment (adoptive mothers’ and fathers’ responsiveness) on the development of socially inhibited, anxious behaviors in children between 18 and 27 months of age. The sample consisted of 275 adoption-linked families, each including an adopted child, adoptive parents, and a birth mother. Results indicated that children whose birth mothers met criteria for the diagnosis of social phobia showed elevated levels of observed behavioral inhibition in a social situation at 27 months of age if their adoptive mothers provided less emotionally and verbally responsive rearing environments at 18 months of age. Conversely, in the context of higher levels of maternal responsiveness, children of birth mothers with a history of social phobia did not show elevated levels of behavioral inhibition. These findings on maternal responsiveness were replicated in a model predicting parent reports of child social anxiety. The findings are discussed in terms of genotype × environment interactions in the intergenerational transmission of social anxiety. PMID:23398764

Effect of ZCR-2060, an antiallergic agent, on antigen-induced immediate- and late-phase increases in airway resistance in sensitized guinea pigs.

PubMed

Abe, T; Yoshida, K; Omata, T; Segawa, Y; Matsuda, K; Nagai, H

1995-01-01

The effect of 2-[2-[4-(diphenylmethyl)-1-piperadinyl]ethoxy] benzoic acid maleate (ZCR-2060) on passive systemic anaphylaxis (PSA) and antigen-induced immediate- and late-phase increase in airway resistance (Rrs) in either passively or actively sensitized guinea pigs were investigated. ZCR-2060 inhibited PSA in guinea pigs. ID50 values of ZCR-2060, ketotifen, terfenadine and cetirizine on PSA were 0.03, 0.02, 0.8 and 0.3 mg/kg, respectively, when administered orally 1 h before the antigen challenge. The protective effect of ZCR-2060 was observed until 12 h before the antigen challenge. Aeroantigen-induce immediate increase in Rrs in passively sensitized guinea pigs with and without metyrapone treatment was inhibited by ZCR-2060, ketotifen, terfenadine and cetirizine. In contrast, prednisolone did not affect the aeroantigen-induced immediate increase in Rrs in animals not treated with metyrapone, but significantly inhibited the metyrapone-induced enhanced immediate response. In actively sensitized animals, the immediate- and late-phase increases in Rrs were observed within 30 min and between 3 and 8 h after the aeroantigen challenge. Pretreatment with metyrapone accelerated both antigen-induced responses. ZCR-2060 (1 mg/kg) significantly inhibited both responses. Ketotifen (1 mg/kg), terfenadine (10 mg/kg) and prednisolone (10 mg/kg) significantly the inhibited the late-phase response, but did not affect the immediate-phase response. In contrast, Cetirizine (10 mg/kg) did not affect either response. The effect of ZCR-2060 on late-phase response was stronger than that of ketotifen, terfenadine and cetirizine, and was almost the same as that of prednisolone. These results suggest that ZCR-2060 has a potent protective effect on immediate- and late-phase increases in Rrs.

Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback

PubMed Central

Just, Armin; Arendshorst, William J

2005-01-01

This rat renal blood flow (RBF) study quantified the impact of nitric oxide synthase (NOS) inhibition on the myogenic response and the balance of autoregulatory mechanisms in the time domain following a 20 mmHg-step increase or decrease in renal arterial pressure (RAP). When RAP was increased, the myogenic component of renal vascular resistance (RVR) rapidly rose within the initial 7–10 s, exhibiting an ∼5 s time constant and providing ∼36% of perfect autoregulation. A secondary rise between 10 and 40 s brought RVR to 95% total autoregulatory efficiency, reflecting tubuloglomerular feedback (TGF) and possibly one or two additional mechanisms. The kinetics were similar after the RAP decrease. Inhibition of NOS (by l-NAME) increased RAP, enhanced the strength (79% autoregulation) and doubled the speed of the myogenic response, and promoted the emergence of RVR oscillations (∼0.2 Hz); the strength (52%) was lower at control RAP. An equi-pressor dose of angiotensin II had no effect on myogenic or total autoregulation. Inhibition of TGF (by furosemide) abolished the l-NAME effect on the myogenic response. RVR responses during furosemide treatment, assuming complete inhibition of TGF, suggest a third mechanism that contributes 10–20% and is independent of TGF, slower than the myogenic response, and abolished by NOS inhibition. The hindlimb circulation displayed a solitary myogenic response similar to the kidney (35% autoregulation) that was not enhanced by l-NAME. We conclude that NO normally restrains the strength and speed of the myogenic response in RBF but not hindlimb autoregulation, an action dependent on TGF, thereby allowing more and slow RAP fluctuations to reach glomerular capillaries. PMID:16223765

Effects of nitric oxide synthase inhibition with or without cyclooxygenase-2 inhibition on resting haemodynamics and responses to exendin-4

PubMed Central

Gardiner, S M; March, J E; Kemp, P A; Bennett, T

2006-01-01

Background and purpose: Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation. Here we measured the effects of acute cyclooxygenase-2 inhibition (with parecoxib), alone and in combination with NOS inhibition (with N G-nitro-L-arginine methyl ester (L-NAME)), on resting cardiovascular variables and on responses to the glucagon-like peptide 1 agonist, exendin-4, which causes regionally-selective vasoconstriction and vasodilatation. Experimental approach: Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious, freely moving state. L-NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle, and exendin-4 was given 60 min after the onset of L-NAME infusion. Key results: Parecoxib had no effect on resting cardiovascular variables or on responses to L-NAME. Exendin-4 caused a pressor response accompanied by tachycardia, mesenteric vasoconstriction and hindquarters vasodilatation. Parecoxib did not affect haemodynamic responses to exendin-4, but L-NAME inhibited its hindquarters vasodilator and tachycardic effects. When combined, L-NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response. Conclusions and implications: Cyclooxygenase-2-derived products do not affect basal haemodynamic status in conscious normotensive rats, or influence the NO system acutely. The inhibitory effects of L-NAME on the hindquarters vasodilator and tachycardic effects of exendin-4 are consistent with a previous study that showed those events to be β-adrenoceptor mediated. The additional effect of parecoxib on responses to exendin-4 in the presence of L-NAME, is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced. PMID:17016494

Peripheral gustatory processing of sweet stimuli by golden hamsters.

PubMed

Frank, Marion E; Formaker, Bradley K; Hettinger, Thomas P

2005-07-15

Behaviors and taste-nerve responses to bitter stimuli are linked to compounds that bind T2 receptors expressed in one subset of taste-bud receptor cells (TRCs); and behavioral and neural responses to sweet stimuli are linked to chemical compounds that bind a T1 receptor expressed in a different TRC subset. Neural and behavioral responses to bitter-sweet mixtures, however, complicate the ostensible bitter and sweet labeled lines. In the golden hamster, Mesocricetus auratus, quinine hydrochloride, the bitter prototype, suppresses chorda tympani (CT) nerve responses to the sweet prototype: sucrose. This bitter-sweet inhibition was tested with concentration series of sucrose and dulcin, a hydrophobic synthetic sweetener that hamsters behaviorally cross-generalize with sucrose. Dulcin, sucrose and other sweeteners activate one subset of CT fibers: S neurons; whereas, quinine activates a separate subset of CT fibers: E neurons. Whole-nerve and S-neuron CT responses to a sweetener concentration series, mixed with 0, 1, 3 and 10 mM quinine, were measured for 0-2.5 s transient and/or 2.6-10 s steady-state response periods. Ten-sec total single-fiber records, aligned at response onset, were averaged for 100 ms bins to identify response oscillations. Quinine inhibition of dulcin and sucrose responses was identical. Each log molar increment in quinine resulted in equivalent declines in response to either sweetener. Furthermore, sucrose response decrements paralleled response increments in quinine-sensitive CT neurons to the same quinine increases. A 1.43 Hz bursting rhythm to the sweeteners was unchanged by quinine inhibition or decreases in sweetener concentration. Taste-bud processing, possibly between-cell inhibition and within-cell negative feedback, must modify signals initiated by T1 receptors before they are transmitted to the brain.

Invariant natural killer T-cell control of type 1 diabetes: a dendritic cell genetic decision of a silver bullet or Russian roulette.

PubMed

Driver, John P; Scheuplein, Felix; Chen, Yi-Guang; Grier, Alexandra E; Wilson, S Brian; Serreze, David V

2010-02-01

In part, activation of invariant natural killer T (iNKT)-cells with the superagonist alpha-galactosylceramide (alpha-GalCer) inhibits the development of T-cell-mediated autoimmune type 1 diabetes in NOD mice by inducing the downstream differentiation of antigen-presenting dendritic cells (DCs) to an immunotolerogenic state. However, in other systems iNKT-cell activation has an adjuvant-like effect that enhances rather than suppresses various immunological responses. Thus, we tested whether in some circumstances genetic variation would enable activated iNKT-cells to support rather than inhibit type 1 diabetes development. We tested whether iNKT-conditioned DCs in NOD mice and a major histocompatibility complex-matched C57BL/6 (B6) background congenic stock differed in capacity to inhibit type 1 diabetes induced by the adoptive transfer of pathogenic AI4 CD8 T-cells. Unlike those of NOD origin, iNKT-conditioned DCs in the B6 background stock matured to a state that actually supported rather than inhibited AI4 T-cell-induced type 1 diabetes. The induction of a differing activity pattern of T-cell costimulatory molecules varying in capacity to override programmed death-ligand-1 inhibitory effects contributes to the respective ability of iNKT-conditioned DCs in NOD and B6 background mice to inhibit or support type 1 diabetes development. Genetic differences inherent to both iNKT-cells and DCs contribute to their varying interactions in NOD and B6.H2(g7) mice. This great variability in the interactions between iNKT-cells and DCs in two inbred mouse strains should raise a cautionary note about considering manipulation of this axis as a potential type 1 diabetes prevention therapy in genetically heterogeneous humans.

Effects of GABAA receptor inhibition on response properties of barrel cortical neurons in C-fiber-depleted rats.

PubMed

Farazifard, Rasoul; Kiani, Roozbeh; Esteky, Hossein

2005-07-19

C-fiber depletion results in expansion of low threshold somatosensory mechanoreceptive fields. In this study, we investigated the role of intact C-fibers in GABAA-mediated inhibition in barrel cortical neurons. We used electronically controlled mechanical stimulation of whiskers to quantitatively examine the responses of barrel cells to whisker displacements. After systemic injection of picrotoxin neuronal responses were recorded at 5 min intervals for 20 min and then at 10 min intervals for 100 min. Picrotoxin injection caused a 3-fold increase in response magnitude of adjacent whisker stimulation and 1.4-fold increase in response magnitude of principal whisker stimulation with a maximum enhancement 50 min after the injection. There was no significant change in spontaneous activity following picrotoxin injection. The response enhancement and receptive field expansion observed in normal rats were completely absent in the C-fiber-depleted rats. These results suggest that the GABAA-mediated inhibition that modulates the receptive field functional organization of the barrel cortex depends on intact C-fibers.

Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.

PubMed

Hempstead, Andrew D; Isberg, Ralph R

2015-12-08

Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.

Nipah Virus V Protein Evades Alpha and Gamma Interferons by Preventing STAT1 and STAT2 Activation and Nuclear Accumulation

PubMed Central

Rodriguez, Jason J.; Parisien, Jean-Patrick; Horvath, Curt M.

2002-01-01

Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V proteins. The V proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V protein escapes IFN by a distinct mechanism involving direct inhibition of STAT protein function. Nipah virus V protein differs from other paramyxovirus V proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT protein subcellular distribution in the steady state, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V protein. As a result, Nipah virus V protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-α and IFN-γ. PMID:12388709

Can't stop the craving: the effect of impulsivity on cue-elicited craving for alcohol in heavy and light social drinkers.

PubMed

Papachristou, Harilaos; Nederkoorn, Chantal; Havermans, Remco; van der Horst, Martje; Jansen, Anita

2012-01-01

A robust finding in the alcohol literature is that heavy and alcohol-dependent drinkers show stronger reactions to alcohol-related cues than light drinkers. However, there are individual differences in the degree of cue-elicited craving. Personality factors appear to be involved in cue reactivity and impulsivity is a possible candidate. The aim of the present study was to examine the role of different aspects of impulsivity in heavy drinking and alcohol cue reactivity in social drinkers. Participants were heavy (n = 13) and light (n = 29) social drinkers who were exposed to neutral and alcohol-related stimuli during a single laboratory session. Trait impulsivity, response inhibition, and sensitivity to reward were assessed with the Barratt Impulsiveness Scale (BIS-11), the Stop Signal Task, and the Card-Arranging Reward Responsivity Objective Test, respectively. Heavy drinkers scored higher on trait impulsivity (BIS-11) than light drinkers. In addition, heavy drinkers reported elevated levels of craving for alcohol, but both in light and heavy drinkers, craving increased equally after exposure to alcohol cues. Impulsivity appeared to moderate this relation: heavy drinkers with ineffective response inhibition showed more craving to alcohol cues, compared to heavy drinkers with adequate response inhibition. In light drinkers, response inhibition did not influence craving to alcohol cues. Different aspects of impulsivity are involved in heavy drinking and perhaps motivate alcohol consumption in a variety of ways. Having a deficient response inhibition appears to be a risk factor for heavy drinkers because it is associated with increased craving to alcohol cues.

Resistance to Rhabdoviridae Infection and Subversion of Antiviral Responses.

PubMed

Blondel, Danielle; Maarifi, Ghizlane; Nisole, Sébastien; Chelbi-Alix, Mounira K

2015-07-07

Interferon (IFN) treatment induces the expression of hundreds of IFN-stimulated genes (ISGs). However, only a selection of their products have been demonstrated to be responsible for the inhibition of rhabdovirus replication in cultured cells; and only a few have been shown to play a role in mediating the antiviral response in vivo using gene knockout mouse models. IFNs inhibit rhabdovirus replication at different stages via the induction of a variety of ISGs. This review will discuss how individual ISG products confer resistance to rhabdoviruses by blocking viral entry, degrading single stranded viral RNA, inhibiting viral translation or preventing release of virions from the cell. Furthermore, this review will highlight how these viruses counteract the host IFN system.

Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses.

PubMed

Santiago, Felix W; Covaleda, Lina M; Sanchez-Aparicio, Maria T; Silvas, Jesus A; Diaz-Vizarreta, Ana C; Patel, Jenish R; Popov, Vsevolod; Yu, Xue-jie; García-Sastre, Adolfo; Aguilar, Patricia V

2014-04-01

Recognition of viral pathogens by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family results in the activation of type I interferon (IFN) responses. To avoid this response, most viruses have evolved strategies that target different essential steps in the activation of host innate immunity. In this study, we report that the nonstructural protein NSs of the newly described severe fever with thrombocytopenia syndrome virus (SFTSV) is a potent inhibitor of IFN responses. The SFTSV NSs protein was found to inhibit the activation of the beta interferon (IFN-β) promoter induced by viral infection and by a RIG-I ligand. Astonishingly, we found that SFTSV NSs interacts with and relocalizes RIG-I, the E3 ubiquitin ligase TRIM25, and TANK-binding kinase 1 (TBK1) into SFTSV NSs-induced cytoplasmic structures. Interestingly, formation of these SFTSV NSs-induced structures occurred in the absence of the Atg7 gene, a gene essential for autophagy. Furthermore, confocal microscopy studies revealed that these SFTSV NSs-induced structures colocalize with Rab5 but not with Golgi apparatus or endoplasmic reticulum markers. Altogether, the data suggest that sequestration of RIG-I signaling molecules into endosome-like structures may be the mechanism used by SFTSV to inhibit IFN responses and point toward a novel mechanism for the suppression of IFN responses. The mechanism by which the newly described SFTSV inhibits host antiviral responses has not yet been fully characterized. In this study, we describe the redistribution of RIG-I signaling components into virus-induced cytoplasmic structures in cells infected with SFTSV. This redistribution correlates with the inhibition of host antiviral responses. Further characterization of the interplay between the viral protein and components of the IFN responses could potentially provide targets for the rational development of therapeutic interventions.

Hijacking of RIG-I Signaling Proteins into Virus-Induced Cytoplasmic Structures Correlates with the Inhibition of Type I Interferon Responses

PubMed Central

Santiago, Felix W.; Covaleda, Lina M.; Sanchez-Aparicio, Maria T.; Silvas, Jesus A.; Diaz-Vizarreta, Ana C.; Patel, Jenish R.; Popov, Vsevolod; Yu, Xue-jie; García-Sastre, Adolfo

2014-01-01

ABSTRACT Recognition of viral pathogens by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family results in the activation of type I interferon (IFN) responses. To avoid this response, most viruses have evolved strategies that target different essential steps in the activation of host innate immunity. In this study, we report that the nonstructural protein NSs of the newly described severe fever with thrombocytopenia syndrome virus (SFTSV) is a potent inhibitor of IFN responses. The SFTSV NSs protein was found to inhibit the activation of the beta interferon (IFN-β) promoter induced by viral infection and by a RIG-I ligand. Astonishingly, we found that SFTSV NSs interacts with and relocalizes RIG-I, the E3 ubiquitin ligase TRIM25, and TANK-binding kinase 1 (TBK1) into SFTSV NSs-induced cytoplasmic structures. Interestingly, formation of these SFTSV NSs-induced structures occurred in the absence of the Atg7 gene, a gene essential for autophagy. Furthermore, confocal microscopy studies revealed that these SFTSV NSs-induced structures colocalize with Rab5 but not with Golgi apparatus or endoplasmic reticulum markers. Altogether, the data suggest that sequestration of RIG-I signaling molecules into endosome-like structures may be the mechanism used by SFTSV to inhibit IFN responses and point toward a novel mechanism for the suppression of IFN responses. IMPORTANCE The mechanism by which the newly described SFTSV inhibits host antiviral responses has not yet been fully characterized. In this study, we describe the redistribution of RIG-I signaling components into virus-induced cytoplasmic structures in cells infected with SFTSV. This redistribution correlates with the inhibition of host antiviral responses. Further characterization of the interplay between the viral protein and components of the IFN responses could potentially provide targets for the rational development of therapeutic interventions. PMID:24478431

Focal hand dystonia: individualized intervention with repeated application of repetitive transcranial magnetic stimulation.

PubMed

Kimberley, Teresa Jacobson; Borich, Michael R; Schmidt, Rebekah L; Carey, James R; Gillick, Bernadette

2015-04-01

To examine for individual factors that may predict response to inhibitory repetitive transcranial magnetic stimulation (rTMS) in focal hand dystonia (FHD); to present the method for determining optimal stimulation to increase inhibition in a given patient; and to examine individual responses to prolonged intervention. Single-subject design to determine optimal parameters to increase inhibition for a given subject and to use the selected parameters once per week for 6 weeks, with 1-week follow-up, to determine response. Clinical research laboratory. A volunteer sample of subjects with FHD (N = 2). One participant had transcranial magnetic stimulation responses indicating impaired inhibition, and the other had responses within normative limits. There were 1200 pulses of 1-Hz rTMS delivered using 4 different stimulation sites/intensity combinations: primary motor cortex at 90% or 110% of resting motor threshold (RMT) and dorsal premotor cortex (PMd) at 90% or 110% of RMT. The parameters producing the greatest within-session increase in cortical silent period (CSP) duration were then used as the intervention. Response variables included handwriting pressure and velocity, subjective symptom rating, CSP, and short latency intracortical inhibition and facilitation. The individual with baseline transcranial magnetic stimulation responses indicating impaired inhibition responded favorably to the repeated intervention, with reduced handwriting force, an increase in the CSP, and subjective report of moderate symptom improvement at 1-week follow-up. The individual with normative baseline responses failed to respond to the intervention. In both subjects, 90% of RMT to the PMd produced the greatest lengthening of the CSP and was used as the intervention. An individualized understanding of neurophysiological measures can be an indicator of responsiveness to inhibitory rTMS in focal dystonia, with further work needed to determine likely responders versus nonresponders. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Functional behavioral analysis and social scripting for the older patient with schizophrenia: a staff development program.

PubMed

Markwick, Laura; Smith, Charlene; Mick, Diane

2014-11-01

Executive functioning is the ability to plan, strategize, organize, and focus on details. Impaired executive functioning plays a significant role in behavior disturbances. Lack of inhibition, impaired abstract reasoning, thought perseverance, rigidity in routine, and lack of insight disrupt social skills and daily life. Autism and schizophrenia present some similar behaviors, including impaired executive functioning, often resulting in pharmacological management as many healthcare professionals receive limited training in executive functioning. Non-pharmacological tools used in autism for behavior management include functional behavioral analysis and social scripting, which help to identify causes of behavior and teach more appropriate behavioral responses. Described here is an educational program for healthcare workers in a long-term care skilled nursing facility, to help them understand the basis for behaviors in individuals with impaired executive function, to use these same tools for behavioral modification techniques, and to help patients learn more appropriate social skills. Program evaluation suggested the educational program was successful in increasing the staff's knowledge and comfort level in addressing the behavioral issues that arise with this population and staff also reported less use of medication as first-line treatment for behavioral issues.

Reward Improves Cancellation and Restraint Inhibition Across Childhood and Adolescence

PubMed Central

Sinopoli, Katia J.; Schachar, Russell; Dennis, Maureen

2011-01-01

Inhibitory control allows for the regulation of thought and action, and interacts with motivational variables, such as reward, to modify behavior adaptively as environments change. We examined the effects of reward on two distinct forms of inhibitory control, cancellation and restraint. Typically developing children and adolescents completed two versions of the stop signal task (cancellation and restraint) under three reward conditions (neutral, low reward, and high reward), where rewards were earned for successful inhibitory control. Rewards improved both cancellation and restraint inhibition, with similar effects of reward on each form of inhibitory control. Rewards did not alter the speed of response execution in either task, suggesting that rewards specifically altered inhibition processes without influencing processes related to response execution. Adolescents were faster and less variable than children when executing and inhibiting their responses. There were similar developmental effects of reward on the speed of inhibitory control, but group differences were found in terms of accuracy of inhibition in the restraint task. These results clarify how reward modulates two different forms of regulatory behavior in children and adolescents. PMID:21744952

DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.

PubMed

Kagoya, Yuki; Nakatsugawa, Munehide; Saso, Kayoko; Guo, Tingxi; Anczurowski, Mark; Wang, Chung-Hsi; Butler, Marcus O; Arrowsmith, Cheryl H; Hirano, Naoto

2018-05-15

Adoptive T-cell therapy is a promising therapeutic approach for cancer patients. The use of allogeneic T-cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T-cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Here we report that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviates allogeneic T-cell responses. DOT1L inhibition reduces miR-181a expression, which in turn increases the ERK phosphatase DUSP6 expression and selectively ameliorates low-avidity T-cell responses through globally suppressing T-cell activation-induced gene expression alterations. The inhibition of DOT1L or DUSP6 overexpression in T cells attenuates the development of graft-versus-host disease, while retaining potent antitumor activity in xenogeneic and allogeneic adoptive immunotherapy models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in adoptive immunotherapy.

Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.

PubMed

Knight, Jason S; Luo, Wei; O'Dell, Alexander A; Yalavarthi, Srilakshmi; Zhao, Wenpu; Subramanian, Venkataraman; Guo, Chiao; Grenn, Robert C; Thompson, Paul R; Eitzman, Daniel T; Kaplan, Mariana J

2014-03-14

Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Apolipoprotein-E (Apoe)(-/-) mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe(-/-) mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.

Inhibition of lymphocyte proliferation and antibody production in vitro by silica, talc, bentonite or Corynebacterium parvum: involvement of peroxidative processes.

PubMed

Hoffeld, J T

1983-05-01

This study was undertaken to determine whether and by what means particles which induce granulomata in vivo can affect murine spleen lymphoproliferative and antibody responses in vitro. Particles of silica, talc, Bentonite or C. parvum cells inhibited lipopolysaccharide- or concanavalin A-stimulated proliferation and sheep red blood cell-induced antibody response in vitro. The inhibition required at least 48 hours exposure of the cells to the particles. The late onset of inhibition and its reproducibility at different cell or mitogen concentrations implicated particle-induced injury to both phagocytes and lymphocytes. Either alpha-tocopherol or 2-mercaptoethanol prevented the particle-induced inhibition of spleen cell responses. alpha-Tocopherol and 2-mercaptoethanol have in common the capacity to protect cells against membrane lipid peroxidation. The inhibitory peroxidative process(es) implicated by these studies are most likely attributable to: (a) stimulation of oxidative metabolism of phagocytic cells by particles; and (b) iron-catalyzed peroxidation directly by the particles. These data may be relevant in understanding the pathogenesis of and devising therapeutic approaches toward various granulomatous conditions.

Altered inhibition-related frontolimbic connectivity in obsessive-compulsive disorder.

PubMed

van Velzen, Laura S; de Wit, Stella J; Ćurĉić-Blake, Branislava; Cath, Daniëlle C; de Vries, Froukje E; Veltman, Dick J; van der Werf, Ysbrand D; van den Heuvel, Odile A

2015-10-01

Recent studies have shown that response inhibition is impaired in patients with obsessive-compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive-compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive-compulsive disorder and their unaffected siblings. Forty-one unmedicated patients with obsessive-compulsive disorder, 17 of their unaffected siblings and 37 healthy controls performed a stop signal task during functional magnetic resonance imaging. Psycho-physiological interaction analysis was used to examine functional connectivity between the following regions of interest: the bilateral inferior frontal gyri, presupplementary motor area, subthalamic nuclei, inferior parietal lobes, anterior cingulate cortex, and amygdala. We then used dynamic causal modeling to investigate the directionality of the networks involved. Patients, and to a lesser extent also their unaffected siblings, show altered connectivity between the inferior frontal gyrus and the amygdala during response inhibition. The follow-up dynamic causal modeling suggests a bottom-up influence of the amygdala on the inferior frontal gyrus in healthy controls, whereas processing occurs top-down in patients with obsessive-compulsive, and in both directions in siblings. Our findings suggest that amygdala activation in obsessive-compulsive disorder interferes differently with the task-related recruitment of the inhibition network, underscoring the role of limbic disturbances in cognitive dysfunctions in obsessive-compulsive disorder. © 2015 Wiley Periodicals, Inc.

Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition.

PubMed

Devin, Jessica K; Pretorius, Mias; Nian, Hui; Yu, Chang; Billings, Frederic T; Brown, Nancy J

2014-05-01

Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition. - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.

Substance P increases Sympathetic Activity during Combined Angiotensin Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition

PubMed Central

Devin, Jessica K.; Pretorius, Mias; Nian, Hui; Yu, Chang; Billings, Frederic T.; Brown, Nancy J.

2014-01-01

Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce post-prandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme. During angiotensin-converting enzyme inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, while bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when angiotensin-converting enzyme is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg p.o. or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat, however, substance P increased heart rate and vascular release of norepinephrine during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. PMID:24516103

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

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

Ribeiro-Filho, Jaime; Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba; Calheiros, Andrea Surrage

Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effectsmore » of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine mechanisms involve inhibition of Ca{sup 2+} influx, and IL-13 and eotaxin secretion. • No significant toxicity was observed in mice orally treated with curine for 7 days. • Curine has the potential for the development of anti-asthmatic drugs.« less

Synergistic inhibition of PARP-1 and NF-κB signaling downregulates immune response against recombinant AAV2 vectors during hepatic gene therapy.

PubMed

Hareendran, Sangeetha; Ramakrishna, Banumathi; Jayandharan, Giridhara R

2016-01-01

Host immune response remains a key obstacle to widespread application of adeno-associated virus (AAV) based gene therapy. Thus, targeted inhibition of the signaling pathways that trigger such immune responses will be beneficial. Previous studies have reported that DNA damage response proteins such as poly(ADP-ribose) polymerase-1 (PARP-1) negatively affect the integration of AAV in the host genome. However, the role of PARP-1 in regulating AAV transduction and the immune response against these vectors has not been elucidated. In this study, we demonstrate that repression of PARP-1 improves the transduction of single-stranded AAV vectors both in vitro (∼174%) and in vivo (two- to 3.4-fold). Inhibition of PARP-1, also significantly downregulated the expression of several proinflammatory and cytokine markers such as TLRs, ILs, NF-κB subunit proteins associated with the host innate response against self-complementary AAV2 vectors. The suppression of the inflammatory response targeted against these vectors was more effective upon combined inhibition of PARP-1 and NF-κB signaling. This strategy also effectively attenuated the AAV capsid-specific cytotoxic T-cell response, with minimal effect on vector transduction, as demonstrated in normal C57BL/6 and hemophilia B mice. These data suggest that targeting specific host cellular proteins could be useful to attenuate the immune barriers to AAV-mediated gene therapy. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Food-specific response inhibition, dietary restraint and snack intake in lean and overweight/obese adults: a moderated-mediation model

PubMed Central

Price, M; Lee, M; Higgs, S

2016-01-01

Background/Objectives: The relationship between response inhibition and obesity is currently unclear. This may be because of inconsistencies in methodology, design limitations and the use of narrow samples. In addition, dietary restraint has not been considered, yet restraint has been reported to moderate performance on behavioural tasks of response inhibition. The aim of this study was to investigate performance on both a food-based and a neutral stimuli go/no-go task, which addresses current design limitations, in lean and overweight/obese adults. The moderating role of dietary restraint in the relationship between body composition, response inhibition and snack intake was also measured. Subjects/Methods: Lean and overweight/obese, males and females (N=116) completed both a food-based and neutral category control go/no-go task, in a fully counterbalanced repeated-measures design. A bogus taste-test was then completed, followed by a self-report measure of dietary restraint. Results: PROCESS moderated-mediation analysis showed that overweight/obese, compared with lean, participants made more errors on the food-based (but not the neutral) go/no-go task, but only when they were low in dietary restraint. Performance on the food-based go/no-go task predicted snack intake across the sample. Increased intake in the overweight, low restrainers was fully mediated by increased errors on the food-based (but not the neutral) go/no-go task. Conclusions: Distinguishing between high and low restrained eaters in the overweight/obese population is crucial in future obesity research incorporating food-based go/no-go tasks. Poor response inhibition to food cues predicts overeating across weight groups, suggesting weight loss interventions and obesity prevention programmes should target behavioural inhibition training in such individuals. PMID:26592733

Food-specific response inhibition, dietary restraint and snack intake in lean and overweight/obese adults: a moderated-mediation model.

PubMed

Price, M; Lee, M; Higgs, S

2016-05-01

The relationship between response inhibition and obesity is currently unclear. This may be because of inconsistencies in methodology, design limitations and the use of narrow samples. In addition, dietary restraint has not been considered, yet restraint has been reported to moderate performance on behavioural tasks of response inhibition. The aim of this study was to investigate performance on both a food-based and a neutral stimuli go/no-go task, which addresses current design limitations, in lean and overweight/obese adults. The moderating role of dietary restraint in the relationship between body composition, response inhibition and snack intake was also measured. Lean and overweight/obese, males and females (N=116) completed both a food-based and neutral category control go/no-go task, in a fully counterbalanced repeated-measures design. A bogus taste-test was then completed, followed by a self-report measure of dietary restraint. PROCESS moderated-mediation analysis showed that overweight/obese, compared with lean, participants made more errors on the food-based (but not the neutral) go/no-go task, but only when they were low in dietary restraint. Performance on the food-based go/no-go task predicted snack intake across the sample. Increased intake in the overweight, low restrainers was fully mediated by increased errors on the food-based (but not the neutral) go/no-go task. Distinguishing between high and low restrained eaters in the overweight/obese population is crucial in future obesity research incorporating food-based go/no-go tasks. Poor response inhibition to food cues predicts overeating across weight groups, suggesting weight loss interventions and obesity prevention programmes should target behavioural inhibition training in such individuals.

Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype.

PubMed

Kindler, Jochen; Weickert, Cynthia Shannon; Schofield, Peter R; Lenroot, Rhoshel; Weickert, Thomas W

2016-12-01

People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippocampal activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Immune Checkpoints in Leprosy: Immunotherapy As a Feasible Approach to Control Disease Progression.

PubMed

Lima, Hayana Ramos; Gasparoto, Thaís Helena; de Souza Malaspina, Tatiana Salles; Marques, Vinícius Rizzo; Vicente, Marina Jurado; Marcos, Elaine Camarinha; Souza, Fabiana Corvolo; Nogueira, Maria Renata Sales; Barreto, Jaison Antônio; Garlet, Gustavo Pompermaier; da Silva, João Santana; Brito-de-Souza, Vânia Nieto; Campanelli, Ana Paula

2017-01-01

Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae . Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae , are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.

Direct Care Workers in the National Drug Abuse Treatment Clinical Trials Network: Characteristics, Opinions, and Beliefs

PubMed Central

McCarty, Dennis; Fuller, Bret E.; Arfken, Cynthia; Miller, Michael; Nunes, Edward V.; Edmundson, Eldon; Copersino, Marc; Floyd, Anthony; Forman, Robert; Laws, Reesa; Magruder, Kathy M.; Oyama, Mark; Sindelar, Jody; Wendt, William W.

2010-01-01

Objective Individuals with direct care responsibilities in 348 drug abuse treatment units were surveyed to obtain a description of the workforce and to assess support for evidence-based therapies. Methods Surveys were distributed to 112 programs participating in the National Drug Abuse Treatment Clinical Trials Network (CTN). Descriptive analyses characterized the workforce. Analyses of covariance tested the effects of job category (counselors, medical staff, manager-supervisors, and support staff) on opinions about evidence-based practices and controlled for the effects of education, modality (outpatient or residential), race, and gender. Results Women made up two-thirds of the CTN workforce. One-third of the workforce had a master’s or doctoral degree. Responses from 1,757 counselors, 908 support staff, 522 managers-supervisors, and 511 medical staff (71% of eligible participants) suggested that the variables that most consistently influenced responses were job category (19 of 22 items) and education (20 of 22 items). Managers-supervisors were the most supportive of evidence-based therapies, and support staff were the least supportive. Generally, individuals with graduate degrees had more positive opinions about evidence-based therapies. Support for using medications and contingency management was modest across job categories. Conclusions The relatively traditional beliefs of support staff could inhibit the introduction of evidence-based practices. Programs initiating changes in therapeutic approaches may benefit from including all employees in change efforts. PMID:17287373

Hypoxia as a therapy for mitochondrial disease.

PubMed

Jain, Isha H; Zazzeron, Luca; Goli, Rahul; Alexa, Kristen; Schatzman-Bone, Stephanie; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E; Zhang, Feng; Goessling, Wolfram; Zapol, Warren M; Mootha, Vamsi K

2016-04-01

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction. Copyright © 2016, American Association for the Advancement of Science.

Arabidopsis Reduces Growth Under Osmotic Stress by Decreasing SPEECHLESS Protein

PubMed Central

Kumari, Archana; Jewaria, Pawan K.; Bergmann, Dominique C.; Kakimoto, Tatsuo

2014-01-01

Plants, which are sessile unlike most animals, have evolved a system to reduce growth under stress; however, the molecular mechanisms of this stress response are not well known. During programmed development, a fraction of the leaf epidermal precursor cells become meristemoid mother cells (MMCs), which are stem cells that produce both stomatal guard cells and epidermal pavement cells. Here we report that Arabidopsis plants, in response to osmotic stress, post-transcriptionally decrease the protein level of SPEECHLESS, the transcription factor promoting MMC identity, through the action of a mitogen-activated protein kinase (MAPK) cascade. The growth reduction under osmotic stress was lessened by inhibition of the MAPK cascade or by a mutation that disrupted the MAPK target amino acids in SPEECHLESS, indicating that Arabidopsis reduces growth under stress by integrating the osmotic stress signal into the MAPK–SPEECHLESS core developmental pathway. PMID:25381317

Brief Report: The Go/No-Go Task Online: Inhibitory Control Deficits in Autism in a Large Sample

ERIC Educational Resources Information Center

Uzefovsky, F.; Allison, C.; Smith, P.; Baron-Cohen, S.

2016-01-01

Autism Spectrum Conditions (ASC, also referred to as Autism Spectrum Disorders) entail difficulties with inhibition: inhibiting action, inhibiting one's own point of view, and inhibiting distractions that may interfere with a response set. However, the association between inhibitory control (IC) and ASC, especially in adulthood, is unclear. The…

Stopping while Going! Response Inhibition Does Not Suffer Dual-Task Interference

ERIC Educational Resources Information Center

Yamaguchi, Motonori; Logan, Gordon D.; Bissett, Patrick G.

2012-01-01

Although dual-task interference is ubiquitous in a variety of task domains, stop-signal studies suggest that response inhibition is not subject to such interference. Nevertheless, no study has directly examined stop-signal performance in a dual-task setting. In two experiments, stop-signal performance was examined in a psychological refractory…

Response Inhibition in Adults with Autism Spectrum Disorder Compared to Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Johnston, Kate; Madden, Anya K.; Bramham, Jessica; Russell, Ailsa J.

2011-01-01

Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are hypothesised to involve core deficits in executive function. Previous studies have found evidence of a double dissociation between the disorders on specific executive functions (planning and response inhibition). To date most research has been conducted with…

Response Inhibition and ADHD Traits: Correlates and Heritability in a Community Sample

ERIC Educational Resources Information Center

Crosbie, J.; Arnold, P.; Paterson, A.; Swanson, J.; Dupuis, A.; Li, X.; Shan, J.; Goodale, T.; Tam, C.; Strug, L. J.; Schachar, R. J.

2013-01-01

Endophenotypes or intermediate phenotypes are of great interest in neuropsychiatric genetics because of their potential for facilitating gene discovery. We evaluated response inhibition, latency and variability measures derived from the stop task as endophenotypes of ADHD by testing whether they were related to ADHD traits in the general…

Response Requirement and Nature of Interpolated Stories in Retroactive Inhibition in Prose.

ERIC Educational Resources Information Center

Van Mondfrans, Adrian P.; And Others

Retroactive inhibition, a loss of memory due to learning other materials between recall and exposure to the original materials, was investigated in relation to prose. Two variables were manipulated in the study: similarity of interpolated stories (dissimilar or similar), and the response requirements (completion-recall or multiple-choice). The 190…

Scutellaria flavonoids inhibit tumor-mediated induction of Treg cells via inhibition of TGF-ß1 activity

USDA-ARS?s Scientific Manuscript database

It has become evident that tumor-induced Treg cell activity is mostly responsible for the sub-optimal response to therapeutic vaccines. Development of neo-adjuvant strategies targeting TGF-ß and Treg cell activity is therefore imperative. Scutellaria extracts or constituent flavonoids have shown e...

Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

USDA-ARS?s Scientific Manuscript database

Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

Improving response inhibition systems in frontotemporal dementia with citalopram

PubMed Central

Rittman, Timothy; Regenthal, Ralf; Robbins, Trevor W.; Rowe, James B.

2015-01-01

Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel-based morphometry confirmed significant atrophy of inferior frontal gyrus, alongside insular, orbitofrontal and temporal cortex in our patient cohort. Together, these data suggest that the dysfunctional prefrontal cortical systems underlying response inhibition deficits in behavioural variant frontotemporal dementia can be partially restored by increasing serotonergic neurotransmission. The results support a translational neuroscience approach to impulsive neurological disorders and indicate the potential for symptomatic treatment of behavioural variant frontotemporal dementia including serotonergic strategies to improve disinhibition. PMID:26001387

Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis

PubMed Central

Chen, Liye; Ridley, Anna; Hammitzsch, Ariane; Al-Mossawi, Mohammad Hussein; Bunting, Helen; Georgiadis, Dimitris; Chan, Antoni; Kollnberger, Simon; Bowness, Paul

2016-01-01

Objective Human leucocyte antigen (HLA)-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly associated with ankylosing spondylitis (AS). ERAP1 is a key aminopeptidase in HLA class I presentation and can potentially alter surface expression of HLA-B27 free heavy chains (FHCs). We studied the effects of ERAP1 silencing/inhibition/variations on HLA-B27 FHC expression and Th17 responses in AS. Methods Flow cytometry was used to measure surface expression of HLA class I in peripheral blood mononuclear cells (PBMCs) from patients with AS carrying different ERAP1 genotypes (rs2287987, rs30187 and rs27044) and in ERAP1-silenced/inhibited/mutated HLA-B27-expressing antigen presenting cells (APCs). ERAP1-silenced/inhibited APCs were cocultured with KIR3DL2CD3ε-reporter cells or AS CD4+ T cells. Th17 responses of AS CD4+ T cells were measured by interleukin (IL)-17A ELISA and Th17 intracellular cytokine staining. FHC cell surface expression and Th17 responses were also measured in AS PBMCs following ERAP1 inhibition. Results The AS-protective ERAP1 variants, K528R and Q730E, were associated with reduced surface FHC expression by monocytes from patients with AS and HLA-B27-expressing APCs. ERAP1 silencing or inhibition in APCs downregulated HLA-B27 FHC surface expression, reduced IL-2 production by KIR3DL2CD3ε-reporter cells and suppressed the Th17 expansion and IL-17A secretion by AS CD4+ T cells. ERAP1 inhibition of AS PBMCs reduced HLA class I FHC surface expression by monocytes and B cells, and suppressed Th17 expansion. Conclusions ERAP1 activity determines surface expression of HLA-B27 FHCs and potentially promotes Th17 responses in AS through binding of HLA-B27 FHCs to KIR3DL2. Our data suggest that ERAP1 inhibition has potential for AS treatment. PMID:26130142

UV-B inhibition of hypocotyl growth in etiolated Arabidopsis thaliana seedlings is a consequence of cell cycle arrest initiated by photodimer accumulation

PubMed Central

Biever, Jessica J.; Brinkman, Doug; Gardner, Gary

2014-01-01

Ultraviolet (UV) radiation is an important constituent of sunlight that determines plant morphology and growth. It induces photomorphogenic responses but also causes damage to DNA. Arabidopsis mutants of the endonucleases that function in nucleotide excision repair, xpf-3 and uvr1-1, showed hypersensitivity to UV-B (280–320nm) in terms of inhibition of hypocotyl growth. SOG1 is a transcription factor that functions in the DNA damage signalling response after γ-irradiation. xpf mutants that carry the sog1-1 mutation showed hypocotyl growth inhibition after UV-B irradiation similar to the wild type. A DNA replication inhibitor, hydroxyurea (HU), also inhibited hypocotyl growth in etiolated seedlings, but xpf-3 was not hypersensitive to HU. UV-B irradiation induced accumulation of the G2/M-specific cell cycle reporter construct CYCB1;1-GUS in wild-type Arabidopsis seedlings that was consistent with the expected accumulation of photodimers and coincided with the time course of hypocotyl growth inhibition after UV-B treatment. Etiolated mutants of UVR8, a recently described UV-B photoreceptor gene, irradiated with UV-B showed inhibition of hypocotyl growth that was not different from that of the wild type, but they lacked UV-B-specific expression of chalcone synthase (CHS), as expected from previous reports. CHS expression after UV-B irradiation was not different in xpf-3 compared with the wild type, nor was it altered after HU treatment. These results suggest that hypocotyl growth inhibition by UV-B light in etiolated Arabidopsis seedlings, a photomorphogenic response, is dictated by signals originating from UV-B absorption by DNA that lead to cell cycle arrest. This process occurs distinct from UVR8 and its signalling pathway responsible for CHS induction. PMID:24591052

Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice.

PubMed

Zhou, Lei; Zhang, Xiaoying; Li, Hui; Niu, Chao; Yu, Dehai; Yang, Guozi; Liang, Xinyue; Wen, Xue; Li, Min; Cui, Jiuwei

2018-04-01

Although low-dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR-induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high-dose radiation (HDR) of 1 Gy. Additionally, the LDR-induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR-activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR-induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Flavonoid Apigenin Inhibits Lipopolysaccharide-Induced Inflammatory Response through Multiple Mechanisms in Macrophages

PubMed Central

Zhang, Xiaoxuan; Wang, Guangji; Gurley, Emily C.; Zhou, Huiping

2014-01-01

Background Apigenin is a non-toxic natural flavonoid that is abundantly present in common fruits and vegetables. It has been reported that apigenin has various beneficial health effects such as anti-inflammation and chemoprevention. Multiple studies have shown that inflammation is an important risk factor for atherosclerosis, diabetes, sepsis, various liver diseases, and other metabolic diseases. Although it has been long realized that apigenin has anti-inflammatory activities, the underlying functional mechanisms are still not fully understood. Methodology and Principal Findings In the present study, we examined the effect of apigenin on LPS-induced inflammatory response and further elucidated the potential underlying mechanisms in human THP-1-induced macrophages and mouse J774A.1 macrophages. By using the PrimePCR array, we were able to identify the major target genes regulated by apigenin in LPS-mediated immune response. The results indicated that apigenin significantly inhibited LPS-induced production of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α through modulating multiple intracellular signaling pathways in macrophages. Apigenin inhibited LPS-induced IL-1β production by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly. Apigenin also prevented LPS-induced IL-6 and IL-1β production by reducing the mRNA stability via inhibiting ERK1/2 activation. In addition, apigenin significantly inhibited TNF-α and IL-1β-induced activation of NF-κB. Conclusion and Significance Apigenin Inhibits LPS-induced Inflammatory Response through multiple mechanisms in macrophages. These results provided important scientific evidences for the potential application of apigenin as a therapeutic agent for inflammatory diseases. PMID:25192391

Intraglomerular inhibition maintains mitral cell response contrast across input frequencies

PubMed Central

Shao, Zuoyi; Puche, Adam C.

2013-01-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MTCs) and external tufted cells (ETCs); ETCs provide additional feed-forward excitation to MTCs. Both are strongly regulated by intraglomerular inhibition that can last up to 1 s and, when blocked, dramatically increases ON-evoked MC spiking. Intraglomerular inhibition thus limits the magnitude and duration of MC spike responses to sensory input. In vivo, sensory input is repetitive, dictated by sniffing rates from 1 to 8 Hz, potentially summing intraglomerular inhibition. To investigate this, we recorded MTC responses to 1- to 8-Hz ON stimulation in slices. Inhibitory postsynaptic current area (charge) following each ON stimulation was unchanged from 1 to 5 Hz and modestly paired-pulse attenuated at 8 Hz, suggesting there is no summation and only limited decrement at the highest input frequencies. Next, we investigated frequency independence of intraglomerular inhibition on MC spiking. MCs respond to single ON shocks with an initial spike burst followed by reduced spiking decaying to baseline. Upon repetitive ON stimulation peak spiking is identical across input frequencies but the ratio of peak-to-minimum rate before the stimulus (max-min) diminishes from 30:1 at 1 Hz to 15:1 at 8 Hz. When intraglomerular inhibition is selectively blocked, peak spike rate is unchanged but trough spiking increases markedly decreasing max-min firing ratios from 30:1 at 1 Hz to 2:1 at 8 Hz. Together, these results suggest intraglomerular inhibition is relatively frequency independent and can “sharpen” MC responses to input across the range of frequencies. This suggests that glomerular circuits can maintain “contrast” in MC encoding during sniff-sampled inputs. PMID:23926045

Intraglomerular inhibition maintains mitral cell response contrast across input frequencies.

PubMed

Shao, Zuoyi; Puche, Adam C; Shipley, Michael T

2013-11-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MTCs) and external tufted cells (ETCs); ETCs provide additional feed-forward excitation to MTCs. Both are strongly regulated by intraglomerular inhibition that can last up to 1 s and, when blocked, dramatically increases ON-evoked MC spiking. Intraglomerular inhibition thus limits the magnitude and duration of MC spike responses to sensory input. In vivo, sensory input is repetitive, dictated by sniffing rates from 1 to 8 Hz, potentially summing intraglomerular inhibition. To investigate this, we recorded MTC responses to 1- to 8-Hz ON stimulation in slices. Inhibitory postsynaptic current area (charge) following each ON stimulation was unchanged from 1 to 5 Hz and modestly paired-pulse attenuated at 8 Hz, suggesting there is no summation and only limited decrement at the highest input frequencies. Next, we investigated frequency independence of intraglomerular inhibition on MC spiking. MCs respond to single ON shocks with an initial spike burst followed by reduced spiking decaying to baseline. Upon repetitive ON stimulation peak spiking is identical across input frequencies but the ratio of peak-to-minimum rate before the stimulus (max-min) diminishes from 30:1 at 1 Hz to 15:1 at 8 Hz. When intraglomerular inhibition is selectively blocked, peak spike rate is unchanged but trough spiking increases markedly decreasing max-min firing ratios from 30:1 at 1 Hz to 2:1 at 8 Hz. Together, these results suggest intraglomerular inhibition is relatively frequency independent and can "sharpen" MC responses to input across the range of frequencies. This suggests that glomerular circuits can maintain "contrast" in MC encoding during sniff-sampled inputs.

Evaluation of pressor and visceromotor reflex responses to bladder distension in urethane anesthetized rats.

PubMed

Blatt, Lauren K; Lashinger, Erin S R; Laping, Nicholas J; Su, Xin

2009-01-01

We tested cardiovascular and visceromotor reflex (VMR) responses to urinary bladder distension (UBD) in urethane anesthetized rats to see if it can replicate the response pattern and the inhibition of bladder nociceptive transmission by analgesics seen in isoflurane anesthetized animals. Female Sprague-Dawley rats under 3% isoflurane anesthesia were acutely instrumented with jugular venous, carotid arterial, and bladder cannulas for drug administration, blood pressure (BP) measurement, and bladder distension, respectively. Needle electrodes were placed directly into the abdominal musculature to measure myoelectrical activity subsequent to phasic UBD (30 sec in 3 min intervals). A cardiovascular response (pressor) and a VMR response (a contraction of abdominal and hind limb musculature) to UBD were evaluated in urethane (1.2 g/kg, i.v.) or isoflurane (1%) anesthetized rats. Pressor and VMR responses to noxious UBD (60 mmHg) were generated under both anesthesics. The thresholds of stimulus response functions for both pressor and VMR responses were not affected by either anesthesics. However, the magnitude of the maximal pressor response was significantly reduced in urethane anesthesia. The analgesics, morphine, and mexiletine, significantly inhibited the VMR response to noxious UBD under both anesthetics, but the intensities of the inhibition from both analgesics under urethane anesthesia were much lower than under isoflurane anesthesia (ID50: 2.07 mg/kg vs. 0.88 mg/kg for morphine, >10 mg/kg vs. 0.47 mg/kg for mexiletine). The rat urinary bladder distension model in urethane anesthetized rats demonstrates a blunted maximal pressor response and a reduced inhibition of visceral nociceptive transmission by analgesics. Neurourol. Urodynam. 28:442-446, 2009. (c) 2008 Wiley-Liss, Inc.

Ethylene Plays Multiple Nonprimary Roles in Modulating the Gravitropic Response in Tomato1

PubMed Central

Madlung, Andreas; Behringer, Friedrich J.; Lomax, Terri L.

1999-01-01

Ethylene is known to interact with auxin in regulating stem growth, and yet evidence for the role of ethylene in tropic responses is contradictory. Our analysis of four mutants of tomato (Lycopersicon esculentum) altered in their response to gravity, auxin, and/or ethylene revealed concentration-dependent modulation of shoot gravitropism by ethylene. Ethylene inhibitors reduce wild-type gravicurvature, and extremely low (0.0005–0.001 μL L−1) ethylene concentrations can restore the reduced gravitropic response of the auxin-resistant dgt (diageotropica) mutant to wild-type levels. Slightly higher concentrations of ethylene inhibit the gravitropic response of all but the ethylene-insensitive nr (never-ripe) mutant. The gravitropic responses of nr and the constitutive-response mutant epi (epinastic) are slightly and significantly delayed, respectively, but otherwise normal. The reversal of shoot gravicurvature by red light in the lz-2(lazy-2) mutant is not affected by ethylene. Taken together, these data indicate that, although ethylene does not play a primary role in the gravitropic response of tomato, low levels of ethylene are necessary for a full gravitropic response, and moderate levels of the hormone specifically inhibit gravicurvature in a manner different from ethylene inhibition of overall growth. PMID:10398726

Ethylene plays multiple nonprimary roles in modulating the gravitropic response in tomato

NASA Technical Reports Server (NTRS)

Madlung, A.; Behringer, F. J.; Lomax, T. L.; Davies, E. (Principal Investigator)

1999-01-01

Ethylene is known to interact with auxin in regulating stem growth, and yet evidence for the role of ethylene in tropic responses is contradictory. Our analysis of four mutants of tomato (Lycopersicon esculentum) altered in their response to gravity, auxin, and/or ethylene revealed concentration-dependent modulation of shoot gravitropism by ethylene. Ethylene inhibitors reduce wild-type gravicurvature, and extremely low (0.0005-0.001 microliter L-1) ethylene concentrations can restore the reduced gravitropic response of the auxin-resistant dgt (diageotropica) mutant to wild-type levels. Slightly higher concentrations of ethylene inhibit the gravitropic response of all but the ethylene-insensitive nr (never-ripe) mutant. The gravitropic responses of nr and the constitutive-response mutant epi (epinastic) are slightly and significantly delayed, respectively, but otherwise normal. The reversal of shoot gravicurvature by red light in the lz-2 (lazy-2) mutant is not affected by ethylene. Taken together, these data indicate that, although ethylene does not play a primary role in the gravitropic response of tomato, low levels of ethylene are necessary for a full gravitropic response, and moderate levels of the hormone specifically inhibit gravicurvature in a manner different from ethylene inhibition of overall growth.

Effect of drug-related cues on response inhibition through abstinence: A pilot study in male heroin abstainers.

PubMed

Su, Bobo; Yang, Ling; Wang, Grace Y; Wang, Sha; Li, Shaomei; Cao, Hua; Zhang, Yan

2017-11-01

Chronic heroin use can cause a deficit of inhibitory function, leading to a loss of control over drug use. Exposure to drug-related cues is considered as one of the contributing factors. However, it is unclear whether there are dynamic changes on the effect of drug-related cues on response inhibition following prolonged abstinence. The present study investigated the effect of drug-related cues on response inhibition in heroin abstainers at different abstinent phases. 26 shorter-term (2-6 months) and 26 longer-term (19-24 months) male heroin abstainers performed on a modified two-choice Oddball task, which included two conditions: in the cued condition, neutral pictures served as the background of standard stimuli (yellow frame) and heroin-related pictures served as the background of deviant stimuli (blue frame), reversed in the controlled conditions. Compared to longer-term abstainers, mean reaction time (RT) for drug deviants in shorter-term abstainers was significantly longer. Shorter-term abstainers also showed markedly slower response to neutral deviants relative to drug deviants, but this tendency was not observed in longer-term abstainers. Nevertheless, both groups had similar RT for standard stimuli regardless of their paired background pictures. Effect of drug-related cues on response inhibition remains at the early stage of abstinence; however, this effect may be reduced following a longer period of drug abstinence. Our findings highlight the importance of assessing and improving the ability of inhibiting drug-related cue reactivity during treatment.

Event-related fields evoked by vocal response inhibition: a comparison of younger and older adults.

PubMed

Castro-Meneses, Leidy J; Johnson, Blake W; Sowman, Paul F

2016-06-01

The current study examined event-related fields (ERFs) evoked by vocal response inhibition in a stimulus-selective stop-signal task. We compared inhibition-related ERFs across a younger and an older group of adults. Behavioural results revealed that stop-signal reaction times (RTs), go-RTs, ignore-stop RTs and failed stop RTs were longer in the older, relative to the younger group by 38, 123, 149 and 116 ms, respectively. The amplitude of the ERF M2 peak (approximately 200 ms after the stop signal) evoked on successful stop trials was larger compared to that evoked on both failed stop and ignore-stop trials. The M4 peak (approximately 450 ms after stop signal) was of larger amplitude in both successful and failed stops compared to ignore-stop trials. In the older group, the M2, M3 and M4 peaks were smaller in amplitude and peaked later in time (by 24, 50 and 76 ms, respectively). We demonstrate that vocal response inhibition-related ERFs exhibit a similar temporal evolution to those previously described for manual response inhibition: an early peak at 200 ms (i.e. M2) that differentiates successful from failed stopping, and a later peak (i.e. M4) that is consistent with a neural marker of response checking and error processing. Across groups, our data support a more general decline of stimulus processing speed with age.

PERK inhibits DNA replication during the Unfolded Protein Response via Claspin and Chk1.

PubMed

Cabrera, E; Hernández-Pérez, S; Koundrioukoff, S; Debatisse, M; Kim, D; Smolka, M B; Freire, R; Gillespie, D A

2017-02-02

Stresses such as hypoxia, nutrient deprivation and acidification disturb protein folding in the endoplasmic reticulum (ER) and activate the Unfolded Protein Response (UPR) to trigger adaptive responses through the effectors, PERK, IRE1 and ATF6. Most of these responses relate to ER homoeostasis; however, here we show that the PERK branch of the UPR also controls DNA replication. Treatment of cells with the non-genotoxic UPR agonist thapsigargin led to a rapid inhibition of DNA synthesis that was attributable to a combination of DNA replication fork slowing and reduced replication origin firing. DNA synthesis inhibition was dependent on the UPR effector PERK and was associated with phosphorylation of the checkpoint adaptor protein Claspin and activation of the Chk1 effector kinase, both of which occurred in the absence of detectable DNA damage. Remarkably, thapsigargin did not inhibit bulk DNA synthesis or activate Chk1 in cells depleted of Claspin, or when Chk1 was depleted or subject to chemical inhibition. In each case thapsigargin-resistant DNA synthesis was due to an increase in replication origin firing that compensated for reduced fork progression. Taken together, our results unveil a new aspect of PERK function and previously unknown roles for Claspin and Chk1 as negative regulators of DNA replication in the absence of genotoxic stress. Because tumour cells proliferate in suboptimal environments, and frequently show evidence of UPR activation, this pathway could modulate the response to DNA replication-targeted chemotherapies.

Within-Subject Correlation Analysis to Detect Functional Areas Associated With Response Inhibition.

PubMed

Yamasaki, Tomoko; Ogawa, Akitoshi; Osada, Takahiro; Jimura, Koji; Konishi, Seiki

2018-01-01

Functional areas in fMRI studies are often detected by brain-behavior correlation, calculating across-subject correlation between the behavioral index and the brain activity related to a function of interest. Within-subject correlation analysis is also employed in a single subject level, which utilizes cognitive fluctuations in a shorter time period by correlating the behavioral index with the brain activity across trials. In the present study, the within-subject analysis was applied to the stop-signal task, a standard task to probe response inhibition, where efficiency of response inhibition can be evaluated by the stop-signal reaction time (SSRT). Since the SSRT is estimated, by definition, not in a trial basis but from pooled trials, the correlation across runs was calculated between the SSRT and the brain activity related to response inhibition. The within-subject correlation revealed negative correlations in the anterior cingulate cortex and the cerebellum. Moreover, the dissociation pattern was observed in the within-subject analysis when earlier vs. later parts of the runs were analyzed: negative correlation was dominant in earlier runs, whereas positive correlation was dominant in later runs. Regions of interest analyses revealed that the negative correlation in the anterior cingulate cortex, but not in the cerebellum, was dominant in earlier runs, suggesting multiple mechanisms associated with inhibitory processes that fluctuate on a run-by-run basis. These results indicate that the within-subject analysis compliments the across-subject analysis by highlighting different aspects of cognitive/affective processes related to response inhibition.