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Sample records for response die modulation

  1. 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…

  2. Laser micromachining of through via interconnects in active die for 3-D multichip module

    NASA Astrophysics Data System (ADS)

    Chu, D.; Miller, W. D.

    One method to increase density in integrated circuits (IC) is to stack die to create a 3-D multichip module (MCM). In the past, special post wafer processing was done to bring interconnects out to the edge of the die. The die were sawed, glued, and stacked. Special processing was done to create interconnects on the edge to provide for interconnects to each of the die. These processes require an IC type fabrication facility (fab) and special processing equipment. In contrast, we have developed packaging assembly methods to create vertical through vias in bond pads of active silicon die, isolate these vias, and metal fill these vias without the use of a special IC fab. These die with through vias can then be joined and stacked to create a 3-D MCM. Vertical through vias in active die are created by laser micromachining using a Nd:YAG laser. Besides the fundamental 1064 nm (infrared) laser wavelength of a Nd:YAG laser, modifications to our Nd:YAG laser allowed us to generate the second harmonic 532 nm (green) laser wavelength and fourth harmonic 266 nm (ultraviolet) laser wavelength in laser micromachining for these vias. Experiments were conducted to determine the best laser wavelengths to use for laser micromachining of vertical through vias in order to minimize damage to the active die. Via isolation experiments were done in order to determine the best method in isolating the bond pads of the die. Die thinning techniques were developed to allow for die thickness as thin as 50 microns. This would allow for high 3-D density when the die are stacked. A method was developed to metal fill the vias with solder using a wire bonder with solder wire.

  3. Laser micromachining of through via interconnects in active die for 3-D multichip module

    SciTech Connect

    Chu, D.; Miller, W.D.

    1995-09-01

    One method to increase density in integrated circuits (IC) is to stack die to create a 3-D multichip module (MCM). In the past, special post wafer processing was done to bring interconnects out to the edge of the die. The die were sawed, glued, and stacked. Special processing was done to create interconnects on the edge to provide for interconnects to each of the die. These processes require an IC type fabrication facility (fab) and special processing equipment. In contrast, we have developed packaging assembly methods to created vertical through vias in bond pads of active silicon die, isolate these vias, and metal fill these vias without the use of a special IC fab. These die with through vias can then be joined and stacked to create a 3-D MCM. Vertical through vias in active die are created by laser micromachining using a Nd:YAG laser. Besides the fundamental 1064 nm (infra-red) laser wavelength of a Nd:YAG laser, modifications to our Nd:YAG laser allowed us to generate the second harmonic 532 nm (green) laser wavelength and fourth harmonic 266nm (ultra violet) laser wavelength in laser micromachining for these vias. Experiments were conducted to determine the best laser wavelengths to use for laser micromachining of vertical through vias in order to minimize damage to the active die. Via isolation experiments were done in order to determine the best method in isolating the bond pads of the die. Die thinning techniques were developed to allow for die thickness as thin as 50 {mu}m. This would allow for high 3-D density when the die are stacked. A method was developed to metal fill the vias with solder using a wire bonder with solder wire.

  4. Rights & Responsibilities. Personnel Management Module.

    ERIC Educational Resources Information Center

    Barker, Gale; And Others

    This module on rights and responsibilities is intended to introduce the hospitality manager or supervisor to sound personnel management practices that comply with the law. The material is presented in a self-instructional format in seven sections. At the beginning of each section is a statement of the objectives that will be achieved as a result…

  5. Modulating macrophage response to biomaterials

    NASA Astrophysics Data System (ADS)

    Zaveri, Toral

    Macrophages recruited to the site of biomaterial implantation are the primary mediators of the chronic foreign body response to implanted materials. Since foreign body response limits performance and functional life of numerous implanted biomaterials/medical devices, various approaches have been investigated to modulate macrophage interactions with biomaterial surfaces to mitigate this response. In this work we have explored two independent approaches to modulate the macrophage inflammatory response to biomaterials. The first approach targets surface integrins, cell surface receptors that mediate cell adhesion to biomaterials through adhesive proteins spontaneously adsorbed on biomaterial surfaces. The second approach involves surface modification of biomaterials using nanotopographic features since nanotopography has been reported to modulate cell adhesion and viability in a cell type-dependent manner. More specifically, Zinc Oxide (ZnO) nanorod surface was investigated for its role in modulating macrophage adhesion and survival in vitro and foreign body response in vivo. For the first approach, we have investigated the role of integrin Mac-1 and RGD-binding integrins in the in-vivo osteolysis response and macrophage inflammatory processes of phagocytosis as well as inflammatory cytokine secretion in response to particulate biomaterials. We have also investigated the in vivo foreign body response (FBR) to subcutaneously implanted biomaterials by evaluating the thickness of fibrous capsule formed around the implants after 2 weeks of implantation. The role of Mac-1 integrin was isolated using a Mac-1 KO mouse and comparing it to a WT control. The role of RGD binding integrins in FBR was investigated by coating the implanted biomaterial with ELVAX(TM) polymer loaded with Echistatin which contains the RGD sequence. For the in-vivo osteolysis study and to study the in-vitro macrophage response to particulate biomaterials, we used the RGD peptide encapsulated in ELVAX

  6. Modulation of the Hypoxic Response.

    PubMed

    Pugh, Christopher W

    2016-01-01

    Hypoxia stimulates a variety of adaptive responses, many mediated via the hypoxia inducible factors (HIF) family of transcriptional complexes. The balance of HIF-1, -2 and -3 controls a variety of genes, directly up-regulating transcription of genes involved in erythropoiesis, angiogenesis, vasomotor tone, metabolic pathways and processes related to cell multiplication and survival, and indirectly reducing the transcription of genes with other effects. HIF transcription factors are heterodimers consisting of an oxygen-regulated alpha chain bound to the constitutive aryl hydrocarbon receptor nuclear translocator. Under circumstances where oxygen is abundant the activity of the alpha chain is blocked by the actions of members of a family of oxygen-, iron- and oxoglutarate-dependent dioxygenase enzymes. Hydroxylation of two critical prolyl residues by the HIF prolyl hydroxylases (PHD1-3) leads to recognition by the von Hippel-Lindau E3 ubiquitin ligase complex, polyubiquitylation of the alpha chain and its consequent destruction by the proteasome. Hydroxylation of an asparaginyl residue by Factor Inhibiting HIF prevents any surviving HIF alpha chains from recruiting p300-CBP proteins, important for maximal transcriptional activation. Under conditions of acute hypoxia enzyme activity is suppressed, the HIF alpha chains are allowed to exist in their active form and target gene transcription is enhanced. In sustained hypoxia, adaptive responses mediated by the HIF pathway reduce oxygen demand and increase oxygen supply and thus ultimately down-regulate the pathway. However, a number of other processes also modulate HIF signalling and the balance between HIF-1 and HIF-2 actions. These include the generation of antisense HIF-1 and micro RNAs, up-regulation of HIF-3 alpha, antagonism of the HIF-p300 interaction by CITED2, increased PHD2 and PHD3 levels and effects on the pool of ankyrins within the cell which compete with HIF for the action of FIH. Additionally, effects on

  7. Spectral density response functions for modulated polarimeters.

    PubMed

    LaCasse, Charles F; Rodríguez-Herrera, Oscar G; Chipman, Russell A; Tyo, J Scott

    2015-11-10

    Conventional imaging devices are often compared using their optical transfer functions (OTFs) in space and their impulse responses in time. Modulated polarimeters cannot be directly compared this way, since they are frequency multiplexed. Here we define a spectral density response function that describes how the spectral density matrix of the Stokes parameters for an object transfers through a modulated polarimeter. This response function facilitates the objective comparison of polarimeters in a way that is analogous to the OTF for conventional imaging systems. The spectral density response is used to calculate a Wiener filter for a rotating analyzer polarimeter as an example of filter optimization for modulated polarimetry. PMID:26560776

  8. Modeling and Analysis of The Pressure Die Casting Using Response Surface Methodology

    SciTech Connect

    Kittur, Jayant K.; Herwadkar, T. V.; Parappagoudar, M. B.

    2010-10-26

    Pressure die casting is successfully used in the manufacture of Aluminum alloys components for automobile and many other industries. Die casting is a process involving many process parameters having complex relationship with the quality of the cast product. Though various process parameters have influence on the quality of die cast component, major influence is seen by the die casting machine parameters and their proper settings. In the present work, non-linear regression models have been developed for making predictions and analyzing the effect of die casting machine parameters on the performance characteristics of die casting process. Design of Experiments (DOE) with Response Surface Methodology (RSM) has been used to analyze the effect of effect of input parameters and their interaction on the response and further used to develop nonlinear input-output relationships. Die casting machine parameters, namely, fast shot velocity, slow shot to fast shot change over point, intensification pressure and holding time have been considered as the input variables. The quality characteristics of the cast product were determined by porosity, hardness and surface rough roughness (output/responses). Design of experiments has been used to plan the experiments and analyze the impact of variables on the quality of casting. On the other-hand Response Surface Methodology (Central Composite Design) is utilized to develop non-linear input-output relationships (regression models). The developed regression models have been tested for their statistical adequacy through ANOVA test. The practical usefulness of these models has been tested with some test cases. These models can be used to make the predictions about different quality characteristics, for the known set of die casting machine parameters, without conducting the experiments.

  9. Regional vegetation die-off in response to global-change-type drought

    PubMed Central

    Breshears, David D.; Cobb, Neil S.; Rich, Paul M.; Price, Kevin P.; Allen, Craig D.; Balice, Randy G.; Romme, William H.; Kastens, Jude H.; Floyd, M. Lisa; Belnap, Jayne; Anderson, Jesse J.; Myers, Orrin B.; Meyer, Clifton W.

    2005-01-01

    Future drought is projected to occur under warmer temperature conditions as climate change progresses, referred to here as global-change-type drought, yet quantitative assessments of the triggers and potential extent of drought-induced vegetation die-off remain pivotal uncertainties in assessing climate-change impacts. Of particular concern is regional-scale mortality of overstory trees, which rapidly alters ecosystem type, associated ecosystem properties, and land surface conditions for decades. Here, we quantify regional-scale vegetation die-off across southwestern North American woodlands in 2002-2003 in response to drought and associated bark beetle infestations. At an intensively studied site within the region, we quantified that after 15 months of depleted soil water content, >90% of the dominant, overstory tree species (Pinus edulis, a piñon) died. The die-off was reflected in changes in a remotely sensed index of vegetation greenness (Normalized Difference Vegetation Index), not only at the intensively studied site but also across the region, extending over 12,000 km2 or more; aerial and field surveys confirmed the general extent of the die-off. Notably, the recent drought was warmer than the previous subcontinental drought of the 1950s. The limited, available observations suggest that die-off from the recent drought was more extensive than that from the previous drought, extending into wetter sites within the tree species' distribution. Our results quantify a trigger leading to rapid, drought-induced die-off of overstory woody plants at subcontinental scale and highlight the potential for such die-off to be more severe and extensive for future global-change-type drought under warmer conditions. PMID:16217022

  10. Regional vegetation die-off in response to global-change-type drought

    USGS Publications Warehouse

    Breshears, D.D.; Cobb, N.S.; Rich, P.M.; Price, K.P.; Allen, C.D.; Balice, R.G.; Romme, W.H.; Kastens, J.H.; Floyd, M. Lisa; Belnap, J.; Anderson, J.J.; Myers, O.B.; Meyer, Clifton W.

    2005-01-01

    Future drought is projected to occur under warmer temperature conditions as climate change progresses, referred to here as global-change-type drought, yet quantitative assessments of the triggers and potential extent of drought-induced vegetation die-off remain pivotal uncertainties in assessing climate-change impacts. Of particular concern is regional-scale mortality of overstory trees, which rapidly alters ecosystem type, associated ecosystem properties, and land surface conditions for decades. Here, we quantify regional-scale vegetation die-off across southwestern North American woodlands in 2002-2003 in response to drought and associated bark beetle infestations. At an intensively studied site within the region, we quantified that after 15 months of depleted soil water content, >90% of the dominant, overstory tree species (Pinus edulis, a pin??on) died. The die-off was reflected in changes in a remotely sensed index of vegetation greenness (Normalized Difference Vegetation Index), not only at the intensively studied site but also across the region, extending over 12,000 km2 or more; aerial and field surveys confirmed the general extent of the die-off. Notably, the recent drought was warmer than the previous subcontinental drought of the 1950s. The limited, available observations suggest that die-off from the recent drought was more extensive than that from the previous drought, extending into wetter sites within the tree species' distribution. Our results quantify a trigger leading to rapid, drought-induced die-off of overstory woody plants at subcontinental scale and highlight the potential for such die-off to be more severe and extensive for future global-change-type drought under warmer conditions. ?? 2005 by The National Academy of Sciences of the USA.

  11. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.

    PubMed

    Martinez, Jennifer; Cunha, Larissa D; Park, Sunmin; Yang, Mao; Lu, Qun; Orchard, Robert; Li, Quan-Zhen; Yan, Mei; Janke, Laura; Guy, Cliff; Linkermann, Andreas; Virgin, Herbert W; Green, Douglas R

    2016-05-01

    Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE. PMID:27096368

  12. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.

    PubMed

    Martinez, Jennifer; Cunha, Larissa D; Park, Sunmin; Yang, Mao; Lu, Qun; Orchard, Robert; Li, Quan-Zhen; Yan, Mei; Janke, Laura; Guy, Cliff; Linkermann, Andreas; Virgin, Herbert W; Green, Douglas R

    2016-05-01

    Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.

  13. Sintered Ag die attach as a solution to improve thermal performance of high power modules

    NASA Astrophysics Data System (ADS)

    Mansi, Mohammed S.

    The move to smaller electronics packages with higher numbers of I/Os has significantly increased power densities. The increase of power density puts more emphasis on finding solutions to improve the thermal performance of electronics packages. In wire bonded chips, the die attach layer plays a significant role in thermal performance as it establishes the main heat dissipation path from the chip. The use of sintered Ag as a die attach material to improve thermal performance is investigated in this research. A thermal simulation tool (FloTHERM) was used to study the thermal performance of five different sintered Ag die attach materials and compare their performance to the performance of silver filled epoxy die attach. Thermal simulation results showed low thermal improvement in the Theta-JA (thetaJA) value while higher thermal improvement in the Theta-JC (thetaJC) value was observed. Also, this research correlates the thermal simulation results with real-world measurements.

  14. Responses towards a dying adult group member in a wild New World monkey.

    PubMed

    Bezerra, Bruna Martins; Keasey, Matthew Philip; Schiel, Nicola; da Silva Souto, Antonio

    2014-04-01

    Compassionate caretaking behaviour towards dying adult group members has been reported as being unique to humans and chimpanzees. Here we describe in detail the reaction of a wild dominant male common marmoset, a neotropical primate, to the accidental death of the dominant female of its group. The male exhibited behaviours towards the dying female that resembled those of chimpanzees and humans. The long-term relationship between the dominant pair (which lasted at least 3.5 years) and their social status in the group may have contributed to the male's behavioural response. The male prevented young individuals from approaching the dying female, behaviour previously observed in chimpanzees. The data provide an interesting insight into compassionate caretaking behaviours in New World primates as well as the pair-bond systems of common marmosets. These are rare observations, and thus their detailed descriptions are essential if we are to create a comparative and enhanced understanding of human and nonhuman primate thanatology. PMID:24566801

  15. Responses towards a dying adult group member in a wild New World monkey.

    PubMed

    Bezerra, Bruna Martins; Keasey, Matthew Philip; Schiel, Nicola; da Silva Souto, Antonio

    2014-04-01

    Compassionate caretaking behaviour towards dying adult group members has been reported as being unique to humans and chimpanzees. Here we describe in detail the reaction of a wild dominant male common marmoset, a neotropical primate, to the accidental death of the dominant female of its group. The male exhibited behaviours towards the dying female that resembled those of chimpanzees and humans. The long-term relationship between the dominant pair (which lasted at least 3.5 years) and their social status in the group may have contributed to the male's behavioural response. The male prevented young individuals from approaching the dying female, behaviour previously observed in chimpanzees. The data provide an interesting insight into compassionate caretaking behaviours in New World primates as well as the pair-bond systems of common marmosets. These are rare observations, and thus their detailed descriptions are essential if we are to create a comparative and enhanced understanding of human and nonhuman primate thanatology.

  16. Characteristics and dying trajectories of adult hospital patients from acute care wards who die following review by the rapid response team.

    PubMed

    Coombs, M A; Nelson, K; Psirides, A J; Suter, N; Pedersen, A

    2016-03-01

    A third of patients reviewed by rapid response teams (RRT) require end-of-life care. However, little is known about the characteristics and management of these patients following RRT review. This paper presents results of a retrospective, descriptive audit that explored the dying trajectory of adult ward inpatients who died outside of intensive care following RRT review. The study setting was a 430-bed tertiary New Zealand hospital during 2013. RRT, inpatient databases and hospital notes were used to identify 100 consecutive adult inpatients who died subsequent to RRT review. Outcome measures included time from RRT review to death, place of death, pre-existing co-morbidities and frequency of medical review. Results demonstrated that patients were old (median 77 years, IQR 63-85years), emergency admissions (n=100) and admitted under a medical specialty (n=71). All but one of the cohort had pre-existing co-morbidities (mean 3.2, SD 1.7), almost a third (n=31) had cancer and 51% had 1-4 previous inpatient admissions within the previous 12 months. The mean length of stay prior to RRT review was 4.9 days (SD 5.5) during which patients were frequently reviewed by senior medical staff (mean 6.8 times, SD 6.9, range 0-44). Twenty per cent of patients died after their first RRT review with a further 40% receiving treatment limitation/palliation. Fifty-two per cent of patients had a pre-existing DNAR. Eighty per cent of patients died in hospital. Whilst the RRT fulfils an unmet need in decision-making at end of life, there is a need to understand what RRT, instead of ward-based or palliative care teams, offers dying patients. PMID:27029659

  17. Attentional Modulation of Eye Torsion Responses

    NASA Technical Reports Server (NTRS)

    Stevenson, Scott B.; Mahadevan, Madhumitha S.; Mulligan, Jeffrey B.

    2016-01-01

    Eye movements generally have both reflexive and voluntary aspects, but torsional eye movements are usually thought of as a reflexive response to image rotation around the line of sight (torsional OKN) or to head roll (torsional VOR). In this study we asked whether torsional responses could be modulated by attention in a case where two stimuli rotated independently, and whether attention would influence the latency of responses. The display consisted of rear-projected radial "pinwheel" gratings, with an inner annulus segment extending from the center to 22 degrees eccentricity, and an outer annulus segment extending from 22 degrees out to 45 degrees eccentricity. The two segments rotated around the center in independent random walks, stepping randomly 4 degrees clockwise or counterclockwise at 60 Hz. Subjects were asked to attend to one or the other while keeping fixation steady at the center of the display. To encourage attention on one or the other segment of the display, subjects were asked to move a joystick in synchrony with the back and forth rotations of one part of the image while ignoring the other. Eye torsion was recorded with the scleral search coil technique, sampled at 500 Hz. All four subjects showed roughly 50% stronger torsion responses to the attended compared to unattended segments. Latency varied from 100 to 150 msec across subjects and was unchanged by attention. These findings suggest that attention can influence eye movement responses that are not typically under voluntary control.

  18. [Modulation of immune response by bacterial lipopolysaccharides].

    PubMed

    Aldapa-Vega, Gustavo; Pastelín-Palacios, Rodolfo; Isibasi, Armando; Moreno-Eutimio, Mario A; López-Macías, Constantino

    2016-01-01

    Lipopolysaccharide (LPS) is a molecule that is profusely found on the outer membrane of Gram-negative bacteria and is also a potent stimulator of the immune response. As the main molecule on the bacterial surface, is also the most biologically active. The immune response of the host is activated by the recognition of LPS through Toll-like receptor 4 (TLR4) and this receptor-ligand interaction is closely linked to LPS structure. Microorganisms have evolved systems to control the expression and structure of LPS, producing structural variants that are used for modulating the host immune responses during infection. Examples of this include Helicobacter pylori, Francisella tularensis, Chlamydia trachomatis and Salmonella spp. High concentrations of LPS can cause fever, increased heart rate and lead to septic shock and death. However, at relatively low concentrations some LPS are highly active immunomodulators, which can induce non-specific resistance to invading microorganisms. The elucidation of the molecular and cellular mechanisms involved in the recognition of LPS and its structural variants has been fundamental to understand inflammation and is currently a pivotal field of research to understand the innate immune response, inflammation, the complex host-pathogen relationship and has important implications for the rational development of new immunomodulators and adjuvants. PMID:27560917

  19. [Modulation of immune response by bacterial lipopolysaccharides].

    PubMed

    Aldapa-Vega, Gustavo; Pastelín-Palacios, Rodolfo; Isibasi, Armando; Moreno-Eutimio, Mario A; López-Macías, Constantino

    2016-01-01

    Lipopolysaccharide (LPS) is a molecule that is profusely found on the outer membrane of Gram-negative bacteria and is also a potent stimulator of the immune response. As the main molecule on the bacterial surface, is also the most biologically active. The immune response of the host is activated by the recognition of LPS through Toll-like receptor 4 (TLR4) and this receptor-ligand interaction is closely linked to LPS structure. Microorganisms have evolved systems to control the expression and structure of LPS, producing structural variants that are used for modulating the host immune responses during infection. Examples of this include Helicobacter pylori, Francisella tularensis, Chlamydia trachomatis and Salmonella spp. High concentrations of LPS can cause fever, increased heart rate and lead to septic shock and death. However, at relatively low concentrations some LPS are highly active immunomodulators, which can induce non-specific resistance to invading microorganisms. The elucidation of the molecular and cellular mechanisms involved in the recognition of LPS and its structural variants has been fundamental to understand inflammation and is currently a pivotal field of research to understand the innate immune response, inflammation, the complex host-pathogen relationship and has important implications for the rational development of new immunomodulators and adjuvants.

  20. Corticofugal modulation of peripheral auditory responses

    PubMed Central

    Terreros, Gonzalo; Delano, Paul H.

    2015-01-01

    The auditory efferent system originates in the auditory cortex and projects to the medial geniculate body (MGB), inferior colliculus (IC), cochlear nucleus (CN) and superior olivary complex (SOC) reaching the cochlea through olivocochlear (OC) fibers. This unique neuronal network is organized in several afferent-efferent feedback loops including: the (i) colliculo-thalamic-cortico-collicular; (ii) cortico-(collicular)-OC; and (iii) cortico-(collicular)-CN pathways. Recent experiments demonstrate that blocking ongoing auditory-cortex activity with pharmacological and physical methods modulates the amplitude of cochlear potentials. In addition, auditory-cortex microstimulation independently modulates cochlear sensitivity and the strength of the OC reflex. In this mini-review, anatomical and physiological evidence supporting the presence of a functional efferent network from the auditory cortex to the cochlear receptor is presented. Special emphasis is given to the corticofugal effects on initial auditory processing, that is, on CN, auditory nerve and cochlear responses. A working model of three parallel pathways from the auditory cortex to the cochlea and auditory nerve is proposed. PMID:26483647

  1. Neuromagnetic responses to frequency modulation of a continuous tone.

    PubMed

    Hari, R; Mäkelä, J P

    1986-01-01

    Neuromagnetic responses to frequency modulation of a continuous tone were studied in nine subjects. The latencies of the transient responses increased and the amplitudes decreased with decreasing speed of modulation. The equivalent dipoles for modulation of a 1,000 Hz tone were slightly but statistically significantly anterior to the dipoles activated by modulation of a 500 Hz tone. The generation mechanisms of N100m are discussed.

  2. Relational responsibility, and not only stewardship, a Roman Catholic view on voluntary euthanasia for dying and non-dying patients.

    PubMed

    Schotsmans, Paul T

    2003-01-01

    The Roman Catholic theological approach to euthanasia is radically prohibitive. The main theological argument for this prohibition is the so-called "stewardship argument": Christians cannot escape accounting to God for stewardship of the bodies given them on earth. This contribution presents an alternative approach based on European existentialist and philosophical traditions. The suggestion is that exploring the fullness of our relational responsibility is more apt for a pluralist--and even secular--debate on the legitimacy of euthanasia.

  3. Relational responsibility, and not only stewardship, a Roman Catholic view on voluntary euthanasia for dying and non-dying patients.

    PubMed

    Schotsmans, Paul T

    2003-01-01

    The Roman Catholic theological approach to euthanasia is radically prohibitive. The main theological argument for this prohibition is the so-called "stewardship argument": Christians cannot escape accounting to God for stewardship of the bodies given them on earth. This contribution presents an alternative approach based on European existentialist and philosophical traditions. The suggestion is that exploring the fullness of our relational responsibility is more apt for a pluralist--and even secular--debate on the legitimacy of euthanasia. PMID:15254997

  4. Generals die in friendly fire, or modeling immune response to HIV

    NASA Astrophysics Data System (ADS)

    Rouzine, Igor M.; Murali-Krishna, Kaja; Ahmed, Rafi

    2005-12-01

    We develop a kinetic model for CD8 T lymphocytes (CTL) whose purpose is to kill cells infected with viruses and intracellular parasites. Using a set of first-order nonlinear differential equations, the model predicts how numbers of different cell types involved in CTL response depend on time. The model postulates that CTL response requires continuous presence of professional antigen-presenting cells (APC) comprised of macrophages and dendritic cells. It assumes that any virus present in excess of a threshold level activates APC that, in turn, activate CTL that expand in number and become armed "effector" cells. In the end, APC are deactivated after virus is cleared. The lack of signal from APC causes effector cells to differentiate, by default, into "transitory cells" that either die, or, in a small part, become long-lived memory cells. Viruses capable of infecting APC will cause premature retirement of effector CTL. If transitory cells encounter virus, which takes place after the premature depletion, CTL become anergic (unresponsive to external stimuli). The model is designed to fit recent experiments on primary CTL response to simian immunodeficiency virus closely related to HIV and lymphocytic choriomeningitis virus. The two viruses are known to infect APC and make them targets for CTL they are supposed to control. Both viruses cause premature depletion and anergy of CTL and persist in the host for life.

  5. Calibration-free absolute frequency response measurement of directly modulated lasers based on additional modulation.

    PubMed

    Zhang, Shangjian; Zou, Xinhai; Wang, Heng; Zhang, Yali; Lu, Rongguo; Liu, Yong

    2015-10-15

    A calibration-free electrical method is proposed for measuring the absolute frequency response of directly modulated semiconductor lasers based on additional modulation. The method achieves the electrical domain measurement of the modulation index of directly modulated lasers without the need for correcting the responsivity fluctuation in the photodetection. Moreover, it doubles measuring frequency range by setting a specific frequency relationship between the direct and additional modulation. Both the absolute and relative frequency response of semiconductor lasers are experimentally measured from the electrical spectrum of the twice-modulated optical signal, and the measured results are compared to those obtained with conventional methods to check the consistency. The proposed method provides calibration-free and accurate measurement for high-speed semiconductor lasers with high-resolution electrical spectrum analysis.

  6. Cellular response to modulated radiation fields

    NASA Astrophysics Data System (ADS)

    Claridge Mackonis, E.; Suchowerska, N.; Zhang, M.; Ebert, M.; McKenzie, D. R.; Jackson, M.

    2007-09-01

    Cell survival following exposure to spatially modulated beams, as created by intensity-modulated radiotherapy (IMRT), is investigated. In vitro experiments were performed using malignant melanoma cells (MM576) exposed to a therapeutic megavoltage photon beam. We compared cell survival in modulated fields with cell survival in uniform control fields. Three different spatial modulations of the field were used: a control 'uniform' field in which all cells in a flask were uniformly exposed; a 'quarter' field in which 25% of cells at one end of the flask were exposed and a 'striped' field in which 25% of cells were exposed in three parallel stripes. The cell survival in both the shielded and unshielded regions of the modulated fields, as determined by a clonogenic assay, were compared to the cell survival in the uniform field. We have distinguished three ways in which cell survival is influenced by the fate of neighbouring cells. The first of these (type I effect) is the previously reported classical Bystander effect, where cell survival is reduced when communicating with irradiated cells. We find two new types of Bystander effect. The type II effect is an observed increase in cell survival when nearby cells receive a lethal dose. The type III effect is an increase in the survival of cells receiving a high dose of radiation, when nearby cells receive a low dose. These observations of the Bystander effects emphasize the need for improved radiobiological models, which include communicated effects and account for the effects of modulated dose distribution.

  7. Simulation of differential die-away instrument's response to asymmetrically burned spent nuclear fuel

    NASA Astrophysics Data System (ADS)

    Martinik, Tomas; Henzl, Vladimir; Grape, Sophie; Svärd, Staffan Jacobsson; Jansson, Peter; Swinhoe, Martyn T.; Tobin, Stephen J.

    2015-07-01

    Previous simulation studies of Differential Die-Away (DDA) instrument's response to active interrogation of spent nuclear fuel from a pressurized water reactor (PWR) yielded promising results in terms of its capability to accurately measure or estimate basic spent fuel assembly (SFA) characteristics, such as multiplication, initial enrichment (IE) and burn-up (BU) as well as the total plutonium content. These studies were however performed only for a subset of idealized SFAs with a symmetric BU with respect to its longitudinal axis. Therefore, to complement the previous results, additional simulations have been performed of the DDA instrument's response to interrogation of asymmetrically burned spent nuclear fuel in order to determine whether detailed assay of SFAs from all 4 sides will be necessary in real life applications or whether a cost and time saving single sided assay could be used to achieve results of similar quality as previously reported in case of symmetrically burned SFAs. The results of this study suggest that DDA instrument response depends on the position of the individual neutron detectors and in fact can be split in two modes. The first mode, measured by the back detectors, is not significantly sensitive to the spatial distribution of fissile isotopes and neutron absorbers, but rather reflects the total amount of both contributors as in the cases of symmetrically burned SFAs. In contrary, the second mode, measured by the front detectors, yields certain sensitivity to the orientation of the asymmetrically burned SFA inside the assaying instrument. This study thus provides evidence that the DDA instrument can potentially be utilized as necessary in both ways, i.e. a quick determination of the average SFA characteristics in a single assay, as well as a more detailed characterization involving several DDA observables through assay of the SFA from all of its four sides that can possibly map the burn-up distribution and/or identify diversion or

  8. Visual modulation of auditory responses in the owl inferior colliculus.

    PubMed

    Bergan, Joseph F; Knudsen, Eric I

    2009-06-01

    The barn owl's central auditory system creates a map of auditory space in the external nucleus of the inferior colliculus (ICX). Although the crucial role visual experience plays in the formation and maintenance of this auditory space map is well established, the mechanism by which vision influences ICX responses remains unclear. Surprisingly, previous experiments have found that in the absence of extensive pharmacological manipulation, visual stimuli do not drive neural responses in the ICX. Here we investigated the influence of dynamic visual stimuli on auditory responses in the ICX. We show that a salient visual stimulus, when coincident with an auditory stimulus, can modulate auditory responses in the ICX even though the same visual stimulus may elicit no neural responses when presented alone. For each ICX neuron, the most effective auditory and visual stimuli were located in the same region of space. In addition, the magnitude of the visual modulation of auditory responses was dependent on the context of the stimulus presentation with novel visual stimuli eliciting consistently larger response modulations than frequently presented visual stimuli. Thus the visual modulation of ICX responses is dependent on the characteristics of the visual stimulus as well as on the spatial and temporal correspondence of the auditory and visual stimuli. These results demonstrate moment-to-moment visual enhancements of auditory responsiveness that, in the short-term, increase auditory responses to salient bimodal stimuli and in the long-term could serve to instruct the adaptive auditory plasticity necessary to maintain accurate auditory orienting behavior. PMID:19321633

  9. An NCME Instructional Module on Polytomous Item Response Theory Models

    ERIC Educational Resources Information Center

    Penfield, Randall David

    2014-01-01

    A polytomous item is one for which the responses are scored according to three or more categories. Given the increasing use of polytomous items in assessment practices, item response theory (IRT) models specialized for polytomous items are becoming increasingly common. The purpose of this ITEMS module is to provide an accessible overview of…

  10. Endocrine Factors Modulating Immune Responses in Pregnancy

    PubMed Central

    Schumacher, Anne; Costa, Serban-Dan; Zenclussen, Ana Claudia

    2014-01-01

    How the semi-allogeneic fetus is tolerated by the maternal immune system remains a fascinating phenomenon. Despite extensive research activity in this field, the mechanisms underlying fetal tolerance are still not well understood. However, there are growing evidences that immune–immune interactions as well as immune–endocrine interactions build up a complex network of immune regulation that ensures fetal survival within the maternal uterus. In the present review, we aim to summarize emerging research data from our and other laboratories on immune modulating properties of pregnancy hormones with a special focus on progesterone, estradiol, and human chorionic gonadotropin. These pregnancy hormones are critically involved in the successful establishment, maintenance, and termination of pregnancy. They suppress detrimental maternal alloresponses while promoting tolerance pathways. This includes the reduction of the antigen-presenting capacity of dendritic cells (DCs), monocytes, and macrophages as well as the blockage of natural killer cells, T and B cells. Pregnancy hormones also support the proliferation of pregnancy supporting uterine killer cells, retain tolerogenic DCs, and efficiently induce regulatory T (Treg) cells. Furthermore, they are involved in the recruitment of mast cells and Treg cells into the fetal–maternal interface contributing to a local accumulation of pregnancy-protective cells. These findings highlight the importance of endocrine factors for the tolerance induction during pregnancy and encourage further research in the field. PMID:24847324

  11. Response to "Exploring the Religious-Spiritual Needs of the Dying."

    ERIC Educational Resources Information Center

    Holden, Janice Miner

    1993-01-01

    Responds to previous article by Douglas C. Smith on exploring the religious-spiritual needs of the dying in which Smith presents psychosocial tools than can be used to assess, examine, and amplify client's religious-spiritual strengths. Compares Smith's work to classic values clarification, addresses issues of counselor judgment and informed…

  12. Hemodynamic responses can modulate the brain oscillations in low frequency

    NASA Astrophysics Data System (ADS)

    Lu, Feng-Mei; Wang, Yi-Feng; Yuan, Zhen

    2016-03-01

    Previous studies have showed that the steady-state responses were able to be used as an effective index for modulating the neural oscillations in the high frequency ranges (> 1 Hz). However, the neural oscillations in low frequency ranges (<1 Hz) remain unknown. In this study, a series of fNIRS experimental tests were conducted to validate if the low frequency bands (0.1 Hz - 0.8 Hz) steady-state hemoglobin responses (SSHbRs) could be evoked and modulate the neural oscillation during a serial reaction time (SRT) task.

  13. FTO modulates fibrogenic responses in obstructive nephropathy

    PubMed Central

    Wang, Chao-Yung; Shie, Shian-Sen; Tsai, Ming-Lung; Yang, Chia-Hung; Hung, Kuo-Chun; Wang, Chun-Chieh; Hsieh, I-Chang; Wen, Ming-Shien

    2016-01-01

    Genome-wide association studies have shown that variants in fat mass and obesity-associated (FTO) gene are robustly associated with body mass index and obesity. These FTO variants are also associated with end stage renal disease and all-cause mortality in chronic kidney diseases. However, the exact role of FTO in kidneys is currently unknown. Here we show that FTO expression is increased after ureteral obstruction and renal fibrosis. Deficiency of the FTO gene attenuates the fibrogenic responses induced by ureteral obstruction in the kidney. Renal tubular cells deficient of FTO produce less α-SMA after TGF-β stimulation. FTO is indispensable for the extracellular matrix synthesis after ureteral obstruction in kidneys. Indeed, global gene transcriptions amplitude is reduced in FTO deficient kidneys after ureteral obstruction. These data establish the importance of FTO in renal fibrosis, which may have potential therapeutic implications. PMID:26727661

  14. Response requirements modulate tactile spatial congruency effects.

    PubMed

    Gallace, Alberto; Soto-Faraco, Salvador; Dalton, Polly; Kreukniet, Bas; Spence, Charles

    2008-11-01

    Several recent studies have provided support for the view that tactile stimuli/events are remapped into an abstract spatial frame of reference beyond the initial somatotopic representation present in the primary somatosensory cortex. Here, we demonstrate for the first time that the extent to which this remapping of tactile stimuli takes place is dependent upon the particular demands imposed by the task that participants have to perform. Participants in the present study responded to either the elevation (up vs. down) or to the anatomical location (finger vs. thumb) of vibrotactile targets presented to one hand, while trying to ignore distractors presented simultaneously to the other hand. The magnitude and direction of the target-distractor congruency effect was measured as participants adopted one of two different postures with each hand (palm-up or palm-down). When the participants used footpedal responses (toe vs. heel; Experiment 1), congruency effects were determined by the relative elevation of the stimuli in external coordinates (same vs. different elevation), regardless of whether the relevant response feature was defined externally or anatomically. Even when participants responded verbally (Experiment 2), the influence of the relative elevation of the stimuli in external space, albeit attenuated, was still observed. However, when the task involved responding with the stimulated finger (four-alternative forced choice; Experiment 3), congruency effects were virtually eliminated. These findings support the view that tactile events can be remapped according to an abstract frame of reference resulting from multisensory integration, but that the frame of reference that is used while performing a particular task may depend to a large extent on the nature of the task demands. PMID:18709500

  15. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed Central

    Vieira, Mônica L.; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C.; Nascimento, Ana Lucia T. O.; Herwald, Heiko

    2016-01-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  16. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed

    Vieira, Mônica L; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C; Nascimento, Ana Lucia T O; Herwald, Heiko

    2016-05-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease.

  17. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed

    Vieira, Mônica L; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C; Nascimento, Ana Lucia T O; Herwald, Heiko

    2016-05-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  18. Caspase-3 modulates regenerative response after stroke.

    PubMed

    Fan, Wenying; Dai, Yiqin; Xu, Haochen; Zhu, Ximin; Cai, Ping; Wang, Lixiang; Sun, Chungang; Hu, Changlong; Zheng, Ping; Zhao, Bing-Qiao

    2014-02-01

    Stroke is a leading cause of long-lasting disability in humans. However, currently there are still no effective therapies available for promoting stroke recovery. Recent studies have shown that the adult brain has the capacity to regenerate neurons after stroke. Although this neurogenic response may be functionally important for brain repair after injury, the mechanisms underlying stroke-induced neurogenesis are not known. Caspase-3 is a major executioner and has been identified as a key mediator of neuronal death in the acute stage of stroke. Recently, however, accumulating data indicate that caspase-3 also participates in various biological processes that do not cause cell death. Here, we show that cleaved caspase-3 was increased in newborn neuronal precursor cells (NPCs) in the subventricular zone (SVZ) and the dentate gyrus during the period of stroke recovery, with no evidence of apoptosis. We observed that cleaved caspase-3 was expressed by NPCs and limited its self-renewal without triggering apoptosis in cultured NPCs from the SVZ of ischemic mice. Moreover, we revealed that caspase-3 negatively regulated the proliferation of NPCs through reducing the phosphorylation of Akt. Importantly, we demonstrated that peptide inhibition of caspase-3 activity significantly promoted the proliferation and migration of SVZ NPCs and resulted in a significant increase in subsequent neuronal regeneration and functional recovery after stroke. Together, our data identify a previously unknown caspase-3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting caspase-3 for treatment of stroke.

  19. The Effect of an Instructional Module on Death and Dying on the Death Anxiety of Emergency Medical Technician Trainees.

    ERIC Educational Resources Information Center

    Coleman, Ted

    1993-01-01

    Examined whether instructional unit on death and dying during emergency medical technician course reduced death anxiety in trainees. Found no significant differences between treatment group (n=28) that received unit and control group (n=25) that did not on pre-, post-, or delayed-tests. Death education apparently had no more influence on death…

  20. Modulation of Response to Environmental Stimulation in Autistic Children.

    ERIC Educational Resources Information Center

    Kootz, John P.; And Others

    1982-01-01

    Autistic children's blood pressure, heart rate, peripheral blood flow (PBF), and peripheral vascular resistance (PVR) were measured during three types of tasks (reaction time, social interaction, at rest). Disturbances in filtering environmental stimulation and modulating response to novelty may be part of the basic pathology of autism apparent…

  1. Reprogramming immune responses via microRNA modulation

    PubMed Central

    Cubillos-Ruiz, Juan R.; Rutkowski, Melanie R; Tchou, Julia; Conejo-Garcia, Jose R.

    2013-01-01

    It is becoming increasingly clear that there are unique sets of miRNAs that have distinct governing roles in several aspects of both innate and adaptive immune responses. In addition, new tools allow selective modulation of the expression of individual miRNAs, both in vitro and in vivo. Here, we summarize recent advances in our understanding of how miRNAs drive the activity of immune cells, and how their modulation in vivo opens new avenues for diagnostic and therapeutic interventions in multiple diseases, from immunodeficiency to cancer. PMID:25285232

  2. Modulation of immune response in experimental Chagas disease

    PubMed Central

    Basso, Beatriz

    2013-01-01

    Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, affects nearly 18 million people in Latin America and 90 million are at risk of infection. The parasite presents two stages of medical importance in the host, the amastigote, intracellular replicating form, and the extracellular trypomastigote, the infective form. Thus infection by T. cruzi induces a complex immune response that involves effectors and regulatory mechanisms. That is why control of the infection requires a strong humoral and cellular immune response; hence, the outcome of host-parasite interaction in the early stages of infection is extremely important. A critical event during this period of the infection is innate immune response, in which the macrophage’s role is vital. Thus, after being phagocytized, the parasite is able to develop intracellularly; however, during later periods, these cells induce its elimination by means of toxic metabolites. In turn, as the infection progresses, adaptive immune response mechanisms are triggered through the TH1 and TH2 responses. Finally, T. cruzi, like other protozoa such as Leishmania and Toxoplasma, have numerous evasive mechanisms to the immune response that make it possible to spread around the host. In our Laboratory we have developed a vaccination model in mice with Trypanosoma rangeli, nonpathogenic to humans, which modulates the immune response to infection by T. cruzi, thus protecting them. Vaccinated animals showed an important innate response (modulation of NO and other metabolites, cytokines, activation of macrophages), a strong adaptive cellular response and significant increase in specific antibodies. The modulation caused early elimination of the parasites, low parasitaemia, the absence of histological lesions and high survival rates. Even though progress has been made in the knowledge of some of these mechanisms, new studies must be conducted which could target further prophylactic and therapeutic trials against T. cruzi

  3. A single die 1.2 V 55 to 95 dB DR delta sigma ADC with configurable modulator and OSR

    NASA Astrophysics Data System (ADS)

    Haijun, Wu; Bin, Li; Huabin, Zhang; Zhengping, Li; Longyue, Zeng

    2014-03-01

    A single die 1.2 V multi-stage noise shaping (Mash) 2-2 delta sigma analog to digital converter (ADC) for wide applications is implemented. The configurable Mash 2-2 modulator with a new decimation filter design is presented to achieve wide and high dynamic range (DR) for multiple practical applications. The novel modulator can be configured as a Mash 2-2 modulator for high precision or a 2-order modulator for low DR. The decimation filter is designed to select the OSR flexibly among cascaded integrator comb (CIC) filter and two half-band filters (HBF). The serial peripheral interface (SPI) can be used to adjust the sampling frequency and the oversampling ratio (OSR). The design was fabricated in a 0.13 μm CMOS process with an area of 0.91 mm2 and a total power of 5.2 mW. The measurement results show that the dynamic range (DR) of the proposed ADC can change from 55 to 95 dB with the configurable OSR from 16 to 256. The spurious free dynamic range (SFDR) and signal-to-noise distortion ratio (SNDR) can get 99 dB and 86.5 dB, respectively.

  4. Serotoninergic modulation of cortical and respiratory responses to episodic hypoxia

    PubMed Central

    2009-01-01

    Biphasic respiratory response to hypoxia in anesthetized animals is accompanied by changes in the EEG mostly in the low EEG frequency bands. Serotonin is a potent modulator of cortical and respiratory activity through 5-HT2 receptors. Present study investigated whether 5-HT2 receptors might be involved in the EEG and respiratory relationship during normoxic and hypoxic respiration assessed from integrated phrenic (Phr) and hypoglossal (HG) nerve activities. EEG signal recorded from the frontal cortex was subjected to power spectral analysis in delta, theta, alpha, and beta frequency bands. Systemic administration of 5-HT2 agonist DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) enhanced tonic and lowered peak phasic respiratory activity, and increased frequency of bursts of Phr and HG activity. At the same time, EEG activity became desynchronized and arterial blood pressure (ABP) increased. Following DOI pretreatment, 11% hypoxia induced an augmented respiratory response in comparison with the response in the baseline condition. ABP fell less then in the control hypoxia. EEG pattern changed less than in the baseline state. Subsequent administration of ketanserin, a 5-HT2 antagonist increased respiratory activity, elicited a synchronization of EEG activity and hypotension. The respiratory response to hypoxia was attenuated and cortical response was more potent in comparison with that after DOI injection. Arterial blood pressure decreased more then during baseline hypoxic response. The results suggest that modulation of cortical synchronization and desynchronization through 5-HT2 receptor active agents may impact to hypoxic respiratory response. PMID:20156721

  5. Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation

    PubMed Central

    Bergsbaken, Tessa; Cookson, Brad T.

    2009-01-01

    Yersinia pestis, the etiological agent of plague, is one of the most deadly pathogens on our planet. This organism shares important attributes with its ancestral progenitor, Yersinia pseudotuberculosis, including a 70-kb virulence plasmid, lymphotropism during growth in the mammalian host, and killing of host macrophages. Infections with both organisms are biphasic, where bacterial replication occurs initially with little inflammation, followed by phagocyte influx, inflammatory cytokine production, and tissue necrosis. During infection, plasmid-encoded attributes facilitate bacterial-induced macrophage death, which results from two distinct processes and corresponds to the inflammatory crescendo observed in vivo: Naïve cells die by apoptosis (noninflammatory), and later in infection, activated macrophages die by pyroptosis (inflammatory). The significance of this redirected cell death for the host is underscored by the importance of phagocyte activation for immunity to Yersinia and the protective role of pyroptosis during host responses to anthrax lethal toxin and infections with Francisella, Legionella, Pseudomonas, and Salmonella. The similarities of Y. pestis and Y. pseudotuberculosis, including conserved, plasmid-encoded functions inducing at least two distinct mechanisms of cell death, indicate that comparative studies are revealing about their critical pathogenic mechanism(s) and host innate immune responses during infection. Validation of this idea and evidence of similar interactions with the host immune system are provided by Y. pseudotuberculosis-priming, cross-protective immunity against Y. pestis. Despite these insights, additional studies indicate much remains to be understood concerning effective host responses against Yersinia, including chromosomally encoded attributes that also contribute to bacterial evasion and modulation of innate and adaptive immune responses. PMID:19734471

  6. Climatic events inducing die-off in Mediterranean shrublands: are species' responses related to their functional traits?

    PubMed

    Lloret, Francisco; de la Riva, Enrique G; Pérez-Ramos, Ignacio M; Marañón, Teodoro; Saura-Mas, Sandra; Díaz-Delgado, Ricardo; Villar, Rafael

    2016-04-01

    Extreme climatic episodes, likely associated with climate change, often result in profound alterations of ecosystems and, particularly, in drastic events of vegetation die-off. Species attributes are expected to explain different biological responses to these environmental alterations. Here we explored how changes in plant cover and recruitment in response to an extreme climatic episode of drought and low temperatures were related to a set of functional traits (of leaves, roots and seeds) in Mediterranean shrubland species of south-west Spain. Remaining aerial green cover 2 years after the climatic event was positively related to specific leaf area (SLA), and negatively to leaf water potential, stable carbon isotope ratio and leaf proline content. However, plant cover resilience, i.e. the ability to attain pre-event values, was positively related to a syndrome of traits distinguished by a higher efficiency of water use and uptake. Thus, higher SLA and lower water-use efficiency characterized species that were able to maintain green biomass for a longer period of time but were less resilient in the medium term. There was a negative relationship between such syndromes and the number of emerging seedlings. Species with small seeds produced more seedlings per adult. Overall, recruitment was positively correlated with species die-off. This study demonstrates the relationship between plant traits and strong environmental pulses related to climate change, providing a functional interpretation of the recently reported episodes of climate-induced vegetation die-off. Our findings reveal the importance of selecting meaningful traits to interpret post-event resilience processes, particularly when combined with demographic attributes.

  7. Climatic events inducing die-off in Mediterranean shrublands: are species' responses related to their functional traits?

    PubMed

    Lloret, Francisco; de la Riva, Enrique G; Pérez-Ramos, Ignacio M; Marañón, Teodoro; Saura-Mas, Sandra; Díaz-Delgado, Ricardo; Villar, Rafael

    2016-04-01

    Extreme climatic episodes, likely associated with climate change, often result in profound alterations of ecosystems and, particularly, in drastic events of vegetation die-off. Species attributes are expected to explain different biological responses to these environmental alterations. Here we explored how changes in plant cover and recruitment in response to an extreme climatic episode of drought and low temperatures were related to a set of functional traits (of leaves, roots and seeds) in Mediterranean shrubland species of south-west Spain. Remaining aerial green cover 2 years after the climatic event was positively related to specific leaf area (SLA), and negatively to leaf water potential, stable carbon isotope ratio and leaf proline content. However, plant cover resilience, i.e. the ability to attain pre-event values, was positively related to a syndrome of traits distinguished by a higher efficiency of water use and uptake. Thus, higher SLA and lower water-use efficiency characterized species that were able to maintain green biomass for a longer period of time but were less resilient in the medium term. There was a negative relationship between such syndromes and the number of emerging seedlings. Species with small seeds produced more seedlings per adult. Overall, recruitment was positively correlated with species die-off. This study demonstrates the relationship between plant traits and strong environmental pulses related to climate change, providing a functional interpretation of the recently reported episodes of climate-induced vegetation die-off. Our findings reveal the importance of selecting meaningful traits to interpret post-event resilience processes, particularly when combined with demographic attributes. PMID:26801493

  8. Modulation of taste responsiveness by the satiation hormone peptide YY.

    PubMed

    La Sala, Michael S; Hurtado, Maria D; Brown, Alicia R; Bohórquez, Diego V; Liddle, Rodger A; Herzog, Herbert; Zolotukhin, Sergei; Dotson, Cedrick D

    2013-12-01

    It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.

  9. Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.

    PubMed

    Thakor, Avnesh S; Allison, Beth J; Niu, Youguo; Botting, Kimberley J; Serón-Ferré, Maria; Herrera, Emilio A; Giussani, Dino A

    2015-08-01

    Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.

  10. Cortisol modulates men's affiliative responses to acute social stress.

    PubMed

    Berger, Justus; Heinrichs, Markus; von Dawans, Bernadette; Way, Baldwin M; Chen, Frances S

    2016-01-01

    The dominant characterization of the physiological and behavioral human stress reaction is the fight-or-flight response. On the other hand, it has been suggested that social affiliation during stressful times ("tend-and-befriend") also represents a common adaptive response to stress, particularly for women. In the current study, we investigate the extent to which men may also show affiliative responses following acute stress. In addition, we examine a potential neuroendocrine modulator of the hypothesized affiliative response. Eighty male students (forty dyads) were recruited to undergo either the Trier Social Stress Test for Groups (TSST-G) or a non-stressful control situation. Subsequently, participants completed a dyadic interaction task and were then asked to report their feelings of psychological closeness to their interaction partner. Although participants assigned to the stress condition did not differ overall on psychological closeness from participants assigned to the control condition, participants with high cortisol responses to the stressor showed significantly higher ratings of psychological closeness to their interaction partner than participants with low cortisol responses. Our findings suggest that men may form closer temporary bonds following stressful situations that are accompanied by a significant cortisol response. We suggest that the traditional characterization of the male stress response in terms of "fight-or-flight" may be incomplete, and that social affiliation may in fact represent a common, adaptive response to stress in men.

  11. The response function of modulated grid Faraday cup plasma instruments

    NASA Technical Reports Server (NTRS)

    Barnett, A.; Olbert, S.

    1986-01-01

    Modulated grid Faraday cup plasma analyzers are a very useful tool for making in situ measurements of space plasmas. One of their great attributes is that their simplicity permits their angular response function to be calculated theoretically. An expression is derived for this response function by computing the trajectories of the charged particles inside the cup. The Voyager Plasma Science (PLS) experiment is used as a specific example. Two approximations to the rigorous response function useful for data analysis are discussed. The theoretical formulas were tested by multi-sensor analysis of solar wind data. The tests indicate that the formulas represent the true cup response function for all angles of incidence with a maximum error of only a few percent.

  12. Micromechanical die attachment surcharge

    DOEpatents

    Filter, William F.; Hohimer, John P.

    2002-01-01

    An attachment structure is disclosed for attaching a die to a supporting substrate without the use of adhesives or solder. The attachment structure, which can be formed by micromachining, functions purely mechanically in utilizing a plurality of shaped pillars (e.g. round, square or polygonal and solid, hollow or slotted) that are formed on one of the die or supporting substrate and which can be urged into contact with various types of mating structures including other pillars, a deformable layer or a plurality of receptacles that are formed on the other of the die or supporting substrate, thereby forming a friction bond that holds the die to the supporting substrate. The attachment structure can further include an alignment structure for precise positioning of the die and supporting substrate to facilitate mounting the die to the supporting substrate. The attachment structure has applications for mounting semiconductor die containing a microelectromechanical (MEM) device, a microsensor or an integrated circuit (IC), and can be used to form a multichip module. The attachment structure is particularly useful for mounting die containing released MEM devices since these devices are fragile and can otherwise be damaged or degraded by adhesive or solder mounting.

  13. Halophyte die-off in response to anthropogenic impacts on tidal flats

    NASA Astrophysics Data System (ADS)

    Lee, Yoon-Kyung; Park, Wook; Choi, Jong-Kuk; Ryu, Joo-Hyung; Won, Joong-Sun

    2014-12-01

    This study analyzed an abrupt change in halophyte populations, especially the annual plant Suaeda japonica. The boundaries and distributions of S. japonica and Phragmites australis were determined based on the decision tree classifier of TerraSAR-X, SAVI of Landsat ETM+, and density slicing of aerial photography. A large patch of S. japonica in the eastern parts of Donggum-do, South Korea, disappeared in 2007, while populations have been stable in the western parts of the island. To understand the reason behind the sudden die-off, mean sea level was analyzed based on gaged tidal data. Sedimentation rate was measured using Vernier caliper and RTK leveling data. Sedimentation rate between 2006 and 2007 was above the threshold at which S. japonica can germinate. After the loss of an 11-ha S. japonica patch from the eastern part of Donggum-do, sedimentation was accelerated because of a decrease in tidal current caused by a series of land reclamation projects. The increased monthly exposure duration due to continuous sediment accretion altered the type of salt marsh. Our results imply that accumulated effects from a series of coastal construction projects around Ganghwa-do can change not only tide and current hydrodynamics, but also sedimentation and erosion rates, which can cause large halophyte patches to disappear.

  14. Lumbopelvic flexibility modulates neuromuscular responses during trunk flexion-extension.

    PubMed

    Sánchez-Zuriaga, Daniel; Artacho-Pérez, Carla; Biviá-Roig, Gemma

    2016-06-01

    Various stimuli such as the flexibility of lumbopelvic structures influence the neuromuscular responses of the trunk musculature, leading to different load sharing strategies and reflex muscle responses from the afferents of lumbopelvic mechanoreceptors. This link between flexibility and neuromuscular response has been poorly studied. The aim of this study was to investigate the relationship between lumbopelvic flexibility and neuromuscular responses of the erector spinae, hamstring and abdominal muscles during trunk flexion-extension. Lumbopelvic movement patterns were measured in 29 healthy women, who were separated into two groups according to their flexibility during trunk flexion-extension. The electromyographic responses of erector spinae, rectus abdominis and biceps femoris were also recorded. Subjects with greater lumbar flexibility had significantly less pelvic flexibility and vice versa. Subjects with greater pelvic flexibility had a higher rate of relaxation and lower levels of hamstring activation during maximal trunk flexion. The neuromuscular response patterns of the hamstrings seem partially modulated by pelvic flexibility. Not so with the lumbar erector spinae and lumbar flexibility, despite the assertions of some previous studies. The results of this study improve our knowledge of the relationships between trunk joint flexibility and neuromuscular responses, a relationship which may play a role in low back pain. PMID:27155332

  15. The immune response and its therapeutic modulation in bronchiectasis.

    PubMed

    Daheshia, Massoud; Prahl, James D; Carmichael, Jacob J; Parrish, John S; Seda, Gilbert

    2012-01-01

    Bronchiectasis (BC) is a chronic pulmonary disease with tremendous morbidity and significant mortality. As pathogen infection has been advocated as a triggering insult in the development of BC, a central role for the immune response in this process seems obvious. Inflammatory cells are present in both the airways as well as the lung parenchyma, and multiple mediators of immune cells including proteases and cytokines or their humoral products are increased locally or in the periphery. Interestingly, a defect in the immune system or suppression of immune response during conditions such as immunodeficiency may well predispose one to the devastating effects of BC. Thus, the outcome of an active immune response as detrimental or protective in the pathogenesis of BC may be dependent on the state of the patient's immunity, the severity of infection, and the magnitude of immune response. Here we reassess the function of the innate and acquired immunity in BC, the major sites of immune response, and the nature of the bioactive mediators. Furthermore, the potential link(s) between an ongoing immune response and structural alterations accompanying the disease and the success of therapies that can modulate the nature and extent of immune response in BC are elaborated upon.

  16. Lumbopelvic flexibility modulates neuromuscular responses during trunk flexion-extension.

    PubMed

    Sánchez-Zuriaga, Daniel; Artacho-Pérez, Carla; Biviá-Roig, Gemma

    2016-06-01

    Various stimuli such as the flexibility of lumbopelvic structures influence the neuromuscular responses of the trunk musculature, leading to different load sharing strategies and reflex muscle responses from the afferents of lumbopelvic mechanoreceptors. This link between flexibility and neuromuscular response has been poorly studied. The aim of this study was to investigate the relationship between lumbopelvic flexibility and neuromuscular responses of the erector spinae, hamstring and abdominal muscles during trunk flexion-extension. Lumbopelvic movement patterns were measured in 29 healthy women, who were separated into two groups according to their flexibility during trunk flexion-extension. The electromyographic responses of erector spinae, rectus abdominis and biceps femoris were also recorded. Subjects with greater lumbar flexibility had significantly less pelvic flexibility and vice versa. Subjects with greater pelvic flexibility had a higher rate of relaxation and lower levels of hamstring activation during maximal trunk flexion. The neuromuscular response patterns of the hamstrings seem partially modulated by pelvic flexibility. Not so with the lumbar erector spinae and lumbar flexibility, despite the assertions of some previous studies. The results of this study improve our knowledge of the relationships between trunk joint flexibility and neuromuscular responses, a relationship which may play a role in low back pain.

  17. The dorsal raphe modulates sensory responsiveness during arousal in zebrafish

    PubMed Central

    Yokogawa, Tohei; Hannan, Markus C.; Burgess, Harold A.

    2012-01-01

    During waking behavior animals adapt their state of arousal in response to environmental pressures. Sensory processing is regulated in aroused states and several lines of evidence imply that this is mediated at least partly by the serotonergic system. However there is little information directly showing that serotonergic function is required for state-dependent modulation of sensory processing. Here we find that zebrafish larvae can maintain a short-term state of arousal during which neurons in the dorsal raphe modulate sensory responsiveness to behaviorally relevant visual cues. Following a brief exposure to water flow, larvae show elevated activity and heightened sensitivity to perceived motion. Calcium imaging of neuronal activity after flow revealed increased activity in serotonergic neurons of the dorsal raphe. Genetic ablation of these neurons abolished the increase in visual sensitivity during arousal without affecting baseline visual function or locomotor activity. We traced projections from the dorsal raphe to a major visual area, the optic tectum. Laser ablation of the tectum demonstrated that this structure, like the dorsal raphe, is required for improved visual sensitivity during arousal. These findings reveal that serotonergic neurons of the dorsal raphe have a state-dependent role in matching sensory responsiveness to behavioral context. PMID:23100441

  18. Social hierarchy modulates neural responses of empathy for pain.

    PubMed

    Feng, Chunliang; Li, Zhihao; Feng, Xue; Wang, Lili; Tian, Tengxiang; Luo, Yue-Jia

    2016-03-01

    Recent evidence indicates that empathic responses to others' pain are modulated by various situational and individual factors. However, few studies have examined how empathy and underlying brain functions are modulated by social hierarchies, which permeate human society with an enormous impact on social behavior and cognition. In this study, social hierarchies were established based on incidental skill in a perceptual task in which all participants were mediumly ranked. Afterwards, participants were scanned with functional magnetic resonance imaging while watching inferior-status or superior-status targets receiving painful or non-painful stimulation. The results revealed that painful stimulation applied to inferior-status targets induced higher activations in the anterior insula (AI) and anterior medial cingulate cortex (aMCC), whereas these empathic brain activations were significantly attenuated in response to superior-status targets' pain. Further, this neural empathic bias to inferior-status targets was accompanied by stronger functional couplings of AI with brain regions important in emotional processing (i.e. thalamus) and cognitive control (i.e. middle frontal gyrus). Our findings indicate that emotional sharing with others' pain is shaped by relative positions in a social hierarchy such that underlying empathic neural responses are biased toward inferior-status compared with superior-status individuals.

  19. A Computational Model of Cellular Response to Modulated Radiation Fields

    SciTech Connect

    McMahon, Stephen J.; Butterworth, Karl T.; McGarry, Conor K.; Trainor, Colman; O'Sullivan, Joe M.; Hounsell, Alan R.; Prise, Kevin M.

    2012-09-01

    Purpose: To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies. Materials and Methods: A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields. Results: The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses. Conclusions: The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.

  20. Tissue engineering tools for modulation of the immune response

    PubMed Central

    Boehler, Ryan M.; Graham, John G.; Shea, Lonnie D.

    2012-01-01

    Tissue engineering scaffolds have emerged as a powerful tool within regenerative medicine. These materials are being designed to create environments that promote regeneration through a combination of: (i) scaffold architecture, (ii) the use of scaffolds as vehicles for transplanting progenitor cells, and/or (iii) localized delivery of inductive factors or genes encoding for these inductive factors. This review describes the techniques associated with each of these components. Additionally, the immune response is increasingly recognized as a factor influencing regeneration. The immune reaction to an implant begins with an acute response to the injury and innate recognition of foreign materials, with the subsequent chronic immune response involving specific recognition of antigens (e.g., transplanted cells) by the adaptive immune response, which can eventually lead to rejection of the implant. Thus, we also describe the impact of each component on the immune response, and strategies (e.g., material design, anti-inflammatory cytokine delivery, and immune cell recruitment/transplantation) to modulate, yet not eliminate, the local immune response in order to promote regeneration, which represents another important tool for regenerative medicine. PMID:21988690

  1. Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

    PubMed Central

    Turroni, Francesca; Taverniti, Valentina; Ruas-Madiedo, Patricia; Duranti, Sabrina; Guglielmetti, Simone; Lugli, Gabriele Andrea; Gioiosa, Laura; Palanza, Paola; Margolles, Abelardo; van Sinderen, Douwe

    2014-01-01

    Here, we describe data obtained from transcriptome profiling of human cell lines and intestinal cells of a murine model upon exposure and colonization, respectively, with Bifidobacterium bifidum PRL2010. Significant changes were detected in the transcription of genes that are known to be involved in innate immunity. Furthermore, results from enzyme-linked immunosorbent assays (ELISAs) showed that exposure to B. bifidum PRL2010 causes enhanced production of interleukin 6 (IL-6) and IL-8 cytokines, presumably through NF-κB activation. The obtained global transcription profiles strongly suggest that Bifidobacterium bifidum PRL2010 modulates the innate immune response of the host. PMID:24242237

  2. Pharmacoepigenomics: an interplay of epigenetic modulation of drug response and modulation of the epigenome by drugs.

    PubMed

    Mendiratta, Shweta; Jain, Shruti; Maini, Jayant; Brahmachari, Vani

    2014-01-01

    Epigenetic modulation captures the lack of correlation between the genotype and the phenotype. It also provides an interface between environment and the genotype leading to functional plasticity of the genome. While drug response can be modulated by the epigenome, the therapeutic intervention by drugs can also be considered as an environmental cue for epigenetic alterations. The effect of genetic polymorphism has accrued considerable interest and population polymorphism leading to variation in drug response is being studied extensively. The available data on the epigenetic marking of the whole genome in different contexts implies that no biological pathway or process in the mammalian system is free of epigenetic influence and thus, drug metabolism would not be an exception. In the light of the fact that the epigenome is not only variable between individuals, but that it also varies between different tissues of the same individual and with the age of the individual, it is still a long journey to transit from the correlation to causal relationship between drug response and the epigenomic variations. The present review is focused on recent developments in the area and a brief discussion of the future prospects and challenges.

  3. Laminar circuit organization and response modulation in mouse visual cortex

    PubMed Central

    Olivas, Nicholas D.; Quintanar-Zilinskas, Victor; Nenadic, Zoran; Xu, Xiangmin

    2012-01-01

    The mouse has become an increasingly important animal model for visual system studies, but few studies have investigated local functional circuit organization of mouse visual cortex. Here we used our newly developed mapping technique combining laser scanning photostimulation (LSPS) with fast voltage-sensitive dye (VSD) imaging to examine the spatial organization and temporal dynamics of laminar circuit responses in living slice preparations of mouse primary visual cortex (V1). During experiments, LSPS using caged glutamate provided spatially restricted neuronal activation in a specific cortical layer, and evoked responses from the stimulated layer to its functionally connected regions were detected by VSD imaging. In this study, we first provided a detailed analysis of spatiotemporal activation patterns at specific V1 laminar locations and measured local circuit connectivity. Then we examined the role of cortical inhibition in the propagation of evoked cortical responses by comparing circuit activity patterns in control and in the presence of GABAa receptor antagonists. We found that GABAergic inhibition was critical in restricting layer-specific excitatory activity spread and maintaining topographical projections. In addition, we investigated how AMPA and NMDA receptors influenced cortical responses and found that blocking AMPA receptors abolished interlaminar functional projections, and the NMDA receptor activity was important in controlling visual cortical circuit excitability and modulating activity propagation. The NMDA receptor antagonist reduced neuronal population activity in time-dependent and laminar-specific manners. Finally, we used the quantitative information derived from the mapping experiments and presented computational modeling analysis of V1 circuit organization. Taken together, the present study has provided important new information about mouse V1 circuit organization and response modulation. PMID:23060751

  4. Ethylene modulates root-wave responses in Arabidopsis.

    PubMed

    Buer, Charles S; Wasteneys, Geoffrey O; Masle, Josette

    2003-06-01

    When stimulated to bend downward by being held at 45 degrees off vertical but unable to penetrate into agar-based media, Arabidopsis roots develop waving and looping growth patterns. Here, we demonstrate that ethylene modulates these responses. We determined that agar-containing plates sealed with low-porosity film generate abiotic ethylene concentrations of 0.1 to 0.3 microL L(-1), whereas in plates wrapped with porous tape, ethylene remains at trace levels. We demonstrate that exogenous ethylene at concentrations as low as a few nanoliters per liter modulates root waving, root growth direction, and looping but through partly different mechanisms. Nutrients and Suc modify the effects of ethylene on root waving. Thus, ethylene had little effect on temporal wave frequency when nutrients were omitted but reduced it significantly on nutrient-supplemented agar. Suc masked the ethylene response. Ethylene consistently suppressed the normal tendency for roots of Landsberg erecta to skew to the right as they grow against hard-agar surfaces and also generated righthanded petiole twisting. Furthermore, ethylene suppressed root looping, a gravity-dependent growth response that was enhanced by high nutrient and Suc availability. Our work demonstrates that cell file twisting is not essential for root waving or skewing to occur. Differential flank growth accounted for both the extreme root waving on zero-nutrient plates and for root skewing. Root twisting was nutrient-dependent and was thus strongly associated with the looping response. The possible role of auxin transport in these responses and the involvement of circadian rhythms are discussed.

  5. Seed Pubescence and Shape Modulate Adaptive Responses to Fire Cues

    PubMed Central

    Gómez-González, Susana; Ojeda, Fernando; Torres-Morales, Patricio; Palma, Jazmín E.

    2016-01-01

    Post-fire recruitment by seeds is regarded as an adaptive response in fire-prone ecosystems. Nevertheless, little is known about which heritable seed traits are functional to the main signals of fire (heat and smoke), thus having the potential to evolve. Here, we explored whether three seed traits (pubescence, dormancy and shape) and fire regime modulate seed response to fire cues(heat and smoke). As a model study system, we used Helenium aromaticum (Asteraceae), a native annual forb from the Chilean matorral, where fires are anthropogenic. We related seed trait values with fitness responses (germination and survival) after exposure to heat-shock and smoke experimental treatments on seeds from 10 H. aromaticum wild populations. We performed a phenotypic selection experiment to examine the relationship of seed traits with post-treatment fitness within a population (adaptive hypothesis). We then explored whether fire frequency in natural habitats was associated with trait expression across populations, and with germination and survival responses to experimental fire-cues. We found that populations subjected to higher fire frequency had, in average, more rounded and pubescent seeds than populations from rarely burned areas. Populations with more rounded and pubescent seeds were more resistant to 80°C heat-shock and smoke treatments.There was correlated selection on seed traits: pubescent-rounded or glabrouscent-elongated seeds had the highest probability of germinating after heat-shock treatments. Seed pubescence and shape in H. aromaticum are heritable traits that modulate adaptive responses to fire. Our results provide new insights into the process of plant adaptation to fire and highlight the relevance of human-made fires as a strong evolutionary agent in the Anthropocene. PMID:27438267

  6. Neuroendocrine system response modulates oxidative cellular damage in burn patients.

    PubMed

    Xie, Xiao-Qi; Shinozawa, Yotaro; Sasaki, Junichi; Takuma, Kiyotsugu; Akaishi, Satoshi; Yamanouchi, Satoshi; Endo, Tomoyuki; Nomura, Ryosuke; Kobayashi, Michio; Kudo, Daisuke; Hojo, Nobuko

    2007-02-01

    Oxygen-derived free radicals play important roles in pathophysiological processes in critically ill patients, but the data characterizing relationships between radicals and neuroendocrine system response are sparse. To search the cue to reduce the oxidative cellular damage from the point of view of neuroendocrine system response, we studied the indicators of neuroendocrine and inflammatory responses excreted in urine in 14 burn patients (42.3 +/- 31.4 years old, and 32.3 +/- 27.6% burn of total body surface area [%TBSA]) during the first seven days post burn. The daily mean amounts of urinary excretion of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a marker of oxidative cellular damage, were above the upper limit of the standard value during the studied period. The total amount of urinary excretion of 8-OHdG in the first day post burn correlated with burn severity indices: %TBSA (r = 0.63, p = 0.021) and burn index (r = 0.70, p = 0.008). The daily urinary excretion of 8-OHdG correlated with the daily urinary excretion of norepinephrine and nitrite plus nitrate (NOx) during the studied period except day 2 post burn, and correlated with the daily urinary excretion of 17-hydroxycorticosteriod (17-OHCS) in days 2, 3, and 7 post burn. These data suggest that oxidative cellular damage correlates with burn severity and neuroendocrine system response modulates inflammation and oxidative cellular damage. Modulation of neuroendocrine system response and inflammation in the treatment in the early phase of burn may be useful to reduce the oxidative cellular damage and to prevent multiple organ failures in patients with extensive burn.

  7. Seed Pubescence and Shape Modulate Adaptive Responses to Fire Cues.

    PubMed

    Gómez-González, Susana; Ojeda, Fernando; Torres-Morales, Patricio; Palma, Jazmín E

    2016-01-01

    Post-fire recruitment by seeds is regarded as an adaptive response in fire-prone ecosystems. Nevertheless, little is known about which heritable seed traits are functional to the main signals of fire (heat and smoke), thus having the potential to evolve. Here, we explored whether three seed traits (pubescence, dormancy and shape) and fire regime modulate seed response to fire cues(heat and smoke). As a model study system, we used Helenium aromaticum (Asteraceae), a native annual forb from the Chilean matorral, where fires are anthropogenic. We related seed trait values with fitness responses (germination and survival) after exposure to heat-shock and smoke experimental treatments on seeds from 10 H. aromaticum wild populations. We performed a phenotypic selection experiment to examine the relationship of seed traits with post-treatment fitness within a population (adaptive hypothesis). We then explored whether fire frequency in natural habitats was associated with trait expression across populations, and with germination and survival responses to experimental fire-cues. We found that populations subjected to higher fire frequency had, in average, more rounded and pubescent seeds than populations from rarely burned areas. Populations with more rounded and pubescent seeds were more resistant to 80°C heat-shock and smoke treatments.There was correlated selection on seed traits: pubescent-rounded or glabrouscent-elongated seeds had the highest probability of germinating after heat-shock treatments. Seed pubescence and shape in H. aromaticum are heritable traits that modulate adaptive responses to fire. Our results provide new insights into the process of plant adaptation to fire and highlight the relevance of human-made fires as a strong evolutionary agent in the Anthropocene. PMID:27438267

  8. Laminar circuit organization and response modulation in mouse visual cortex.

    PubMed

    Olivas, Nicholas D; Quintanar-Zilinskas, Victor; Nenadic, Zoran; Xu, Xiangmin

    2012-01-01

    The mouse has become an increasingly important animal model for visual system studies, but few studies have investigated local functional circuit organization of mouse visual cortex. Here we used our newly developed mapping technique combining laser scanning photostimulation (LSPS) with fast voltage-sensitive dye (VSD) imaging to examine the spatial organization and temporal dynamics of laminar circuit responses in living slice preparations of mouse primary visual cortex (V1). During experiments, LSPS using caged glutamate provided spatially restricted neuronal activation in a specific cortical layer, and evoked responses from the stimulated layer to its functionally connected regions were detected by VSD imaging. In this study, we first provided a detailed analysis of spatiotemporal activation patterns at specific V1 laminar locations and measured local circuit connectivity. Then we examined the role of cortical inhibition in the propagation of evoked cortical responses by comparing circuit activity patterns in control and in the presence of GABAa receptor antagonists. We found that GABAergic inhibition was critical in restricting layer-specific excitatory activity spread and maintaining topographical projections. In addition, we investigated how AMPA and NMDA receptors influenced cortical responses and found that blocking AMPA receptors abolished interlaminar functional projections, and the NMDA receptor activity was important in controlling visual cortical circuit excitability and modulating activity propagation. The NMDA receptor antagonist reduced neuronal population activity in time-dependent and laminar-specific manners. Finally, we used the quantitative information derived from the mapping experiments and presented computational modeling analysis of V1 circuit organization. Taken together, the present study has provided important new information about mouse V1 circuit organization and response modulation.

  9. SPHERICAL DIE

    DOEpatents

    Livingston, J.P.

    1959-01-27

    A die is presented for pressing powdered materials into a hemispherical shape of uniforin density and wall thickness comprising a fcmale and male die element held in a stationary spaced relation with the space being equivalent to the wall thickness and defining the hemispherical shape, a pressing ring linearly moveable along the male die element, an inlet to fill the space with powdered materials, a guiding system for moving the pressing ring along the male die element so as to press the powdered material and a heating system for heating the male element so that the powdered material is heated while being pressed.

  10. Do plants modulate biomass allocation in response to petroleum pollution?

    PubMed

    Nie, Ming; Yang, Qiang; Jiang, Li-Fen; Fang, Chang-Ming; Chen, Jia-Kuan; Li, Bo

    2010-12-23

    Biomass allocation is an important plant trait that responds plastically to environmental heterogeneities. However, the effects on this trait of pollutants owing to human activities remain largely unknown. In this study, we investigated the response of biomass allocation of Phragmites australis to petroleum pollution by a ¹³CO₂ pulse-labelling technique. Our data show that plant biomass significantly decreased under petroleum pollution, but the root-shoot ratio for both plant biomass and ¹³C increased with increasing petroleum concentration, suggesting that plants could increase biomass allocation to roots in petroleum-polluted soil. Furthermore, assimilated ¹³C was found to be significantly higher in soil, microbial biomass and soil respiration after soils were polluted by petroleum. These results suggested that the carbon released from roots is rapidly turned over by soil microbes under petroleum pollution. This study found that plants can modulate biomass allocation in response to petroleum pollution.

  11. Auditory Cortex Basal Activity Modulates Cochlear Responses in Chinchillas

    PubMed Central

    León, Alex; Elgueda, Diego; Silva, María A.; Hamamé, Carlos M.; Delano, Paul H.

    2012-01-01

    Background The auditory efferent system has unique neuroanatomical pathways that connect the cerebral cortex with sensory receptor cells. Pyramidal neurons located in layers V and VI of the primary auditory cortex constitute descending projections to the thalamus, inferior colliculus, and even directly to the superior olivary complex and to the cochlear nucleus. Efferent pathways are connected to the cochlear receptor by the olivocochlear system, which innervates outer hair cells and auditory nerve fibers. The functional role of the cortico-olivocochlear efferent system remains debated. We hypothesized that auditory cortex basal activity modulates cochlear and auditory-nerve afferent responses through the efferent system. Methodology/Principal Findings Cochlear microphonics (CM), auditory-nerve compound action potentials (CAP) and auditory cortex evoked potentials (ACEP) were recorded in twenty anesthetized chinchillas, before, during and after auditory cortex deactivation by two methods: lidocaine microinjections or cortical cooling with cryoloops. Auditory cortex deactivation induced a transient reduction in ACEP amplitudes in fifteen animals (deactivation experiments) and a permanent reduction in five chinchillas (lesion experiments). We found significant changes in the amplitude of CM in both types of experiments, being the most common effect a CM decrease found in fifteen animals. Concomitantly to CM amplitude changes, we found CAP increases in seven chinchillas and CAP reductions in thirteen animals. Although ACEP amplitudes were completely recovered after ninety minutes in deactivation experiments, only partial recovery was observed in the magnitudes of cochlear responses. Conclusions/Significance These results show that blocking ongoing auditory cortex activity modulates CM and CAP responses, demonstrating that cortico-olivocochlear circuits regulate auditory nerve and cochlear responses through a basal efferent tone. The diversity of the obtained effects

  12. Performance evaluation of partial response continuous phase modulation: Discriminator detection

    NASA Astrophysics Data System (ADS)

    Trachtman, Eyal

    1989-09-01

    The principles of continuous phase modulation (CPM) are reviewed and signalling schemes based on it are discussed. The discriminator detector is widely used to detect CPM signals on band limited channels; it is a non-coherent detector which is widely used in mobile communication applications in which fading makes coherent detection difficult; it is suitable for frequency hopping systems. The detector's inferior response to that of a coherent detector can be compensated by suitable design. The performance is compared of various receivers which use the discriminator detector, using an especially written computer simulation. Receiver schemes considered included: Full response signal with integrate and dump filter; Integrate and dump filter with differential symbol detection; zero forcing linear equalization with symbol detection; Decision feedback equalization (DFE); Maximum likelihood sequence estimation; and Tomlinson filter configuration. The Tomlinson filter configuration, which has not previously been used in a CPM communication system, was compared with the other systems with respect to performance and complexity. For all CPM and detection schemes there are optimum values of h, the modulation index and there is no benefit in increasing the value of h and, therefore the bandwidth, beyond this value. Results are presented for various signal schemes, which indicate that detectability performance can be improved and bandwidth reduced by using a partial response CPM. There is a tradeoff between detectability performance and bandwidth, as a function of the baseband pulse duration. It was found that quaternary signal schemes gave better detectability performance than binary schemes, for the same bit-rates. The simulation results indicated that the Tomlinson-DFE configuration was effective for the partial response M-ary CPM channel with discriminator detection; spectral efficiency was not seriously degraded by precoding using the Tomlinson filter, and there was no

  13. Frequency modulated sweep responses in the medial geniculate nucleus.

    PubMed

    Lui, B; Mendelson, J R

    2003-12-01

    A basic feature of communication signals is a dynamic change in frequency. One stimulus that lends itself well to investigating the frequency changes contained in these signals is the frequency modulated (FM) sweep. While many studies have investigated FM sweep responses in the auditory midbrain and cortex, relatively few have examined them in the thalamus. To this end, we investigated the responses of single units in the ventral division of the medial geniculate nucleus (MGNv) of the rat to FM sweeps. Both upward- (changing from low to high frequency) and downward-directed (changing from high to low frequency) FM sweeps were presented at four rates of frequency modulation (i.e., speed). Results showed that the majority (76%) of the cells preferred fast or medium FM sweeps. For direction selectivity, just under half of the units (47%) exhibited a preference for the direction of FM sweep. The results suggest that there is a greater degree of direction but not speed selectivity at progressively higher levels in the auditory pathway.

  14. Psychotherapy with the dying patient.

    PubMed

    Schwartz, A M; Karasu, T B

    1977-01-01

    This paper develops and describes encounters with dying patients and their families and looks for consesus of patterns and responses of possible help in confronting this situation. It offers positive suggestions for those providing care for dying patients but also acknowledges that only an intellectual grasp of the situation is not sufficient qualification for caring for the dying.

  15. Simulation of differential die-away instrument’s response to asymmetrically burned spent nuclear fuel

    SciTech Connect

    Martinik, Tomas; Henzl, Vladimir; Grape, Sophie; Svard, Staffan Jacobsson; Jansson, Peter; Swinhoe, Martyn T.; Tobin, Stephen J.

    2015-03-04

    Here, previous simulation studies of Differential Die–Away (DDA) instrument’s response to active interrogation of spent nuclear fuel from a pressurized water reactor (PWR) yielded promising results in terms of its capability to accurately measure or estimate basic spent fuel assembly (SFA) characteristics, such as multiplication, initial enrichment (IE) and burn-up (BU) as well as the total plutonium content. These studies were however performed only for a subset of idealized SFAs with a symmetric BU with respect to its longitudinal axis. Therefore, to complement the previous results, additional simulations have been performed of the DDA instrument’s response to interrogation of asymmetrically burned spent nuclear fuel in order to determine whether detailed assay of SFAs from all 4 sides will be necessary in real life applications or whether a cost and time saving single sided assay could be used to achieve results of similar quality as previously reported in case of symmetrically burned SFAs.

  16. Voluntary modulation of anterior cingulate response to negative feedback.

    PubMed

    Shane, Matthew S; Weywadt, Christina R

    2014-01-01

    Anterior cingulate and medial frontal cortex (dACC/mFC) response to negative feedback represents the actions of a generalized error-monitoring system critical for the management of goal-directed behavior. Magnitude of dACC/mFC response to negative feedback correlates with levels of post-feedback behavioral change, and with proficiency of operant learning processes. With this in mind, it follows that an ability to alter dACC/mFC response to negative feedback may lead to representative changes in operant learning proficiency. To this end, the present study investigated the extent to which healthy individuals would show modulation of their dACC/mFC response when instructed to try to either maximize or minimize their neural response to the presentation of contingent negative feedback. Participants performed multiple runs of a standard time-estimation task, during which they received feedback regarding their ability to accurately estimate a one-second duration. On Watch runs, participants were simply instructed to try to estimate as closely as possible the one second duration. On Increase and Decrease runs, participants performed the same task, but were instructed to "try to increase [decrease] their brain's response every time they received negative feedback". Results indicated that participants showed changes in dACC/mFC response under these differing instructional conditions: dACC/mFC activity following negative feedback was higher in the Increase condition, and dACC activity trended lower in the Decrease condition, compared to the Watch condition. Moreover, dACC activity correlated with post-feedback performance adjustments, and these adjustments were highest in the Increase condition. Potential implications for neuromodulation and facilitated learning are discussed. PMID:25376010

  17. Omega-3 fatty acids modulate neonatal cytokine response to endotoxin.

    PubMed

    Espiritu, Michael M; Lin, Hong; Foley, Elizabeth; Tsang, Valerie; Rhee, Eunice; Perlman, Jeffrey; Cunningham-Rundles, Susanna

    2016-08-01

    Neonatal immune response is characterized by an uncompensated pro-inflammatory response that can lead to inflammation-related morbidity and increased susceptibility to infection. We investigated the effects of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) pre-treatment on cytokine secretion to low-concentration endotoxin (lipopolysaccharide, LPS) in THP-1 monocytes and neonatal cord blood (CB) from healthy full-term infants. Pre-treatment of THP-1 cells, with either n-3 PUFA at 25 or 100 μM significantly reduced IL-6, IL-10, and IL-12 secretion while DHA, but not EPA, reduced TNF-α response to LPS. DHA inhibition was stronger compared to EPA and effective at the low concentration. The same concentrations of n-3 PUFAs inhibited IL-12 but not IL-10 cytokine response in whole CB from 9 infants pre-treated for 24 h. To assess clinical relevance for acute response to LPS, the effects of low-concentration DHA at 25 μM or 12.5 μM were assessed before and after LPS exposure of isolated CB mononuclear cells from 20 infants for 1 h. When added before or after LPS, physiologic DHA treatment produced significant concentration-dependent inhibition of TNF-α, IL-6, IL-1β, and IL-8 secretion. The results demonstrate prophylactic and therapeutic modulation of neonatal cytokine response to LPS and provide proof-of-concept that low-concentration administration of n-3 PUFA could attenuate or resolve neonatal inflammatory response.

  18. Neural response to reward anticipation is modulated by Gray's impulsivity.

    PubMed

    Hahn, Tim; Dresler, Thomas; Ehlis, Ann-Christine; Plichta, Michael M; Heinzel, Sebastian; Polak, Thomas; Lesch, Klaus-Peter; Breuer, Felix; Jakob, Peter M; Fallgatter, Andreas J

    2009-07-15

    According to the Reinforcement Sensitivity Theory (RST), Gray's dimension of impulsivity, reflecting human trait reward sensitivity, determines the extent to which stimuli activate the Behavioural Approach System (BAS). The potential neural underpinnings of the BAS, however, remain poorly understood. In the present study, we examined the association between Gray's impulsivity as defined by the RST and event-related fMRI BOLD-response to anticipation of reward in twenty healthy human subjects in brain regions previously associated with reward processing. Anticipation of reward during a Monetary Incentive Delay Task elicited activation in key components of the human reward circuitry such as the ventral striatum, the amygdala and the orbitofrontal cortex. Interindividual differences in Gray's impulsivity accounted for a significant amount of variance of the reward-related BOLD-response in the ventral striatum and the orbitofrontal cortex. Specifically, higher trait reward sensitivity was associated with increased activation in response to cues indicating potential reward. Extending previous evidence, here we show that variance in functional brain activation during anticipation of reward is attributed to interindividual differences regarding Gray's dimension of impulsivity. Thus, trait reward sensitivity contributes to the modulation of responsiveness in major components of the human reward system which thereby display a core property of the BAS. Generally, fostering our understanding of the neural underpinnings of the association of reward-related interindividual differences in affective traits might aid researchers in quest for custom-tailored treatments of psychiatric disorders, further disentangling the complex relationship between personality traits, emotion, and health.

  19. CD28 Aptamers as Powerful Immune Response Modulators

    PubMed Central

    Pastor, Fernando; Soldevilla, Mario M; Villanueva, Helena; Kolonias, Despina; Inoges, Susana; de Cerio, Ascensión L; Kandzia, Romy; Klimyuk, Victor; Gleba, Yuri; Gilboa, Eli; Bendandi, Maurizio

    2013-01-01

    CD28 is one of the main costimulatory receptors responsible for the proper activation of T lymphocytes. We have isolated two aptamers that bind to the CD28 receptor. As a monomer, one of them interfered with the binding of CD28 to its ligand (B7), precluding the costimulatory signal, whereas the other one was inactive. However, dimerization of any of the anti-CD28 aptamers was sufficient to provide an artificial costimulatory signal. No antibody has featured a dual function (i.e., the ability to work as agonist and antagonist) to date. Two different agonistic structures were engineered for each anti-CD28 aptamer. One showed remarkably improved costimulatory properties, surpassing the agonistic effect of an anti-CD28 antibody. Moreover, we showed in vivo that the CD28 agonistic aptamer is capable of enhancing the cellular immune response against a lymphoma idiotype and of prolonging survival of mice which receive the aptamer together with an idiotype vaccine. The CD28 aptamers described in this work could be used to modulate the immune response either blocking the interaction with B7 or enhancing vaccine-induced immune responses in cancer immunotherapy. PMID:23756353

  20. "Our babies shall not die": a community's response to medical neglect.

    PubMed

    Jacobs, S E

    1979-01-01

    The free neighborhood health center in a Midwest U.S. town was developed in response to a report that indicated that infant mortality rates were higher for the Black community than for the community-at-large. The health center soon took on the full range of health problems brought by clients regardless of client's race, ethnicity, or income. The processes for managing health care problems in an environment where racism was the rule rather than the exception are considered in this study.

  1. Simulation of differential die-away instrument’s response to asymmetrically burned spent nuclear fuel

    DOE PAGES

    Martinik, Tomas; Henzl, Vladimir; Grape, Sophie; Svard, Staffan Jacobsson; Jansson, Peter; Swinhoe, Martyn T.; Tobin, Stephen J.

    2015-03-04

    Here, previous simulation studies of Differential Die–Away (DDA) instrument’s response to active interrogation of spent nuclear fuel from a pressurized water reactor (PWR) yielded promising results in terms of its capability to accurately measure or estimate basic spent fuel assembly (SFA) characteristics, such as multiplication, initial enrichment (IE) and burn-up (BU) as well as the total plutonium content. These studies were however performed only for a subset of idealized SFAs with a symmetric BU with respect to its longitudinal axis. Therefore, to complement the previous results, additional simulations have been performed of the DDA instrument’s response to interrogation of asymmetricallymore » burned spent nuclear fuel in order to determine whether detailed assay of SFAs from all 4 sides will be necessary in real life applications or whether a cost and time saving single sided assay could be used to achieve results of similar quality as previously reported in case of symmetrically burned SFAs.« less

  2. Cohesin modulates transcription of estrogen-responsive genes.

    PubMed

    Antony, Jisha; Dasgupta, Tanushree; Rhodes, Jenny M; McEwan, Miranda V; Print, Cristin G; O'Sullivan, Justin M; Horsfield, Julia A

    2015-03-01

    The cohesin complex has essential roles in cell division, DNA damage repair and gene transcription. The transcriptional function of cohesin is thought to derive from its ability to connect distant regulatory elements with gene promoters. Genome-wide binding of cohesin in breast cancer cells frequently coincides with estrogen receptor alpha (ER), leading to the hypothesis that cohesin facilitates estrogen-dependent gene transcription. We found that cohesin modulates the expression of only a subset of genes in the ER transcription program, either activating or repressing transcription depending on the gene target. Estrogen-responsive genes most significantly influenced by cohesin were enriched in pathways associated with breast cancer progression such as PI3K and ErbB1. In MCF7 breast cancer cells, cohesin depletion enhanced transcription of TFF1 and TFF2, and was associated with increased ER binding and increased interaction between TFF1 and its distal enhancer situated within TMPRSS3. In contrast, cohesin depletion reduced c-MYC mRNA and was accompanied by reduced interaction between a distal enhancer of c-MYC and its promoters. Our data indicates that cohesin is not a universal facilitator of ER-induced transcription and can even restrict enhancer-promoter communication. We propose that cohesin modulates transcription of estrogen-dependent genes to achieve appropriate directionality and amplitude of expression.

  3. Personality traits modulate neural responses to emotions expressed in music.

    PubMed

    Park, Mona; Hennig-Fast, Kristina; Bao, Yan; Carl, Petra; Pöppel, Ernst; Welker, Lorenz; Reiser, Maximilian; Meindl, Thomas; Gutyrchik, Evgeny

    2013-07-26

    Music communicates and evokes emotions. The number of studies on the neural correlates of musical emotion processing is increasing but few have investigated the factors that modulate these neural activations. Previous research has shown that personality traits account for individual variability of neural responses. In this study, we used functional magnetic resonance imaging (fMRI) to investigate how the dimensions Extraversion and Neuroticism are related to differences in brain reactivity to musical stimuli expressing the emotions happiness, sadness and fear. 12 participants (7 female, M=20.33 years) completed the NEO-Five Factor Inventory (NEO-FFI) and were scanned while performing a passive listening task. Neurofunctional analyses revealed significant positive correlations between Neuroticism scores and activations in bilateral basal ganglia, insula and orbitofrontal cortex in response to music expressing happiness. Extraversion scores were marginally negatively correlated with activations in the right amygdala in response to music expressing fear. Our findings show that subjects' personality may have a predictive power in the neural correlates of musical emotion processing and should be considered in the context of experimental group homogeneity.

  4. Spectral quality of light modulates emotional brain responses in humans.

    PubMed

    Vandewalle, G; Schwartz, S; Grandjean, D; Wuillaume, C; Balteau, E; Degueldre, C; Schabus, M; Phillips, C; Luxen, A; Dijk, D J; Maquet, P

    2010-11-01

    Light therapy can be an effective treatment for mood disorders, suggesting that light is able to affect mood state in the long term. As a first step to understand this effect, we hypothesized that light might also acutely influence emotion and tested whether short exposures to light modulate emotional brain responses. During functional magnetic resonance imaging, 17 healthy volunteers listened to emotional and neutral vocal stimuli while being exposed to alternating 40-s periods of blue or green ambient light. Blue (relative to green) light increased responses to emotional stimuli in the voice area of the temporal cortex and in the hippocampus. During emotional processing, the functional connectivity between the voice area, the amygdala, and the hypothalamus was selectively enhanced in the context of blue illumination, which shows that responses to emotional stimulation in the hypothalamus and amygdala are influenced by both the decoding of vocal information in the voice area and the spectral quality of ambient light. These results demonstrate the acute influence of light and its spectral quality on emotional brain processing and identify a unique network merging affective and ambient light information.

  5. Modulation of vaccine response by concomitant probiotic administration

    PubMed Central

    Maidens, Catherine; Childs, Caroline; Przemska, Agnieszka; Dayel, Iman Bin; Yaqoob, Parveen

    2013-01-01

    Evidence suggests that probiotic bacteria modulate both innate and adaptive immunity in the host, and in some situations can result in reduced severity of common illnesses, such as acute rotavirus infection and respiratory infections. Responses to vaccination are increasingly being used to provide high quality information on the immunomodulatory effects of dietary components in humans. The present review focuses on the effect of probiotic administration upon vaccination response. The majority of studies investigating the impact of probiotics on responses to vaccination have been conducted in healthy adults, and at best they show modest effects of probiotics on serum or salivary IgA titres. Studies in infants and in elderly subjects are very limited, and it is too early to draw any firm conclusions regarding the potential for probiotics to act as adjuvants in vaccination. Although some studies are comparable in terms of duration of the intervention, age and characteristics of the subjects, most differ in terms of the probiotic selected. Further well designed, randomized, placebo‐controlled studies are needed to understand fully the immunomodulatory properties of probiotics, whether the effects exerted are strain‐dependent and age‐dependent and their clinical relevance in enhancing immune protection following vaccination. PMID:22845346

  6. Attention modulates the dorsal striatum response to love stimuli.

    PubMed

    Langeslag, Sandra J E; van der Veen, Frederik M; Röder, Christian H

    2014-02-01

    In previous functional magnetic resonance imaging (fMRI) studies concerning romantic love, several brain regions including the caudate and putamen have consistently been found to be more responsive to beloved-related than control stimuli. In those studies, infatuated individuals were typically instructed to passively view the stimuli or to think of the viewed person. In the current study, we examined how the instruction to attend to, or ignore the beloved modulates the response of these brain areas. Infatuated individuals performed an oddball task in which pictures of their beloved and friend served as targets and distractors. The dorsal striatum showed greater activation for the beloved than friend, but only when they were targets. The dorsal striatum actually tended to show less activation for the beloved than the friend when they were distractors. The longer the love and relationship duration, the smaller the response of the dorsal striatum to beloved-distractor stimuli was. We interpret our findings in terms of reinforcement learning. By virtue of using a cognitive task with a full factorial design, we show that the dorsal striatum is not activated by beloved-related information per se, but only by beloved-related information that is attended.

  7. Modulation of Primary Immune Response by Different Vaccine Adjuvants

    PubMed Central

    Ciabattini, Annalisa; Pettini, Elena; Fiorino, Fabio; Pastore, Gabiria; Andersen, Peter; Pozzi, Gianni; Medaglini, Donata

    2016-01-01

    Adjuvants contribute to enhancing and shaping the vaccine immune response through different modes of action. Here early biomarkers of adjuvanticity after primary immunization were investigated using four different adjuvants combined with the chimeric tuberculosis vaccine antigen H56. C57BL/6 mice were immunized by the subcutaneous route with different vaccine formulations, and the modulation of primary CD4+ T cell and B cell responses was assessed within draining lymph nodes, blood, and spleen, 7 and 12 days after priming. Vaccine formulations containing the liposome system CAF01 or a squalene-based oil-in-water emulsion (o/w squalene), but not aluminum hydroxide (alum) or CpG ODN 1826, elicited a significant primary antigen-specific CD4+ T cell response compared to antigen alone, 7 days after immunization. The effector function of activated CD4+ T cells was skewed toward a Th1/Th17 response by CAF01, while a Th1/Th2 response was elicited by o/w squalene. Differentiation of B cells in short-lived plasma cells, and subsequent early H56-specific IgG secretion, was observed in mice immunized with o/w squalene or CpG adjuvants. Tested adjuvants promoted the germinal center reaction with different magnitude. These results show that the immunological activity of different adjuvants can be characterized by profiling early immunization biomarkers after primary immunization. These data and this approach could give an important contribution to the rational development of heterologous prime–boost vaccine immunization protocols. PMID:27781036

  8. Titanium surface hydrophilicity modulates the human macrophage inflammatory cytokine response.

    PubMed

    Alfarsi, Mohammed A; Hamlet, Stephen M; Ivanovski, Saso

    2014-01-01

    Increased titanium surface hydrophilicity has been shown to accelerate dental implant osseointegration. Macrophages are important in the early inflammatory response to surgical implant placement and influence the subsequent healing response. This study investigated the modulatory effect of a hydrophilic titanium surface on the inflammatory cytokine expression profile in a human macrophage cell line (THP-1). Genes for 84 cytokines, chemokines, and their receptors were analyzed following exposure to (1) polished (SMO), (2) micro-rough sand blasted, acid etched (SLA), and (3) hydrophilic-modified SLA (modSLA) titanium surfaces for 1 and 3 days. By day 3, the SLA surface elicited a pro-inflammatory response compared to the SMO surface with statistically significant up-regulation of 16 genes [Tumor necrosis factor (TNF) Interleukin (IL)-1β, Chemokine (C-C motif) ligand (CCL)-1, 2, 3, 4, 18, 19, and 20, Chemokine (C-X-C motif) ligand (CXCL)-1, 5, 8 and 12, Chemokine (C-C motif) receptor (CCR)-7, Lymphotoxin-beta (LTB), and Leukotriene B4 receptor (LTB4R)]. This effect was countered by the modSLA surface, which down-regulated the expression of 10 genes (TNF, IL-1α and β, CCL-1, 3, 19 and 20, CXCL-1 and 8, and IL-1 receptor type 1), while two were up-regulated (osteopontin and CCR5) compared to the SLA surface. These cytokine gene expression changes were confirmed by decreased levels of corresponding protein secretion in response to modSLA compared to SLA. These results show that a hydrophilic titanium surface can modulate human macrophage pro-inflammatory cytokine gene expression and protein secretion. An attenuated pro-inflammatory response may be an important molecular mechanism for faster and/or improved wound healing.

  9. Estradiol modulates Kiss1 neuronal response to ghrelin

    PubMed Central

    Frazao, Renata; Lemko, Heather M. Dungan; da Silva, Regina P.; Ratra, Dhirender V.; Lee, Charlotte E.; Williams, Kevin W.; Zigman, Jeffrey M.

    2014-01-01

    Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-α (ERα) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the co-xpression of GHSR mRNA and ERα selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol-treated (OVX + E2; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX + E2 and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E2 increase GHSR mRNA expression, modifying the colocalization rate with ERα and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E2 alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology. PMID:24473434

  10. YY1 modulates taxane response in epithelial ovarian cancer

    SciTech Connect

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2008-10-10

    The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1

  11. Periaqueductal gray matter modulates the hypercapnic ventilatory response.

    PubMed

    Lopes, Luana T; Patrone, Luis G A; Bícego, Kênia C; Coimbra, Norberto C; Gargaglioni, Luciane H

    2012-08-01

    The periaqueductal gray (PAG) is a midbrain structure directly involved in the modulation of defensive behaviors. It has direct projections to several central nuclei that are involved in cardiorespiratory control. Although PAG stimulation is known to elicit respiratory responses, the role of the PAG in the CO(2)-drive to breathe is still unknown. The present study assessed the effect of chemical lesion of the dorsolateral and dorsomedial and ventrolateral/lateral PAG (dlPAG, dmPAG, and vPAG, respectively) on cardiorespiratory and thermal responses to hypercapnia. Ibotenic acid (IBO) or vehicle (PBS, Sham group) was injected into the dlPAG, dmPAG, or vPAG of male Wistar rats. Rats with lesions outside the dlPAG, dmPAG, or vPAG were considered as negative controls (NC). Pulmonary ventilation (VE: ), mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) were measured in unanesthetized rats during normocapnia and hypercapnic exposure (5, 15, 30 min, 7 % CO(2)). IBO lesioning of the dlPAG/dmPAG caused 31 % and 26.5 % reductions of the respiratory response to CO(2) (1,094.3 ± 115 mL/kg/min) compared with Sham (1,589.5 ± 88.1 mL/kg/min) and NC groups (1,488.2 ± 47.7 mL/kg/min), respectively. IBO lesioning of the vPAG caused 26.6 % and 21 % reductions of CO(2) hyperpnea (1,215.3 ± 108.6 mL/kg/min) compared with Sham (1,657.3 ± 173.9 mL/kg/min) and NC groups (1,537.6 ± 59.3). Basal VE: , MAP, HR, and Tb were not affected by dlPAG, dmPAG, or vPAG lesioning. The results suggest that dlPAG, dmPAG, and vPAG modulate hypercapnic ventilatory responses in rats but do not affect MAP, HR, or Tb regulation in resting conditions or during hypercapnia.

  12. Hormonal modulation of the heat shock response: insights from fish with divergent cortisol stress responses.

    PubMed

    LeBlanc, Sacha; Höglund, Erik; Gilmour, Kathleen M; Currie, Suzanne

    2012-01-01

    Acute temperature stress in animals results in increases in heat shock proteins (HSPs) and stress hormones. There is evidence that stress hormones influence the magnitude of the heat shock response; however, their role is equivocal. To determine whether and how stress hormones may affect the heat shock response, we capitalized on two lines of rainbow trout specifically bred for their high (HR) and low (LR) cortisol response to stress. We predicted that LR fish, with a low cortisol but high catecholamine response to stress, would induce higher levels of HSPs after acute heat stress than HR trout. We found that HR fish have significantly higher increases in both catecholamines and cortisol compared with LR fish, and LR fish had no appreciable stress hormone response to heat shock. This unexpected finding prevented further interpretation of the hormonal modulation of the heat shock response but provided insight into stress-coping styles and environmental stress. HR fish also had a significantly greater and faster heat shock response and less oxidative protein damage than LR fish. Despite these clear differences in the physiological and cellular responses to heat shock, there were no differences in the thermal tolerance of HR and LR fish. Our results support the hypothesis that responsiveness to environmental change underpins the physiological differences in stress-coping styles. Here, we demonstrate that the heat shock response is a distinguishing feature of the HR and LR lines and suggest that it may have been coselected with the hormonal responses to stress.

  13. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity

    PubMed Central

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  14. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity.

    PubMed

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin; Henriques-Normark, Birgitta; Olliver, Marie

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  15. Modulation of host responses by oral commensal bacteria

    PubMed Central

    Devine, Deirdre A.; Marsh, Philip D.; Meade, Josephine

    2015-01-01

    Immunomodulatory commensal bacteria are proposed to be essential for maintaining healthy tissues, having multiple roles including priming immune responses to ensure rapid and efficient defences against pathogens. The default state of oral tissues, like the gut, is one of inflammation which may be balanced by regulatory mechanisms and the activities of anti-inflammatory resident bacteria that modulate Toll-like receptor (TLR) signalling or NF-κB activation, or influence the development and activities of immune cells. However, the widespread ability of normal resident organisms to suppress inflammation could impose an unsustainable burden on the immune system and compromise responses to pathogens. Immunosuppressive resident bacteria have been isolated from the mouth and, for example, may constitute 30% of the resident streptococci in plaque or on the tongue. Their roles in oral health and dysbiosis remain to be determined. A wide range of bacterial components and/or products can mediate immunomodulatory activity, raising the possibility of development of alternative strategies for therapy and health promotion using probiotics, prebiotics, or commensal-derived immunomodulatory molecules. PMID:25661061

  16. Living and dying for sex. A theory of aging based on the modulation of cell cycle signaling by reproductive hormones.

    PubMed

    Bowen, Richard L; Atwood, Craig S

    2004-01-01

    A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms. The theory also puts forth a new definition of aging - any change in an organism over time. This definition includes not only the changes associated with the loss of function (i.e. senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development). Using this definition, the rate of aging would be synonymous with the rate of change. The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth. Therefore, 'fetal aging' would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death. We suggest that these factors also are responsible for regulating aging throughout life. Thus, whatever controls mitogenesis, differentiation and cell death must also control aging. Since life-extending modalities consistently affect reproduction, and reproductive hormones are known to regulate mitogenesis and differentiation, we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging). In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones. Longevity inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/Akt/Forkhead pathway. This is exemplified by genetic alterations in Caenorhabditis elegans where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events. In summary, we propose that the hormones that

  17. Temperature modulates phototrophic periphyton response to chronic copper exposure.

    PubMed

    Lambert, Anne Sophie; Dabrin, Aymeric; Morin, Soizic; Gahou, Josiane; Foulquier, Arnaud; Coquery, Marina; Pesce, Stéphane

    2016-01-01

    Streams located in vineyard areas are highly prone to metal pollution. In a context of global change, aquatic systems are generally subjected to multi-stress conditions due to multiple chemical and/or physical pressures. Among various environmental factors that modulate the ecological effects of toxicants, special attention should be paid to climate change, which is driving an increase in extreme climate events such as sharp temperature rises. In lotic ecosystems, periphyton ensures key ecological functions such as primary production and nutrient cycling. However, although the effects of metals on microbial communities are relatively well known, there is scant data on possible interactions between temperature increase and metal pollution. Here we led a study to evaluate the influence of temperature on the response of phototrophic periphyton to copper (Cu) exposure. Winter communities, collected in a 8 °C river water, were subjected for six weeks to four thermal conditions in microcosms in presence or not of Cu (nominal concentration of 15 μg L(-1)). At the initial river temperature (8 °C), our results confirmed the chronic impact of Cu on periphyton, both in terms of structure (biomass, distribution of algal groups, diatomic composition) and function (photosynthetic efficiency). At higher temperatures (13, 18 and 23 °C), Cu effects were modulated. Indeed, temperature increase reduced Cu effects on algal biomass, algal class proportions, diatom assemblage composition and photosynthetic efficiency. This reduction of Cu effects on periphyton may be related to lower bioaccumulation of Cu and/or to selection of more Cu-tolerant species at higher temperatures. PMID:26608872

  18. Modulation of Autophagy by Sorafenib: Effects on Treatment Response

    PubMed Central

    Prieto-Domínguez, Nestor; Ordóñez, Raquel; Fernández, Anna; García-Palomo, Andres; Muntané, Jordi; González-Gallego, Javier; Mauriz, José L.

    2016-01-01

    The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5′ AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance. PMID:27375485

  19. Temperature modulates phototrophic periphyton response to chronic copper exposure.

    PubMed

    Lambert, Anne Sophie; Dabrin, Aymeric; Morin, Soizic; Gahou, Josiane; Foulquier, Arnaud; Coquery, Marina; Pesce, Stéphane

    2016-01-01

    Streams located in vineyard areas are highly prone to metal pollution. In a context of global change, aquatic systems are generally subjected to multi-stress conditions due to multiple chemical and/or physical pressures. Among various environmental factors that modulate the ecological effects of toxicants, special attention should be paid to climate change, which is driving an increase in extreme climate events such as sharp temperature rises. In lotic ecosystems, periphyton ensures key ecological functions such as primary production and nutrient cycling. However, although the effects of metals on microbial communities are relatively well known, there is scant data on possible interactions between temperature increase and metal pollution. Here we led a study to evaluate the influence of temperature on the response of phototrophic periphyton to copper (Cu) exposure. Winter communities, collected in a 8 °C river water, were subjected for six weeks to four thermal conditions in microcosms in presence or not of Cu (nominal concentration of 15 μg L(-1)). At the initial river temperature (8 °C), our results confirmed the chronic impact of Cu on periphyton, both in terms of structure (biomass, distribution of algal groups, diatomic composition) and function (photosynthetic efficiency). At higher temperatures (13, 18 and 23 °C), Cu effects were modulated. Indeed, temperature increase reduced Cu effects on algal biomass, algal class proportions, diatom assemblage composition and photosynthetic efficiency. This reduction of Cu effects on periphyton may be related to lower bioaccumulation of Cu and/or to selection of more Cu-tolerant species at higher temperatures.

  20. Polyamine depletion inhibits the autophagic response modulating Trypanosoma cruzi infectivity

    PubMed Central

    Vanrell, María C.; Cueto, Juan A.; Barclay, Jeremías J.; Carrillo, Carolina; Colombo, María I.; Gottlieb, Roberta A.; Romano, Patricia S.

    2013-01-01

    Autophagy is a cell process that in normal conditions serves to recycle cytoplasmic components and aged or damaged organelles. The autophagic pathway has been implicated in many physiological and pathological situations, even during the course of infection by intracellular pathogens. Many compounds are currently used to positively or negatively modulate the autophagic response. Recently it was demonstrated that the polyamine spermidine is a physiological inducer of autophagy in eukaryotic cells. We have previously shown that the etiological agent of Chagas disease, the protozoan parasite Trypanosoma cruzi, interacts with autophagic compartments during host cell invasion and that preactivation of autophagy significantly increases host cell colonization by this parasite. In the present report we have analyzed the effect of polyamine depletion on the autophagic response of the host cell and on T. cruzi infectivity. Our data showed that depleting intracellular polyamines by inhibiting the biosynthetic enzyme ornithine decarboxylase with difluoromethylornithine (DFMO) suppressed the induction of autophagy in response to starvation or rapamycin treatment in two cell lines. This effect was associated with a decrease in the levels of LC3 and ATG5, two proteins required for autophagosome formation. As a consequence of inhibiting host cell autophagy, DFMO impaired T. cruzi colonization, indicating that polyamines and autophagy facilitate parasite infection. Thus, our results point to DFMO as a novel autophagy inhibitor. While other autophagy inhibitors such as wortmannin and 3-methyladenine are nonspecific and potentially toxic, DFMO is an FDA-approved drug that may have value in limiting autophagy and the spread of the infection in Chagas disease and possibly other pathological settings. PMID:23697944

  1. ASPIRE (Awareness of Sexual Prejudice Is the Responsibility of Educators) Module 4: Strategies for Change.

    ERIC Educational Resources Information Center

    Livonia Public Schools, MI.

    This fourth of four workshop modules in the Project ASPIRE (Awareness of Sexual Prejudice Is the Responsibility of Educators) series deals with developing skills to help eliminate sex-role stereotyping within the school setting. (See Note about other modules.) The module helps workshop participants (1) become aware of federal guidelines and…

  2. ASPIRE (Awareness of Sexual Prejudice Is the Responsibility of Educators) Module 2: Sexism in Education.

    ERIC Educational Resources Information Center

    Livonia Public Schools, MI.

    This second of four workshop modules in the Project ASPIRE (Awareness of Sexual Prejudice is the Responsibility of Educators) series deals with developing awareness of how sex-role stereotyping affects the vocational and life-style aspirations and decisions of students. (See Note about other modules.) The module helps workshop participants (1)…

  3. ASPIRE (Awareness of Sexual Prejudice Is the Responsibility of Educators) Module 3: Evaluating Instructional Materials.

    ERIC Educational Resources Information Center

    Livonia Public Schools, MI.

    This third of four workshop modules in the Project ASPIRE (Awareness of Sexual Prejudice is the Responsibility of Educators) series deals with analyzing and developing procedures for dealing with sexual stereotypes and biases reflected in learning and counseling materials with the schools. (See Note about other modules.) The module helps workshop…

  4. Tamibarotene modulates the local immune response in experimental periodontitis.

    PubMed

    Jin, Ying; Wang, Linyuan; Liu, Dixin; Lin, Xiaoping

    2014-12-01

    Tamibarotene (Am80), a synthetic retinoic acid receptor (RAR), is an agonist with high specificity for RARα and RARβ. Retinoid agonists have been shown to inhibit Th17 cell polarization and to enhance forkhead box P3 (Foxp3) expression during the course of inflammatory diseases. The aim of this study was to evaluate the previously unrecognized role of Am80 in regulating the immune responses of periodontitis within the oral microenvironment. The experimental model of periodontitis in mice was induced by oral infection with Porphyromonas gingivalis (P. gingivalis) W83. Our results indicated that Am80 effectively suppressed alveolar bone resorption induced by P. gingivalis W83 and decreased the number of osteoclasts. We clarified that these effects were closely associated with the reduced percentage of CD4(+) retinoid-related orphan receptor (ROR)γt(+) cells and increased the percentage of CD4(+) Foxp3(+) cells in the gingival tissues, cervical lymph nodes (CLNs), and spleen. Furthermore, in P. gingivalis-infected mice, Am80 down-regulated mRNA expression levels of interleukin-17A (IL-17A), receptor activator of nuclear factor-kappa beta ligand (RANKL), monocyte chemotactic protein-1 (MCP-1), IL-6, and IL-1β. Simultaneously, Am80 up-regulated expression levels of IL-10 and transforming growth factor-β1 (TGF-β1) in gingival tissues and the CLNs. Our results suggest that Am80 could protect against periodontal bone resorption, primarily through the modulation of immune responses in the oral microenvironment, and demonstrate the potential of Am80 as a novel clinical strategy for preventing periodontitis.

  5. Keratinocytes can modulate and directly initiate nociceptive responses

    PubMed Central

    Baumbauer, Kyle M; DeBerry, Jennifer J; Adelman, Peter C; Miller, Richard H; Hachisuka, Junichi; Lee, Kuan Hsien; Ross, Sarah E; Koerber, H Richard; Davis, Brian M; Albers, Kathryn M

    2015-01-01

    How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing. DOI: http://dx.doi.org/10.7554/eLife.09674.001 PMID:26329459

  6. BCL6 modulation of acute lymphoblastic leukemia response to chemotherapy

    PubMed Central

    Slone, William L.; Moses, Blake S.; Hare, Ian; Evans, Rebecca; Piktel, Debbie; Gibson, Laura F.

    2016-01-01

    The bone marrow niche has a significant impact on acute lymphoblastic leukemia (ALL) cell phenotype. Of clinical relevance is the frequency with which quiescent leukemic cells, in this niche, survive treatment and contribute to relapse. This study suggests that marrow microenvironment regulation of BCL6 in ALL is one factor that may be involved in the transition between proliferative and quiescent states of ALL cells. Utilizing ALL cell lines, and primary patient tumor cells we observed that tumor cell BCL6 protein abundance is decreased in the presence of primary human bone marrow stromal cells (BMSC) and osteoblasts (HOB). Chemical inhibition, or shRNA knockdown, of BCL6 in ALL cells resulted in diminished ALL proliferation. As many chemotherapy regimens require tumor cell proliferation for optimal efficacy, we investigated the consequences of constitutive BCL6 expression in leukemic cells during co-culture with BMSC or HOB. Forced chronic expression of BCL6 during co-culture with BMSC or HOB sensitized the tumor to chemotherapy induced cell death. Combination treatment of caffeine, which increases BCL6 expression in ALL cells, with chemotherapy extended the event free survival of mice. These data suggest that BCL6 is one factor, modulated by microenvironment derived cues that may contribute to regulation of ALL therapeutic response. PMID:27015556

  7. Hyaluronidase Modulates Inflammatory Response and Accelerates the Cutaneous Wound Healing

    PubMed Central

    Fronza, Marcio; Caetano, Guilherme F.; Leite, Marcel N.; Bitencourt, Claudia S.; Paula-Silva, Francisco W. G.; Andrade, Thiago A. M.; Frade, Marco A. C.; Merfort, Irmgard; Faccioli, Lúcia H.

    2014-01-01

    Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders. PMID:25393024

  8. Fetal Sex Modulates Developmental Response to Maternal Malnutrition

    PubMed Central

    Gonzalez-Bulnes, Antonio; Torres-Rovira, Laura; Astiz, Susana; Ovilo, Cristina; Sanchez-Sanchez, Raul; Gomez-Fidalgo, Ernesto; Perez-Solana, Mariluz; Martin-Lluch, Mercedes; Garcia-Contreras, Consuelo; Vazquez-Gomez, Marta

    2015-01-01

    The incidence of obesity and metabolic diseases is dramatically high in rapidly developing countries. Causes have been related to intrinsic ethnic features with development of a thrifty genotype for adapting to food scarcity, prenatal programming by undernutrition, and postnatal exposure to obesogenic lifestyle. Observational studies in humans and experimental studies in animal models evidence that the adaptive responses of the offspring may be modulated by their sex. In the contemporary context of world globalization, the new question arising is the existence and extent of sex-related differences in developmental and metabolic traits in case of mixed-race. Hence, in the current study, using a swine model, we compared male and female fetuses that were crossbred from mothers with thrifty genotype and fathers without thrifty genotype. Female conceptuses evidence stronger protective strategies for their adequate growth and postnatal survival. In brief, both male and female fetuses developed a brain-sparing effect but female fetuses were still able to maintain the development of other viscerae than the brain (mainly liver, intestine and kidneys) at the expense of carcass development. Furthermore, these morphometric differences were reinforced by differences in nutrient availability (glucose and cholesterol) favoring female fetuses with severe developmental predicament. These findings set the basis for further studies aiming to increase the knowledge on the interaction between genetic and environmental factors in the determination of adult phenotype PMID:26544862

  9. Frequency Modulated Translocational Oscillations of Nrf2 Mediate the Antioxidant Response Element Cytoprotective Transcriptional Response

    PubMed Central

    Xue, Mingzhan; Momiji, Hiroshi; Rabbani, Naila; Barker, Guy; Bretschneider, Till; Shmygol, Anatoly; Rand, David A.

    2015-01-01

    Abstract Aims: Stress responsive signaling coordinated by nuclear factor erythroid 2-related factor 2 (Nrf2) provides an adaptive response for protection of cells against toxic insults, oxidative stress and metabolic dysfunction. Nrf2 regulates a battery of protective genes by binding to regulatory antioxidant response elements (AREs). The aim of this study was to examine how Nrf2 signals cell stress status and regulates transcription to maintain homeostasis. Results: In live cell microscopy we observed that Nrf2 undergoes autonomous translocational frequency-modulated oscillations between cytoplasm and nucleus. Oscillations occurred in quiescence and when cells were stimulated at physiological levels of activators, they decrease in period and amplitude and then evoke a cytoprotective transcriptional response. We propose a mechanism whereby oscillations are produced by negative feedback involving successive de-phosphorylation and phosphorylation steps. Nrf2 was inactivated in the nucleus and reactivated on return to the cytoplasm. Increased frequency of Nrf2 on return to the cytoplasm with increased reactivation or refresh-rate under stress conditions activated the transcriptional response mediating cytoprotective effects. The serine/threonine-protein phosphatase PGAM5, member of the Nrf2 interactome, was a key regulatory component. Innovation: We found that Nrf2 is activated in cells without change in total cellular Nrf2 protein concentration. Regulation of ARE-linked protective gene transcription occurs rather through translocational oscillations of Nrf2. We discovered cytoplasmic refresh rate of Nrf2 is important in maintaining and regulating the transcriptional response and links stress challenge to increased cytoplasmic surveillance. We found silencing and inhibition of PGAM5 provides potent activation of Nrf2. Conclusion: Frequency modulated translocational oscillations of Nrf2 mediate the ARE-linked cytoprotective transcriptional response. Antioxid. Redox

  10. Study of response nonuniformity for the LHCb calorimeter module and the prototype of the CBM calorimeter module

    SciTech Connect

    Korolko, I. E.; Prokudin, M. S.

    2009-02-15

    A spatial nonuniformity of the response to high-energy muons is studied in the modules of the LHCb electromagnetic calorimeter and the prototype of the calorimeter module with lead plates and scintillator tiles 0.5 mm thick. The nonuniformity of the response of the inner LHCb modules to 50-GeV electrons is also measured. Software is developed for a thorough simulation of light collection in scintillator plates of a shashlik calorimeter. A model is elaborated to describe light transmission from the initial scintillation to the wavelength-shifting fiber with a subsequent reradiation and propagation of light over the fiber to the photodetector. The results of the simulation are in good agreement with data.

  11. Transient Response of Cadmium Telluride Modules to Light Exposure: Preprint

    SciTech Connect

    Deline, C.; del Cueto, J.; Albin, D. S.; Petersen, C.; Tyler, L.; TamizhMani, G.

    2011-07-01

    Commercial cadmium telluride (CdTe) photovoltaic (PV) modules from three different manufacturers were monitored for performance changes during indoor and outdoor light-exposure. Short-term transients in Voc were recorded on some modules, with characteristic times of ~1.1 hours. Outdoor performance data shows a similar drop in Voc after early morning light exposure. Preliminary analysis of FF changes show light-induced changes on multiple time scales, including a long time scale.

  12. Characterization and analysis of electrically controlled metamaterial terahertz modulators using the current response method

    NASA Astrophysics Data System (ADS)

    Zhou, Zhen; Chen, YongLi; Feng, LiShuang

    2015-11-01

    Two electrically controlled metamaterial terahertz (THz) modulators with different configurations of metamaterial elements and electrodes are characterized and analyzed by the current response method, which demonstrates the effectiveness of configuration modifications of metamaterial elements and electrodes for the improvements of modulation performances, and determines the key factor influencing the modulation speed. Additionally, the results of characterization and comparison are verified using a dynamic characteristic measurement system and good agreements are achieved, which demonstrates the more convenient current response method can be used to characterize the electrically controlled metamaterial THz modulator.

  13. Odorant response properties of individual neurons in an olfactory glomerular module

    PubMed Central

    Kikuta, Shu; Fletcher, Max L.; Homma, Ryota; Yamasoba, Tatsuya; Nagayama, Shin

    2013-01-01

    Summary Neuronal networks that are directly associated with glomeruli in the olfactory bulb are thought to comprise functional modules. However, this has not yet been experimentally proven. In this study, we explored the anatomical and functional architecture of glomerular modules using in vivo two-photon calcium imaging. Surprisingly, the deep portions of the glomerular modules showed considerable spatial overlap with other modules. Juxtaglomerular cells showed similar excitatory odorant response profiles to presynaptic olfactory sensory neuron inputs. Mitral cells exhibited a more sharply tuned molecular receptive range compared to juxtaglomerular cells, and their odorant response profiles varied depending on their interneuronal horizontal distances. These data suggest that glomerular modules are composed of functionally distinct neurons, and that homogenous odor inputs to each glomerulus may be parsed and processed in different fashions within the modules before being sent to higher olfactory centers. PMID:23522047

  14. The Waukesha Turbocharger Control Module: A tool for improved engine efficiency and response

    SciTech Connect

    Zurlo, J.R.; Reinbold, E.O.; Mueller, J.

    1996-12-31

    The Waukesha Turbocharger Control Module allows optimum control of turbochargers on lean burn gaseous fueled engines. The Turbocharger Control Module is user programmed to provide either maximum engine efficiency or best engine response to load changes. In addition, the Turbocharger Control Module prevents undesirable turbocharger surge. The Turbocharger Control Module consists of an electronic control box, engine speed, intake manifold pressure, ambient temperature sensors, and electric actuators driving compressor bypass and wastegate valves. The Turbocharger Control Module expands the steady state operational environment of the Waukesha AT27GL natural gas engine from sea level to 1,525 m altitude with one turbocharger match and improves the engine speed turn down by 80 RPM. Finally, the Turbocharger Control Module improves engine response to load changes.

  15. Dies1/VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation

    PubMed Central

    Oliveira, Patrícia; Carvalho, Joana; Rocha, Sara; Azevedo, Mafalda; Reis, Inês; Camilo, Vânia; Sousa, Bárbara; Valente, Sofia; Paredes, Joana; Almeida, Raquel; Huntsman, David; Oliveira, Carla

    2016-01-01

    Dies1/VISTA induces embryonic stem-cell differentiation, via BMP-pathway, but also acts as inflammation regulator and immune-response modulator. Dies1 inhibition in a melanoma-mouse model led to increased tumour-infiltrating T-cells and decreased tumour growth, emphasizing Dies1 relevance in tumour-microenvironment. Dies1 is involved in cell de/differentiation, inflammation and cancer processes, which mimic those associated with Epithelial-to-Mesenchymal-Transition (EMT). Despite this axis linking Dies1 with EMT and cancer, its expression, modulation and relevance in these contexts is unknown. To address this, we analysed Dies1 expression, its regulation by promoter-methylation and miR-125a-5p overexpression, and its association with BMP-pathway downstream-effectors, in a TGFβ1-induced EMT-model, cancer cell-lines and primary samples. We detected promoter-methylation as a mechanism controlling Dies1 expression in our EMT-model and in several cancer cell-lines. We showed that the relationship between Dies1 expression and BMP-pathway effectors observed in the EMT-model, was not present in all cell-lines, suggesting that Dies1 has other cell-specific effectors, beyond the BMP-pathway. We further demonstrated that: Dies1 expression loss is a recurrent event in GC, caused by promoter methylation and/or miR-125a-5p overexpression and; GC-microenvironment myofibroblasts overexpress Dies1. Our findings highlight Dies1 as a novel player in GC, with distinct roles within tumour cells and in the tumour-microenvironment. PMID:27721458

  16. RCRA, Superfund and EPCRA hotline training module. Introduction to: the Superfund response program (updated February 1998); Directive

    SciTech Connect

    1998-06-01

    This module includes the following: Regulatory Summary (Definitions; National Contingency Plan; Notification or Discovery; Response Process; Removal Process; Remedial Process; Community Involvement; State Role; Natural Resource Damage Assessments; Federal Facility Response; and Contractor Support); and Module Summary.

  17. Seeing red: affect modulation and chromatic color responses on the Rorschach.

    PubMed

    Malone, Johanna C; Stein, Michelle B; Slavin-Mulford, Jenelle; Bello, Iruma; Sinclair, S Justin; Blais, Mark A

    2013-01-01

    Psychoanalytic theories suggest that color perception on the Rorschach relates to affective modulation. However, this idea has minimal empirical support. Using a clinical sample, the authors explored the cognitive and clinical correlates of Rorschach color determinants and differences among four affective modulation subtypes: Controlled, Balanced, Under-Controlled, and Flooded. Subtypes were differentiated by measures of affective regulation, reality testing/confusion, and personality traits. Initial support for the relationship of chromatic color response styles and affective modulation was found. PMID:23428172

  18. Noise-modulated-microwave-induced response in snail neurons

    SciTech Connect

    Lin, J.C.; Arber, S.L.

    1983-01-01

    Helix aspersa neurons were irradiated with noise-amplitude-modulated microwaves (carrier frequency 2450 MHz, 20% AM, 0-20 kHz, specific absorption rate 6.8 and 14.4 mW/g). It was found that such an exposure caused an appearance of high frequency bursts and a rise in membrane resistance.

  19. Transient Response of Cadmium Telluride Modules to Light Exposure

    SciTech Connect

    Deline, C.; Del Cueto, J.; Albin, D. S.; Petersen, C.; Tyler, L.; TamizhMani, G.

    2011-01-01

    Commercial cadmium telluride (CdTe) photovoltaic (PV) modules from three different manufacturers were monitored for performance changes during indoor and outdoor light-exposure. Short-term transients in V{sub oc} were recorded on some modules, with characteristic times of {approx}1.1 hours. Outdoor performance data shows a similar drop in V{sub oc} after early morning light exposure. Preliminary analysis of FF changes show light-induced changes on multiple time scales, including a long time scale. Multiple methods of measuring {beta}V{sub oc} resulted in a range of values on the same CdTe PV module between -0.25%/C and -0.4%/C, possibly due to concurrent light-induced V{sub oc} transients and temperature changes. This paper highlights the need for rapid performance measurement of PV samples following light exposure and the possibility of incorrect results when using outdoor light exposure to collect values of {beta}V{sub oc} for CdTe modules.

  20. Development and Evaluation of the SUMIT Microcomputer Module Entitled 'Predator Functional Response'.

    ERIC Educational Resources Information Center

    Shaltz, Mark B.

    An experiment was conducted that compared the teaching effectiveness of a computer assisted instructional module and a lecture-discussion. The module, Predator Functional Response (PFR), was developed as part of the SUMIT (Single-concept User-adaptable Microcomputer-based Instructional Technique) project. A class of 30 students was randomly…

  1. Porous Matrix Stiffness Modulates Response to Targeted Therapy in Breast Carcinoma.

    PubMed

    Liu, Cuiying; Li, Xiang; Hua, Wenda; Li, Jianjun; Han, Xinxiao; Ha, Qing; Feng, Jiantao; Liao, Fulong; Li, Dongguo; Han, Dong

    2016-09-01

    Porous matrix stiffness modulates response to targeted therapy. Poroelastic behavior within porous matrix may modulate the molecule events in cell-matrix and cell-cell interaction like the complex formation of human epidermal growth factor receptor-2 (HER2)-Src-α6β4 integrin, influencing the targeted therapy with lapatinib.

  2. Research communications research communications Tree die-off in response to global change-type drought: Mortality insights from a decade of plant water potential measurements

    USGS Publications Warehouse

    Breshears, D.D.; Myers, O.B.; Meyer, Clifton W.; Barnes, F.J.; Zou, C.B.; Allen, C.D.; McDowell, N.G.; Pockman, W. T.

    2009-01-01

    Global climate change is projected to produce warmer, longer, and more frequent droughts, referred to here as "global change-type droughts", which have the potential to trigger widespread tree die-off. However, droughtinduced tree mortality cannot be predicted with confidence, because long-term field observations of plant water stress prior to, and culminating in, mortality are rare, precluding the development and testing of mechanisms. Here, we document plant water stress in two widely distributed, co-occurring species, pi??on pine (Pinus edulis) and juniper (Juniperus monosperma), over more than a decade, leading up to regional-scale die-off of pi??on pine trees in response to global change-related drought. Pi??on leaf water potentials remained substantially below their zero carbon assimilation point for at least 10 months prior to dying, in contrast to those of juniper, which rarely dropped below their zero-assimilation point. These data suggest that pi??on mortality was driven by protracted water stress, leading to carbon starvation and associated increases in susceptibility to other disturbances (eg bark beetles), a finding that should help to improve predictions of mortality during drought. ?? The Ecological Society of America.

  3. Optimization of coherent optical OFDM transmitter using DP-IQ modulator with nonlinear response

    NASA Astrophysics Data System (ADS)

    Chang, Sun Hyok; Kang, Hun-Sik; Moon, Sang-Rok; Lee, Joon Ki

    2016-07-01

    In this paper, we investigate the performance of dual polarization orthogonal frequency division multiplexing (DP-OFDM) signal generation when the signal is generated by a DP-IQ optical modulator. The DP-IQ optical modulator is made of four parallel Mach-Zehnder modulators (MZMs) which have nonlinear responses and limited extinction ratios. We analyze the effects of the MZM in the DP-OFDM signal generation by numerical simulation. The operating conditions of the DP-IQ modulator are optimized to have the best performance of the DP-OFDM signal.

  4. Is dying young worse than dying old?

    PubMed

    Jecker, N S; Schneiderman, L J

    1994-02-01

    In contemporary Western society, people experience the deaths of older and younger persons differently. We are disposed to feel that the death of a small child is a greater injustice than the death of an older adult, and we experience correspondingly greater sorrow, anger, regret or bitterness when a very young person dies. This article examines these responses critically to determine whether they are backed by ethical considerations that reason can discern and defend. We contrast contemporary attitudes with those of ancient Greece and show the relevance that different attitudes toward death have for health care decision making.

  5. Effects of excitation intensity on the photocurrent response of thin film silicon solar modules

    NASA Technical Reports Server (NTRS)

    Kim, Q.; Shumka, A.; Trask, J.

    1986-01-01

    Photocurrent responses of amorphous thin film silicon solar modules at room temperature were studied at different excitation intensities using various monochromatic light sources. Photocurrent imaging techniques have been effectively used to locate rapidly, and non-destructively, failure and defect sites in the multilayer thin film device. Differences observed in the photocurrent response characteristics for two different cells in the same amorphous thin film silicon solar module suggest the possibility of the formation of dissimilarly active devices, even though the module is processed in the same fabrication process. Possible mechanisms are discussed.

  6. Pharmacological modulation of aversive responsiveness in honey bees

    PubMed Central

    Tedjakumala, Stevanus R.; Aimable, Margaux; Giurfa, Martin

    2014-01-01

    Within a honey bee colony, individuals performing different tasks exhibit different sensitivities to noxious stimuli. Noxious-stimulus sensitivity can be quantified in harnessed bees by measuring the sting extension response (SER) to a series of increasing voltages. Biogenic amines play a crucial role in the control of insect responsiveness. Whether or not these neurotransmitters affect the central control of aversive responsiveness, and more specifically of electric-shock responsiveness, remains unknown. Here we studied the involvement of the biogenic amines octopamine, dopamine and serotonin, and of the ecdysteroid 20-hydroxyecdisone in the central control of sting responsiveness to electric shocks. We injected pharmacological antagonists of these signaling pathways into the brain of harnessed bees and determined the effect of blocking these different forms of neurotransmission on shock responsiveness. We found that both octopamine and 20-hydroxyecdisone are dispensable for shock responsiveness while dopamine and serotonin act as down-regulators of sting responsiveness. As a consequence, antagonists of these two biogenic amines induce an increase in shock responsiveness to shocks of intermediate voltage; serotonin, can also increase non-specific responsiveness. We suggest that different classes of dopaminergic neurons exist in the bee brain and we define at least two categories: an instructive class mediating aversive labeling of conditioned stimuli in associative learning, and a global gain-control class which down-regulates responsiveness upon perception of noxious stimuli. Serotonergic signaling together with down-regulating dopaminergic signaling may play an essential role in attentional processes by suppressing responses to irrelevant, non-predictive stimuli, thereby allowing efficient behavioral performances. PMID:24431993

  7. Waking State: Rapid Variations Modulate Neural and Behavioral Responses

    PubMed Central

    McGinley, Matthew J.; Vinck, Martin; Reimer, Jacob; Batista-Brito, Renata; Zagha, Edward; Cadwell, Cathryn R.

    2015-01-01

    The state of the brain and body constantly varies on rapid and slow time scales. These variations contribute to the apparent noisiness of sensory responses at both the neural and behavioral level. Recent investigations of rapid state changes in awake, behaving animals have provided insight into the mechanisms by which optimal sensory encoding and behavioral performance are achieved. Fluctuations in state, as indexed by pupillometry, impact both the “signal” (sensory evoked response) and the “noise” (spontaneous activity) of cortical responses. By taking these fluctuations into account, neural response (co-)variability is significantly reduced, revealing the brain to be more reliable and predictable than previously thought. PMID:26402600

  8. Regulating the ethylene response of a plant by modulation of F-box proteins

    SciTech Connect

    Guo, Hongwei; Ecker, Joseph R

    2014-01-07

    The relationship between F-box proteins and proteins invovled in the ethylene response in plants is described. In particular, F-box proteins may bind to proteins involved in the ethylene response and target them for degradation by the ubiquitin/proteasome pathway. The transcription factor EIN3 is a key transcription factor mediating ethylne-regulated gene expression and morphological responses. EIN3 is degraded through a ubiquitin/proteasome pathway mediated by F-box proteins EBF1 and EBF2. The link between F-box proteins and the ethylene response is a key step in modulating or regulating the response of a plant to ethylene. Described herein are transgenic plants having an altered sensitivity to ethylene, and methods for making transgenic plant haing an althered sensitivity to ethylene by modulating the level of activity of F-box proteins. Methods of altering the ethylene response in a plant by modulating the activity or expression of an F-box protein are described. Also described are methods of identifying compounds that modulate the ethylene response in plants by modulating the level of F-box protein expression or activity.

  9. Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization.

    PubMed

    Domínguez-Soto, Angeles; de las Casas-Engel, Mateo; Bragado, Rafael; Medina-Echeverz, José; Aragoneses-Fenoll, Laura; Martín-Gayo, Enrique; van Rooijen, Nico; Berraondo, Pedro; Toribio, María L; Moro, María A; Cuartero, Isabel; Castrillo, Antonio; Sancho, David; Sánchez-Torres, Carmen; Bruhns, Pierre; Sánchez-Ramón, Silvia; Corbí, Angel L

    2014-11-15

    Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti-inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages. In vivo, IVIg modified the polarization of tumor-associated myeloid cells in a Fcεr1γ chain-dependent manner, modulated cytokine blood levels in tumor-bearing animals, and impaired tumor progression via FcγRIII (CD16), FcγRIV, and FcRγ engagement, the latter two effects being macrophage mediated. Therefore, IVIg immunomodulatory activity is dependent on the polarization state of the responding macrophages, and its ability to trigger a M2-to-M1 macrophage polarization switch might be therapeutically useful in cancer, in which proinflammatory or immunogenic functions should be promoted.

  10. Personality traits modulate emotional and physiological responses to stress.

    PubMed

    Childs, Emma; White, Tara L; de Wit, Harriet

    2014-09-01

    An individual's susceptibility to psychological and physical disorders associated with chronic stress exposure, for example, cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease. This study examined the relationships between personality and acute responses to stress in 125 healthy adults, using hierarchical linear regression. We assessed personality traits using the Multidimensional Personality Questionnaire (MPQ-BF), and responses to acute stress (cortisol, heart rate, blood pressure, mood) using a standardized laboratory psychosocial stress task, the Trier Social Stress Test. Individuals with high Negative Emotionality exhibited greater emotional distress and lower blood pressure responses to the Trier Social Stress Test. Individuals with high agentic Positive Emotionality exhibited prolonged heart rate responses to stress, whereas those with high communal Positive Emotionality exhibited smaller cortisol and blood pressure responses. Separate personality traits differentially predicted emotional, cardiovascular, and cortisol responses to a psychosocial stressor in healthy volunteers. Future research investigating the association of personality with chronic stress-related disease may provide further clues to the relationship between acute stress reactivity and susceptibility to disease.

  11. Personality traits modulate emotional and physiological responses to stress

    PubMed Central

    Childs, Emma; White, Tara L.; de Wit, Harriet

    2014-01-01

    An individual’s susceptibility to psychological and physical disorders associated with chronic stress exposure e.g., cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease. This study examined relationships between personality and acute responses to stress in 125 healthy adults, using hierarchical linear regression. We assessed personality traits using the Multidimensional Personality Questionnaire (MPQ-BF), and responses to acute stress (cortisol, heart rate, blood pressure, mood) using a standardised laboratory psychosocial stress task, the Trier Social Stress Test (TSST). Individuals with high Negative Emotionality exhibited greater emotional distress and lower blood pressure responses to the TSST. Individuals with high Agentic Positive Emotionality exhibited prolonged heart rate responses to stress, whereas those with high Communal Positive Emotionality exhibited smaller cortisol and blood pressure responses. Separate personality traits differentially predicted emotional, cardiovascular, and cortisol responses to a psychosocial stressor in healthy volunteers. Future research investigating the association of personality with chronic stress-related disease may provide further clues to the relationship between acute stress reactivity and susceptibility to disease. PMID:25036730

  12. Strategic modulation of response inhibition in task-switching

    PubMed Central

    Grzyb, Kai Robin; Hübner, Ronald

    2013-01-01

    Residual activations from previous task performance usually prime the system toward response repetition. However, when the task switches, the repetition of a response (RR) produces longer reaction times and higher error rates. Some researchers assumed that these RR costs reflect strategic inhibition of just executed responses and that this serves for preventing perseveration errors. We investigated whether the basic level of response inhibition is adapted to the overall risk of response perseveration. In a series of 3 experiments, we presented different proportions of stimuli that carry either a high or a low risk of perseveration. Additionally, the discriminability of high- and low-risk stimuli was varied. The results indicate that individuals apply several processing and control strategies, depending on the mixture of stimulus types. When discriminability was high, control was adapted on a trial-by trial basis, which presumably reduces mental effort (Experiment 1). When trial-based strategies were prevented, RR costs for low-risk stimuli varied with the overall proportion of high-risk stimuli (Experiments 2 and 3), indicating an adaptation of the basic level of response inhibition. PMID:23986730

  13. Complex linguistic rules modulate early auditory brain responses.

    PubMed

    Sun, Yue; Giavazzi, Maria; Adda-Decker, Martine; Barbosa, Leonardo S; Kouider, Sid; Bachoud-Lévi, Anne-Catherine; Jacquemot, Charlotte; Peperkamp, Sharon

    2015-10-01

    During speech perception, listeners compensate for phonological rules of their language. For instance, English place assimilation causes green boat to be typically pronounced as greem boat; English listeners, however, perceptually compensate for this rule and retrieve the intended sound (n). Previous research using EEG has focused on rules with clear phonetic underpinnings, showing that perceptual compensation occurs at an early stage of speech perception. We tested whether this early mechanism also accounts for the compensation for more complex rules. We examined compensation for French voicing assimilation, a rule with abstract phonological restrictions on the contexts in which it applies. Our results reveal that perceptual compensation for this rule by French listeners modulates an early ERP component. This is evidence that early stages of speech sound categorization are sensitive to complex phonological rules of the native language.

  14. Oxidative stress modulates theophylline effects on steroid responsiveness.

    PubMed

    Marwick, John A; Wallis, Gillian; Meja, Koremu; Kuster, Bernhard; Bouwmeester, Tewis; Chakravarty, Probir; Fletcher, Danielle; Whittaker, Paul A; Barnes, Peter J; Ito, Kazuhiro; Adcock, Ian M; Kirkham, Paul A

    2008-12-19

    Oxidative stress is a central factor in many chronic inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease (COPD). Oxidative stress reduces the anti-inflammatory corticosteroid action and may therefore contribute to the relative corticosteroid insensitivity seen in these diseases. Low concentrations of theophylline can restore the anti-inflammatory action of corticosteroids in oxidant exposed cells, however the mechanism remains unknown. Here, we demonstrate that a low concentration of theophylline restores corticosteroid repression of pro-inflammatory mediator release and histone acetylation in oxidant exposed cells. Global gene expression analysis shows that theophylline regulates distinct pathways in naïve and oxidant exposed cells and reverses oxidant mediated modulated of pathways. Furthermore, quantitative chemoproteomics revealed that theophylline has few high affinity targets in naive cells but an elevated affinity in oxidant stressed cells. In conclusion, oxidative stress alters theophylline binding profile and gene expression which may result in restoration of corticosteroid function. PMID:18951874

  15. Selective modulation of cell response on engineered fractal silicon substrates

    PubMed Central

    Gentile, Francesco; Medda, Rebecca; Cheng, Ling; Battista, Edmondo; Scopelliti, Pasquale E.; Milani, Paolo; Cavalcanti-Adam, Elisabetta A.; Decuzzi, Paolo

    2013-01-01

    A plethora of work has been dedicated to the analysis of cell behavior on substrates with ordered topographical features. However, the natural cell microenvironment is characterized by biomechanical cues organized over multiple scales. Here, randomly rough, self-affinefractal surfaces are generated out of silicon,where roughness Ra and fractal dimension Df are independently controlled. The proliferation rates, the formation of adhesion structures, and the morphology of 3T3 murine fibroblasts are monitored over six different substrates. The proliferation rate is maximized on surfaces with moderate roughness (Ra ~ 40 nm) and large fractal dimension (Df ~ 2.4); whereas adhesion structures are wider and more stable on substrates with higher roughness (Ra ~ 50 nm) and lower fractal dimension (Df ~ 2.2). Higher proliferation occurson substrates exhibiting densely packed and sharp peaks, whereas more regular ridges favor adhesion. These results suggest that randomly roughtopographies can selectively modulate cell behavior. PMID:23492898

  16. Stress-response balance drives the evolution of a network module and its host genome

    PubMed Central

    González, Caleb; Ray, Joe Christian J; Manhart, Michael; Adams, Rhys M; Nevozhay, Dmitry; Morozov, Alexandre V; Balázsi, Gábor

    2015-01-01

    Stress response genes and their regulators form networks that underlie drug resistance. These networks often have an inherent tradeoff: their expression is costly in the absence of stress, but beneficial in stress. They can quickly emerge in the genomes of infectious microbes and cancer cells, protecting them from treatment. Yet, the evolution of stress resistance networks is not well understood. Here, we use a two-component synthetic gene circuit integrated into the budding yeast genome to model experimentally the adaptation of a stress response module and its host genome in three different scenarios. In agreement with computational predictions, we find that: (i) intra-module mutations target and eliminate the module if it confers only cost without any benefit to the cell; (ii) intra- and extra-module mutations jointly activate the module if it is potentially beneficial and confers no cost; and (iii) a few specific mutations repeatedly fine-tune the module's noisy response if it has excessive costs and/or insufficient benefits. Overall, these findings reveal how the timing and mechanisms of stress response network evolution depend on the environment. PMID:26324468

  17. An NCME Instructional Module on Latent DIF Analysis Using Mixture Item Response Models

    ERIC Educational Resources Information Center

    Cho, Sun-Joo; Suh, Youngsuk; Lee, Woo-yeol

    2016-01-01

    The purpose of this ITEMS module is to provide an introduction to differential item functioning (DIF) analysis using mixture item response models. The mixture item response models for DIF analysis involve comparing item profiles across latent groups, instead of manifest groups. First, an overview of DIF analysis based on latent groups, called…

  18. Biting intentions modulate digastric reflex responses to sudden unloading of the jaw.

    PubMed

    Johansson, Anders S; Pruszynski, J Andrew; Edin, Benoni B; Westberg, Karl-Gunnar

    2014-09-01

    Reflex responses in jaw-opening muscles can be evoked when a brittle object cracks between the teeth and suddenly unloads the jaw. We hypothesized that this reflex response is flexible and, as such, is modulated according to the instructed goal of biting through an object. Study participants performed two different biting tasks when holding a peanut half stacked on a chocolate piece between their incisors. In one task, they were asked to split the peanut half only (single-split task), and in the other task, they were asked to split both the peanut and the chocolate in one action (double-split task). In both tasks, the peanut split evoked a jaw-opening muscle response, quantified from electromyogram (EMG) recordings of the digastric muscle in a window 20-60 ms following peanut split. Consistent with our hypothesis, we found that the jaw-opening muscle response in the single-split trials was about twice the size of the jaw-opening muscle response in the double-split trials. A linear model that predicted the jaw-opening muscle response on a single-trial basis indicated that task settings played a significant role in this modulation but also that the presplit digastric muscle activity contributed to the modulation. These findings demonstrate that, like reflex responses to mechanical perturbations in limb muscles, reflex responses in jaw muscles not only show gain-scaling but also are modulated by subject intent.

  19. Sputtered protective coatings for die casting dies

    NASA Technical Reports Server (NTRS)

    Mirtich, M. J.; Nieh, C. Y.; Wallace, J. F.

    1981-01-01

    This investigation determined whether selected ion beam sputtered coatings on H-13 die steel would have the potential of improving the thermal fatigue behavior of the steel used as a die in aluminum die casting. The coatings were selected to test candidate insulators and metals capable of providing protection of the die surface. The studies indicate that 1 micrometer thick W and Pt coatings reduced the thermal fatigue more than any other coating tested and are candidates to be used on a die surface to increase die life.

  20. Mechanisms of nutrient modulation of the immune response.

    PubMed

    Cunningham-Rundles, Susanna; McNeeley, David F; Moon, Aeri

    2005-06-01

    Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.

  1. Attention does not modulate neural responses to social stimuli in autism spectrum disorders.

    PubMed

    Bird, Geoffrey; Catmur, Caroline; Silani, Giorgia; Frith, Chris; Frith, Uta

    2006-07-15

    We investigated whether individuals with autism spectrum disorders (ASD) would show attentional modulation for social (face) and non-social (house) stimuli. Sixteen individuals with ASD and 16 matched control participants completed a task in which pairs of face and house stimuli were present on every trial, with one of the pairs randomly assigned to attended locations and the other to unattended locations. Both mass-univariate (SPM) and region of interest analyses suggested that responses to houses were modulated by attention in both groups, but that only the control participants demonstrated attentional modulation of face-selective regions. Thus, the participants with ASD demonstrated a lack of attentional modulation which was particularly evident for the social stimulus. Analyses of effective connectivity indicated that these results were due to a failure of attention to modulate connectivity between extrastriate areas and V1. We discuss how these results may suggest a mechanism to explain the reduced salience of social stimuli in ASD. PMID:16616862

  2. Exosomal membrane molecules are potent immune response modulators

    PubMed Central

    2010-01-01

    Exosomes are endosome-derived vesicles (40–100 nm) formed during the formation of multi-vesicular bodies (MVBs). Occasionally, the MVBs fuse with the plasma membrane releasing their intra-luminal vesicles into the extracellular media, which are then known as exosomes. Different cell types such as B-cells, dendritic cells, platelets, reticulocytes and macrophages can release exosomes and current research in this area is more focused towards exosomes released by antigen-presenting cells. Exosomes have recently been shown to be immunomodulatory and the mechanism of immune response initiation by them is beginning to emerge. Besides molecules present inside the lumen of exosomes, it has been suggested that certain exosomal membrane molecules can interact with their surface receptors on the target cells thereby inducing an immunomodulatory response. In this review, Hsp70 and galectin-5, two immunogenic molecules present on exosomal membrane, are discussed in detail for initiating this response. PMID:21057626

  3. Advantages of Extracellular Ubiquitin in Modulation of Immune Responses

    PubMed Central

    2016-01-01

    T and B lymphocytes play a central role in protecting the human body from infectious pathogens but occasionally they can escape immune tolerance, become activated, and induce autoimmune diseases. All deregulated cellular processes are associated with improper functioning of the ubiquitin-proteasome system (UPS) in eukaryotic cells. The role of ubiquitin in regulation of immune responses and in autoimmune diseases is only beginning to emerge. Ubiquitin is found in intra- and extracellular fluids and is involved in regulation of numerous cellular processes. Extracellular ubiquitin ascribed a role in lymphocyte differentiation. It regulates differentiation and maturation of hematopoietic cell lines. Ubiquitination is involved in initiation, propagation, and termination of immune responses. Disrupted ubiquitination can lead to autoimmunity. Recent observations showed that it can suppress immune response and prevent inflammation. Exogenous ubiquitin may provide good potential as a new tool for targeted therapy for immune mediated disorders of various etiologies. PMID:27642236

  4. Advantages of Extracellular Ubiquitin in Modulation of Immune Responses

    PubMed Central

    2016-01-01

    T and B lymphocytes play a central role in protecting the human body from infectious pathogens but occasionally they can escape immune tolerance, become activated, and induce autoimmune diseases. All deregulated cellular processes are associated with improper functioning of the ubiquitin-proteasome system (UPS) in eukaryotic cells. The role of ubiquitin in regulation of immune responses and in autoimmune diseases is only beginning to emerge. Ubiquitin is found in intra- and extracellular fluids and is involved in regulation of numerous cellular processes. Extracellular ubiquitin ascribed a role in lymphocyte differentiation. It regulates differentiation and maturation of hematopoietic cell lines. Ubiquitination is involved in initiation, propagation, and termination of immune responses. Disrupted ubiquitination can lead to autoimmunity. Recent observations showed that it can suppress immune response and prevent inflammation. Exogenous ubiquitin may provide good potential as a new tool for targeted therapy for immune mediated disorders of various etiologies.

  5. Advantages of Extracellular Ubiquitin in Modulation of Immune Responses.

    PubMed

    Sujashvili, Rusudan

    2016-01-01

    T and B lymphocytes play a central role in protecting the human body from infectious pathogens but occasionally they can escape immune tolerance, become activated, and induce autoimmune diseases. All deregulated cellular processes are associated with improper functioning of the ubiquitin-proteasome system (UPS) in eukaryotic cells. The role of ubiquitin in regulation of immune responses and in autoimmune diseases is only beginning to emerge. Ubiquitin is found in intra- and extracellular fluids and is involved in regulation of numerous cellular processes. Extracellular ubiquitin ascribed a role in lymphocyte differentiation. It regulates differentiation and maturation of hematopoietic cell lines. Ubiquitination is involved in initiation, propagation, and termination of immune responses. Disrupted ubiquitination can lead to autoimmunity. Recent observations showed that it can suppress immune response and prevent inflammation. Exogenous ubiquitin may provide good potential as a new tool for targeted therapy for immune mediated disorders of various etiologies. PMID:27642236

  6. Do competitors modulate rare plant response to precipitation change?

    USGS Publications Warehouse

    Levine, J.M.; Kathryn, Mceachern A.; Cowan, C.

    2010-01-01

    Ecologists increasingly suspect that climate change will directly impact species physiology, demography, and phenology, but also indirectly affect these measures via changes to the surrounding community. Unfortunately, few studies examine both the direct and indirect pathways of impact. Doing so is important because altered competitive pressures can reduce or magnify the direct responses of a focal species to climate change. Here, we examine the effects of changing rainfall on three rare annual plant species in the presence and absence of competition on the California Channel Islands. We used rain-out shelters and hand watering to exclude and augment early, late, and season-long rainfall, spanning the wide range of precipitation change forecast for the region. In the absence of competition, droughts reduced the population growth rates of two of three focal annuals, while increased rainfall was only sometimes beneficial, As compared to the focal species, the dominant competitors were more sensitive to the precipitation treatments, benefiting from increased season-long precipitation and harmed by droughts. Importantly, the response of two of three competitors to the precipitation treatments tended to be positively correlated with those of the focal annuals. Although this leads to the expectation that increased competition will counter the direct benefits of favorable conditions, such indirect effects of precipitation change proved weak to nonexistent in our experiment. Competitors had little influence on the precipitation response of two focal species, due to their low sensitivity to competition and highly variable precipitation responses. Competition did affect how our third focal species responded to precipitation change, but this effect only approached significance, and whether it truly resulted from competitor response to precipitation change was unclear. Our work suggests that even when competitors respond to climate change, these responses may have little

  7. Do competitors modulate rare plant response to precipitation change?

    PubMed

    Levine, Jonathan M; McEachern, A Kathryn; Cowan, Clark

    2010-01-01

    Ecologists increasingly suspect that climate change will directly impact species physiology, demography, and phenology, but also indirectly affect these measures via changes to the surrounding community. Unfortunately, few studies examine both the direct and indirect pathways of impact. Doing so is important because altered competitive pressures can reduce or magnify the direct responses of a focal species to climate change. Here, we examine the effects of changing rainfall on three rare annual plant species in the presence and absence of competition on the California Channel Islands. We used rain-out shelters and hand watering to exclude and augment early, late, and season-long rainfall, spanning the wide range of precipitation change forecast for the region. In the absence of competition, droughts reduced the population growth rates of two of three focal annuals, while increased rainfall was only sometimes beneficial. As compared to the focal species, the dominant competitors were more sensitive to the precipitation treatments, benefiting from increased season-long precipitation and harmed by droughts. Importantly, the response of two of three competitors to the precipitation treatments tended to be positively correlated with those of the focal annuals. Although this leads to the expectation that increased competition will counter the direct benefits of favorable conditions, such indirect effects of precipitation change proved weak to nonexistent in our experiment. Competitors had little influence on the precipitation response of two focal species, due to their low sensitivity to competition and highly variable precipitation responses. Competition did affect how our third focal species responded to precipitation change, but this effect only approached significance, and whether it truly resulted from competitor response to precipitation change was unclear. Our work suggests that even when competitors respond to climate change, these responses may have little

  8. Modulation of the locomotor response to amphetamine by corticosterone.

    PubMed

    Cador, M; Dulluc, J; Mormède, P

    1993-10-01

    In the present experiments, we investigated the influence of chronic modifications of circulating levels of corticosterone on the locomotor response to amphetamine. Different groups of rats were adrenalectomized and implanted subcutaneously with pellets releasing different amounts of corticosterone (0-200 mg). A wide range of corticosterone concentrations was reached in order to saturate selectively either the type I (mineralocorticoid) or the type II (glucocorticoid) corticosteroid receptors. The locomotor response to d-amphetamine (1.5 mg/kg) was studied 10-14 days later. We found that adrenalectomy reduced the response to d-amphetamine by 33% and that a normal response was restored with pellets releasing physiological concentrations of corticosterone (50-mg pellets), and was potentiated in animals with pellets releasing high amounts of corticosterone mimicking chronic stress situations (200-mg pellets). The correlation between plasma corticosterone concentration, locomotor activity following d-amphetamine and thymus weight, which is a reliable indicator of glucocorticoid action, shows that the influence of the locomotor response to d-amphetamine administration is likely to be mediated via a type II receptor. Since the locomotor activating effect of peripheral administration of d-amphetamine has been shown to depend on the integrity of the dopaminergic innervation of the nucleus accumbens, the effect of d-amphetamine at different doses (0, 1, 3, 10 micrograms/microliter) injected directly into the nucleus accumbens was studied. The results demonstrated that removing the circulating corticosterone induced a similar decrease of the locomotor activity elicited by d-amphetamine injection in the nucleus accumbens. This response was restored in animals with the 50- and 200-mg pellets.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8284048

  9. Growth plate cartilage shows different strain patterns in response to static versus dynamic mechanical modulation.

    PubMed

    Kaviani, Rosa; Londono, Irene; Parent, Stefan; Moldovan, Florina; Villemure, Isabelle

    2016-08-01

    Longitudinal growth of long bones and vertebrae occurs in growth plate cartilage. This process is partly regulated by mechanical forces, which are one of the underlying reasons for progression of growth deformities such as idiopathic adolescent scoliosis and early-onset scoliosis. This concept of mechanical modulation of bone growth is also exploited in the development of fusionless treatments of these deformities. However, the optimal loading condition for the mechanical modulation of growth plate remains to be identified. The objective of this study was to evaluate the effects of in vitro static versus dynamic modulation and of dynamic loading parameters, such as frequency and amplitude, on the mechanical responses and histomorphology of growth plate explants. Growth plate explants from distal ulnae of 4-week-old swines were extracted and randomly distributed among six experimental groups: baseline ([Formula: see text]), control ([Formula: see text]), static ([Formula: see text]) and dynamic ([Formula: see text]). For static and dynamic groups, mechanical modulation was performed in vitro using an Indexed CartiGen bioreactor. A stress relaxation test combined with confocal microscopy and digital image correlation was used to characterize the mechanical responses of each explant in terms of peak stress, equilibrium stress, equilibrium modulus of elasticity and strain pattern. Histomorphometrical measurements were performed on toluidine blue tissue sections using a semi-automatic custom-developed MATLAB toolbox. Results suggest that compared to dynamic modulation, static modulation changes the strain pattern of the tissue and thus is more detrimental for tissue biomechanics, while the histomorphological parameters are not affected by mechanical modulation. Also, under dynamic modulation, changing the frequency or amplitude does not affect the biomechanical response of the tissue. Results of this study will be useful in finding optimal and non-damaging parameters

  10. Growth plate cartilage shows different strain patterns in response to static versus dynamic mechanical modulation.

    PubMed

    Kaviani, Rosa; Londono, Irene; Parent, Stefan; Moldovan, Florina; Villemure, Isabelle

    2016-08-01

    Longitudinal growth of long bones and vertebrae occurs in growth plate cartilage. This process is partly regulated by mechanical forces, which are one of the underlying reasons for progression of growth deformities such as idiopathic adolescent scoliosis and early-onset scoliosis. This concept of mechanical modulation of bone growth is also exploited in the development of fusionless treatments of these deformities. However, the optimal loading condition for the mechanical modulation of growth plate remains to be identified. The objective of this study was to evaluate the effects of in vitro static versus dynamic modulation and of dynamic loading parameters, such as frequency and amplitude, on the mechanical responses and histomorphology of growth plate explants. Growth plate explants from distal ulnae of 4-week-old swines were extracted and randomly distributed among six experimental groups: baseline ([Formula: see text]), control ([Formula: see text]), static ([Formula: see text]) and dynamic ([Formula: see text]). For static and dynamic groups, mechanical modulation was performed in vitro using an Indexed CartiGen bioreactor. A stress relaxation test combined with confocal microscopy and digital image correlation was used to characterize the mechanical responses of each explant in terms of peak stress, equilibrium stress, equilibrium modulus of elasticity and strain pattern. Histomorphometrical measurements were performed on toluidine blue tissue sections using a semi-automatic custom-developed MATLAB toolbox. Results suggest that compared to dynamic modulation, static modulation changes the strain pattern of the tissue and thus is more detrimental for tissue biomechanics, while the histomorphological parameters are not affected by mechanical modulation. Also, under dynamic modulation, changing the frequency or amplitude does not affect the biomechanical response of the tissue. Results of this study will be useful in finding optimal and non-damaging parameters

  11. Modulation of V1 Spike Response by Temporal Interval of Spatiotemporal Stimulus Sequence

    PubMed Central

    Kim, Taekjun; Kim, HyungGoo R.; Kim, Kayeon; Lee, Choongkil

    2012-01-01

    The spike activity of single neurons of the primary visual cortex (V1) becomes more selective and reliable in response to wide-field natural scenes compared to smaller stimuli confined to the classical receptive field (RF). However, it is largely unknown what aspects of natural scenes increase the selectivity of V1 neurons. One hypothesis is that modulation by surround interaction is highly sensitive to small changes in spatiotemporal aspects of RF surround. Such a fine-tuned modulation would enable single neurons to hold information about spatiotemporal sequences of oriented stimuli, which extends the role of V1 neurons as a simple spatiotemporal filter confined to the RF. In the current study, we examined the hypothesis in the V1 of awake behaving monkeys, by testing whether the spike response of single V1 neurons is modulated by temporal interval of spatiotemporal stimulus sequence encompassing inside and outside the RF. We used two identical Gabor stimuli that were sequentially presented with a variable stimulus onset asynchrony (SOA): the preceding one (S1) outside the RF and the following one (S2) in the RF. This stimulus configuration enabled us to examine the spatiotemporal selectivity of response modulation from a focal surround region. Although S1 alone did not evoke spike responses, visual response to S2 was modulated for SOA in the range of tens of milliseconds. These results suggest that V1 neurons participate in processing spatiotemporal sequences of oriented stimuli extending outside the RF. PMID:23091631

  12. Differential modulation by extracellular ATP of carotid chemosensory responses.

    PubMed

    Spergel, D; Lahiri, S

    1993-06-01

    The possibility that the carotid body has ATP surface receptors that mediate O2 chemoreception was tested. To distinguish between the event(s) initiating chemoreception and those at the neurotransmitter level, we also tested the chemosensory response to nicotine before and after ATP administration. Carotid bodies from cats anesthetized with pentobarbital sodium were perfused and superfused in vitro with modified Tyrode solution (PCO2 < 1 Torr, pH 7.4, 36 degrees C) equilibrated at PO2 > 400 or approximately 150 Torr while chemosensory discharge was recorded extracellularly. ATP and adenosine 5'-[gamma-thio]triphosphate stimulated discharge with similar dose dependence, whereas adenosine had little effect. ATP infusion for > or = 2 min evoked an initial stimulation of discharge followed by a decline to baseline (desensitization). Desensitization did not affect the response to hypoxia (perfusate flow interruption) but inhibited the response to nicotine (4-nmol pulse). Therefore, 1) the carotid body has surface ATP receptors that may mediate the chemosensory response to nicotine but not to hypoxia and 2) nicotinic receptors are not required for carotid body O2 chemoreception. PMID:8366007

  13. Immune response modulation by curcumin in a latex allergy model

    PubMed Central

    Kurup, Viswanath P; Barrios, Christy S; Raju, Raghavan; Johnson, Bryon D; Levy, Michael B; Fink, Jordan N

    2007-01-01

    Background There has been a worldwide increase in allergy and asthma over the last few decades, particularly in industrially developed nations. This resulted in a renewed interest to understand the pathogenesis of allergy in recent years. The progress made in the pathogenesis of allergic disease has led to the exploration of novel alternative therapies, which include herbal medicines as well. Curcumin, present in turmeric, a frequently used spice in Asia has been shown to have anti-allergic and inflammatory potential. Methods We used a murine model of latex allergy to investigate the role of curcumin as an immunomodulator. BALB/c mice were exposed to latex allergens and developed latex allergy with a Th2 type of immune response. These animals were treated with curcumin and the immunological and inflammatory responses were evaluated. Results Animals exposed to latex showed enhanced serum IgE, latex specific IgG1, IL-4, IL-5, IL-13, eosinophils and inflammation in the lungs. Intragastric treatment of latex-sensitized mice with curcumin demonstrated a diminished Th2 response with a concurrent reduction in lung inflammation. Eosinophilia in curcumin-treated mice was markedly reduced, co-stimulatory molecule expression (CD80, CD86, and OX40L) on antigen-presenting cells was decreased, and expression of MMP-9, OAT, and TSLP genes was also attenuated. Conclusion These results suggest that curcumin has potential therapeutic value for controlling allergic responses resulting from exposure to allergens. PMID:17254346

  14. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  15. Human Neuromagnetic Steady-State Responses to Amplitude-Modulated Tones, Speech, and Music

    PubMed Central

    Parkkonen, Lauri; Hari, Riitta

    2014-01-01

    Objectives: Auditory steady-state responses that can be elicited by various periodic sounds inform about subcortical and early cortical auditory processing. Steady-state responses to amplitude-modulated pure tones have been used to scrutinize binaural interaction by frequency-tagging the two ears’ inputs at different frequencies. Unlike pure tones, speech and music are physically very complex, as they include many frequency components, pauses, and large temporal variations. To examine the utility of magnetoencephalographic (MEG) steady-state fields (SSFs) in the study of early cortical processing of complex natural sounds, the authors tested the extent to which amplitude-modulated speech and music can elicit reliable SSFs. Design: MEG responses were recorded to 90-s-long binaural tones, speech, and music, amplitude-modulated at 41.1 Hz at four different depths (25, 50, 75, and 100%). The subjects were 11 healthy, normal-hearing adults. MEG signals were averaged in phase with the modulation frequency, and the sources of the resulting SSFs were modeled by current dipoles. After the MEG recording, intelligibility of the speech, musical quality of the music stimuli, naturalness of music and speech stimuli, and the perceived deterioration caused by the modulation were evaluated on visual analog scales. Results: The perceived quality of the stimuli decreased as a function of increasing modulation depth, more strongly for music than speech; yet, all subjects considered the speech intelligible even at the 100% modulation. SSFs were the strongest to tones and the weakest to speech stimuli; the amplitudes increased with increasing modulation depth for all stimuli. SSFs to tones were reliably detectable at all modulation depths (in all subjects in the right hemisphere, in 9 subjects in the left hemisphere) and to music stimuli at 50 to 100% depths, whereas speech usually elicited clear SSFs only at 100% depth. The hemispheric balance of SSFs was toward the right hemisphere

  16. Snake modulates constriction in response to prey's heartbeat.

    PubMed

    Boback, Scott M; Hall, Allison E; McCann, Katelyn J; Hayes, Amanda W; Forrester, Jeffrey S; Zwemer, Charles F

    2012-06-23

    Many species of snakes use constriction-the act of applying pressure via loops of their trunk-to subdue and kill their prey. Constriction is costly and snakes must therefore constrict their prey just long enough to ensure death. However, it remains unknown how snakes determine when their prey is dead. Here, we demonstrate that boas (Boa constrictor) have the remarkable ability to detect a heartbeat in their prey and, based on this signal, modify the pressure and duration of constriction accordingly. We monitored pressure generated by snakes as they struck and constricted warm cadaveric rats instrumented with a simulated heart. Snakes responded to the beating heart by constricting longer and with greater total pressure than when constricting rats with no heartbeat. When the heart was stopped midway through the constriction, snakes abandoned constriction shortly after the heartbeat ceased. Furthermore, snakes naive to live prey also responded to the simulated heart, suggesting that this behaviour is at least partly innate. These results are an example of how snakes integrate physiological cues from their prey to modulate a complex and ancient behavioural pattern.

  17. Adult attachment style modulates neural responses in a mentalizing task.

    PubMed

    Schneider-Hassloff, H; Straube, B; Nuscheler, B; Wemken, G; Kircher, T

    2015-09-10

    Adult attachment style (AAS) is a personality trait that affects social cognition. Behavioral data suggest that AAS influences mentalizing proficiency, i.e. the ability to predict and explain people's behavior with reference to mental states, but the neural correlates are unknown. We here tested how the AAS dimensions "avoidance" (AV) and "anxiety" (ANX) modulate neural correlates of mentalizing. We measured brain activation using functional magnetic resonance imaging (fMRI) in 164 healthy subjects during an interactive mentalizing paradigm (Prisoner's Dilemma Game). AAS was assessed with the Relationship Scales Questionnaire, including the subscales AV and ANX. Our task elicited a strong activation of the mentalizing network, including bilateral precuneus, (anterior, middle, and posterior) cingulate cortices, temporal poles, inferior frontal gyri (IFG), temporoparietal junctions, superior medial frontal gyri as well as right medial orbital frontal gyrus, superior temporal gyrus, middle frontal gyrus (MFG), and amygdala. We found that AV is positively and ANX negatively correlated with task-associated neural activity in the right amygdala, MFG, midcingulate cortex, and superior parietal lobule, and in bilateral IFG. These data suggest that avoidantly attached adults activate brain areas implicated in emotion regulation and cognitive control to a larger extent than anxiously attached individuals during mentalizing. PMID:26162239

  18. Modulation of immune responses in stress by Yoga.

    PubMed

    Arora, Sarika; Bhattacharjee, Jayashree

    2008-07-01

    Stress is a constant factor in today's fastpaced life that can jeopardize our health if left unchecked. It is only in the last half century that the role of stress in every ailment from the common cold to AIDS has been emphasized, and the mechanisms involved in this process have been studied. Stress influences the immune response presumably through the activation of the hypothalamic-pituitary adrenal axis, hypothalamic pituitary-gonadal axis, and the sympathetic-adrenal-medullary system. Various neurotransmitters, neuropeptides, hormones, and cytokines mediate these complex bidirectional interactions between the central nervous system (CNS) and the immune system. The effects of stress on the immune responses result in alterations in the number of immune cells and cytokine dysregulation. Various stress management strategies such as meditation, yoga, hypnosis, and muscle relaxation have been shown to reduce the psychological and physiological effects of stress in cancers and HIV infection. This review aims to discuss the effect of stress on the immune system and examine how relaxation techniques such as Yoga and meditation could regulate the cytokine levels and hence, the immune responses during stress.

  19. A plant histaminase modulates cardiac anaphylactic response in guinea pig.

    PubMed

    Masini, Emanuela; Vannacci, Alfredo; Marzocca, Cosimo; Mannaioni, Pier Francesco; Befani, Olivia; Federico, Rodolfo; Toma, Alessandro; Mondovì, Bruno

    2002-08-30

    The effect of a copper amine oxidase (histaminase) purified from the pea seedling as free or immobilized enzyme on the response to specific antigen was studied in isolated hearts from actively sensitized guinea pigs. In vitro challenge with the specific antigen of hearts from actively sensitized animals evokes a positive inotropic and chronotropic effect, a coronary constriction, followed by dilation and an increase in the amount of histamine and nitrites, the oxidation product of nitric oxide, in the perfusates. In the presence of both forms of histaminases, the positive inotropic and chronotropic responses as well as the coronary constriction and the release of histamine were fully blocked. The amount of nitrites, appearing in the perfusates when anaphylaxis is elicited in the presence of both forms of histaminases, is significantly increased, as well as nitric oxide synthase activity and cyclic GMP content in cardiac tissue, while cardiac calcium overload was significantly prevented. These observations demonstrate that the decrease in the anaphylactic release of histamine and the subsequent abatement of the cardiac response to antigen can be accounted for by the inactivation by histaminase of the released histamine and by a stimulation of endogenous nitric oxide production. PMID:12200124

  20. A circuit for pupil orienting responses: implications for cognitive modulation of pupil size.

    PubMed

    Wang, Chin-An; Munoz, Douglas P

    2015-08-01

    Pupil size, as a component of orienting, changes rapidly in response to local salient events in the environment, in addition to its well-known illumination-dependent modulation. Recent research has shown that visual, auditory, or audiovisual stimuli can elicit transient pupil dilation, and the timing and size of the evoked responses are systematically modulated by stimulus salience. Moreover, weak microstimulation of the superior colliculus (SC), a midbrain structure involved in eye movements and attention, evokes similar transient pupil dilation, suggesting that the SC coordinates the orienting response which includes transient pupil dilation. Projections from the SC to the pupil control circuitry provide a novel neural substrate underlying pupil modulation by various cognitive processes.

  1. Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex

    PubMed Central

    Walter, Susanna A.; Forsgren, Mikael; Lundengård, Karin; Simon, Rozalyn; Torkildsen Nilsson, Maritha; Söderfeldt, Birgitta; Lundberg, Peter; Engström, Maria

    2016-01-01

    Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms. PMID:26930498

  2. Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex.

    PubMed

    Walter, Susanna A; Forsgren, Mikael; Lundengård, Karin; Simon, Rozalyn; Torkildsen Nilsson, Maritha; Söderfeldt, Birgitta; Lundberg, Peter; Engström, Maria

    2016-01-01

    Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

  3. Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex.

    PubMed

    Walter, Susanna A; Forsgren, Mikael; Lundengård, Karin; Simon, Rozalyn; Torkildsen Nilsson, Maritha; Söderfeldt, Birgitta; Lundberg, Peter; Engström, Maria

    2016-01-01

    Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms. PMID:26930498

  4. Affective Modulation of the Startle Response among Children at High and Low Risk for Anxiety Disorders

    PubMed Central

    Kujawa, Autumn; Glenn, Catherine R.; Hajcak, Greg; Klein, Daniel N.

    2016-01-01

    Background Identifying early markers of risk for anxiety disorders in children may aid in understanding underlying mechanisms and informing prevention efforts. Affective modulation of the startle response indexes sensitivity to pleasant and unpleasant environmental contexts and has been shown to relate to anxiety, yet the extent to which abnormalities in affect-modulated startle reflect vulnerability for anxiety disorders in children has yet to be examined. The current study assessed the effects of parental psychopathology on affective modulation of startle in offspring. Methods Nine-year-old children (N=144) with no history of anxiety or depressive disorders completed a passive picture viewing task in which eye blink startle responses were measured during the presentation of pleasant, neutral, and unpleasant images. Results Maternal anxiety was associated with distinct patterns of affective modulation of startle in offspring, such that children with maternal histories of anxiety showed potentiation of the startle response while viewing unpleasant images, but not attenuation during pleasant images, whereas children with no maternal history of anxiety exhibited attenuation of the startle response during pleasant images, but did not exhibit unpleasant potentiation—even when controlling for child symptoms of anxiety and depression. No effects of maternal depression or paternal psychopathology were observed. Conclusions These findings suggest that both enhanced startle responses in unpleasant conditions and failure to inhibit startle responses in pleasant conditions may reflect early-emerging vulnerabilities that contribute to the later development of anxiety disorders. PMID:25913397

  5. Modulation of cellular responses on engineered polyurethane implants.

    PubMed

    Khandwekar, Anand; Rho, Cho K

    2012-09-01

    An in vivo rat cage implant system was used to study the effect of polyurethane surface chemistries on protein adsorption, macrophage adhesion, foreign-body giant cell formation (FBGCs), cellular apoptosis, and cytokine response. Polyurethanes with zwitterionic, anionic, and cationic chemistries were developed. The changes in the surface topography of the materials were determined using atomic force microscopy and the wettability by dynamic contact angle measurements. The in vitro protein adsorption studies revealed higher protein adsorption on cationic surfaces when compared with the base, while adsorption was significantly reduced on zwitterionic (**p < 0.01) and anionic (*p < 0.05) polyurethanes. Analysis of the exudates surrounding the materials revealed no differences between surfaces in the types or levels of cells present. Conversely, the proportion of adherent cells undergoing apoptosis, as determined by annexin V-FITC staining, increased significantly on anionic followed by zwitterionic surfaces (60 + 5.0 and 38 + 3.7%) when compared with the base. Additionally, zwitterionic and anionic substrates provided decreased rates of macrophage adhesion and fusion into FBGCs, whereas cationic surfaces promoted macrophage adhesion and FBGC formation. Visualization of the F-actin cytoskeleton by Alexa Fluor 488 phalloidin showed a significant delay in the cytoskeletal fusion response on zwitterionic and the anionic surfaces. The real-time polymerase chain reaction (PCR) analysis of proinflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-10) and pro-wound healing cytokines (IL-4 and TGF-β) revealed differential cytokine responses. Cationic substrates that triggered stimulation of TNF-α and IL-4 were associated with more spread cells and higher FBGCs, whereas zwitterionic and anionic substrates that suppressed these cytokines levels were associated with less spread cells and few FBGCs. These studies have revealed that zwitterionic and anionic

  6. Drought episode modulates the response of river biofilms to triclosan.

    PubMed

    Proia, L; Vilches, C; Boninneau, C; Kantiani, L; Farré, M; Romaní, A M; Sabater, S; Guasch, H

    2013-02-01

    The consequences of global change on rivers include altered flow regime, and entrance of compounds that may be toxic to biota. When water is scarce, a reduced dilution capacity may amplify the effects of chemical pollution. Therefore, studying the response of natural communities to compromised water flow and to toxicants is critical for assessing how global change may affect river ecosystems. This work aims to investigate how an episode of drought might influence the response of river biofilms to pulses of triclosan (TCS). The objectives were to assess the separate and combined effects of simulated drought (achieved through drastic flow alteration) and of TCS exposure on biofilms growing in artificial channels. Thus, three-week-old biofilms were studied under four conditions: Control (normal water flow); Simulated Drought (1 week reduced flow+2 days interrupted flow); TCS only (normal water flow plus a 48-h pulse of TCS); and Simulated Drought+TCS. All channels were then left for 2 weeks under steady flow conditions, and their responses and recovery were studied. Several descriptors of biofilms were analyzed before and after each step. Flow reduction and subsequent interruption were found to provoke an increase in extracellular phosphatase activity, bacterial mortality and green algae biomass. The TCS pulses severely affected biofilms: they drastically reduced photosynthetic efficiency, the viability of bacteria and diatoms, and phosphate uptake. Latent consequences evidenced significant combined effects caused by the two stressors. The biofilms exposed only to TCS recovered far better than those subjected to both altered flow and subsequent TCS exposure: the latter suffered more persistent consequences, indicating that simulated drought amplified the toxicity of this compound. This finding has implications for river ecosystems, as it suggests that the toxicity of pollutants to biofilms may be exacerbated following a drought.

  7. Modulating the pituitary-adrenal response to stress

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.

    1975-01-01

    Serotonin is believed to be a transmitter or regulator of neuronal function. A possible relationship between the pituitary-adrenal secretion of steroids and brain serotonin in the rat was investigated by evaluating the effects of altering brain 5-hydroxy tryptamine (HT) levels on the daily fluctuation of plasma corticosterone and on the response of the pituitary-adrenal system to a stressful or noxious stimulus in the rat. The approach was either to inhibit brain 5-HT synthesis with para-chlorophenyl alanine or to raise its level with precursors such as tryptophan or 5-hydroxy tryptophan.

  8. Acoustic change responses to amplitude modulation: a method to quantify cortical temporal processing and hemispheric asymmetry

    PubMed Central

    Han, Ji Hye; Dimitrijevic, Andrew

    2015-01-01

    Objective: Sound modulation is a critical temporal cue for the perception of speech and environmental sounds. To examine auditory cortical responses to sound modulation, we developed an acoustic change stimulus involving amplitude modulation (AM) of ongoing noise. The AM transitions in this stimulus evoked an acoustic change complex (ACC) that was examined parametrically in terms of rate and depth of modulation and hemispheric symmetry. Methods: Auditory cortical potentials were recorded from 64 scalp electrodes during passive listening in two conditions: (1) ACC from white noise to 4, 40, 300 Hz AM, with varying AM depths of 100, 50, 25% lasting 1 s and (2) 1 s AM noise bursts at the same modulation rate. Behavioral measures included AM detection from an attend ACC condition and AM depth thresholds (i.e., a temporal modulation transfer function, TMTF). Results: The N1 response of the ACC was large to 4 and 40 Hz and small to the 300 Hz AM. In contrast, the opposite pattern was observed with bursts of AM showing larger responses with increases in AM rate. Brain source modeling showed significant hemispheric asymmetry such that 4 and 40 Hz ACC responses were dominated by right and left hemispheres respectively. Conclusion: N1 responses to the ACC resembled a low pass filter shape similar to a behavioral TMTF. In the ACC paradigm, the only stimulus parameter that changes is AM and therefore the N1 response provides an index for this AM change. In contrast, an AM burst stimulus contains both AM and level changes and is likely dominated by the rise time of the stimulus. The hemispheric differences are consistent with the asymmetric sampling in time hypothesis suggesting that the different hemispheres preferentially sample acoustic time across different time windows. Significance: The ACC provides a novel approach to studying temporal processing at the level of cortex and provides further evidence of hemispheric specialization for fast and slow stimuli. PMID:25717291

  9. 'Green revolution' genes encode mutant gibberellin response modulators.

    PubMed

    Peng, J; Richards, D E; Hartley, N M; Murphy, G P; Devos, K M; Flintham, J E; Beales, J; Fish, L J; Worland, A J; Pelica, F; Sudhakar, D; Christou, P; Snape, J W; Gale, M D; Harberd, N P

    1999-07-15

    World wheat grain yields increased substantially in the 1960s and 1970s because farmers rapidly adopted the new varieties and cultivation methods of the so-called 'green revolution'. The new varieties are shorter, increase grain yield at the expense of straw biomass, and are more resistant to damage by wind and rain. These wheats are short because they respond abnormally to the plant growth hormone gibberellin. This reduced response to gibberellin is conferred by mutant dwarfing alleles at one of two Reduced height-1 (Rht-B1 and Rht-D1) loci. Here we show that Rht-B1/Rht-D1 and maize dwarf-8 (d8) are orthologues of the Arabidopsis Gibberellin Insensitive (GAI) gene. These genes encode proteins that resemble nuclear transcription factors and contain an SH2-like domain, indicating that phosphotyrosine may participate in gibberellin signalling. Six different orthologous dwarfing mutant alleles encode proteins that are altered in a conserved amino-terminal gibberellin signalling domain. Transgenic rice plants containing a mutant GAI allele give reduced responses to gibberellin and are dwarfed, indicating that mutant GAI orthologues could be used to increase yield in a wide range of crop species.

  10. Complex response of a food-web module to symmetric and asymmetric migration between several patches.

    PubMed

    Ristl, Konstantin; Plitzko, Sebastian J; Drossel, Barbara

    2014-08-01

    We investigate the stability of a diamond food-web module on two patches coupled by migration in terms of robustness, which is the proportion of surviving species in the system. The parameters are chosen such that the dynamics on an isolated patch have a periodic attractor with all four species present as well as an attractor where the prey that is preferred by the top predator dies out. The migration rate and the migration bias between the two patches are varied, resulting in a surprisingly complex relation between migration rate and robustness. In particular, while the degree of synchronization usually increases with increasing migration rate, robustness can increase as well as decrease. We find that the main results also hold when the number of patches is larger. Different types of connectivity patterns between patches can lead to different extent of migration bias if the migration rate out of each patch is the same.

  11. Aggression differentially modulates brain responses to fearful and angry faces: an exploratory study.

    PubMed

    Lu, Hui; Wang, Yu; Xu, Shuang; Wang, Yifeng; Zhang, Ruiping; Li, Tsingan

    2015-08-19

    Aggression is reported to modulate neural responses to the threatening information. However, whether aggression can modulate neural response to different kinds of threatening facial expressions (angry and fearful expressions) remains unknown. Thus, event-related potentials were measured in individuals (13 high aggressive, 12 low aggressive) exposed to neutral, angry, and fearful facial expressions while performing a frame-distinguishing task, irrespective of the emotional valence of the expressions. Highly aggressive participants showed no distinct neural responses between the three facial expressions. In addition, compared with individuals with low aggression, highly aggressive individuals showed a decreased frontocentral response to fearful faces within 250-300 ms and to angry faces within 400-500 ms of exposure. These results indicate that fearful faces represent a more threatening signal requiring a quick cognitive response during the early stage of facial processing, whereas angry faces elicit a stronger response during the later processing stage because of its eminent emotional significance. The present results represent the first known evidence that aggression is associated with different neural responses to fearful and angry faces. By exploring the distinct temporal responses to fearful and angry faces modulated by aggression, this study more precisely characterizes the cognitive characteristics of aggressive individuals. PMID:26164452

  12. Aggression differentially modulates brain responses to fearful and angry faces: an exploratory study.

    PubMed

    Lu, Hui; Wang, Yu; Xu, Shuang; Wang, Yifeng; Zhang, Ruiping; Li, Tsingan

    2015-08-19

    Aggression is reported to modulate neural responses to the threatening information. However, whether aggression can modulate neural response to different kinds of threatening facial expressions (angry and fearful expressions) remains unknown. Thus, event-related potentials were measured in individuals (13 high aggressive, 12 low aggressive) exposed to neutral, angry, and fearful facial expressions while performing a frame-distinguishing task, irrespective of the emotional valence of the expressions. Highly aggressive participants showed no distinct neural responses between the three facial expressions. In addition, compared with individuals with low aggression, highly aggressive individuals showed a decreased frontocentral response to fearful faces within 250-300 ms and to angry faces within 400-500 ms of exposure. These results indicate that fearful faces represent a more threatening signal requiring a quick cognitive response during the early stage of facial processing, whereas angry faces elicit a stronger response during the later processing stage because of its eminent emotional significance. The present results represent the first known evidence that aggression is associated with different neural responses to fearful and angry faces. By exploring the distinct temporal responses to fearful and angry faces modulated by aggression, this study more precisely characterizes the cognitive characteristics of aggressive individuals.

  13. Effects of GABA modulators on the repeated acquisition of response sequences in squirrel monkeys.

    PubMed Central

    Campbell, Una C; Winsauer, Peter J; Stevenson, Michael W; Moerschbaecher, Joseph M

    2004-01-01

    The present study investigated the effects of positive and negative GABA(A) modulators under three different baselines of repeated acquisition in squirrel monkeys in which the monkeys acquired a three-response sequence on three keys under a second-order fixed-ratio (FR) schedule of food reinforcement. In two of these baselines, the second-order FR schedule and the discriminative stimuli for the response sequence were manipulated ("chain-strained" and "tandem-strained"). In the third baseline condition, response-independent tail shock was presented during acquisition of the response sequence. All of these baselines maintained high error levels and produced slow rates of acquisition. Under both the chain-strained and tandem-strained conditions, the positive GABA(A) modulator triazolam (0.0032-0.1 mg/kg) and the negative GABA(A) modulators beta-CCE (ethyl-beta-carboline-3-carboxylate; 0.01-1 mg/kg), beta-CCM (methyl-beta-carboline-3-carboxylate; 0.0032-0.1 mg/kg), and FG-7142 (methyl-beta-carboline-3-carboxamide; 0.18-10 mg/kg) dose-dependently decreased overall response rate compared to administration of saline (control). Under the same two conditions, triazolam and the negative GABA(A) modulators also increased the percentage of errors; however, the effects on accuracy frequently depended on the baseline condition and the particular modulator. In contrast, triazolam only decreased errors and enhanced acquisition in the presence of concurrent response-independent tail shock when compared to saline administration under this condition. The neutral GABA(A) modulator, flumazenil (1 mg/kg), had no effect on rate or accuracy of responding when administered alone, but antagonized the rate-decreasing and error-increasing effects produced by the negative GABA(A) modulators. Together, these data suggest that the effects of both the positive and negative GABAA modulators on acquisition can be similar in squirrel monkeys (i.e., both types of modulator may produce rate

  14. Modulation of immune responses by immunotherapy in allergic diseases.

    PubMed

    Cavkaytar, Ozlem; Akdis, Cezmi A; Akdis, Mübeccel

    2014-08-01

    Allergen immunotherapy (AIT) has been used for 100 years and until now different immunoregulatory pathways have been shown to take place in its mechanisms of action. It is characterized by administration of the causative allergen and is shown to be clinically efficient even after discontinuation of therapy particularly in allergic respiratory diseases, bee venom allergy, and food allergy. Generation of antigen/allergen-specific peripheral tolerance is the key mechanism during immunotherapy. It is mediated by development of T and B regulatory cells, IgG4 isotype allergen-specific antibodies and the involvement of multiple suppressor factors, which lead to decreased tissue inflammation, early and late phase responses. Describing novel regulatory mechanisms in the process of immune tolerance induction will help to identify treatment modalities not only for allergic disorders, but also for autoimmune diseases, organ transplantation, chronic infections, and cancer.

  15. The thalamic intergeniculate leaflet modulates photoperiod responsiveness in Siberian hamsters.

    PubMed

    Freeman, David A; Dhandapani, Krishnan M; Goldman, Bruce D

    2004-11-26

    Siberian hamsters are seasonal breeders that use changes in day length to synchronize their reproductive effort with those times of the year most favorable for successful reproduction. The ability of Siberian hamsters to measure and respond to changes in day length depends upon accurate photoentrainment of the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. Two pathways have been characterized through which entraining stimuli reach the SCN: the retinohypothalamic tract (RHT), which transmits light information from the retinae, and the geniculohypothalamic tract (GHT) from the intergeniculate leaflet of the thalamus (IGL), which is involved in transmitting both photic and nonphotic cues. Ablating the IGL/GHT results in only modest alterations in entrainment to static day lengths and fails to interfere with seasonal responses induced by transfer from static long day to static short day lengths. Because several studies suggest that the IGL may be involved in tracking the time of dusk and dawn, we sought to determine whether an intact IGL is necessary for hamsters to respond to a simulated natural photoperiod (SNP) in which the time of dusk and dawn gradually changes in a pattern approximating the rate of change in day length that occurs during autumn at the latitude this species inhabits in nature. The results indicate that neurochemical lesions of the IGL alter both the pattern of circadian entrainment and photoperiodic responsiveness of Siberian hamsters to an SNP. Both intact and IGL-lesioned hamsters exhibited testicular regression in shortening day lengths, but only IGL-intact hamsters exhibited seasonal pelage molt.

  16. Vestibular activation differentially modulates human early visual cortex and V5/MT excitability and response entropy.

    PubMed

    Seemungal, Barry M; Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC.

  17. Dissociable Neural Response Signatures for Slow Amplitude and Frequency Modulation in Human Auditory Cortex

    PubMed Central

    Henry, Molly J.; Obleser, Jonas

    2013-01-01

    Natural auditory stimuli are characterized by slow fluctuations in amplitude and frequency. However, the degree to which the neural responses to slow amplitude modulation (AM) and frequency modulation (FM) are capable of conveying independent time-varying information, particularly with respect to speech communication, is unclear. In the current electroencephalography (EEG) study, participants listened to amplitude- and frequency-modulated narrow-band noises with a 3-Hz modulation rate, and the resulting neural responses were compared. Spectral analyses revealed similar spectral amplitude peaks for AM and FM at the stimulation frequency (3 Hz), but amplitude at the second harmonic frequency (6 Hz) was much higher for FM than for AM. Moreover, the phase delay of neural responses with respect to the full-band stimulus envelope was shorter for FM than for AM. Finally, the critical analysis involved classification of single trials as being in response to either AM or FM based on either phase or amplitude information. Time-varying phase, but not amplitude, was sufficient to accurately classify AM and FM stimuli based on single-trial neural responses. Taken together, the current results support the dissociable nature of cortical signatures of slow AM and FM. These cortical signatures potentially provide an efficient means to dissect simultaneously communicated slow temporal and spectral information in acoustic communication signals. PMID:24205309

  18. Modulations in oscillatory activity with amplitude asymmetry can produce cognitively relevant event-related responses

    PubMed Central

    van Dijk, Hanneke; van der Werf, Jurrian; Mazaheri, Ali; Medendorp, W. Pieter; Jensen, Ole

    2009-01-01

    Event-related responses and oscillatory activity are typically regarded as manifestations of different neural processes. Recent work has nevertheless revealed a mechanism by which slow event-related responses are created as a direct consequence of modulations in brain oscillations with nonsinusoidal properties. It remains unknown if this mechanism applies to cognitively relevant event-related responses. Here, we investigated whether sustained event-related fields (ERFs) measured during working memory maintenance can be explained by modulations in oscillatory power. In particular, we focused on contralateral delayed activity (CDA) typically observed in working memory tasks in which hemifield specific attention is manipulated. Using magnetoencephalography, we observed sustained posterior ERFs following the presentation of the memory target. These ERFs were systematically lateralized with respect to the hemisphere in which the target was presented. A strikingly similar pattern emerged for modulations in alpha (9–13 Hz) power. The alpha power and ERF lateralization were strongly correlated over subjects. Based on a mechanistic argument pertaining to the nonsinusoidal properties of the alpha activity, we conclude that the ERFs modulated by working memory are likely to be directly produced by the modulations in oscillatory alpha activity. Given that posterior alpha activity typically reflects disengagement, we conclude that the CDA is not attributable to an additive process reflecting memory maintenance per se but, rather, is a consequence of how attentional resources are allocated. PMID:20080773

  19. Optically addressed and submillisecond response phase only liquid crystal spatial light modulator

    NASA Astrophysics Data System (ADS)

    Zhao, Xiangjie; Duan, Jiazhu; Zhang, Dayong; Luo, Yongquan

    2014-10-01

    Liquid crystal based phase only spatial light modulator has attracted many research interests since last decades because of its superior advantage. Until now the liquid crystal spatial light modulator has been applied in many fields, but the response speed of nematic LC limited its further application. In this paper, an optically addressed phase only LC spatial light modulator was proposed based on polymer network liquid crystal. Morphology effect on the light scattering of PNLC was studied, which was mainly consisted of fiber and fiber bundles. The morphology nearly determined the light scattering and electro-optical property. Due to the high threshold voltage, to address the PNLC phase modulator was also concerned. Optical addressing method was proposed, in which BSO crystal was selected to replace one of the glass substrate. The response speed of PNLC was so fast that the reorientation of liquid crystal director will follow the change of effective voltage applied on LC layer, which was related with the voltage signal and especially with electron transport of photo-induced carriers due to diffusion and drift. The on state dynamic response of phase change was investigated. Based on this device, beam steering was also achieved by loading 488nm laser strip on the optical addressed phase only spatial light modulator.

  20. Driving time modulates accommodative response and intraocular pressure.

    PubMed

    Vera, Jesús; Diaz-Piedra, Carolina; Jiménez, Raimundo; Morales, José M; Catena, Andrés; Cardenas, David; Di Stasi, Leandro L

    2016-10-01

    Driving is a task mainly reliant on the visual system. Most of the time, while driving, our eyes are constantly focusing and refocusing between the road and the dashboard or near and far traffic. Thus, prolonged driving time should produce visual fatigue. Here, for the first time, we investigated the effects of driving time, a common inducer of driver fatigue, on two ocular parameters: the accommodative response (AR) and the intraocular pressure (IOP). A pre/post-test design has been used to assess the impact of driving time on both indices. Twelve participants (out of 17 recruited) completed the study (5 women, 24.42±2.84years old). The participants were healthy and active drivers with no visual impairment or pathology. They drove for 2h in a virtual driving environment. We assessed AR and IOP before and after the driving session, and also collected subjective measures of arousal and fatigue. We found that IOP and AR decreased (i.e., the accommodative lag increased) after the driving session (p=0.03 and p<0.001, respectively). Moreover, the nearest distances tested (20cm, 25cm, and 33cm) induced the highest decreases in AR (corrected p-values<0.05). Consistent with these findings, the subjective levels of arousal decreased and levels of fatigue increased after the driving session (all p-values<0.001). These results represent an innovative step towards an objective, valid, and reliable assessment of fatigue-impaired driving based on visual fatigue signs. PMID:27235337

  1. The epicardium as modulator of the cardiac autonomic response during early development.

    PubMed

    Kelder, Tim P; Duim, Sjoerd N; Vicente-Steijn, Rebecca; Végh, Anna M D; Kruithof, Boudewijn P T; Smits, Anke M; van Bavel, Thomas C; Bax, Noortje A M; Schalij, Martin J; Gittenberger-de Groot, Adriana C; DeRuiter, Marco C; Goumans, Marie-José; Jongbloed, Monique R M

    2015-12-01

    The cardiac autonomic nervous system (cANS) modulates heart rate, contraction force and conduction velocity. The embryonic chicken heart already responds to epinephrine prior to establishment of the cANS. The aim of this study was to define the regions of the heart that might participate in modulating the early autonomic response to epinephrine. Immunofluorescence analysis reveals expression of neural markers tubulin beta-3 chain and neural cell adhesion molecule in the epicardium during early development. In addition, expression of the β2 adrenergic receptor, the receptor for epinephrine, was found in the epicardium. Ex-ovo micro-electrode recordings in hearts with inhibition of epicardial outgrowth showed a significantly reduced response of the heart rate to epinephrine compared to control hearts. This study suggests a role for the epicardium as autonomic modulator during early cardiac development. PMID:26527381

  2. Startle response and prepulse inhibition modulation by positive- and negative-induced affect.

    PubMed

    De la Casa, Luis Gonzalo; Mena, Auxiliadora; Puentes, Andrea

    2014-02-01

    The startle response, a set of reflex behaviours intended to prepare the organism to face a potentially threatening stimulus, can be modulated by several factors as, for example, changes in affective state, or previous presentation of a weak stimulus (a phenomenon termed Pre-Pulse Inhibition [PPI]). In this paper we analyse whether the induction of positive or negative affective states in the participants modulates the startle response and the PPI phenomenon. The results revealed a decrease of the startle response and an increase of the PPI effect when registered while the participants were exposed to pleasant images (Experiment 1), and an increase of the startle response and of the PPI effect when they were exposed to a video-clip of unpleasant content (Experiment 2). These data are interpreted considering that changes in affective states correlate with changes in the startle reflex intensity, but changes in PPI might be the result of an attentional process.

  3. Startle response and prepulse inhibition modulation by positive- and negative-induced affect.

    PubMed

    De la Casa, Luis Gonzalo; Mena, Auxiliadora; Puentes, Andrea

    2014-02-01

    The startle response, a set of reflex behaviours intended to prepare the organism to face a potentially threatening stimulus, can be modulated by several factors as, for example, changes in affective state, or previous presentation of a weak stimulus (a phenomenon termed Pre-Pulse Inhibition [PPI]). In this paper we analyse whether the induction of positive or negative affective states in the participants modulates the startle response and the PPI phenomenon. The results revealed a decrease of the startle response and an increase of the PPI effect when registered while the participants were exposed to pleasant images (Experiment 1), and an increase of the startle response and of the PPI effect when they were exposed to a video-clip of unpleasant content (Experiment 2). These data are interpreted considering that changes in affective states correlate with changes in the startle reflex intensity, but changes in PPI might be the result of an attentional process. PMID:24188916

  4. Project S.P.I.C.E.: Special Partnership in Career Education. Rights and Responsibility Teaching Module.

    ERIC Educational Resources Information Center

    Emerson, Debby H.; And Others

    The rights and responsibility teaching module is one of a series of six modules prepared by Project SPICE (Special Partnership in Career Education) as a means of providing career awareness information to educable mentally handicapped students (ages 11-to-13 years). After an overview, a module profile is provided which charts the activities, and…

  5. SU-E-T-97: Dependence Of Optically Stimulated Luminescent Dosimeter (OSLD) Out Of Field Response On Volumetric Modulated Arc Therapy (VMAT) Field Modulation

    SciTech Connect

    Ware, S; Clouser, E

    2014-06-01

    Purpose: To determine the out of field response of Microstar ii OSLDs as a function of field modulation and distance in VMAT plan delivery. This work has potential application in fetal dose monitoring or measurements on cardiac pacemakers Methods: VMAT plans were created in Eclipse and optimized to varying degrees of modulation. Three plans were chosen to represent low, medium and high degrees of modulation (modulation factors as defined by MU/cGy). Plans were delivered to slabs of solid water with dimensions 60cm length, 30cm width, and 10cm height. For each modulation factor, 2 OSLDs were placed at 1cm depth with out of field distances of 1, 2, 3, 5, 8 and 10cm and the plan delivered isocentrically to a depth of 5cm. This technique was repeated for a Farmer Chamber by incrementing the table by the appropriate distance. The charge readings for the Farmer Chamber were converted to dose and the ratios taken as functions of modulation factors and distances out of field Results: Examination of the results as a function of out of field distance shows a trend of increasing OSLD/Farmer Chamber ratios for all modulation factors. The slopes appear to be roughly equivalent for all modulation factors investigated. Results as a function of modulation showed a downward trend for all out of field distances, with the greatest differences seen at 5cm and 8cm Conclusion: This study demonstrates that the response of OSLD dosimeters change as a function of out of field distance and modulation. The differences seen are within the stated accuracy of the system for the out of field distances and modulations investigated. Additional investigation is warranted to see if the OSLD response changes appreciably with longer out of field distances or wider ranges of modulation.

  6. AI-2 biosynthesis module in a magnetic nanofactory alters bacterial response via localized synthesis and delivery.

    PubMed

    Fernandes, Rohan; Bentley, William E

    2009-02-01

    Nanofactories are nano-dimensioned and comprised of modules serving various functions that alter the response of targeted cells when deployed by locally synthesizing and delivering cargo to the surfaces of the targeted cells. In its basic form, a nanofactory consists of a minimum of two functional modules: a cell capture module and a synthesis module. In this work, magnetic nanofactories that alter the response of targeted bacteria by the localized synthesis and delivery of the "universal" bacterial quorum sensing signal molecule autoinducer AI-2 are demonstrated. The magnetic nanofactories consist of a cell capture module (chitosan-mag nanoparticles) and an AI-2 biosynthesis module that contains both AI-2 biosynthetic enzymes Pfs and LuxS on a fusion protein (His-LuxS-Pfs-Tyr, HLPT) assembled together. HLPT is hypothesized to be more efficient than its constituent enzymes (used separately) at conversion of the substrate SAH to product AI-2 on account of the proximity of the two enzymes within the fusion protein. HLPT is demonstrated to be more active than the constituent enzymes, Pfs and LuxS, over a wide range of experimental conditions. The magnetic nanofactories (containing bound HLPT) are also demonstrated to be more active than free, unbound HLPT. They are also shown to elicit an increased response in targeted Escherichia coli cells, due to the localized synthesis and delivery of AI-2, when compared to the response produced by the addition of AI-2 directly to the cells. Studies investigating the universality of AI-2 and unraveling AI-2 based quorum sensing in bacteria using magnetic nanofactories are envisioned. The prospects of using such multi-modular nanofactories in developing the next generation of antimicrobials based on intercepting and interrupting quorum sensing based signaling are discussed.

  7. An NCME Instructional Module on Estimating Item Response Theory Models Using Markov Chain Monte Carlo Methods

    ERIC Educational Resources Information Center

    Kim, Jee-Seon; Bolt, Daniel M.

    2007-01-01

    The purpose of this ITEMS module is to provide an introduction to Markov chain Monte Carlo (MCMC) estimation for item response models. A brief description of Bayesian inference is followed by an overview of the various facets of MCMC algorithms, including discussion of prior specification, sampling procedures, and methods for evaluating chain…

  8. Stress Response Recruits the Hippocampal Endocannabinoid System for the Modulation of Fear Memory

    ERIC Educational Resources Information Center

    Alvares, Lucas de Oliveira; Engelke, Douglas Senna; Diehl, Felipe; Scheffer-Teixeira, Robson; Haubrich, Josue; Cassini, Lindsey de Freitas; Molina, Victor Alejandro; Quillfeldt, Jorge Alberto

    2010-01-01

    The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress…

  9. Individual Differences in Mathematical Competence Modulate Brain Responses to Arithmetic Errors: An fMRI Study

    ERIC Educational Resources Information Center

    Ansari, Daniel; Grabner, Roland H.; Koschutnig, Karl; Reishofer, Gernot; Ebner, Franz

    2011-01-01

    Data from both neuropsychological and neuroimaging studies have implicated the left inferior parietal cortex in calculation. Comparatively less attention has been paid to the neural responses associated with the commission of calculation errors and how the processing of arithmetic errors is modulated by individual differences in mathematical…

  10. An Evaluation of the Response Modulation Hypothesis in Relation to Attention-Deficit/ Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Farmer, Richard F.; Rucklidge, Julia J.

    2006-01-01

    Several hypotheses related to Newman's (e.g., Patterson & Newman, 1993) response modulation hypothesis were examined among adolescents with attention-deficit/hyperactivity disorder (ADHD; n = 18) and normal controls (n = 23). Consistent with predictions, youth with ADHD committed more passive avoidance errors (PAEs) than controls during the latter…

  11. Baseline and Modulated Acoustic Startle Responses in Adolescent Girls with Posttraumatic Stress Disorder

    ERIC Educational Resources Information Center

    Lipschitz, Deborah S.; Mayes, Linda M.; Rasmusson, Ann M.; Anyan, Walter; Billingslea, Eileen; Gueorguieva, Ralitza; Southwick, Steven M.

    2005-01-01

    Objective: To assess baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder (PTSD). Method: Twenty-eight adolescent girls with PTSD and 23 healthy control girls were recruited for participation in the study. Acoustic stimuli were bursts of white noise of 104 dB presented biaurally through…

  12. An NCME Instructional Module on Item-Fit Statistics for Item Response Theory Models

    ERIC Educational Resources Information Center

    Ames, Allison J.; Penfield, Randall D.

    2015-01-01

    Drawing valid inferences from item response theory (IRT) models is contingent upon a good fit of the data to the model. Violations of model-data fit have numerous consequences, limiting the usefulness and applicability of the model. This instructional module provides an overview of methods used for evaluating the fit of IRT models. Upon completing…

  13. Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

    PubMed

    Mayhew, S D; Mullinger, K J; Ostwald, D; Porcaro, C; Bowtell, R; Bagshaw, A P; Francis, S T

    2016-06-01

    In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of

  14. Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

    PubMed

    Mayhew, S D; Mullinger, K J; Ostwald, D; Porcaro, C; Bowtell, R; Bagshaw, A P; Francis, S T

    2016-06-01

    In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of

  15. A surface ice module for wind turbine dynamic response simulation using FAST

    DOE PAGES

    Yu, Bingbin; Karr, Dale G.; Song, Huimin; Sirnivas, Senu

    2016-06-03

    It is a fact that developing offshore wind energy has become more and more serious worldwide in recent years. Many of the promising offshore wind farm locations are in cold regions that may have ice cover during wintertime. The challenge of possible ice loads on offshore wind turbines raises the demand of modeling capacity of dynamic wind turbine response under the joint action of ice, wind, wave, and current. The simulation software FAST is an open source computer-aided engineering (CAE) package maintained by the National Renewable Energy Laboratory. In this paper, a new module of FAST for assessing the dynamicmore » response of offshore wind turbines subjected to ice forcing is presented. In the ice module, several models are presented which involve both prescribed forcing and coupled response. For conditions in which the ice forcing is essentially decoupled from the structural response, ice forces are established from existing models for brittle and ductile ice failure. For conditions in which the ice failure and the structural response are coupled, such as lock-in conditions, a rate-dependent ice model is described, which is developed in conjunction with a new modularization framework for FAST. In this paper, analytical ice mechanics models are presented that incorporate ice floe forcing, deformation, and failure. For lower speeds, forces slowly build until the ice strength is reached and ice fails resulting in a quasi-static condition. For intermediate speeds, the ice failure can be coupled with the structural response and resulting in coinciding periods of the ice failure and the structural response. A third regime occurs at high speeds of encounter in which brittle fracturing of the ice feature occurs in a random pattern, which results in a random vibration excitation of the structure. An example wind turbine response is simulated under ice loading of each of the presented models. This module adds to FAST the capabilities for analyzing the response of wind

  16. Response of Rhesus Macaques (Macaca mulatta) to the Body of a Group Member That Died from a Fatal Attack

    PubMed Central

    Buhl, Jacqueline S.; Aure, Bonn; Ruiz-Lambides, Angelina; Gonzalez-Martinez, Janis; Platt, Michael L.; Brent, Lauren J. N.

    2013-01-01

    Among animals that form social bonds, the death of a conspecific may be a significant social event, representing the loss of an ally and resulting in disruptions to the dominance hierarchy. Despite this potential biological importance, we have only limited knowledge of animals' reactions to the death of a group member. This is particularly true of responses to dead adults, as most reports describe the responses of mothers to dead infants. Here, we describe in detail and provide video evidence of the behavioral responses of a group of free-ranging rhesus macaques (Macaca mulatta) immediately after the death of a mid-ranking adult male as a result of a fatal attack. High-ranking male members of the group, suspected to have carried out the attack, dragged and bit the dead body, exhibiting a rate of aggression 20 times greater than baseline levels. Lower-ranking individuals approached and inspected the body by looking closely, smelling, and grooming the fur. There was inconclusive evidence that these rhesus macaques found the death of a conspecific stressful: Levels of grooming between group members after the fatal attack were significantly higher than baseline levels, and higher than levels of grooming after nonfatal attacks. However, when grooming levels were adjusted based on the assumption that individuals positioned close to the body, i.e., those visible to researchers, were more likely to be engaged in grooming than those positioned farther away, this difference from baseline was no longer significant. The rate of self-directed behaviors after the fatal attack was also not different from baseline. Many of the behaviors we observed directed toward the body (aggression, inspection) have been previously reported in chimpanzees and geladas, and are similar to reactions sometimes displayed by humans. As such, this report represents a potentially valuable contribution the nascent field of nonhuman primate thanatology. PMID:23459587

  17. Response of Rhesus Macaques (Macaca mulatta) to the Body of a Group Member That Died from a Fatal Attack.

    PubMed

    Buhl, Jacqueline S; Aure, Bonn; Ruiz-Lambides, Angelina; Gonzalez-Martinez, Janis; Platt, Michael L; Brent, Lauren J N

    2012-08-01

    Among animals that form social bonds, the death of a conspecific may be a significant social event, representing the loss of an ally and resulting in disruptions to the dominance hierarchy. Despite this potential biological importance, we have only limited knowledge of animals' reactions to the death of a group member. This is particularly true of responses to dead adults, as most reports describe the responses of mothers to dead infants. Here, we describe in detail and provide video evidence of the behavioral responses of a group of free-ranging rhesus macaques (Macaca mulatta) immediately after the death of a mid-ranking adult male as a result of a fatal attack. High-ranking male members of the group, suspected to have carried out the attack, dragged and bit the dead body, exhibiting a rate of aggression 20 times greater than baseline levels. Lower-ranking individuals approached and inspected the body by looking closely, smelling, and grooming the fur. There was inconclusive evidence that these rhesus macaques found the death of a conspecific stressful: Levels of grooming between group members after the fatal attack were significantly higher than baseline levels, and higher than levels of grooming after nonfatal attacks. However, when grooming levels were adjusted based on the assumption that individuals positioned close to the body, i.e., those visible to researchers, were more likely to be engaged in grooming than those positioned farther away, this difference from baseline was no longer significant. The rate of self-directed behaviors after the fatal attack was also not different from baseline. Many of the behaviors we observed directed toward the body (aggression, inspection) have been previously reported in chimpanzees and geladas, and are similar to reactions sometimes displayed by humans. As such, this report represents a potentially valuable contribution the nascent field of nonhuman primate thanatology. PMID:23459587

  18. Response of Rhesus Macaques (Macaca mulatta) to the Body of a Group Member That Died from a Fatal Attack.

    PubMed

    Buhl, Jacqueline S; Aure, Bonn; Ruiz-Lambides, Angelina; Gonzalez-Martinez, Janis; Platt, Michael L; Brent, Lauren J N

    2012-08-01

    Among animals that form social bonds, the death of a conspecific may be a significant social event, representing the loss of an ally and resulting in disruptions to the dominance hierarchy. Despite this potential biological importance, we have only limited knowledge of animals' reactions to the death of a group member. This is particularly true of responses to dead adults, as most reports describe the responses of mothers to dead infants. Here, we describe in detail and provide video evidence of the behavioral responses of a group of free-ranging rhesus macaques (Macaca mulatta) immediately after the death of a mid-ranking adult male as a result of a fatal attack. High-ranking male members of the group, suspected to have carried out the attack, dragged and bit the dead body, exhibiting a rate of aggression 20 times greater than baseline levels. Lower-ranking individuals approached and inspected the body by looking closely, smelling, and grooming the fur. There was inconclusive evidence that these rhesus macaques found the death of a conspecific stressful: Levels of grooming between group members after the fatal attack were significantly higher than baseline levels, and higher than levels of grooming after nonfatal attacks. However, when grooming levels were adjusted based on the assumption that individuals positioned close to the body, i.e., those visible to researchers, were more likely to be engaged in grooming than those positioned farther away, this difference from baseline was no longer significant. The rate of self-directed behaviors after the fatal attack was also not different from baseline. Many of the behaviors we observed directed toward the body (aggression, inspection) have been previously reported in chimpanzees and geladas, and are similar to reactions sometimes displayed by humans. As such, this report represents a potentially valuable contribution the nascent field of nonhuman primate thanatology.

  19. Are teachers of children and young adolescents responsive to suicide prevention training modules? Yes.

    PubMed

    Davidson, M W; Range, L M

    1999-01-01

    Both before and after a 1-hour suicide prevention training module, 75 elementary teachers-in-training read a 4-sentence vignette about a suicidal student ("Pat"), then completed 8 questions about their responses. Compared with pretraining, at post-training these teachers were more likely to say that they would send or escort Pat to the counselor's office, use written or verbal no-suicide agreements, call Pat's parents, believe Pat to be serious rather than simply seeking attention, and feel comfortable handling a similar situation. Increased proactive attitudes after one hour of training imply that teachers would benefit from periodic suicide awareness and prevention training modules.

  20. Response to dynamical modulation of the optical lattice for fermions in the Hubbard model

    SciTech Connect

    Xu Zhaoxin; Yang Shuxiang; Sheehy, Daniel E.; Moreno, Juana; Jarrell, Mark; Chiesa, Simone; Su Shiquan; Scalettar, Richard T.

    2011-08-15

    Fermionic atoms in a periodic optical lattice provide a realization of the single-band Hubbard model. Using quantum Monte Carlo simulations along with the maximum-entropy method, we evaluate the effect of a time-dependent perturbative modulation of the optical lattice amplitude on atomic correlations, revealed in the fraction of doubly occupied sites. We find that the effect of modulation depends strongly on the filling--the response of the double occupation is significantly different in the half-filled Mott insulator from that in the doped Fermi liquid region.

  1. Size matters: plasticity in metabolic scaling shows body-size may modulate responses to climate change.

    PubMed

    Carey, Nicholas; Sigwart, Julia D

    2014-08-01

    Variability in metabolic scaling in animals, the relationship between metabolic rate ( R: ) and body mass ( M: ), has been a source of debate and controversy for decades. R: is proportional to MB: , the precise value of B: much debated, but historically considered equal in all organisms. Recent metabolic theory, however, predicts B: to vary among species with ecology and metabolic level, and may also vary within species under different abiotic conditions. Under climate change, most species will experience increased temperatures, and marine organisms will experience the additional stressor of decreased seawater pH ('ocean acidification'). Responses to these environmental changes are modulated by myriad species-specific factors. Body-size is a fundamental biological parameter, but its modulating role is relatively unexplored. Here, we show that changes to metabolic scaling reveal asymmetric responses to stressors across body-size ranges; B: is systematically decreased under increasing temperature in three grazing molluscs, indicating smaller individuals were more responsive to warming. Larger individuals were, however, more responsive to reduced seawater pH in low temperatures. These alterations to the allometry of metabolism highlight abiotic control of metabolic scaling, and indicate that responses to climate warming and ocean acidification may be modulated by body-size.

  2. Size matters: plasticity in metabolic scaling shows body-size may modulate responses to climate change

    PubMed Central

    Carey, Nicholas; Sigwart, Julia D.

    2014-01-01

    Variability in metabolic scaling in animals, the relationship between metabolic rate (R) and body mass (M), has been a source of debate and controversy for decades. R is proportional to Mb, the precise value of b much debated, but historically considered equal in all organisms. Recent metabolic theory, however, predicts b to vary among species with ecology and metabolic level, and may also vary within species under different abiotic conditions. Under climate change, most species will experience increased temperatures, and marine organisms will experience the additional stressor of decreased seawater pH (‘ocean acidification’). Responses to these environmental changes are modulated by myriad species-specific factors. Body-size is a fundamental biological parameter, but its modulating role is relatively unexplored. Here, we show that changes to metabolic scaling reveal asymmetric responses to stressors across body-size ranges; b is systematically decreased under increasing temperature in three grazing molluscs, indicating smaller individuals were more responsive to warming. Larger individuals were, however, more responsive to reduced seawater pH in low temperatures. These alterations to the allometry of metabolism highlight abiotic control of metabolic scaling, and indicate that responses to climate warming and ocean acidification may be modulated by body-size. PMID:25122741

  3. Size matters: plasticity in metabolic scaling shows body-size may modulate responses to climate change.

    PubMed

    Carey, Nicholas; Sigwart, Julia D

    2014-08-01

    Variability in metabolic scaling in animals, the relationship between metabolic rate ( R: ) and body mass ( M: ), has been a source of debate and controversy for decades. R: is proportional to MB: , the precise value of B: much debated, but historically considered equal in all organisms. Recent metabolic theory, however, predicts B: to vary among species with ecology and metabolic level, and may also vary within species under different abiotic conditions. Under climate change, most species will experience increased temperatures, and marine organisms will experience the additional stressor of decreased seawater pH ('ocean acidification'). Responses to these environmental changes are modulated by myriad species-specific factors. Body-size is a fundamental biological parameter, but its modulating role is relatively unexplored. Here, we show that changes to metabolic scaling reveal asymmetric responses to stressors across body-size ranges; B: is systematically decreased under increasing temperature in three grazing molluscs, indicating smaller individuals were more responsive to warming. Larger individuals were, however, more responsive to reduced seawater pH in low temperatures. These alterations to the allometry of metabolism highlight abiotic control of metabolic scaling, and indicate that responses to climate warming and ocean acidification may be modulated by body-size. PMID:25122741

  4. Ingroup favoritism or the black sheep effect: Perceived intentions modulate subjective responses to aggressive interactions.

    PubMed

    Wang, Lei; Zheng, Jiehui; Meng, Liang; Lu, Qiang; Ma, Qingguo

    2016-07-01

    Social categorization plays an important role in provoking the victim's responses to aggressive interactions. Pioneering studies suggested that uncertainty in the perpetrator's hostile intention influences whether ingroup favoritism or the black sheep effect (ingroup strictness) will be manifested to a greater extent. However, when the hostile intention is ambiguous, subjective perception of the perpetrator's intention may still be quite different due to the inherent information gap between participants, and this discrepancy in perceived intentions may further modulate subjective responses to social aggression. In the present study, subjects played as responders of the Ultimatum Game, and received varied offers proposed by either ingroup or outgroup members. Electrophysiological results showed that, when proposers were perceived to be intentional, unfair offers from ingroups elicited significantly larger Feedback-related Negativity (FRN) than those from outgroups, potentially providing neural evidence for the black sheep effect. The opposite FRN pattern was observed when proposers were perceived to be unintentional, which might suggest ingroup favoritism. Interestingly, despite contrary neural patterns, perceived intentions did not modulate behavioral response to aggressive interactions. Thus, converging results suggested that, when the perpetrator's hostile intention remained ambiguous, perceived intentions modulated the victim's electrophysiological response while not the rational behavioral response to aggressive interactions. PMID:26851770

  5. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

    PubMed Central

    Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

    2015-01-01

    The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

  6. Local modulation of human brain responses by circadian rhythmicity and sleep debt.

    PubMed

    Muto, Vincenzo; Jaspar, Mathieu; Meyer, Christelle; Kussé, Caroline; Chellappa, Sarah L; Degueldre, Christian; Balteau, Evelyne; Shaffii-Le Bourdiec, Anahita; Luxen, André; Middleton, Benita; Archer, Simon N; Phillips, Christophe; Collette, Fabienne; Vandewalle, Gilles; Dijk, Derk-Jan; Maquet, Pierre

    2016-08-12

    Human performance is modulated by circadian rhythmicity and homeostatic sleep pressure. Whether and how this interaction is represented at the regional brain level has not been established. We quantified changes in brain responses to a sustained-attention task during 13 functional magnetic resonance imaging sessions scheduled across the circadian cycle, during 42 hours of wakefulness and after recovery sleep, in 33 healthy participants. Cortical responses showed significant circadian rhythmicity, the phase of which varied across brain regions. Cortical responses also significantly decreased with accrued sleep debt. Subcortical areas exhibited primarily a circadian modulation that closely followed the melatonin profile. These findings expand our understanding of the mechanisms involved in maintaining cognition during the day and its deterioration during sleep deprivation and circadian misalignment. PMID:27516598

  7. Modulation of Efector Caspase Cleavage Determines Response of Breast and Lung Tumor Cell Lines to Chemotherapy

    PubMed Central

    Odonkor, Charles Amoatey; Achilefu, Samuel

    2010-01-01

    In spite of compelling evidence implicating caspases in drug-induced apoptosis, how tumors modulate caspase expression and activity to overcome the cytotoxicity of anticancer agents is not fully understood. To address this issue, we investigated the role of caspases-3 and 7 in determining the response of breast and lung tumor cell lines to chemotherapy. We found that an early and late apoptotic response correlated with weak and strong cellular caspase-activation, respectively. The results highlight an underappreciated relationship of temporal apoptotic response with caspase-activation and drug-resistance. Moreover, the extent of tumor growth restoration after drug withdrawal was dependent on the degree of endogenous blockage of caspase-3 and caspase-7 cleavages. This points to an unrecognized role of caspase modulation in tumor recurrence and suggests that targeting caspase cleavage is a rational approach to increasing potency of cancer drugs. PMID:19241192

  8. Differential modulation of auditory responses to attended and unattended speech in different listening conditions

    PubMed Central

    Kong, Ying-Yee; Mullangi, Ala; Ding, Nai

    2014-01-01

    This study investigates how top-down attention modulates neural tracking of the speech envelope in different listening conditions. In the quiet conditions, a single speech stream was presented and the subjects paid attention to the speech stream (active listening) or watched a silent movie instead (passive listening). In the competing speaker (CS) conditions, two speakers of opposite genders were presented diotically. Ongoing electroencephalographic (EEG) responses were measured in each condition and cross-correlated with the speech envelope of each speaker at different time lags. In quiet, active and passive listening resulted in similar neural responses to the speech envelope. In the CS conditions, however, the shape of the cross-correlation function was remarkably different between the attended and unattended speech. The cross-correlation with the attended speech showed stronger N1 and P2 responses but a weaker P1 response compared with the cross-correlation with the unattended speech. Furthermore, the N1 response to the attended speech in the CS condition was enhanced and delayed compared with the active listening condition in quiet, while the P2 response to the unattended speaker in the CS condition was attenuated compared with the passive listening in quiet. Taken together, these results demonstrate that top-down attention differentially modulates envelope-tracking neural activity at different time lags and suggest that top-down attention can both enhance the neural responses to the attended sound stream and suppress the responses to the unattended sound stream. PMID:25124153

  9. Computational identification of genetic subnetwork modules associated with maize defense response to Fusarium verticillioides

    PubMed Central

    2015-01-01

    Background Maize, a crop of global significance, is vulnerable to a variety of biotic stresses resulting in economic losses. Fusarium verticillioides (teleomorph Gibberella moniliformis) is one of the key fungal pathogens of maize, causing ear rots and stalk rots. To better understand the genetic mechanisms involved in maize defense as well as F. verticillioides virulence, a systematic investigation of the host-pathogen interaction is needed. The aim of this study was to computationally identify potential maize subnetwork modules associated with its defense response against F. verticillioides. Results We obtained time-course RNA-seq data from B73 maize inoculated with wild type F. verticillioides and a loss-of-virulence mutant, and subsequently established a computational pipeline for network-based comparative analysis. Specifically, we first analyzed the RNA-seq data by a cointegration-correlation-expression approach, where maize genes were jointly analyzed with known F. verticillioides virulence genes to find candidate maize genes likely associated with the defense mechanism. We predicted maize co-expression networks around the selected maize candidate genes based on partial correlation, and subsequently searched for subnetwork modules that were differentially activated when inoculated with two different fungal strains. Based on our analysis pipeline, we identified four potential maize defense subnetwork modules. Two were directly associated with maize defense response and were associated with significant GO terms such as GO:0009817 (defense response to fungus) and GO:0009620 (response to fungus). The other two predicted modules were indirectly involved in the defense response, where the most significant GO terms associated with these modules were GO:0046914 (transition metal ion binding) and GO:0046686 (response to cadmium ion). Conclusion Through our RNA-seq data analysis, we have shown that a network-based approach can enhance our understanding of the

  10. A Computational Model of Inferior Colliculus Responses to Amplitude Modulated Sounds in Young and Aged Rats

    PubMed Central

    Rabang, Cal F.; Parthasarathy, Aravindakshan; Venkataraman, Yamini; Fisher, Zachery L.; Gardner, Stephanie M.; Bartlett, Edward L.

    2012-01-01

    The inferior colliculus (IC) receives ascending excitatory and inhibitory inputs from multiple sources, but how these auditory inputs converge to generate IC spike patterns is poorly understood. Simulating patterns of in vivo spike train data from cellular and synaptic models creates a powerful framework to identify factors that contribute to changes in IC responses, such as those resulting in age-related loss of temporal processing. A conductance-based single neuron IC model was constructed, and its responses were compared to those observed during in vivo IC recordings in rats. IC spike patterns were evoked using amplitude-modulated tone or noise carriers at 20–40 dB above threshold and were classified as low-pass, band-pass, band-reject, all-pass, or complex based on their rate modulation transfer function tuning shape. Their temporal modulation transfer functions were also measured. These spike patterns provided experimental measures of rate, vector strength, and firing pattern for comparison with model outputs. Patterns of excitatory and inhibitory synaptic convergence to IC neurons were based on anatomical studies and generalized input tuning for modulation frequency. Responses of modeled ascending inputs were derived from experimental data from previous studies. Adapting and sustained IC intrinsic models were created, with adaptation created via calcium-activated potassium currents. Short-term synaptic plasticity was incorporated into the model in the form of synaptic depression, which was shown to have a substantial effect on the magnitude and time course of the IC response. The most commonly observed IC response sub-types were recreated and enabled dissociation of inherited response properties from those that were generated in IC. Furthermore, the model was used to make predictions about the consequences of reduction in inhibition for age-related loss of temporal processing due to a reduction in GABA seen anatomically with age. PMID:23129994

  11. The urge-to-cough and cough motor response modulation by the central effects of nicotine

    PubMed Central

    Davenport, Paul W.; Vovk, Andrea; Duke, Rita K.; Bolser, Donald C.; Robertson, Erin

    2011-01-01

    The urge-to-cough is a respiratory sensation that precedes the cough motor response. Since affective state modulates the perception of respiratory sensations such as dyspnoea, we wanted to test whether nicotine, an anxiolytic, would modulate the urge-to-cough and hence, the cough motor response. We hypothesized that withdrawal from and administration of nicotine in smoking subjects would modulate their anxiety levels, urge-to-cough and cough motor response to capsaicin stimulation. Twenty smoking (SM) adults (8F, 12M; 22 ± 3 years; 2.9 ± 2.0 pack years) and matched non-smoking (NS) controls (22 ± 2 years) were presented with randomized concentrations of capsaicin (0–200 µM) before and after nicotine (SM only) gum and/or placebo (SM and NS) gum. Subjects rated their urge-to-cough using a Borg scale at the end of each capsaicin presentation. Cough number and cough motor pattern were determined from airflow tracings. Subjects completed State-Trait Anxiety Inventory (STAI) questionnaires before and after gum administration. SM subjects that withdrew from cigarette smoking for 12 h exhibited an increase in anxiety scores, a greater number of coughs and higher urge-to-cough ratings compared to NS subjects. Administration of nicotine gum reduced anxiety scores, cough number and urge-to-cough ratings to match the NS subjects. There was no effect of placebo gum on any of the measured parameters in the SM and NS groups. The results from this study suggest that modulation of the central neural state with nicotine withdrawal and administration in young smoking adults is associated with a change in anxiety levels which in turn modulates the perceptual and motor response to irritant cough stimulants. PMID:19100331

  12. The urge-to-cough and cough motor response modulation by the central effects of nicotine.

    PubMed

    Davenport, Paul W; Vovk, Andrea; Duke, Rita K; Bolser, Donald C; Robertson, Erin

    2009-04-01

    The urge-to-cough is a respiratory sensation that precedes the cough motor response. Since affective state modulates the perception of respiratory sensations such as dyspnoea, we wanted to test whether nicotine, an anxiolytic, would modulate the urge-to-cough and hence, the cough motor response. We hypothesized that withdrawal from and administration of nicotine in smoking subjects would modulate their anxiety levels, urge-to-cough and cough motor response to capsaicin stimulation. Twenty smoking (SM) adults (8F, 12M; 22+/-3 years; 2.9+/-2.0 pack years) and matched non-smoking (NS) controls (22+/-2 years) were presented with randomized concentrations of capsaicin (0-200 microM) before and after nicotine (SM only) gum and/or placebo (SM and NS) gum. Subjects rated their urge-to-cough using a Borg scale at the end of each capsaicin presentation. Cough number and cough motor pattern were determined from airflow tracings. Subjects completed State-Trait Anxiety Inventory (STAI) questionnaires before and after gum administration. SM subjects that withdrew from cigarette smoking for 12 h exhibited an increase in anxiety scores, a greater number of coughs and higher urge-to-cough ratings compared to NS subjects. Administration of nicotine gum reduced anxiety scores, cough number and urge-to-cough ratings to match the NS subjects. There was no effect of placebo gum on any of the measured parameters in the SM and NS groups. The results from this study suggest that modulation of the central neural state with nicotine withdrawal and administration in young smoking adults is associated with a change in anxiety levels which in turn modulates the perceptual and motor response to irritant cough stimulants. PMID:19100331

  13. A class of reduced-complexity Viterbi detectors for partial response continuous phase modulation

    NASA Astrophysics Data System (ADS)

    Svensson, A.; Sundberg, C.-E.; Aulin, T.

    1984-10-01

    Partial response continuous phase modulation (CPM) gives constant envelope digital modulation schemes with excellent power spectra. Both narrow main lobe and low spectral tails can be achieved. When these signals are detected in an optimum coherent maximum likelihood sequence detector (Viterbi detector), power efficient schemes can also be designed, sometimes at the expense of receiver complexity. This paper describes a general class of simple Viterbi detectors with reduced complexity compared to the optimum case. The key idea is that the approximate receiver is based on a less complex CPM scheme than the transmitted scheme. The asymptotically optimum reduced-complexity receiver is found for a variety of transmitted schemes and various complexity reduction factors, for a specific class of receivers and modulation indexes. A new distance measure is introduced for the performance analysis. Smooth schemes based on raised cosine pulses are analyzed and simulated for the case of simplified reception. A graceful performance degradation occurs with the reduction of complexity.

  14. Specificity of the Human Frequency Following Response for Carrier and Modulation Frequency Assessed Using Adaptation.

    PubMed

    Gockel, Hedwig E; Krugliak, Alexandra; Plack, Christopher J; Carlyon, Robert P

    2015-12-01

    The frequency following response (FFR) is a scalp-recorded measure of phase-locked brainstem activity to stimulus-related periodicities. Three experiments investigated the specificity of the FFR for carrier and modulation frequency using adaptation. FFR waveforms evoked by alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. The first experiment investigated peristimulus adaptation of the FFR for pure and complex tones as a function of stimulus frequency and fundamental frequency (F0). It showed more adaptation of the FFR in response to sounds with higher frequencies or F0s than to sounds with lower frequency or F0s. The second experiment investigated tuning to modulation rate in the FFR. The FFR to a complex tone with a modulation rate of 213 Hz was not reduced more by an adaptor that had the same modulation rate than by an adaptor with a different modulation rate (90 or 504 Hz), thus providing no evidence that the FFR originates mainly from neurons that respond selectively to the modulation rate of the stimulus. The third experiment investigated tuning to audio frequency in the FFR using pure tones. An adaptor that had the same frequency as the target (213 or 504 Hz) did not generally reduce the FFR to the target more than an adaptor that differed in frequency (by 1.24 octaves). Thus, there was no evidence that the FFR originated mainly from neurons tuned to the frequency of the target. Instead, the results are consistent with the suggestion that the FFR for low-frequency pure tones at medium to high levels mainly originates from neurons tuned to higher frequencies. Implications for the use and interpretation of the FFR are discussed. PMID:26162415

  15. Near-infrared Light Responsive Synthetic c-di-GMP Module for Optogenetic Applications

    PubMed Central

    2015-01-01

    Enormous potential of cell-based therapeutics is hindered by the lack of effective means to control genetically engineered cells in mammalian tissues. Here, we describe a synthetic module for remote photocontrol of engineered cells that can be adapted for such applications. The module involves photoactivated synthesis of cyclic dimeric GMP (c-di-GMP), a stable small molecule that is not produced by higher eukaryotes and therefore is suitable for orthogonal regulation. The key component of the photocontrol module is an engineered bacteriophytochrome diguanylate cyclase, which synthesizes c-di-GMP from GTP in a light-dependent manner. Bacteriophytochromes are particularly attractive photoreceptors because they respond to light in the near-infrared window of the spectrum, where absorption by mammalian tissues is minimal, and also because their chromophore, biliverdin IXα, is naturally available in mammalian cells. The second component of the photocontrol module, a c-di-GMP phosphodiesterase, maintains near-zero background levels of c-di-GMP in the absence of light, which enhances the photodynamic range of c-di-GMP concentrations. In the E. coli model used in this study, the intracellular c-di-GMP levels could be upregulated by light by >50-fold. Various c-di-GMP-responsive proteins and riboswitches identified in bacteria can be linked downstream of the c-di-GMP-mediated photocontrol module for orthogonal regulation of biological activities in mammals as well as in other organisms lacking c-di-GMP signaling. Here, we linked the photocontrol module to a gene expression output via a c-di-GMP-responsive transcription factor and achieved a 40-fold photoactivation of gene expression. PMID:24926804

  16. Near-infrared light responsive synthetic c-di-GMP module for optogenetic applications.

    PubMed

    Ryu, Min-Hyung; Gomelsky, Mark

    2014-11-21

    Enormous potential of cell-based therapeutics is hindered by the lack of effective means to control genetically engineered cells in mammalian tissues. Here, we describe a synthetic module for remote photocontrol of engineered cells that can be adapted for such applications. The module involves photoactivated synthesis of cyclic dimeric GMP (c-di-GMP), a stable small molecule that is not produced by higher eukaryotes and therefore is suitable for orthogonal regulation. The key component of the photocontrol module is an engineered bacteriophytochrome diguanylate cyclase, which synthesizes c-di-GMP from GTP in a light-dependent manner. Bacteriophytochromes are particularly attractive photoreceptors because they respond to light in the near-infrared window of the spectrum, where absorption by mammalian tissues is minimal, and also because their chromophore, biliverdin IXα, is naturally available in mammalian cells. The second component of the photocontrol module, a c-di-GMP phosphodiesterase, maintains near-zero background levels of c-di-GMP in the absence of light, which enhances the photodynamic range of c-di-GMP concentrations. In the E. coli model used in this study, the intracellular c-di-GMP levels could be upregulated by light by >50-fold. Various c-di-GMP-responsive proteins and riboswitches identified in bacteria can be linked downstream of the c-di-GMP-mediated photocontrol module for orthogonal regulation of biological activities in mammals as well as in other organisms lacking c-di-GMP signaling. Here, we linked the photocontrol module to a gene expression output via a c-di-GMP-responsive transcription factor and achieved a 40-fold photoactivation of gene expression.

  17. Temporal response of ganglion cells of the macaque retina to cone-specific modulation

    NASA Astrophysics Data System (ADS)

    Yeh, T.; Lee, B. B.; Kremers, J.

    1995-03-01

    The temporal response of cone inputs to macaque retinal ganglion cells were compared with cone-specific sinusoidal modulation used to isolate each cone type. For all cell types of the parvocellular (PC) pathway, temporal responsivity was similar for short (S)-, middle (M)-, and long (L)-wavelength-sensitive cone inputs, apart from small latency differences between inputs to center and surround. The temporal response resembled that expected from receptor physiology. Responses of cells of the magnocellular pathway to M- or L-cone modulation showed more complex properties indicative of postreceptoral processing. Human psychophysical temporal-sensitivity functions were acquired with S-cone modulation under conditions similar to those for the physiological measurements. Ratios of psychophysical to physiological data from S-cone cells (the only cells that respond to this stimulus) yielded an estimate of the central filter acting upon PC-pathway signals. The filter characteristic could be described by a four-stage low-pass filter with corner frequency 3-5 Hz.

  18. Insight in modulation of inflammation in response to diclofenac intervention: a human intervention study

    PubMed Central

    2010-01-01

    Background Chronic systemic low-grade inflammation in obese subjects is associated with health complications including cardiovascular diseases, insulin resistance and diabetes. Reducing inflammatory responses may reduce these risks. However, available markers of inflammatory status inadequately describe the complexity of metabolic responses to mild anti-inflammatory therapy. Methods To address this limitation, we used an integrative omics approach to characterize modulation of inflammation in overweight men during an intervention with the non-steroidal anti-inflammatory drug diclofenac. Measured parameters included 80 plasma proteins, >300 plasma metabolites (lipids, free fatty acids, oxylipids and polar compounds) and an array of peripheral blood mononuclear cells (PBMC) gene expression products. These measures were submitted to multivariate and correlation analysis and were used for construction of biological response networks. Results A panel of genes, proteins and metabolites, including PGE2 and TNF-alpha, were identified that describe a diclofenac-response network (68 genes in PBMC, 1 plasma protein and 4 plasma metabolites). Novel candidate markers of inflammatory modulation included PBMC expression of annexin A1 and caspase 8, and the arachidonic acid metabolite 5,6-DHET. Conclusion In this study the integrated analysis of a wide range of parameters allowed the development of a network of markers responding to inflammatory modulation, thereby providing insight into the complex process of inflammation and ways to assess changes in inflammatory status associated with obesity. Trial registration The study is registered as NCT00221052 in clinicaltrials.gov database. PMID:20178593

  19. Hypoxia response in asthma: differential modulation on inflammation and epithelial injury.

    PubMed

    Ahmad, Tanveer; Kumar, Manish; Mabalirajan, Ulaganathan; Pattnaik, Bijay; Aggarwal, Shilpi; Singh, Ranjana; Singh, Suchita; Mukerji, Mitali; Ghosh, Balaram; Agrawal, Anurag

    2012-07-01

    Oxygen-sensing prolyl-hydroxylase (PHD)-2 negatively regulates hypoxia-inducible factor (HIF)1-α and suppresses the hypoxic response. Hypoxia signaling is thought to be proinflammatory but also attenuates cellular injury and apoptosis. Although increased hypoxic response has been noted in asthma, its functional relevance is unknown. The objectives of this study were to dissect the mechanisms and role of the hypoxic response in asthma pathophysiology. Experimental studies were conducted in mice using acute and chronic allergic models of asthma. The hypoxic response in allergically inflamed lungs was modulated by using pharmacologic PHD inhibitors (ethyl-3-4-dihydroxybenzoic acid [DHB], 1-10 mg/kg) or siRNA-mediated genetic knockdowns. Increased hypoxia response led to exacerbation of the asthma phenotype, with HIF-1α knockdown being beneficial. Chronically inflamed lungs from mice treated with 10 mg/kg DHB showed diffuse up-regulation of the hypoxia response, severe airway remodeling, and inflammation. Fatal asphyxiation during methacholine challenge was noted. However, bronchial epithelium restricted up-regulation of the hypoxia response seen with low-dose DHB (1 mg/kg) reduced epithelial injury and attenuated the asthmatic phenotype. Up-regulation of the hypoxia response was associated with increased expression of CX3CR1, a lymphocyte survival factor, and increased inflammatory cell infiltrate. This study shows that an exaggerated hypoxia response may contribute to airway inflammation, remodeling, and the development of asthma. However, the hypoxia response may also be protective of epithelial apoptosis at lower levels, and the net effects of modulating the hypoxia response may vary based on the context.

  20. When the forest dies: the response of forest soil fungi to a bark beetle-induced tree dieback.

    PubMed

    Stursová, Martina; Snajdr, Jaroslav; Cajthaml, Tomáš; Bárta, Jiří; Santrůčková, Hana; Baldrian, Petr

    2014-09-01

    Coniferous forests cover extensive areas of the boreal and temperate zones. Owing to their primary production and C storage, they have an important role in the global carbon balance. Forest disturbances such as forest fires, windthrows or insect pest outbreaks have a substantial effect on the functioning of these ecosystems. Recent decades have seen an increase in the areas affected by disturbances in both North America and Europe, with indications that this increase is due to both local human activity and global climate change. Here we examine the structural and functional response of the litter and soil microbial community in a Picea abies forest to tree dieback following an invasion of the bark beetle Ips typographus, with a specific focus on the fungal community. The insect-induced disturbance rapidly and profoundly changed vegetation and nutrient availability by killing spruce trees so that the readily available root exudates were replaced by more recalcitrant, polymeric plant biomass components. Owing to the dramatic decrease in photosynthesis, the rate of decomposition processes in the ecosystem decreased as soon as the one-time litter input had been processed. The fungal community showed profound changes, including a decrease in biomass (2.5-fold in the litter and 12-fold in the soil) together with the disappearance of fungi symbiotic with tree roots and a relative increase in saprotrophic taxa. Within the latter group, successive changes reflected the changing availability of needle litter and woody debris. Bacterial biomass appeared to be either unaffected or increased after the disturbance, resulting in a substantial increase in the bacterial/fungal biomass ratio. PMID:24671082

  1. When the forest dies: the response of forest soil fungi to a bark beetle-induced tree dieback

    PubMed Central

    Štursová, Martina; Šnajdr, Jaroslav; Cajthaml, Tomáš; Bárta, Jiří; Šantrůčková, Hana; Baldrian, Petr

    2014-01-01

    Coniferous forests cover extensive areas of the boreal and temperate zones. Owing to their primary production and C storage, they have an important role in the global carbon balance. Forest disturbances such as forest fires, windthrows or insect pest outbreaks have a substantial effect on the functioning of these ecosystems. Recent decades have seen an increase in the areas affected by disturbances in both North America and Europe, with indications that this increase is due to both local human activity and global climate change. Here we examine the structural and functional response of the litter and soil microbial community in a Picea abies forest to tree dieback following an invasion of the bark beetle Ips typographus, with a specific focus on the fungal community. The insect-induced disturbance rapidly and profoundly changed vegetation and nutrient availability by killing spruce trees so that the readily available root exudates were replaced by more recalcitrant, polymeric plant biomass components. Owing to the dramatic decrease in photosynthesis, the rate of decomposition processes in the ecosystem decreased as soon as the one-time litter input had been processed. The fungal community showed profound changes, including a decrease in biomass (2.5-fold in the litter and 12-fold in the soil) together with the disappearance of fungi symbiotic with tree roots and a relative increase in saprotrophic taxa. Within the latter group, successive changes reflected the changing availability of needle litter and woody debris. Bacterial biomass appeared to be either unaffected or increased after the disturbance, resulting in a substantial increase in the bacterial/fungal biomass ratio. PMID:24671082

  2. Perceptual demand modulates activation of human auditory cortex in response to task-irrelevant sounds.

    PubMed

    Sabri, Merav; Humphries, Colin; Verber, Matthew; Mangalathu, Jain; Desai, Anjali; Binder, Jeffrey R; Liebenthal, Einat

    2013-09-01

    In the visual modality, perceptual demand on a goal-directed task has been shown to modulate the extent to which irrelevant information can be disregarded at a sensory-perceptual stage of processing. In the auditory modality, the effect of perceptual demand on neural representations of task-irrelevant sounds is unclear. We compared simultaneous ERPs and fMRI responses associated with task-irrelevant sounds across parametrically modulated perceptual task demands in a dichotic-listening paradigm. Participants performed a signal detection task in one ear (Attend ear) while ignoring task-irrelevant syllable sounds in the other ear (Ignore ear). Results revealed modulation of syllable processing by auditory perceptual demand in an ROI in middle left superior temporal gyrus and in negative ERP activity 130-230 msec post stimulus onset. Increasing the perceptual demand in the Attend ear was associated with a reduced neural response in both fMRI and ERP to task-irrelevant sounds. These findings are in support of a selection model whereby ongoing perceptual demands modulate task-irrelevant sound processing in auditory cortex.

  3. A phenomenological model of peripheral and central neural responses to amplitude-modulated tones

    NASA Astrophysics Data System (ADS)

    Nelson, Paul C.; Carney, Laurel H.

    2004-10-01

    A phenomenological model with time-varying excitation and inhibition was developed to study possible neural mechanisms underlying changes in the representation of temporal envelopes along the auditory pathway. A modified version of an existing auditory-nerve model [Zhang et al., J. Acoust. Soc. Am. 109, 648-670 (2001)] was used to provide inputs to higher hypothetical processing centers. Model responses were compared directly to published physiological data at three levels: the auditory nerve, ventral cochlear nucleus, and inferior colliculus. Trends and absolute values of both average firing rate and synchrony to the modulation period were accurately predicted at each level for a wide range of stimulus modulation depths and modulation frequencies. The diversity of central physiological responses was accounted for with realistic variations of model parameters. Specifically, enhanced synchrony in the cochlear nucleus and rate-tuning to modulation frequency in the inferior colliculus were predicted by choosing appropriate relative strengths and time courses of excitatory and inhibitory inputs to postsynaptic model cells. The proposed model is fundamentally different than others that have been used to explain the representation of envelopes in the mammalian midbrain, and it provides a computational tool for testing hypothesized relationships between physiology and psychophysics. .

  4. Reproduction and modulation of the stress response: an experimental test in the house sparrow

    PubMed Central

    Lendvai, Ádám Zoltán; Giraudeau, Mathieu; Chastel, Olivier

    2006-01-01

    The stress response is highly variable among individuals, but the causes of this variation remain largely unknown. In response to stressors, vertebrates secrete elevated levels of glucocorticoids which enhance survival, but concurrently interfere with reproduction. We tested the hypothesis that individuals flexibly modulate their stress response with respect to the reproductive value of their brood in free-living house sparrows (Passer domesticus). We experimentally increased or decreased clutch size during the nestling period and found that parents tending enlarged clutches responded less strongly to a stressor than those tending reduced clutches. In addition, we examined whether individuals responded less strongly to a stressor as the breeding season progressed and future reproductive opportunities declined. We found that the stress response decreased with breeding date during the birds' first breeding attempt, but it remained constant during their second breeding attempt. Within-individual variability in the stress response was related to the brood size manipulations the birds received in their two consecutive breeding attempts. These results provide the first experimental support for the hypothesis that individuals actively modulate their stress response with respect to the value of current reproduction. PMID:17164203

  5. Nitric Oxide Modulates the Temporal Properties of the Glutamate Response in Type 4 OFF Bipolar Cells

    PubMed Central

    Vielma, Alex H.; Agurto, Adolfo; Valdés, Joaquín; Palacios, Adrián G.; Schmachtenberg, Oliver

    2014-01-01

    Nitric oxide (NO) is involved in retinal signal processing, but its cellular actions are only partly understood. An established source of retinal NO are NOACs, a group of nNOS-expressing amacrine cells which signal onto bipolar, other amacrine and ganglion cells in the inner plexiform layer. Here, we report that NO regulates glutamate responses in morphologically and electrophysiologically identified type 4 OFF cone bipolar cells through activation of the soluble guanylyl cyclase-cGMP-PKG pathway. The glutamate response of these cells consists of two components, a fast phasic current sensitive to kainate receptor agonists, and a secondary component with slow kinetics, inhibited by AMPA receptor antagonists. NO shortened the duration of the AMPA receptor-dependent component of the glutamate response, while the kainate receptor-dependent component remained unchanged. Application of 8-Br-cGMP mimicked this effect, while inhibition of soluble guanylate cyclase or protein kinase G prevented it, supporting a mechanism involving a cGMP signaling pathway. Notably, perfusion with a NOS-inhibitor prolonged the duration of the glutamate response, while the NO precursor L-arginine shortened it, in agreement with a modulation by endogenous NO. Furthermore, NO accelerated the response recovery during repeated stimulation of type 4 cone bipolar cells, suggesting that the temporal response properties of this OFF bipolar cell type are regulated by NO. These results reveal a novel cellular mechanism of NO signaling in the retina, and represent the first functional evidence of NO modulating OFF cone bipolar cells. PMID:25463389

  6. Insulin signaling genes modulate nicotine-induced behavioral responses in Caenorhabditis elegans.

    PubMed

    Wescott, Seth A; Ronan, Elizabeth A; Xu, X Z Shawn

    2016-02-01

    Insulin signaling has been suggested to modulate nicotine dependence, but the underlying genetic evidence has been lacking. Here, we used the nematode, Caenorhabditis elegans, to investigate whether genetic alterations in the insulin signaling pathway affect behavioral responses to nicotine. For this, we challenged drug-naive C. elegans with an acute dose of nicotine (100 μmol/l) while recording changes in their locomotion speed. Although nicotine treatment stimulated locomotion speed in wild-type C. elegans, the same treatment reduced locomotion speed in mutants defective in insulin signaling. This phenotype could be suppressed by mutations in daf-16, a gene encoding a FOXO transcription factor that acts downstream of insulin signaling. Our data suggest that insulin signaling genes, daf-2, age-1, pdk-1, akt-1, and akt-2, modulate behavioral responses to nicotine in C. elegans, indicating a genetic link between nicotine behavior and insulin signaling.

  7. Displaced capillary dies

    DOEpatents

    Kalejs, Juris P.; Chalmers, Bruce; Surek, Thomas

    1984-01-01

    An asymmetrical shaped capillary die made exclusively of graphite is used to grow silicon ribbon which is capable of being made into solar cells that are more efficient than cells produced from ribbon made using a symmetrically shaped die.

  8. Displaced capillary dies

    DOEpatents

    Kalejs, Juris P.; Chalmers, Bruce; Surek, Thomas

    1982-01-01

    An asymmetrical shaped capillary die made exclusively of graphite is used to grow silicon ribbon which is capable of being made into solar cells that are more efficient than cells produced from ribbon made using a symmetrically shaped die.

  9. Packaged die heater

    SciTech Connect

    Spielberger, Richard; Ohme, Bruce Walker; Jensen, Ronald J.

    2011-06-21

    A heater for heating packaged die for burn-in and heat testing is described. The heater may be a ceramic-type heater with a metal filament. The heater may be incorporated into the integrated circuit package as an additional ceramic layer of the package, or may be an external heater placed in contact with the package to heat the die. Many different types of integrated circuit packages may be accommodated. The method provides increased energy efficiency for heating the die while reducing temperature stresses on testing equipment. The method allows the use of multiple heaters to heat die to different temperatures. Faulty die may be heated to weaken die attach material to facilitate removal of the die. The heater filament or a separate temperature thermistor located in the package may be used to accurately measure die temperature.

  10. Modulation of Immune Response by Organophosphorus Pesticides: Fishes as a Potential Model in Immunotoxicology

    PubMed Central

    Díaz-Resendiz, K. J. G.; Toledo-Ibarra, G. A.; Girón-Pérez, M. I.

    2015-01-01

    Immune response is modulated by different substances that are present in the environment. Nevertheless, some of these may cause an immunotoxic effect. In this paper, the effect of organophosphorus pesticides (frequent substances spilled in aquatic ecosystems) on the immune system of fishes and in immunotoxicology is reviewed. Furthermore, some cellular and molecular mechanisms that might be involved in immunoregulation mechanisms of organophosphorus pesticides are discussed. PMID:25973431

  11. Perturbation-evoked responses in primary motor cortex are modulated by behavioral context.

    PubMed

    Omrani, Mohsen; Pruszynski, J Andrew; Murnaghan, Chantelle D; Scott, Stephen H

    2014-12-01

    Corrective responses to external perturbations are sensitive to the behavioral task being performed. It is believed that primary motor cortex (M1) forms part of a transcortical pathway that contributes to this sensitivity. Previous work has identified two distinct phases in the perturbation response of M1 neurons, an initial response starting ∼20 ms after perturbation onset that does not depend on the intended motor action and a task-dependent response that begins ∼40 ms after perturbation onset. However, this invariant initial response may reflect ongoing postural control or a task-independent response to the perturbation. The present study tested these two possibilities by examining if being engaged in an ongoing postural task before perturbation onset modulated the initial perturbation response in M1. Specifically, mechanical perturbations were applied to the shoulder and/or elbow while the monkey maintained its hand at a central target or when it was watching a movie and not required to respond to the perturbation. As expected, corrective movements, muscle stretch responses, and M1 population activity in the late perturbation epoch were all significantly diminished in the movie task. Strikingly, initial perturbation responses (<40 ms postperturbation) remained the same across tasks, suggesting that the initial phase of M1 activity constitutes a task-independent response that is sensitive to the properties of the mechanical perturbation but not the goal of the ongoing motor task.

  12. Materials approaches for modulating neural tissue responses to implanted microelectrodes through mechanical and biochemical means

    PubMed Central

    Sommakia, Salah; Lee, Heui C.; Gaire, Janak; Otto, Kevin J.

    2014-01-01

    Implantable intracortical microelectrodes face an uphill struggle for widespread clinical use. Their potential for treating a wide range of traumatic and degenerative neural disease is hampered by their unreliability in chronic settings. A major factor in this decline in chronic performance is a reactive response of brain tissue, which aims to isolate the implanted device from the rest of the healthy tissue. In this review we present a discussion of materials approaches aimed at modulating the reactive tissue response through mechanical and biochemical means. Benefits and challenges associated with these approaches are analyzed, and the importance of multimodal solutions tested in emerging animal models are presented. PMID:25530703

  13. Regulating the ethylene response of a plant by modulation of F-box proteins

    DOEpatents

    Guo, Hongwei; Ecker, Joseph R.

    2011-03-08

    The invention relates to transgenic plants having reduced sensitivity to ethylene as a result of having a recombinant nucleic acid encoding an F-box protein that interacts with a EIN3 involved in an ethylene response of plants, and a method of producing a transgenic plant with reduced ethylene sensitivity by transforming the plant with a nucleic acid sequence encoding an F-box protein. The inventions also relates to methods of altering the ethylene response in a plant by modulating the activity or expression of an F-box protein.

  14. Care of the Dying Adolescent

    PubMed Central

    MacDonald, Faye

    1979-01-01

    This is a description of the obstacles encountered in the management of one 17 year old patient dying with malignant melanoma. Various areas are seen to contribute to the difficulties including the “health care system” (specifically the hospital environment), the patient himself, his family, his disease and its treatment, and his physician(s). An increased awareness of the difficulties would be helpful to those of us not frequently encountering the responsibility of caring for a dying adolescent. The details have been left vague or slightly changed in this real case to respect the privacy of those involved. PMID:21297759

  15. Modulation of Auditory Responses to Speech vs. Nonspeech Stimuli during Speech Movement Planning

    PubMed Central

    Daliri, Ayoub; Max, Ludo

    2016-01-01

    Previously, we showed that the N100 amplitude in long latency auditory evoked potentials (LLAEPs) elicited by pure tone probe stimuli is modulated when the stimuli are delivered during speech movement planning as compared with no-speaking control conditions. Given that we probed the auditory system only with pure tones, it remained unknown whether the nature and magnitude of this pre-speech auditory modulation depends on the type of auditory stimulus. Thus, here, we asked whether the effect of speech movement planning on auditory processing varies depending on the type of auditory stimulus. In an experiment with nine adult subjects, we recorded LLAEPs that were elicited by either pure tones or speech syllables when these stimuli were presented prior to speech onset in a delayed-response speaking condition vs. a silent reading control condition. Results showed no statistically significant difference in pre-speech modulation of the N100 amplitude (early stages of auditory processing) for the speech stimuli as compared with the nonspeech stimuli. However, the amplitude of the P200 component (later stages of auditory processing) showed a statistically significant pre-speech modulation that was specific to the speech stimuli only. Hence, the overall results from this study indicate that, immediately prior to speech onset, modulation of the auditory system has a general effect on early processing stages but a speech-specific effect on later processing stages. This finding is consistent with the hypothesis that pre-speech auditory modulation may play a role in priming the auditory system for its role in monitoring auditory feedback during speech production. PMID:27242494

  16. Controlled release strategies for modulating immune responses to promote tissue regeneration.

    PubMed

    Dumont, Courtney M; Park, Jonghyuck; Shea, Lonnie D

    2015-12-10

    Advances in the field of tissue engineering have enhanced the potential of regenerative medicine, yet the efficacy of these strategies remains incomplete, and is limited by the innate and adaptive immune responses. The immune response associated with injury or disease combined with that mounted to biomaterials, transplanted cells, proteins, and gene therapies vectors can contribute to the inability to fully restore tissue function. Blocking immune responses such as with anti-inflammatory or immunosuppressive agents are either ineffective, as the immune response contributes significantly to regeneration, or have significant side effects. This review describes targeted strategies to modulate the immune response in order to limit tissue damage following injury, promote an anti-inflammatory environment that leads to regeneration, and induce antigen (Ag)-specific tolerance that can target degenerative diseases that destroy tissues and promote engraftment of transplanted cells. Focusing on targeted immuno-modulation, we describe local delivery techniques to sites of inflammation as well as systemic approaches that preferentially target subsets of immune populations.

  17. OZONE DIFFERENTIALLY MODULATES AIRWAY RESPONSIVENESS IN ATOPIC VERSUS NONATOPIC GUINEA PIGS

    PubMed Central

    Schlesinger, Richard B.; Cohen, Mitchell D.; Gordon, Terry; Nadziejko, Christine; Zelikoff, Judith T.; Sisco, Maureen; Regal, Jean F.; Ménache, Margaret G.

    2010-01-01

    While acute exposures to ozone (O3) can alter airway responsiveness, effects from long-term exposures at low concentrations are less clear. This study assessed whether such exposures could induce nonspecific hyperresponsiveness in nonatopic (nonsensitized) guinea pigs and/ or could exacerbate the pre-existing hyperresponsive state in atopic ( sensitized) animals, and whether gender was a factor modulating any effect of O3. Responsiveness was measured during and following exposures to 0.1 and 0.3 ppm O3 for 4 h/day, 4 days/ wk for 24 wk in male and female nonsensitized animals, those sensitized to allergen (ovalbumin) prior to initiation of O3 exposures, and those sensitized concurrently with exposures. Ozone did not produce hyperresponsiveness in nonsensitized animals, but did exacerbate hyperresponsiveness to both specific and nonspecific bronchoprovocation challenges in sensitized animals, an effect that persisted through at least 4 wk after exposures ended. Gender was not a factor modulating response to O3. Induced effects on responsiveness were not associated with numbers of eosinophils in the lungs nor with any chronic pulmonary inflammatory response, but were correlated with antigen-specific antibodies in blood. This study supports a role for chronic O3 exposure in the exacerbation of airways dysfunction in a certain segment of the general population, namely, those demonstrating atopy. PMID:12028802

  18. Modulation of Immune Responses by Exosomes Derived from Antigen-Presenting Cells

    PubMed Central

    Shenoda, Botros B.; Ajit, Seena K.

    2016-01-01

    Exosome-mediated signaling is important in mediating the inflammatory response. To exert their biological or pathophysiological functions in the recipient cells, exosomes deliver a diverse array of biomacromolecules including long and short coding and non-coding RNAs, proteins, and lipids. Exosomes secreted by antigen-presenting cells can confer therapeutic benefits by attenuating or stimulating the immune response. Exosomes play a crucial role in carrying and presenting functional major histocompatibility peptide complexes to modulate antigen-specific T cell responses. Exosomes from Dendritic Cells (DCs) can activate T and B cells and have been explored for their immunostimulatory properties in cancer therapy. The immunosuppressive properties of exosomes derived from macrophages and DCs can reduce inflammation in animal models for several inflammatory disorders. This review focuses on the protective role of exosomes in attenuating inflammation or augmenting immune response, emphasizing studies on exosomes derived from DCs and macrophages.

  19. Modulation of Immune Responses by Exosomes Derived from Antigen-Presenting Cells

    PubMed Central

    Shenoda, Botros B.; Ajit, Seena K.

    2016-01-01

    Exosome-mediated signaling is important in mediating the inflammatory response. To exert their biological or pathophysiological functions in the recipient cells, exosomes deliver a diverse array of biomacromolecules including long and short coding and non-coding RNAs, proteins, and lipids. Exosomes secreted by antigen-presenting cells can confer therapeutic benefits by attenuating or stimulating the immune response. Exosomes play a crucial role in carrying and presenting functional major histocompatibility peptide complexes to modulate antigen-specific T cell responses. Exosomes from Dendritic Cells (DCs) can activate T and B cells and have been explored for their immunostimulatory properties in cancer therapy. The immunosuppressive properties of exosomes derived from macrophages and DCs can reduce inflammation in animal models for several inflammatory disorders. This review focuses on the protective role of exosomes in attenuating inflammation or augmenting immune response, emphasizing studies on exosomes derived from DCs and macrophages. PMID:27660518

  20. Modulation of Immune Responses by Exosomes Derived from Antigen-Presenting Cells.

    PubMed

    Shenoda, Botros B; Ajit, Seena K

    2016-01-01

    Exosome-mediated signaling is important in mediating the inflammatory response. To exert their biological or pathophysiological functions in the recipient cells, exosomes deliver a diverse array of biomacromolecules including long and short coding and non-coding RNAs, proteins, and lipids. Exosomes secreted by antigen-presenting cells can confer therapeutic benefits by attenuating or stimulating the immune response. Exosomes play a crucial role in carrying and presenting functional major histocompatibility peptide complexes to modulate antigen-specific T cell responses. Exosomes from Dendritic Cells (DCs) can activate T and B cells and have been explored for their immunostimulatory properties in cancer therapy. The immunosuppressive properties of exosomes derived from macrophages and DCs can reduce inflammation in animal models for several inflammatory disorders. This review focuses on the protective role of exosomes in attenuating inflammation or augmenting immune response, emphasizing studies on exosomes derived from DCs and macrophages. PMID:27660518

  1. Conservation of Modules but not Phenotype in Bacterial Response to Environmental Stress

    SciTech Connect

    Timberlake, Sonia; Joachimiak, Marcin; Joyner, Dominique; Chakraborty, Romy; Baumohl, Jason; Dehal, Paramvir; Arkin, Adam; Hazen, Terry; Alm, Eric

    2010-05-17

    Microbes live in changing environments and change their phenotype via gene regulation in response. Although this transcriptional response is important for fitness, very little is known about how it evolves in microbes. We started by asking a number of high-level questions about the evolution of transcriptional phenotype: (1) To what extent is transcriptional response conserved, i.e. do conserved genes respond similarly to the same condition; (2) To what extent are transcriptional modules conserved; and (3) Does there exist a general stress response to a variety of stressors? To illuminate these questions, we analyzed more than 500 microarray experiments across the bacterial domain. We looked for conservation of transcriptional regulation both in close sister species and vastly divergent clades. In addition, we produced and analyzed an extensive in-house compendium of environmental stress data in three metal-reducing bacteria.

  2. Fast-response IR spatial light modulators with a polymer network liquid crystal

    NASA Astrophysics Data System (ADS)

    Peng, Fenglin; Chen, Haiwei; Tripathi, Suvagata; Twieg, Robert J.; Wu, Shin-Tson

    2015-03-01

    Liquid crystals (LC) have widespread applications for amplitude modulation (e.g. flat panel displays) and phase modulation (e.g. beam steering). For phase modulation, a 2π phase modulo is required. To extend the electro-optic application into infrared region (MWIR and LWIR), several key technical challenges have to be overcome: 1. low absorption loss, 2. high birefringence, 3. low operation voltage, and 4. fast response time. After three decades of extensive development, an increasing number of IR devices adopting LC technology have been demonstrated, such as liquid crystal waveguide, laser beam steering at 1.55μm and 10.6 μm, spatial light modulator in the MWIR (3~5μm) band, dynamic scene projectors for infrared seekers in the LWIR (8~12μm) band. However, several fundamental molecular vibration bands and overtones exist in the MWIR and LWIR regions, which contribute to high absorption coefficient and hinder its widespread application. Therefore, the inherent absorption loss becomes a major concern for IR devices. To suppress IR absorption, several approaches have been investigated: 1) Employing thin cell gap by choosing a high birefringence liquid crystal mixture; 2) Shifting the absorption bands outside the spectral region of interest by deuteration, fluorination and chlorination; 3) Reducing the overlap vibration bands by using shorter alkyl chain compounds. In this paper, we report some chlorinated LC compounds and mixtures with a low absorption loss in the near infrared and MWIR regions. To achieve fast response time, we have demonstrated a polymer network liquid crystal with 2π phase change at MWIR and response time less than 5 ms.

  3. B1-kinin receptors modulate Mesobuthus tamulus venom-induced vasosensory reflex responses in anesthetized rats

    PubMed Central

    Singh, Sanjeev K.; Deshpande, Shripad B.

    2016-01-01

    Objective: Intra-arterial injection of Mesobuthus tamulus (BT) venom produces reflex vasosensory responses modulating cardiorespiratory parameters in albino rats. The present study was conducted to understand the role of kinin receptors in modulating vasosensory reflexes evoked by BT venom. Materials and Methods: In urethane-anesthetized rats, tracheostomy was performed to keep the airway patent. The femoral artery was cannulated proximally, as well as distally, to record the blood pressure (BP) and to inject the chemicals, respectively. Electrocardiographic and respiratory excursions were recorded to compute the heart rate (HR) and respiratory rate (RR). A group of animals was pretreated with saline/kinin receptor antagonists intra-arterially (B1/B2 receptor antagonists) before the injection of venom. Results: After intra-arterial injection of BT venom (1 mg/kg), there was an immediate increase in RR, which reached to 40% within 30 s, followed by a decrease of 40%. Further, there was sustained increase in RR (50%) up to 60 min. The BP started to increase at 40 s, peaking at 5 min (50%), and remained above the initial level up to 60 min. The bradycardiac response started after 5 min which peaked (50% of initial) at 25 min and remained at that level up to 60 min. In B1 receptor antagonist (des-Arg) pretreated animals, venom-induced cardiovascular responses were attenuated (by 20–25% in mean arterial pressure and HR) significantly but not in B2 receptor antagonist (Hoe-140) pretreated animals. Either of the antagonists failed to alter the RR responses. Conclusions: BT venom-induced vasosensory reflex responses modulating cardiovascular parameters are mediated via B1-kinin receptors in anesthetized rats. PMID:27756949

  4. Quantifying attentional modulation of auditory-evoked cortical responses from single-trial electroencephalography

    PubMed Central

    Choi, Inyong; Rajaram, Siddharth; Varghese, Lenny A.; Shinn-Cunningham, Barbara G.

    2013-01-01

    Selective auditory attention is essential for human listeners to be able to communicate in multi-source environments. Selective attention is known to modulate the neural representation of the auditory scene, boosting the representation of a target sound relative to the background, but the strength of this modulation, and the mechanisms contributing to it, are not well understood. Here, listeners performed a behavioral experiment demanding sustained, focused spatial auditory attention while we measured cortical responses using electroencephalography (EEG). We presented three concurrent melodic streams; listeners were asked to attend and analyze the melodic contour of one of the streams, randomly selected from trial to trial. In a control task, listeners heard the same sound mixtures, but performed the contour judgment task on a series of visual arrows, ignoring all auditory streams. We found that the cortical responses could be fit as weighted sum of event-related potentials evoked by the stimulus onsets in the competing streams. The weighting to a given stream was roughly 10 dB higher when it was attended compared to when another auditory stream was attended; during the visual task, the auditory gains were intermediate. We then used a template-matching classification scheme to classify single-trial EEG results. We found that in all subjects, we could determine which stream the subject was attending significantly better than by chance. By directly quantifying the effect of selective attention on auditory cortical responses, these results reveal that focused auditory attention both suppresses the response to an unattended stream and enhances the response to an attended stream. The single-trial classification results add to the growing body of literature suggesting that auditory attentional modulation is sufficiently robust that it could be used as a control mechanism in brain–computer interfaces (BCIs). PMID:23576968

  5. Serotonin modulates the effects of Pavlovian aversive predictions on response vigor.

    PubMed

    Crockett, Molly J; Clark, Luke; Apergis-Schoute, Annemieke M; Morein-Zamir, Sharon; Robbins, Trevor W

    2012-09-01

    Updated theoretical accounts of the role of serotonin (5-HT) in motivation propose that 5-HT operates at the intersection of aversion and inhibition, promoting withdrawal in the face of aversive predictions. However, the specific cognitive mechanisms through which 5-HT modulates withdrawal behavior remain poorly understood. Behavioral inhibition in response to punishments reflects at least two concurrent processes: instrumental aversive predictions linking stimuli, responses, and punishments, and Pavlovian aversive predictions linking stimuli and punishments irrespective of response. In the current study, we examined to what extent 5-HT modulates the impact of instrumental vs Pavlovian aversive predictions on behavioral inhibition. We used acute tryptophan depletion to lower central 5-HT levels in healthy volunteers, and observed behavior in a novel task designed to measure the influence of Pavlovian and instrumental aversive predictions on choice (response bias) and response vigor (response latencies). After placebo treatment, participants were biased against responding on the button that led to punishment, and they were slower to respond in a punished context, relative to a non-punished context. Specifically, participants slowed their responses in the presence of stimuli predictive of punishments. Tryptophan depletion removed the bias against responding on the punished button, and abolished slowing in the presence of punished stimuli, irrespective of response. We suggest that this set of results can be explained by a role for 5-HT in Pavlovian aversive predictions. These findings suggest additional specificity for the influence of 5-HT on aversively motivated behavioral inhibition and extend recent models of the role of 5-HT in aversive predictions. PMID:22643930

  6. HIGH PRESSURE DIES

    DOEpatents

    Wilson, W.B.

    1960-05-31

    A press was invented for subjecting specimens of bismuth, urania, yttria, or thoria to high pressures and temperatures. The press comprises die parts enclosing a space in which is placed an electric heater thermally insulated from the die parts so as not to damage them by heat. The die parts comprise two opposed inner frustoconical parts and an outer part having a double frustoconical recess receiving the inner parts. The die space decreases in size as the inner die parts move toward one another against the outer part and the inner parts, though very hard, do not fracture because of the mode of support provided by the outer part.

  7. [Harmony in dying].

    PubMed

    Meyer, H

    1990-02-13

    Dying and death have scarcely before our time preoccupied so many. Some even seem to thrive from thanatology. Do we physicians however consecrate patience and time to the dying of our next or our patients? Did we learn in medical school or with our patients to assist a dying person? Did we search for answers to death and dying by asking philosophers, physicians or musicians? Can we follow their reasoning in profit for our patients or for ourselves? Harmony in death can possibly be found in a harmonious life in our splendid and humane profession. Modest personal experience enriched by reflections tries imperfectly to bring harmony as hope to our dying.

  8. Goal-dependent modulation of the long-latency stretch response at the shoulder, elbow, and wrist.

    PubMed

    Weiler, Jeffrey; Gribble, Paul L; Pruszynski, J Andrew

    2015-12-01

    Many studies have demonstrated that muscle activity 50-100 ms after a mechanical perturbation (i.e., the long-latency stretch response) can be modulated in a manner that reflects voluntary motor control. These previous studies typically assessed modulation of the long-latency stretch response from individual muscles rather than how this response is concurrently modulated across multiple muscles. Here we investigated such concurrent modulation by having participants execute goal-directed reaches to visual targets after mechanical perturbations of the shoulder, elbow, or wrist while measuring activity from six muscles that articulate these joints. We found that shoulder, elbow, and wrist muscles displayed goal-dependent modulation of the long-latency stretch response, that the relative magnitude of participants' goal-dependent activity was similar across muscles, that the temporal onset of goal-dependent muscle activity was not reliably different across the three joints, and that shoulder muscles displayed goal-dependent activity appropriate for counteracting intersegmental dynamics. We also observed that the long-latency stretch response of wrist muscles displayed goal-dependent modulation after elbow perturbations and that the long-latency stretch response of elbow muscles displayed goal-dependent modulation after wrist perturbations. This pattern likely arises because motion at either joint could bring the hand to the visual target and suggests that the nervous system rapidly exploits such simple kinematic redundancy when processing sensory feedback to support goal-directed actions.

  9. The magnitude of the stomatal response to blue light : modulation by atmospheric humidity.

    PubMed

    Assmann, S M; Grantz, D A

    1990-06-01

    The effect of leaf-air vapor pressure difference (VPD) on the magnitude of the stomatal response to blue light was investigated in soybean (Glycine max) by administering blue light pulses (22 seconds by 120 micromoles per square meter per second) at different levels of VPD and temperature. At 20 degrees C and 25 degrees C, the magnitude of the integrated conductance response decreased with increasing VPD (0.4 to 2.6 kiloPascals), due to an earlier onset of stomatal closure that terminated the pulse response. In contrast, at 30 degrees C this magnitude increased with rising VPD (0.9 to 3.5 kiloPascals), due to an increasing maximum excursion of the conductance response despite the accelerated onset of stomatal closure. When the feedforward response of stomata to humidity caused steady state transpiration to decrease with increasing VPD, the magnitude of the pulse-induced conductance response correlated with VPD rather than with transpiration. This suggests that water relations or metabolite movements within epidermal rather than bulk leaf tissue interacted with guard cell photobiological properties in regulating the magnitude of the blue light response. VPD modulation of pulse magnitude could reduce water loss during stomatal responses to transient illumination in natural light environments. PMID:16667526

  10. Trait Mindfulness Modulates Neuroendocrine and Affective Responses to Social Evaluative Threat

    PubMed Central

    Brown, Kirk Warren; Weinstein, Netta; Creswell, J. David

    2016-01-01

    Background Individual differences in mindfulness have been associated with numerous self-report indicators of stress, but research has not examined how mindfulness may buffer neuroendocrine and psychological stress responses under controlled laboratory conditions. The present study investigated the role of trait mindfulness in buffering cortisol and affective responses to a social evaluative stress challenge versus a control task. Methods Participants completed measures of trait mindfulness, perceived stress, anxiety, and fear of negative evaluation before being randomized to complete the Trier Social Stress Test (TSST; Kirschbaum et al., 1993) or a control task. At points throughout the session, participants provided five saliva samples to assess cortisol response patterns, and completed four self-report measures of anxiety and negative affect to assess psychological responses. Results In accord with hypotheses, higher trait mindfulness predicted lower cortisol responses to the TSST, relative to the control task, as well as lower anxiety and negative affect. These relations remained significant when controlling for the role of other variables that predicted cortisol and affective responses. Conclusions The findings suggest that trait mindfulness modulates cortisol and affective responses to an acute social stressor. Further research is needed to understand the neural pathways through which mindfulness impacts these responses. PMID:22626868

  11. 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.

  12. N2pc is modulated by stimulus-stimulus, but not by stimulus-response incompatibilities.

    PubMed

    Cespón, J; Galdo-Álvarez, S; Díaz, F

    2013-04-01

    Studies of the N2pc in Simon-type tasks have revealed inconsistent results. That is, N2pc was only modulated when a stimulus-stimulus (S-S) overlap covaries with the stimulus-response (S-R) overlap. The present study aimed to establish whether N2pc is modulated by the S-R or by the S-S overlap. Therefore, we designed a Simon task requiring response to a colour stimulus (an arrow) with two irrelevant dimensions (position and direction). The following conditions were thus generated: compatible direction-compatible position (CDCP); incompatible direction-compatible position (IDCP); compatible direction-incompatible position (CDIP); and incompatible direction-incompatible position (IDIP). In IDCP and CDIP, both irrelevant dimensions conveyed contradictory spatial information (S-S incompatibility), while compatibility between both irrelevant dimensions occurred in CDCP and IDIP (the direction indicated was compatible with stimulus position). The N2pc amplitude was smaller in IDCP and CDIP than in CDCP and IDIP, what suggests that N2pc was modulated by S-S incompatibility and not by S-R incompatibilities. PMID:23380335

  13. Responsive nanoporous metals: recoverable modulations on strength and shape by watering.

    PubMed

    Ye, Xing-Long; Liu, Ling-Zhi; Jin, Hai-Jun

    2016-08-12

    Many biological materials can readily modulate their mechanical properties and shape by interacting with water in the surrounding environment, which is essential to their high performance in application. In contrast, typical inorganic materials (such as the metals) cannot change their strength and shape without involving thermal/mechanical treatments. By introducing nano-scale porous structure and exploiting a simple physical concept-the water-capillarity in nanopores, here we report that a 'dead' metal can be transformed into a 'smart' material with water-responsive properties. We demonstrate that the apparent strength, volume and shape of nanoporous Au and Au(Pt) can be modulated in situ, dramatically and recoverably, in response to water-dipping and partial-drying. The amplitude of strength-modulation reaches 20 MPa, which is nearly 50% of the yield strength at initial state. This approach also leads to reversible length change up to 1.3% in nanoporous Au and a large reversible bending motion of a bi-layer strip with tip displacement of ∼20 mm, which may be used for actuation. This method is simple and effective, occurring in situ under ambient conditions and requiring no external power, analogous to biological materials. The findings may open up novel applications in many areas such as micro-robotics and bio-medical devices. PMID:27347850

  14. Responsive nanoporous metals: recoverable modulations on strength and shape by watering

    NASA Astrophysics Data System (ADS)

    Ye, Xing-Long; Liu, Ling-Zhi; Jin, Hai-Jun

    2016-08-01

    Many biological materials can readily modulate their mechanical properties and shape by interacting with water in the surrounding environment, which is essential to their high performance in application. In contrast, typical inorganic materials (such as the metals) cannot change their strength and shape without involving thermal/mechanical treatments. By introducing nano-scale porous structure and exploiting a simple physical concept—the water-capillarity in nanopores, here we report that a ‘dead’ metal can be transformed into a ‘smart’ material with water-responsive properties. We demonstrate that the apparent strength, volume and shape of nanoporous Au and Au(Pt) can be modulated in situ, dramatically and recoverably, in response to water-dipping and partial-drying. The amplitude of strength-modulation reaches 20 MPa, which is nearly 50% of the yield strength at initial state. This approach also leads to reversible length change up to 1.3% in nanoporous Au and a large reversible bending motion of a bi-layer strip with tip displacement of ∼20 mm, which may be used for actuation. This method is simple and effective, occurring in situ under ambient conditions and requiring no external power, analogous to biological materials. The findings may open up novel applications in many areas such as micro-robotics and bio-medical devices.

  15. Empathic neural responses are modulated by the perceived fairness of others.

    PubMed

    Singer, Tania; Seymour, Ben; O'Doherty, John P; Stephan, Klaas E; Dolan, Raymond J; Frith, Chris D

    2006-01-26

    The neural processes underlying empathy are a subject of intense interest within the social neurosciences. However, very little is known about how brain empathic responses are modulated by the affective link between individuals. We show here that empathic responses are modulated by learned preferences, a result consistent with economic models of social preferences. We engaged male and female volunteers in an economic game, in which two confederates played fairly or unfairly, and then measured brain activity with functional magnetic resonance imaging while these same volunteers observed the confederates receiving pain. Both sexes exhibited empathy-related activation in pain-related brain areas (fronto-insular and anterior cingulate cortices) towards fair players. However, these empathy-related responses were significantly reduced in males when observing an unfair person receiving pain. This effect was accompanied by increased activation in reward-related areas, correlated with an expressed desire for revenge. We conclude that in men (at least) empathic responses are shaped by valuation of other people's social behaviour, such that they empathize with fair opponents while favouring the physical punishment of unfair opponents, a finding that echoes recent evidence for altruistic punishment.

  16. IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism.

    PubMed

    Merlo, Lauren M F; DuHadaway, James B; Grabler, Samantha; Prendergast, George C; Muller, Alexander J; Mandik-Nayak, Laura

    2016-06-01

    Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer, and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self-antigens; however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity. In experiments with IDO2-deficient mice, adoptive transplant experiments demonstrated that IDO2 expression in B cells was both necessary and sufficient to support robust arthritis development. IDO2 function in B cells was contingent on a cognate, Ag-specific interaction to exert its immunomodulatory effects on arthritis development. We confirmed a similar requirement in an established model of contact hypersensitivity, in which IDO2-expressing B cells are required for a robust inflammatory response. Mechanistic investigations showed that IDO2-deficient B cells lacked the ability to upregulate the costimulatory marker CD40, suggesting IDO2 acts at the T-B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Overall, our findings revealed that IDO2 expression by B cells modulates autoimmune responses by supporting the cross talk between autoreactive T and B cells.

  17. Empathic neural responses are modulated by the perceived fairness of others.

    PubMed

    Singer, Tania; Seymour, Ben; O'Doherty, John P; Stephan, Klaas E; Dolan, Raymond J; Frith, Chris D

    2006-01-26

    The neural processes underlying empathy are a subject of intense interest within the social neurosciences. However, very little is known about how brain empathic responses are modulated by the affective link between individuals. We show here that empathic responses are modulated by learned preferences, a result consistent with economic models of social preferences. We engaged male and female volunteers in an economic game, in which two confederates played fairly or unfairly, and then measured brain activity with functional magnetic resonance imaging while these same volunteers observed the confederates receiving pain. Both sexes exhibited empathy-related activation in pain-related brain areas (fronto-insular and anterior cingulate cortices) towards fair players. However, these empathy-related responses were significantly reduced in males when observing an unfair person receiving pain. This effect was accompanied by increased activation in reward-related areas, correlated with an expressed desire for revenge. We conclude that in men (at least) empathic responses are shaped by valuation of other people's social behaviour, such that they empathize with fair opponents while favouring the physical punishment of unfair opponents, a finding that echoes recent evidence for altruistic punishment. PMID:16421576

  18. Modulated ferromagnetic ordering and the magnetocaloric response of Eu{sub 4}PdMg

    SciTech Connect

    Ryan, D. H. Legros, Anaëlle; Niehaus, Oliver; Pöttgen, Rainer; Cadogan, J. M.; Flacau, R.

    2015-05-07

    Neutron powder diffraction confirms that the primary ordering mode in Eu{sub 4}PdMg is ferromagnetic with a europium moment of 6.5(2) μ{sub B}. {sup 151}Eu Mössbauer spectroscopy shows that the unusual linear temperature dependence of the magnetisation reported for this system is an intrinsic property and not an artefact of the applied field. The form and temperature evolution of the {sup 151}Eu Mössbauer spectra strongly suggest that there is an incommensurate modulation to the magnetic structure that modifies the basic ferromagnetic order. This modulated structure may be the origin of the broad magnetocaloric response previously observed in Eu{sub 4}PdMg.

  19. Analytical modeling and structural response of a stretched-membrane reflective module

    SciTech Connect

    Murphy, L.M.; Sallis, D.V.

    1984-06-01

    The optical and structural load deformation response behavior of a uniform pressure-loaded stretched-membrane reflective module subject to nonaxisymmetric support constraints is studied in this report. To aid in the understanding of this behavior, an idealized analytical model is developed and implemented and predictions are compared with predictions based on the detailed structural analysis code NASTRAN. Single structural membrane reflector modules are studied in this analysis. In particular, the interaction of the frame-membrane combination and variations in membrane pressure loading and tension are studied in detail. Variations in the resulting lateral shear load on the frame, frame lateral support, and frame twist as a function of distance between the supports are described as are the resulting optical effects. Results indicate the need to consider the coupled deformation problem as the lateral frame deformations are amplified by increasing the membrane tension. The importance of accurately considering the effects of different membrane attachment approaches is also demonstrated.

  20. Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity

    PubMed Central

    Zhang, Rumin; Kavana, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins. PMID:27116909

  1. Tropospheric Response to Modulational Excitation of Dust Acoustic Perturbartions in Earth's Ionosphere

    NASA Astrophysics Data System (ADS)

    Kopnin, S. I.; Popel, S. I.; Yu, M. Y.

    2011-11-01

    It is shown that, during Perseid, Geminid, Orionid, and Leonid meteor showers, the excitation of low-frequency dust acoustic perturbations by modulational instability in the Earth's ionosphere can lead to the generation of infrasonic waves. The processes accompanying the propagation of these waves in Earth's troposphere are considered, and the possibility of observing the waves from the Earth's surface is discussed, as well as the possible onset of acoustic gravitational vortex structures in the region of dust acoustic perturbations. The generation of such structures during Perseid, Geminid, Orionid, and Leonid meteor showers can show up as an increase in the intensity of green nightglow by an amount on the order of 10% and can be attributed to the formation of nonlinear (vortex) structures at altitudes of 110-120 km. Thus the modulational excitation of the dust acoustic perturbations in the ionosphere has tropospherical response: it influences physical processes and observations in Earth's troposphere.

  2. Glucose administration does not modulate prolactin response to exercise, TRH or haloperidol injection.

    PubMed

    Vigas, M; Jezová, D

    1994-01-01

    Glucose was found to exert an In vitro regulatory effect on prolactin secretion. Its role in the modulation of stimulated secretion of prolactin in man is, however, not clear. To evaluate the effect of hyperglycaemia on prolactin release, three stimulatory tests with different mechanisms of stimulation were employed. Healthy male subjects served as volunteers during submaximal exercise, TRH test (0.2 mg i.v.) and administration of haloperidol (2 mg i.v.). Glucose (100 g in 400 ml) or an equal volume of water was given 30 min before the tests. Blood for glucose and prolactin analysis was taken via an indwelling catheter. The plasma prolactin concentration increased in response to each of the stimuli applied. However, the prolactin increase during hyperglycaemia did not differ from values obtained in tests performed in normoglycaemia after water administration. These results indicate that prolactin release in healthy man is not modulated by hyperglycaemia. PMID:7711007

  3. Response and fluctuations of a two-state signaling module with feedback

    NASA Astrophysics Data System (ADS)

    Gopalakrishnan, Manoj; Borowski, Peter; Jülicher, Frank; Zapotocky, Martin

    2007-08-01

    We study the stochastic kinetics of a signaling module consisting of a two-state stochastic point process with negative feedback. In the active state, a product is synthesized which increases the active-to-inactive transition rate of the process. We analyze this simple autoregulatory module using a path-integral technique based on the temporal statistics of state flips of the process. We develop a systematic framework to calculate averages, autocorrelations, and response functions by treating the feedback as a weak perturbation. Explicit analytical results are obtained to first order in the feedback strength. Monte Carlo simulations are performed to test the analytical results in the weak feedback limit and to investigate the strong feedback regime. We conclude by relating some of our results to experimental observations in the olfactory and visual sensory systems.

  4. Is Baseline Cardiac Autonomic Modulation Related to Performance and Physiological Responses Following a Supramaximal Judo Test?

    PubMed Central

    Blasco-Lafarga, Cristina; Martínez-Navarro, Ignacio; Mateo-March, Manuel

    2013-01-01

    Little research exists concerning Heart Rate (HR) Variability (HRV) following supramaximal efforts focused on upper-body explosive strength-endurance. Since they may be very demanding, it seems of interest to analyse the relationship among performance, lactate and HR dynamics (i.e. HR, HRV and complexity) following them; as well as to know how baseline cardiac autonomic modulation mediates these relationships. The present study aimed to analyse associations between baseline and post-exercise HR dynamics following a supramaximal Judo test, and their relationship with lactate, in a sample of 22 highly-trained male judoists (20.70±4.56 years). A large association between the increase in HR from resting to exercise condition and performance suggests that individuals exerted a greater sympathetic response to achieve a better performance (Rating of Perceived Exertion: 20; post-exercise peak lactate: 11.57±2.24 mmol/L; 95.76±4.13 % of age-predicted HRmax). Athletes with higher vagal modulation and lower sympathetic modulation at rest achieved both a significant larger ∆HR and a faster post-exercise lactate removal. A enhanced resting parasympathetic modulation might be therefore related to a further usage of autonomic resources and a better immediate metabolic recovery during supramaximal exertions. Furthermore, analyses of variance displayed a persistent increase in α1 and a decrease in lnRMSSD along the 15 min of recovery, which are indicative of a diminished vagal modulation together with a sympathovagal balance leaning to sympathetic domination. Eventually, time-domain indices (lnRMSSD) showed no lactate correlations, while nonlinear indices (α1 and lnSaEn) appeared to be moderate to strongly correlated with it, thus pointing to shared mechanisms between neuroautonomic and metabolic regulation. PMID:24205273

  5. Modulation of cytokine responses in Corynebacterium parvum-primed endotoxemic mice by centrally administered cannabinoid ligands.

    PubMed

    Smith, S R; Terminelli, C; Denhardt, G

    2001-08-01

    The cannabinoid receptor agonists [(-)-11-hydoxy-Delta(8)tetrahydrocannabinol-dimethylheptyl] (HU-210) and [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl[pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthalenyl) methanone] (WIN 55212-2) were previously shown to downregulate inflammatory cytokines (tumor necrosis factor alpha and interleukin-12) and to upregulate antiinflammatory interleukin-10 when administered intraperitoneally (i.p.) to mice before an endotoxin challenge. Cytokine modulation coincided with the onset of behavioral changes that are associated with cannabinoid agonist activated central cannabinoid CB(1) receptors. Both effects were antagonized by [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] (SR141716A) a selective cannabinoid CB(1) receptor antagonist. In the present study, we have investigated further the apparent role of central CB(1) cannabinoid receptors in cytokine modulation by HU-210 and WIN 55212-2. When administered intracerebroventricularly (i.c.v.), the drugs modulated cytokine responses at doses that were threefold to fourfold lower than those found effective by the i.p. route. SR141716A blocked cytokine modulation when coadministered centrally with the agonists, while a selective cannabinoid CB(2) receptor antagonist, (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-choro-3 methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide) (SR144528) had no effect. Surprisingly, SR144528 was found to modulate cytokines itself when injected i.c.v. PMID:11672577

  6. Soluble Mediators in Platelet Concentrates Modulate Dendritic Cell Inflammatory Responses in an Experimental Model of Transfusion.

    PubMed

    Perros, Alexis J; Christensen, Anne-Marie; Flower, Robert L; Dean, Melinda M

    2015-10-01

    The transfusion of platelet concentrates (PCs) is widely used to treat thrombocytopenia and severe trauma. Ex vivo storage of PCs is associated with a storage lesion characterized by partial platelet activation and the release of soluble mediators, such as soluble CD40 ligand (sCD40L), RANTES, and interleukin (IL)-8. An in vitro whole blood culture transfusion model was employed to assess whether mediators present in PC supernatants (PC-SNs) modulated dendritic cell (DC)-specific inflammatory responses (intracellular staining) and the overall inflammatory response (cytometric bead array). Lipopolysaccharide (LPS) was included in parallel cultures to model the impact of PC-SNs on cell responses following toll-like receptor-mediated pathogen recognition. The impact of both the PC dose (10%, 25%) and ex vivo storage period was investigated [day 2 (D2), day 5 (D5), day 7 (D7)]. PC-SNs alone had minimal impact on DC-specific inflammatory responses and the overall inflammatory response. However, in the presence of LPS, exposure to PC-SNs resulted in a significant dose-associated suppression of the production of DC IL-12, IL-6, IL-1α, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein (MIP)-1β and storage-associated suppression of the production of DC IL-10, TNF-α, and IL-8. For the overall inflammatory response, IL-6, TNF-α, MIP-1α, MIP-1β, and inflammatory protein (IP)-10 were significantly suppressed and IL-8, IL-10, and IL-1β significantly increased following exposure to PC-SNs in the presence of LPS. These data suggest that soluble mediators present in PCs significantly suppress DC function and modulate the overall inflammatory response, particularly in the presence of an infectious stimulus. Given the central role of DCs in the initiation and regulation of the immune response, these results suggest that modulation of the DC inflammatory profile is a probable mechanism contributing to transfusion-related complications. PMID:26133961

  7. Response of cardiac autonomic modulation after a single exposure to musical auditory stimulation.

    PubMed

    Ferreira, Lucas L; Vanderlei, Luiz Carlos M; Guida, Heraldo L; de Abreu, Luiz Carlos; Garner, David M; Vanderlei, Franciele M; Ferreira, Celso; Valenti, Vitor E

    2015-01-01

    The acute effects after exposure to different styles of music on cardiac autonomic modulation assessed through heart rate variability (HRV) analysis have not yet been well elucidated. We aimed to investigate the recovery response of cardiac autonomic modulation in women after exposure to musical auditory stimulation of different styles. The study was conducted on 30 healthy women aged between 18 years and 30 years. We did not include subjects having previous experience with musical instruments and those who had an affinity for music styles. The volunteers remained at rest for 10 min and were exposed to classical baroque (64-84 dB) and heavy metal (75-84 dB) music for 10 min, and their HRV was evaluated for 30 min after music cessation. We analyzed the following HRV indices: Standard deviation of normal-to-normal (SDNN) intervals, root mean square of successive differences (RMSSD), percentage of normal-to-normal 50 (pNN50), low frequency (LF), high frequency (HF), and LF/HF ratio. SDNN, LF in absolute units (ms 2 ) and normalized (nu), and LF/HF ratio increased while HF index (nu) decreased after exposure to classical baroque music. Regarding the heavy metal music style, it was observed that there were increases in SDNN, RMSSD, pNN50, and LF (ms 2 ) after the musical stimulation. In conclusion, the recovery response of cardiac autonomic modulation after exposure to auditory stimulation with music featured an increased global activity of both systems for the two musical styles, with a cardiac sympathetic modulation for classical baroque music and a cardiac vagal tone for the heavy metal style.

  8. Response of cardiac autonomic modulation after a single exposure to musical auditory stimulation.

    PubMed

    Ferreira, Lucas L; Vanderlei, Luiz Carlos M; Guida, Heraldo L; de Abreu, Luiz Carlos; Garner, David M; Vanderlei, Franciele M; Ferreira, Celso; Valenti, Vitor E

    2015-01-01

    The acute effects after exposure to different styles of music on cardiac autonomic modulation assessed through heart rate variability (HRV) analysis have not yet been well elucidated. We aimed to investigate the recovery response of cardiac autonomic modulation in women after exposure to musical auditory stimulation of different styles. The study was conducted on 30 healthy women aged between 18 years and 30 years. We did not include subjects having previous experience with musical instruments and those who had an affinity for music styles. The volunteers remained at rest for 10 min and were exposed to classical baroque (64-84 dB) and heavy metal (75-84 dB) music for 10 min, and their HRV was evaluated for 30 min after music cessation. We analyzed the following HRV indices: Standard deviation of normal-to-normal (SDNN) intervals, root mean square of successive differences (RMSSD), percentage of normal-to-normal 50 (pNN50), low frequency (LF), high frequency (HF), and LF/HF ratio. SDNN, LF in absolute units (ms 2 ) and normalized (nu), and LF/HF ratio increased while HF index (nu) decreased after exposure to classical baroque music. Regarding the heavy metal music style, it was observed that there were increases in SDNN, RMSSD, pNN50, and LF (ms 2 ) after the musical stimulation. In conclusion, the recovery response of cardiac autonomic modulation after exposure to auditory stimulation with music featured an increased global activity of both systems for the two musical styles, with a cardiac sympathetic modulation for classical baroque music and a cardiac vagal tone for the heavy metal style. PMID:25774614

  9. Response of cardiac autonomic modulation after a single exposure to musical auditory stimulation

    PubMed Central

    Ferreira, Lucas L.; Vanderlei, Luiz Carlos M.; Guida, Heraldo L.; de Abreu, Luiz Carlos; Garner, David M.; Vanderlei, Franciele M.; Ferreira, Celso; Valenti, Vitor E.

    2015-01-01

    The acute effects after exposure to different styles of music on cardiac autonomic modulation assessed through heart rate variability (HRV) analysis have not yet been well elucidated. We aimed to investigate the recovery response of cardiac autonomic modulation in women after exposure to musical auditory stimulation of different styles. The study was conducted on 30 healthy women aged between 18 years and 30 years. We did not include subjects having previous experience with musical instruments and those who had an affinity for music styles. The volunteers remained at rest for 10 min and were exposed to classical baroque (64-84 dB) and heavy metal (75-84 dB) music for 10 min, and their HRV was evaluated for 30 min after music cessation. We analyzed the following HRV indices: Standard deviation of normal-to-normal (SDNN) intervals, root mean square of successive differences (RMSSD), percentage of normal-to-normal 50 (pNN50), low frequency (LF), high frequency (HF), and LF/HF ratio. SDNN, LF in absolute units (ms2) and normalized (nu), and LF/HF ratio increased while HF index (nu) decreased after exposure to classical baroque music. Regarding the heavy metal music style, it was observed that there were increases in SDNN, RMSSD, pNN50, and LF (ms2) after the musical stimulation. In conclusion, the recovery response of cardiac autonomic modulation after exposure to auditory stimulation with music featured an increased global activity of both systems for the two musical styles, with a cardiac sympathetic modulation for classical baroque music and a cardiac vagal tone for the heavy metal style. PMID:25774614

  10. Oxytocin modulates fMRI responses to facial expression in macaques.

    PubMed

    Liu, Ning; Hadj-Bouziane, Fadila; Jones, Katherine B; Turchi, Janita N; Averbeck, Bruno B; Ungerleider, Leslie G

    2015-06-16

    Increasing evidence has shown that oxytocin (OT), a mammalian hormone, modifies the way social stimuli are perceived and the way they affect behavior. Thus, OT may serve as a treatment for psychiatric disorders, many of which are characterized by dysfunctional social behavior. To explore the neural mechanisms mediating the effects of OT in macaque monkeys, we investigated whether OT would modulate functional magnetic resonance imaging (fMRI) responses in face-responsive regions (faces vs. blank screen) evoked by the perception of various facial expressions (neutral, fearful, aggressive, and appeasing). In the placebo condition, we found significantly increased activation for emotional (mainly fearful and appeasing) faces compared with neutral faces across the face-responsive regions. OT selectively, and differentially, altered fMRI responses to emotional expressions, significantly reducing responses to both fearful and aggressive faces in face-responsive regions while leaving responses to appeasing as well as neutral faces unchanged. We also found that OT administration selectively reduced functional coupling between the amygdala and areas in the occipital and inferior temporal cortex during the viewing of fearful and aggressive faces, but not during the viewing of neutral or appeasing faces. Taken together, our results indicate homologies between monkeys and humans in the neural circuits mediating the effects of OT. Thus, the monkey may be an ideal animal model to explore the development of OT-based pharmacological strategies for treating patients with dysfunctional social behavior. PMID:26015576

  11. Cytokinin modulates proteomic, transcriptomic and growth responses to temperature shocks in Arabidopsis.

    PubMed

    Cerný, Martin; Jedelský, Petr L; Novák, Jan; Schlosser, Andreas; Brzobohatý, Břetislav

    2014-07-01

    As sessile organisms, plants must sense environmental conditions and adjust their growth and development processes accordingly, through adaptive responses regulated by various internal factors, including hormones. A key environmental factor is temperature, but temperature-sensing mechanisms are not fully understood despite intense research. We investigated proteomic responses to temperature shocks (15 min cold or heat treatments) with and without exogenous applications of cytokinin in Arabidopsis. Image and mass spectrometric analysis of the two-dimensionally separated proteins detected 139 differentially regulated spots, in which 148 proteins were identified, most of which have not been previously linked to temperature perception. More than 70% of the temperature-shock response proteins were modulated by cytokinin, mostly in a similar manner as heat shock. Data mining of previous transcriptomic datasets supported extensive interactions between temperature and cytokinin signalling. The biological significance of this finding was tested by assaying an independent growth response of Arabidopsis seedlings to heat stress: hypocotyl elongation. This response was strongly inhibited in mutants with deficiencies in cytokinin signalling or endogenous cytokinin levels. Thus, cytokinins may directly participate in heat signalling in plants. Finally, large proportions of both temperature-shock and cytokinin responsive proteomes co-localize to the chloroplast, which might therefore host a substantial proportion of the temperature response machinery.

  12. HLA class II genes modulate vaccine-induced antibody responses to affect HIV-1 acquisition

    PubMed Central

    Prentice, Heather A.; Tomaras, Georgia D.; Geraghty, Daniel E.; Apps, Richard; Fong, Youyi; Ehrenberg, Philip K.; Rolland, Morgane; Kijak, Gustavo H.; Krebs, Shelly J.; Nelson, Wyatt; DeCamp, Allan; Shen, Xiaoying; Yates, Nicole L.; Zolla-Pazner, Susan; Nitayaphan, Sorachai; Rerks-Ngarm, Supachai; Kaewkungwal, Jaranit; Pitisuttithum, Punnee; Ferrari, Guido; Juliana McElrath, M.; Montefiori, David C.; Bailer, Robert T.; Koup, Richard A.; O’Connell, Robert J.; Robb, Merlin L.; Michael, Nelson L.; Gilbert, Peter B.; Kim, Jerome H.; Thomas, Rasmi

    2016-01-01

    In the RV144 vaccine trial, two antibody responses were found to correlate with HIV-1 acquisition. Because human leukocyte antigen (HLA) class II–restricted CD4+ T cells are involved in antibody production, we tested whether HLA class II genotypes affected HIV-1–specific antibody levels and HIV-1 acquisition in 760 individuals. Indeed, antibody responses correlated with acquisition only in the presence of single host HLA alleles. Envelope (Env)–specific immunoglobulin A (IgA) antibodies were associated with increased risk of acquisition specifically in individuals with DQB1*06. IgG antibody responses to Env amino acid positions 120 to 204 were higher and were associated with decreased risk of acquisition and increased vaccine efficacy only in the presence of DPB1*13. Screening IgG responses to overlapping peptides spanning Env 120–204 and viral sequence analysis of infected individuals defined differences in vaccine response that were associated with the presence of DPB1*13 and could be responsible for the protection observed. Overall, the underlying genetic findings indicate that HLA class II modulated the quantity, quality, and efficacy of antibody responses in the RV144 trial. PMID:26180102

  13. Interactions between Starch, Lipids, and Proteins in Foods: Microstructure Control for Glycemic Response Modulation.

    PubMed

    Parada, Javier; Santos, Jose L

    2016-10-25

    In real food, starch is usually forming part of a matrix with lipids and proteins. However, research on this ternary system and interactions between such food components has been scarce so far. The control of food microstructure is crucial to determine the product properties, including sensorial and nutritionals ones. This paper reviews the microstructural principles of interactions between starch, lipids, and proteins in foods as well as their effect on postprandial glycemic response, considering human intrinsic differences on postprandial glycemic responses. Several lines of research support the hypothesis that foods without rapidly digestible starch will not mandatorily generate the lowest postprandial glycemic response, highlighting that the full understanding of food microstructure, which modulates starch digestion, plays a key role on food design from a nutritional viewpoint.

  14. Predicting invasive species impacts: a community module functional response approach reveals context dependencies.

    PubMed

    Paterson, Rachel A; Dick, Jaimie T A; Pritchard, Daniel W; Ennis, Marilyn; Hatcher, Melanie J; Dunn, Alison M

    2015-03-01

    Predatory functional responses play integral roles in predator-prey dynamics, and their assessment promises greater understanding and prediction of the predatory impacts of invasive species. Other interspecific interactions, however, such as parasitism and higher-order predation, have the potential to modify predator-prey interactions and thus the predictive capability of the comparative functional response approach. We used a four-species community module (higher-order predator; focal native or invasive predators; parasites of focal predators; native prey) to compare the predatory functional responses of native Gammarus duebeni celticus and invasive Gammarus pulex amphipods towards three invertebrate prey species (Asellus aquaticus, Simulium spp., Baetis rhodani), thus, quantifying the context dependencies of parasitism and a higher-order fish predator on these functional responses. Our functional response experiments demonstrated that the invasive amphipod had a higher predatory impact (lower handling time) on two of three prey species, which reflects patterns of impact observed in the field. The community module also revealed that parasitism had context-dependent influences, for one prey species, with the potential to further reduce the predatory impact of the invasive amphipod or increase the predatory impact of the native amphipod in the presence of a higher-order fish predator. Partial consumption of prey was similar for both predators and occurred increasingly in the order A. aquaticus, Simulium spp. and B. rhodani. This was associated with increasing prey densities, but showed no context dependencies with parasitism or higher-order fish predator. This study supports the applicability of comparative functional responses as a tool to predict and assess invasive species impacts incorporating multiple context dependencies.

  15. The contribution of surprise to the prediction based modulation of fMRI responses.

    PubMed

    Amado, Catarina; Hermann, Petra; Kovács, Petra; Grotheer, Mareike; Vidnyánszky, Zoltán; Kovács, Gyula

    2016-04-01

    In recent years, several functional magnetic resonance imaging (fMRI) studies showed that correct stimulus predictions reduce the neural responses when compared to surprising events (Egner et al., 2010). Further, it has been shown that such fulfilled expectations enhance the magnitude of repetition suppression (RS, i.e. a decreased neuronal response after the repetition of a given stimulus) in face selective visual cortex as well (Summerfield et al., 2008). Current MEG and neuroimaging studies suggest that the underlying mechanisms of expectation effects are independent from these of RS (Grotheer and Kovács, 2015; Todorovic and Lange, 2012). However, it is not clear as of today how perceptual expectations modulate the neural responses: is the difference between correctly predicted and surprising stimuli due to a genuine response reduction for correctly predicted stimuli or is it due to an increased response for surprising stimuli? Therefore, here we used a modified version of the paradigm of Grotheer and Kovács (2015) to induce predictions independently from repetition probability by presenting pairs of faces (female, male or infant) that were either repeated or alternating. Orthogonally to this, predictions were manipulated by the gender of the first face within each pair so that it signaled high, low or equal probability of repetitions. An unpredicted, neutral condition with equal probabilities for alternating and repeated trials was used to identify the role of surprising and enhancing modulations. Similarly, to Grotheer and Kovács (2015), we found significant RS and significant expectation effect in the FFA. Importantly, we observed larger response for surprising events in comparison to the neutral and correctly predicted conditions for alternating trials. Altogether, these results emphasize the role of surprise in prediction effects. PMID:26873275

  16. Predicting invasive species impacts: a community module functional response approach reveals context dependencies.

    PubMed

    Paterson, Rachel A; Dick, Jaimie T A; Pritchard, Daniel W; Ennis, Marilyn; Hatcher, Melanie J; Dunn, Alison M

    2015-03-01

    Predatory functional responses play integral roles in predator-prey dynamics, and their assessment promises greater understanding and prediction of the predatory impacts of invasive species. Other interspecific interactions, however, such as parasitism and higher-order predation, have the potential to modify predator-prey interactions and thus the predictive capability of the comparative functional response approach. We used a four-species community module (higher-order predator; focal native or invasive predators; parasites of focal predators; native prey) to compare the predatory functional responses of native Gammarus duebeni celticus and invasive Gammarus pulex amphipods towards three invertebrate prey species (Asellus aquaticus, Simulium spp., Baetis rhodani), thus, quantifying the context dependencies of parasitism and a higher-order fish predator on these functional responses. Our functional response experiments demonstrated that the invasive amphipod had a higher predatory impact (lower handling time) on two of three prey species, which reflects patterns of impact observed in the field. The community module also revealed that parasitism had context-dependent influences, for one prey species, with the potential to further reduce the predatory impact of the invasive amphipod or increase the predatory impact of the native amphipod in the presence of a higher-order fish predator. Partial consumption of prey was similar for both predators and occurred increasingly in the order A. aquaticus, Simulium spp. and B. rhodani. This was associated with increasing prey densities, but showed no context dependencies with parasitism or higher-order fish predator. This study supports the applicability of comparative functional responses as a tool to predict and assess invasive species impacts incorporating multiple context dependencies. PMID:25265905

  17. Predicting invasive species impacts: a community module functional response approach reveals context dependencies

    PubMed Central

    Paterson, Rachel A; Dick, Jaimie T A; Pritchard, Daniel W; Ennis, Marilyn; Hatcher, Melanie J; Dunn, Alison M

    2015-01-01

    Summary Predatory functional responses play integral roles in predator–prey dynamics, and their assessment promises greater understanding and prediction of the predatory impacts of invasive species. Other interspecific interactions, however, such as parasitism and higher-order predation, have the potential to modify predator–prey interactions and thus the predictive capability of the comparative functional response approach. We used a four-species community module (higher-order predator; focal native or invasive predators; parasites of focal predators; native prey) to compare the predatory functional responses of native Gammarus duebeni celticus and invasive Gammarus pulex amphipods towards three invertebrate prey species (Asellus aquaticus, Simulium spp., Baetis rhodani), thus, quantifying the context dependencies of parasitism and a higher-order fish predator on these functional responses. Our functional response experiments demonstrated that the invasive amphipod had a higher predatory impact (lower handling time) on two of three prey species, which reflects patterns of impact observed in the field. The community module also revealed that parasitism had context-dependent influences, for one prey species, with the potential to further reduce the predatory impact of the invasive amphipod or increase the predatory impact of the native amphipod in the presence of a higher-order fish predator. Partial consumption of prey was similar for both predators and occurred increasingly in the order A. aquaticus, Simulium spp. and B. rhodani. This was associated with increasing prey densities, but showed no context dependencies with parasitism or higher-order fish predator. This study supports the applicability of comparative functional responses as a tool to predict and assess invasive species impacts incorporating multiple context dependencies. PMID:25265905

  18. The Mammalian Circadian Clock Gene Per2 Modulates Cell Death in Response to Oxidative Stress

    PubMed Central

    Magnone, Maria Chiara; Langmesser, Sonja; Bezdek, April Candice; Tallone, Tiziano; Rusconi, Sandro; Albrecht, Urs

    2015-01-01

    Living in the earth’s oxygenated environment forced organisms to develop strategies to cope with the damaging effects of molecular oxygen known as reactive oxygen species (ROS). Here, we show that Per2, a molecular component of the mammalian circadian clock, is involved in regulating a cell’s response to oxidative stress. Mouse embryonic fibroblasts (MEFs) containing a mutation in the Per2 gene are more resistant to cytotoxic effects mediated by ROS than wild-type cells, which is paralleled by an altered regulation of bcl-2 expression in Per2 mutant MEFs. The elevated survival rate and alteration of NADH/NAD+ ratio in the mutant cells is reversed by introduction of the wild-type Per2 gene. Interestingly, clock synchronized cells display a time dependent sensitivity to paraquat, a ROS inducing agent. Our observations indicate that the circadian clock is involved in regulating the fate of a cell to survive or to die in response to oxidative stress, which could have implications for cancer development and the aging process. PMID:25628599

  19. Modulation of Neuronal Responses by Exogenous Attention in Macaque Primary Visual Cortex.

    PubMed

    Wang, Feng; Chen, Minggui; Yan, Yin; Zhaoping, Li; Li, Wu

    2015-09-30

    Visual perception is influenced by attention deployed voluntarily or triggered involuntarily by salient stimuli. Modulation of visual cortical processing by voluntary or endogenous attention has been extensively studied, but much less is known about how involuntary or exogenous attention affects responses of visual cortical neurons. Using implanted microelectrode arrays, we examined the effects of exogenous attention on neuronal responses in the primary visual cortex (V1) of awake monkeys. A bright annular cue was flashed either around the receptive fields of recorded neurons or in the opposite visual field to capture attention. A subsequent grating stimulus probed the cue-induced effects. In a fixation task, when the cue-to-probe stimulus onset asynchrony (SOA) was <240 ms, the cue induced a transient increase of neuronal responses to the probe at the cued location during 40-100 ms after the onset of neuronal responses to the probe. This facilitation diminished and disappeared after repeated presentations of the same cue but recurred for a new cue of a different color. In another task to detect the probe, relative shortening of monkey's reaction times for the validly cued probe depended on the SOA in a way similar to the cue-induced V1 facilitation, and the behavioral and physiological cueing effects remained after repeated practice. Flashing two cues simultaneously in the two opposite visual fields weakened or diminished both the physiological and behavioral cueing effects. Our findings indicate that exogenous attention significantly modulates V1 responses and that the modulation strength depends on both novelty and task relevance of the stimulus. Significance statement: Visual attention can be involuntarily captured by a sudden appearance of a conspicuous object, allowing rapid reactions to unexpected events of significance. The current study discovered a correlate of this effect in monkey primary visual cortex. An abrupt, salient, flash enhanced neuronal

  20. Modulation of Neuronal Responses by Exogenous Attention in Macaque Primary Visual Cortex.

    PubMed

    Wang, Feng; Chen, Minggui; Yan, Yin; Zhaoping, Li; Li, Wu

    2015-09-30

    Visual perception is influenced by attention deployed voluntarily or triggered involuntarily by salient stimuli. Modulation of visual cortical processing by voluntary or endogenous attention has been extensively studied, but much less is known about how involuntary or exogenous attention affects responses of visual cortical neurons. Using implanted microelectrode arrays, we examined the effects of exogenous attention on neuronal responses in the primary visual cortex (V1) of awake monkeys. A bright annular cue was flashed either around the receptive fields of recorded neurons or in the opposite visual field to capture attention. A subsequent grating stimulus probed the cue-induced effects. In a fixation task, when the cue-to-probe stimulus onset asynchrony (SOA) was <240 ms, the cue induced a transient increase of neuronal responses to the probe at the cued location during 40-100 ms after the onset of neuronal responses to the probe. This facilitation diminished and disappeared after repeated presentations of the same cue but recurred for a new cue of a different color. In another task to detect the probe, relative shortening of monkey's reaction times for the validly cued probe depended on the SOA in a way similar to the cue-induced V1 facilitation, and the behavioral and physiological cueing effects remained after repeated practice. Flashing two cues simultaneously in the two opposite visual fields weakened or diminished both the physiological and behavioral cueing effects. Our findings indicate that exogenous attention significantly modulates V1 responses and that the modulation strength depends on both novelty and task relevance of the stimulus. Significance statement: Visual attention can be involuntarily captured by a sudden appearance of a conspicuous object, allowing rapid reactions to unexpected events of significance. The current study discovered a correlate of this effect in monkey primary visual cortex. An abrupt, salient, flash enhanced neuronal

  1. Adaptive Physiological Response to Perceived Scarcity as a Mechanism of Sensory Modulation of Life Span

    PubMed Central

    Waterson, Michael J.; Chan, Tammy P.

    2015-01-01

    Chemosensation is a potent modulator of organismal physiology and longevity. In Drosophila, loss of recognition of diverse tastants has significant and bidirectional life-span effects. Recently published results revealed that when flies were unable to taste water, they increased its internal generation, which may have subsequently altered life span. To determine whether similar adaptive responses occur in other contexts, we explored the impact of sensory deficiency of other metabolically important molecules. Trehalose is a major circulating carbohydrate in the fly that is recognized by the gustatory receptor Gr5a. Gr5a mutant flies are short lived, and we found that they specifically increased whole-body and circulating levels of trehalose, but not other carbohydrates, likely through upregulation of de novo synthesis. dILP2 transcript levels were increased in Gr5a mutants, a possible response intended to reduce hypertrehalosemia, and likely a contributing factor to their reduced life span. Together, these data suggest that compensatory physiological responses to perceived environmental scarcity, which are designed to alleviate the ostensive shortage, may be a common outcome of sensory manipulation. We suggest that future investigations into the mechanisms underlying sensory modulation of aging may benefit by focusing on direct or indirect consequences of physiological changes that are designed to correct perceived disparity with the environment. PMID:25878032

  2. The paradox of histone deacetylase inhibitor-mediated modulation of cellular responses to radiation.

    PubMed

    Karagiannis, Tom C; El-Osta, Assam

    2006-02-01

    Given the widespread use of radiotherapy in cancer, there has been a longstanding interest in the development of chemical compounds that can modify cellular responses to ionizing radiation. Additionally, recent terrorism threats suggesting attacks with 'dirty bombs' containing combinations of radioactive isotopes with conventional explosives, has increased the interest in compounds that can protect from radiation injury. Histone deacetylase inhibitors represent a new class of compounds that can modulate the effects of radiation. Research with histone deacetylase inhibitors has largely focussed on the consequences of their ability to alter gene transcription via histone acetylation and on their properties as anti-cancer agents. They have been shown to cause cell cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. In addition to their intrinsic anti-cancer properties, numerous studies have demonstrated that histone deacetylase inhibitors can modulate cellular responses to other toxicity-inducing modalities including ionizing radiation. The consensus is that histone deacetylase inhibitors markedly enhance the sensitivity of cells to radiation by altering numerous molecular pathways. Intriguingly, a report has also shown that histone deacetylase inhibitors can reduce radiation induced acute and late skin damage using a well-established animal model of cutaneous radiation syndrome. Hence, there is an emerging interest in potential use of histone deacetylase inhibitors as radiation sensitizers or protectors. This review focuses on the different mechanisms by which histone deacetylase inhibitors modify cellular responses to ionizing radiation. PMID:16418577

  3. Task modulations of racial bias in neural responses to others' suffering.

    PubMed

    Sheng, Feng; Liu, Qiang; Li, Hong; Fang, Fang; Han, Shihui

    2014-03-01

    Recent event related brain potential research observed a greater frontal activity to pain expressions of racial in-group than out-group members and such racial bias in neural responses to others' suffering was modulated by task demands that emphasize race identity or painful feeling. However, as pain expressions activate multiple brain regions in the pain matrix, it remains unclear which part of the neural circuit in response to others' suffering undergoes modulations by task demands. We scanned Chinese adults, using functional MRI, while they categorized Asian and Caucasian faces with pain or neutral expressions in terms of race or identified painful feelings of each individual face. We found that pain vs. neutral expressions of Asian but not Caucasian faces activated the anterior cingulate (ACC) and anterior insular (AI) activity during race judgments. However, pain compared to race judgments increased ACC and AI activity to pain expressions of Caucasian but not Asian faces. Moreover, race judgments induced increased activity in the dorsal medial prefrontal cortex whereas pain judgments increased activity in the bilateral temporoparietal junction. The results suggest that task demands emphasizing an individual's painful feeling increase ACC/AI activities to pain expressions of racial out-group members and reduce the racial bias in empathic neural responses.

  4. Modulation of Temporal Precision in Thalamic Population Responses to Natural Visual Stimuli

    PubMed Central

    Desbordes, Gaëlle; Jin, Jianzhong; Alonso, Jose-Manuel; Stanley, Garrett B.

    2010-01-01

    Natural visual stimuli have highly structured spatial and temporal properties which influence the way visual information is encoded in the visual pathway. In response to natural scene stimuli, neurons in the lateral geniculate nucleus (LGN) are temporally precise – on a time scale of 10–25 ms – both within single cells and across cells within a population. This time scale, established by non stimulus-driven elements of neuronal firing, is significantly shorter than that of natural scenes, yet is critical for the neural representation of the spatial and temporal structure of the scene. Here, a generalized linear model (GLM) that combines stimulus-driven elements with spike-history dependence associated with intrinsic cellular dynamics is shown to predict the fine timing precision of LGN responses to natural scene stimuli, the corresponding correlation structure across nearby neurons in the population, and the continuous modulation of spike timing precision and latency across neurons. A single model captured the experimentally observed neural response, across different levels of contrasts and different classes of visual stimuli, through interactions between the stimulus correlation structure and the nonlinearity in spike generation and spike history dependence. Given the sensitivity of the thalamocortical synapse to closely timed spikes and the importance of fine timing precision for the faithful representation of natural scenes, the modulation of thalamic population timing over these time scales is likely important for cortical representations of the dynamic natural visual environment. PMID:21151356

  5. Adaptive Physiological Response to Perceived Scarcity as a Mechanism of Sensory Modulation of Life Span.

    PubMed

    Waterson, Michael J; Chan, Tammy P; Pletcher, Scott D

    2015-09-01

    Chemosensation is a potent modulator of organismal physiology and longevity. In Drosophila, loss of recognition of diverse tastants has significant and bidirectional life-span effects. Recently published results revealed that when flies were unable to taste water, they increased its internal generation, which may have subsequently altered life span. To determine whether similar adaptive responses occur in other contexts, we explored the impact of sensory deficiency of other metabolically important molecules. Trehalose is a major circulating carbohydrate in the fly that is recognized by the gustatory receptor Gr5a. Gr5a mutant flies are short lived, and we found that they specifically increased whole-body and circulating levels of trehalose, but not other carbohydrates, likely through upregulation of de novo synthesis. dILP2 transcript levels were increased in Gr5a mutants, a possible response intended to reduce hypertrehalosemia, and likely a contributing factor to their reduced life span. Together, these data suggest that compensatory physiological responses to perceived environmental scarcity, which are designed to alleviate the ostensive shortage, may be a common outcome of sensory manipulation. We suggest that future investigations into the mechanisms underlying sensory modulation of aging may benefit by focusing on direct or indirect consequences of physiological changes that are designed to correct perceived disparity with the environment. PMID:25878032

  6. c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis.

    PubMed

    Vázquez, Mary C; Vargas, Lina M; Inestrosa, Nibaldo C; Alvarez, Alejandra R

    2009-07-01

    APP intracellular domain (AICD) has been proposed as a transcriptional inductor that moves to the nucleus with the adaptor protein Fe65 and regulates transcription. The two proteins, APP and Fe65, can be phosphorylated by c-Abl kinase. Neprilysin has been proposed as a target gene for AICD. We found that AICD expression is decreased by treatment with STI-571, a c-Abl inhibitor, suggesting a modulation of AICD transcription by c-Abl kinase. We observed interaction between c-Abl kinase, the AICD fragment and the Fe65 adaptor protein. In addition, STI-571 reduces apoptosis in APPSw, and the apoptotic response induced by Fe65 over-expression was inhibited by with the expression of a kinase dead (KD) c-Abl and enhanced by over-expression of WT-c-Abl. However, in the APPSw cells, the ability of the KD-c-Abl to protect against Fe65 was reduced. Finally, in APPSw clone, we detected higher trans-activation of the pro-apoptotic p73 isoform, TAp73 promoter. Our results show that c-Abl modulates AICD dependent cellular responses, transcriptional induction as well as the apoptotic response, which could participate in the onset and progression of the neurodegenerative pathology, observed in Alzheimer's disease (AD).

  7. GABAergic and glycinergic inhibition modulate monaural auditory response properties in the avian superior olivary nucleus.

    PubMed

    Coleman, W L; Fischl, M J; Weimann, S R; Burger, R M

    2011-05-01

    The superior olivary nucleus (SON) is the primary source of inhibition in the avian auditory brainstem. While much is known about the role of inhibition at the SON's target nuclei, little is known about how the SON itself processes auditory information or how inhibition modulates these properties. Additionally, the synaptic physiology of inhibitory inputs within the SON has not been described. We investigated these questions using in vivo and in vitro electrophysiological techniques in combination with immunohistochemistry in the chicken, an organism for which the auditory brainstem has otherwise been well characterized. We provide a thorough characterization of monaural response properties in the SON and the influence of inhibitory input in shaping these features. We found that the SON contains a heterogeneous mixture of response patterns to acoustic stimulation and that in most neurons these responses are modulated by both GABAergic and glycinergic inhibitory inputs. Interestingly, many SON neurons tuned to low frequencies have robust phase-locking capability and the precision of this phase locking is enhanced by inhibitory inputs. On the synaptic level, we found that evoked and spontaneous inhibitory postsynaptic currents (IPSCs) within the SON are also mediated by both GABAergic and glycinergic inhibition in all neurons tested. Analysis of spontaneous IPSCs suggests that most SON cells receive a mixture of both purely GABAergic terminals, as well as terminals from which GABA and glycine are coreleased. Evidence for glycinergic signaling within the SON is a novel result that has important implications for understanding inhibitory function in the auditory brainstem.

  8. Cardiac sympathetic modulation in response to apneas/hypopneas through heart rate variability analysis.

    PubMed

    Chouchou, Florian; Pichot, Vincent; Barthélémy, Jean-Claude; Bastuji, Hélène; Roche, Frédéric

    2014-01-01

    Autonomic dysfunction is recognized to contribute to cardiovascular consequences in obstructive sleep apnea/hypopnea syndrome (OSAHS) patients who present predominant cardiovascular sympathetic activity that persists during wakefulness. Here, we examined 1) the factors that influence sympathetic cardiac modulation in response to apneas/hypopneas; and 2) the influence of autonomic activity during apneas/hypopneas on CA. Sixteen OSAHS patients underwent in-hospital polysomnography. RR interval (RR) and RR spectral analysis using wavelet transform were used to study parasympathetic (high frequency power: HF(WV)) and sympathetic (low frequency power: LF(WV) and LF(WV)/HF(WV) ratio) activity before and after apnea/hypopnea termination. Autonomic cardiac modulations were compared according to sleep stage, apnea/hypopnea type and duration, arterial oxygen saturation, and presence of CA. At apnea/hypopnea termination, RR decreased (p<0.001) while LF(WV) (p = 0.001) and LF(WV)/HF(WV) ratio (p = 0.001) increased. Only RR and LF(WV)/HF(WV) ratio changes were higher when apneas/hypopneas produced CA (p = 0.030 and p = 0.035, respectively) or deep hypoxia (p = 0.023 and p = 0.046, respectively). Multivariate statistical analysis showed that elevated LF(WV) (p = 0.006) and LF(WV)/HF(WV) ratio (p = 0.029) during apneas/hypopneas were independently related to higher CA occurrence. Both the arousal and hypoxia processes may contribute to sympathetic cardiovascular overactivity by recurrent cardiac sympathetic modulation in response to apneas/hypopneas. Sympathetic overactivity also may play an important role in the acute central response to apneas/hypopneas, and in the sleep fragmentation.

  9. Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

    PubMed Central

    Gerö, Domokos; Szoleczky, Petra; Módis, Katalin; Pribis, John P.; Al-Abed, Yousef; Yang, Huan; Chevan, Sangeeta; Billiar, Timothy R.; Tracey, Kevin J.; Szabo, Csaba

    2013-01-01

    High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. PMID:23799067

  10. Die singulation method

    DOEpatents

    Swiler, Thomas P [Albuquerque, NM; Garcia, Ernest J [Albuquerque, NM; Francis, Kathryn M [Rio Rancho, NM

    2014-01-07

    A method is disclosed for singulating die from a semiconductor substrate (e.g. a semiconductor-on-insulator substrate or a bulk silicon substrate) containing an oxide layer (e.g. silicon dioxide or a silicate glass) and one or more semiconductor layers (e.g. monocrystalline or polycrystalline silicon) located above the oxide layer. The method etches trenches through the substrate and through each semiconductor layer about the die being singulated, with the trenches being offset from each other around at least a part of the die so that the oxide layer between the trenches holds the substrate and die together. The trenches can be anisotropically etched using a Deep Reactive Ion Etching (DRIE) process. After the trenches are etched, the oxide layer between the trenches can be etched away with a HF etchant to singulate the die. A release fixture can be located near one side of the substrate to receive the singulated die.

  11. Die singulation method

    DOEpatents

    Swiler, Thomas P.; Garcia, Ernest J.; Francis, Kathryn M.

    2013-06-11

    A method is disclosed for singulating die from a semiconductor substrate (e.g. a semiconductor-on-insulator substrate or a bulk silicon substrate) containing an oxide layer (e.g. silicon dioxide or a silicate glass) and one or more semiconductor layers (e.g. monocrystalline or polycrystalline silicon) located above the oxide layer. The method etches trenches through the substrate and through each semiconductor layer about the die being singulated, with the trenches being offset from each other around at least a part of the die so that the oxide layer between the trenches holds the substrate and die together. The trenches can be anisotropically etched using a Deep Reactive Ion Etching (DRIE) process. After the trenches are etched, the oxide layer between the trenches can be etched away with an HF etchant to singulate the die. A release fixture can be located near one side of the substrate to receive the singulated die.

  12. Immunobiotic Bifidobacteria Strains Modulate Rotavirus Immune Response in Porcine Intestinal Epitheliocytes via Pattern Recognition Receptor Signaling

    PubMed Central

    Miyazaki, Ayako; Soma, Junichi; Suda, Yoshihito; Aso, Hisashi; Nochi, Tomonori; Iwabuchi, Noriyuki; Xiao, Jin-zhong; Saito, Tadao; Villena, Julio; Kitazawa, Haruki

    2016-01-01

    In this work, we aimed to characterize the antiviral response of an originally established porcine intestinal epithelial cell line (PIE cells) by evaluating the molecular innate immune response to rotavirus (RVs). In addition, we aimed to select immunomodulatory bacteria with antiviral capabilities. PIE cells were inoculated with RVs isolated from different host species and the infective titers and the molecular innate immune response were evaluated. In addition, the protection against RVs infection and the modulation of immune response by different lactic acid bacteria (LAB) strains was studied. The RVs strains OSU (porcine) and UK (bovine) effectively infected PIE cells. Our results also showed that RVs infection in PIE cells triggered TLR3-, RIG-I- and MDA-5-mediated immune responses with activation of IRF3 and NF-κB, induction of IFN-β and up-regulation of the interferon stimulated genes MxA and RNase L. Among the LAB strains tested, Bifidobacterium infantis MCC12 and B. breve MCC1274 significantly reduced RVs titers in infected PIE cells. The beneficial effects of both bifidobacteria were associated with reduction of A20 expression, and improvements of IRF-3 activation, IFN-β production, and MxA and RNase L expressions. These results indicate the value of PIE cells for studying RVs molecular innate immune response in pigs and for the selection of beneficial bacteria with antiviral capabilities. PMID:27023883

  13. Serotonin modulates responses to species-specific vocalizations in the inferior colliculus.

    PubMed

    Hurley, Laura M; Pollak, George D

    2005-06-01

    Neuromodulators such as serotonin are capable of altering the neural processing of stimuli across many sensory modalities. In the inferior colliculus, a major midbrain auditory gateway, serotonin alters the way that individual neurons respond to simple tone bursts and linear frequency modulated sweeps. The effects of serotonin are complex, and vary among neurons. How serotonin transforms the responses to spectrotemporally complex sounds of the type normally heard in natural settings has been poorly examined. To explore this issue further, the effects of iontophoretically applied serotonin on the responses of individual inferior colliculus neurons to a variety of recorded species-specific vocalizations were examined. These experiments were performed in the Mexican free-tailed bat, a species that uses a rich repertoire of vocalizations for the purposes of communication as well as echolocation. Serotonin frequently changed the number of recorded calls that were capable of evoking a response from individual neurons, sometimes increasing (15% of serotonin-responsive neurons), but usually decreasing (62% of serotonin-responsive neurons), this number. A functional consequence of these serotonin-evoked changes would be to change the population response to species-specific vocalizations. PMID:15830241

  14. Melatonin treatment prevents modulation of cell-mediated immune response induced by propoxur in rats.

    PubMed

    Suke, Sanvidhan G; Pathak, Rahul; Ahmed, Rafat S; Tripathi, A K; Banerjee, B D

    2008-08-01

    The effect of melatonin, a major secretory product of the pineal gland, in attenuation of propoxur (2-isopropoxy phenyl N-methyl carbamate)-induced modulation of cell-mediated immune (CMI) response was studied in rats. Male Wistar albino rats were exposed to propoxur (a widely used pesticide) orally (10 mg/kg) and/or melatonin (10 mg/kg) orally for 4 weeks. CMI was measured by delayed-type hypersensitivity (DTH), leucocyte and macrophage migration inhibition (LMI and MMI) responses and estimation of cytokines TNF-alpha and IFN-gamma levels. Rats exposed to propoxur for 4 weeks showed significant decrease in DTH, LMI and MMI responses. Propoxur also suppressed TNF-alpha and IFN-gamma production significantly. Administration of melatonin alone caused a significant increase in DTH response. Although there were no changes in the LMI and MMI response, the cytokine levels were significantly increased, as compared to control. Co-administration of melatonin along with propoxur significantly nullified the effect of the pesticide on the CMI response, except DTH and reversed levels of cytokines to near control/normal values. Thus, melatonin treatment considerably attenuated immunomodulation caused by sub-chronic treatment of propoxur in experimental animals.

  15. Cyclin-Dependent Kinase Inhibitor 1a (p21) Modulates Response to Cocaine and Motivated Behaviors.

    PubMed

    Scholpa, Natalie E; Briggs, Sherri B; Wagner, John J; Cummings, Brian S

    2016-04-01

    This study investigated the functional role of cyclin-dependent kinase inhibitor 1a (Cdkn1a or p21) in cocaine-induced responses using a knockout mouse model. Acute locomotor activity after cocaine administration (15 mg/kg, i.p.) was decreased in p21(-/-) mice, whereas cocaine-induced place preference was enhanced. Interestingly, κ-opioid-induced place aversion was also significantly enhanced. Concentration-dependent analysis of locomotor activity in response to cocaine demonstrated a rightward shift in the p21(-/-) mice. Pretreatment with a 5-hydroxytryptamine receptor antagonist did not alter the enhancement of cocaine-induced conditioned place preference in p21(-/-) mice, indicating a lack of involvement of serotonergic signaling in this response. Cocaine exposure increased p21 expression exclusively in the ventral sector of the hippocampus of rodents after either contingent or noncontingent drug administration. Increased p21 expression was accompanied by increased histone acetylation of the p21 promoter region in rats. Finally, increased neurogenesis in the dorsal hippocampus of p21(-/-) mice was also observed. These results show that functional loss of p21 altered the acute locomotor response to cocaine and the conditioned responses to either rewarding or aversive stimuli. Collectively, these findings demonstrate a previously unreported involvement of p21 in modulating responses to cocaine and in motivated behaviors.

  16. Sharks modulate their escape behavior in response to predator size, speed and approach orientation.

    PubMed

    Seamone, Scott; Blaine, Tristan; Higham, Timothy E

    2014-12-01

    Escape responses are often critical for surviving predator-prey interactions. Nevertheless, little is known about how predator size, speed and approach orientation impact escape performance, especially in larger prey that are primarily viewed as predators. We used realistic shark models to examine how altering predatory behavior and morphology (size, speed and approach orientation) influences escape behavior and performance in Squalus acanthias, a shark that is preyed upon by apex marine predators. Predator models induced C-start escape responses, and increasing the size and speed of the models triggered a more intense response (increased escape turning rate and acceleration). In addition, increased predator size resulted in greater responsiveness from the sharks. Among the responses, predator approach orientation had the most significant impact on escapes, such that the head-on approach, as compared to the tail-on approach, induced greater reaction distances and increased escape turning rate, speed and acceleration. Thus, the anterior binocular vision in sharks renders them less effective at detecting predators approaching from behind. However, it appears that sharks compensate by performing high-intensity escapes, likely induced by the lateral line system, or by a sudden visual flash of the predator entering their field of view. Our study reveals key aspects of escape behavior in sharks, highlighting the modulation of performance in response to predator approach.

  17. Immunobiotic Bifidobacteria Strains Modulate Rotavirus Immune Response in Porcine Intestinal Epitheliocytes via Pattern Recognition Receptor Signaling.

    PubMed

    Ishizuka, Takamasa; Kanmani, Paulraj; Kobayashi, Hisakazu; Miyazaki, Ayako; Soma, Junichi; Suda, Yoshihito; Aso, Hisashi; Nochi, Tomonori; Iwabuchi, Noriyuki; Xiao, Jin-zhong; Saito, Tadao; Villena, Julio; Kitazawa, Haruki

    2016-01-01

    In this work, we aimed to characterize the antiviral response of an originally established porcine intestinal epithelial cell line (PIE cells) by evaluating the molecular innate immune response to rotavirus (RVs). In addition, we aimed to select immunomodulatory bacteria with antiviral capabilities. PIE cells were inoculated with RVs isolated from different host species and the infective titers and the molecular innate immune response were evaluated. In addition, the protection against RVs infection and the modulation of immune response by different lactic acid bacteria (LAB) strains was studied. The RVs strains OSU (porcine) and UK (bovine) effectively infected PIE cells. Our results also showed that RVs infection in PIE cells triggered TLR3-, RIG-I- and MDA-5-mediated immune responses with activation of IRF3 and NF-κB, induction of IFN-β and up-regulation of the interferon stimulated genes MxA and RNase L. Among the LAB strains tested, Bifidobacterium infantis MCC12 and B. breve MCC1274 significantly reduced RVs titers in infected PIE cells. The beneficial effects of both bifidobacteria were associated with reduction of A20 expression, and improvements of IRF-3 activation, IFN-β production, and MxA and RNase L expressions. These results indicate the value of PIE cells for studying RVs molecular innate immune response in pigs and for the selection of beneficial bacteria with antiviral capabilities. PMID:27023883

  18. Roles of dopamine receptors in mediating acute modulation of immunological responses in Macrobrachium rosenbergii.

    PubMed

    Chang, Zhong-Wen; Ke, Zhi-Han; Chang, Chin-Chyuan

    2016-02-01

    Dopamine (DA) was found to influence the immunological responses and resistance to pathogen infection in invertebrates. To clarify the possible modulation of DA through dopamine receptors (DAR) against acute environmental stress, the levels of DA, glucose and lactate in the haemolymph of Macrobrachium rosenbergii under hypo- and hyperthermal stresses were measured. The changes in immune parameters such as total haemocyte count (THC), differential haemocyte count (DHC), phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and phagocytic activity (PA) were evaluated in prawns which received DAR antagonists (SCH23390, SCH, D1 antagonist; domperidone, DOM, D2 antagonist; chlorpromazine, CH, D1+2 antagonist) followed by hypo- (15 °C) and hyperthermal (34 °C) stresses. In addition, pharmacological analysis of the effect DA modulation was studied in haemocytes incubated with DA and DAR antagonists. The results revealed a significant increase in haemolymph DA accompanied with upregulated levels of glucose and lactate in prawns exposed to both hypo- and hyperthermal stresses in 2 h. In addition, a significant decrease in RBs per haemocyte was noted in prawns which received DAR antagonists when they exposed to hyperthermal stress for 30 min. In in vitro test, antagonism on RBs, SOD and GPx activity of haemocytes were further evidenced through D1, D1, D1+D2 DARs, respectively, in the meantime, no significant difference in PO activity and PA was observed among the treatment groups. These results suggest that the upregulation of DA, glucose and lactate in haemolymph might be the response to acute thermal stress for the demand of energy, and the DAR occupied by its antagonistic action impart no effect on immunological responses except RBs in vivo even though the modulation mediated through D1 DAR was further evidenced in RBs, SOD and GPx activities in vitro. It is therefore concluded that thermal

  19. Effects of Spectral Degradation on Attentional Modulation of Cortical Auditory Responses to Continuous Speech.

    PubMed

    Kong, Ying-Yee; Somarowthu, Ala; Ding, Nai

    2015-12-01

    This study investigates the effect of spectral degradation on cortical speech encoding in complex auditory scenes. Young normal-hearing listeners were simultaneously presented with two speech streams and were instructed to attend to only one of them. The speech mixtures were subjected to noise-channel vocoding to preserve the temporal envelope and degrade the spectral information of speech. Each subject was tested with five spectral resolution conditions (unprocessed speech, 64-, 32-, 16-, and 8-channel vocoder conditions) and two target-to-masker ratio (TMR) conditions (3 and 0 dB). Ongoing electroencephalographic (EEG) responses and speech comprehension were measured in each spectral and TMR condition for each subject. Neural tracking of each speech stream was characterized by cross-correlating the EEG responses with the envelope of each of the simultaneous speech streams at different time lags. Results showed that spectral degradation and TMR both significantly influenced how top-down attention modulated the EEG responses to the attended and unattended speech. That is, the EEG responses to the attended and unattended speech streams differed more for the higher (unprocessed, 64 ch, and 32 ch) than the lower (16 and 8 ch) spectral resolution conditions, as well as for the higher (3 dB) than the lower TMR (0 dB) condition. The magnitude of differential neural modulation responses to the attended and unattended speech streams significantly correlated with speech comprehension scores. These results suggest that severe spectral degradation and low TMR hinder speech stream segregation, making it difficult to employ top-down attention to differentially process different speech streams. PMID:26362546

  20. Effects of Spectral Degradation on Attentional Modulation of Cortical Auditory Responses to Continuous Speech.

    PubMed

    Kong, Ying-Yee; Somarowthu, Ala; Ding, Nai

    2015-12-01

    This study investigates the effect of spectral degradation on cortical speech encoding in complex auditory scenes. Young normal-hearing listeners were simultaneously presented with two speech streams and were instructed to attend to only one of them. The speech mixtures were subjected to noise-channel vocoding to preserve the temporal envelope and degrade the spectral information of speech. Each subject was tested with five spectral resolution conditions (unprocessed speech, 64-, 32-, 16-, and 8-channel vocoder conditions) and two target-to-masker ratio (TMR) conditions (3 and 0 dB). Ongoing electroencephalographic (EEG) responses and speech comprehension were measured in each spectral and TMR condition for each subject. Neural tracking of each speech stream was characterized by cross-correlating the EEG responses with the envelope of each of the simultaneous speech streams at different time lags. Results showed that spectral degradation and TMR both significantly influenced how top-down attention modulated the EEG responses to the attended and unattended speech. That is, the EEG responses to the attended and unattended speech streams differed more for the higher (unprocessed, 64 ch, and 32 ch) than the lower (16 and 8 ch) spectral resolution conditions, as well as for the higher (3 dB) than the lower TMR (0 dB) condition. The magnitude of differential neural modulation responses to the attended and unattended speech streams significantly correlated with speech comprehension scores. These results suggest that severe spectral degradation and low TMR hinder speech stream segregation, making it difficult to employ top-down attention to differentially process different speech streams.

  1. Extrusion die and method

    DOEpatents

    Lipp, G. Daniel

    1994-04-26

    A method and die apparatus for manufacturing a honeycomb body of rhombic cell cross-section by extrusion through an extrusion die of triangular cell discharge slot configuration, the die incorporating feedholes at selected slot intersections only, such that slot segments communicating directly with the feedholes discharge web material and slot segments not so connected do not discharge web material, whereby a rhombic cell cross-section in the extruded body is provided.

  2. The Ambiguous Dying Syndrome

    ERIC Educational Resources Information Center

    Bern-Klug, Mercedes

    2004-01-01

    More than one-half of the 2.4 million deaths that will occur in the United States in 2004 will be immediately preceded by a time in which the likelihood of dying can best be described as "ambiguous." Many people die without ever being considered "dying" or "at the end of life." These people may miss out on the opportunity to close important…

  3. Responses of macaque ganglion cells to the relative phase of heterochromatically modulated lights.

    PubMed Central

    Smith, V C; Lee, B B; Pokorny, J; Martin, P R; Valberg, A

    1992-01-01

    1. We measured the response of macaque ganglion cells to sinusoidally modulated red and green lights as the relative phase, theta, of the lights was varied. 2. At low frequencies, red-green ganglion cells of the parvocellular (PC-) pathway with opponent inputs from middle-wavelength sensitive (M-) and long-wavelength sensitive (L-) cones were minimally sensitive to luminance modulation (theta = 0 deg) and maximally sensitive to chromatic modulation (theta = 180 deg). With increasing frequency, the phase, theta, of minimal amplitude gradually changed, in opposite directions for cells with M- and L-cone centres. 3. At high frequencies (at and above 20 Hz), phasic cells of the magnocellular (MC-) pathway were maximally responsive when theta approximately 0 deg and minimally responsive when theta approximately 180 deg, as expected from an achromatic mechanism. At lower frequencies, the phase of minimal response shifted, for both on- and off-centre cells, to values of theta intermediate between 0 and 180 deg. This phase asymmetry was absent if the centre alone was stimulated with a small field. 4. For PC-pathway cells, it was possible to provide an account of response phase as a function of theta, using a model involving three parameters; phases of the L- and M-cone mechanisms and a L/M cone weighting term. For red-green cells, the phase parameters were monotonically related to temporal frequency and revealed a centre-surround phase difference. The phase difference was linear with a slope of 1-3 deg Hz-1. If this represents a latency difference, it would be 3-8 ms. Otherwise, temporal properties of the M- and L-cones appeared similar if not identical. By addition of a scaling term, the model could be extended to give an adequate account of the amplitude of responses. 5. We were able to activate selectively the surrounds of cells with short-wavelength (S-) cone input to their centres, and so were able to assess L/M cone weighting to the surround. M- and L-cone inputs

  4. Sputtered protective coatings for die casting dies

    NASA Technical Reports Server (NTRS)

    Mirtich, M. J.; Nieh, C.-Y.; Wallace, J. F.

    1981-01-01

    Three experimental research designs investigating candidate materials and processes involved in protective die surface coating procedures by sputter deposition, using ion beam technologies, are discussed. Various pre-test results show that none of the coatings remained completely intact for 15,000 test cycles. The longest lifetime was observed for coatings such as tungsten, platinum, and molybdenum which reduced thermal fatigue, but exhibited oxidation and suppressed crack initiation only as long as the coating did not fracture. Final test results confirmed earlier findings and coatings with Pt and W proved to be the candidate materials to be used on a die surface to increase die life. In the W-coated specimens, which remained intact on the surface after thermal fatigue testing, no oxidation was found under the coating, although a few cracks formed on the surface where the coating broke down. Further research is planned.

  5. Polarisation response of delay dependent absorption modulation in strong field dressed helium atoms probed near threshold

    NASA Astrophysics Data System (ADS)

    Simpson, E. R.; Sanchez-Gonzalez, A.; Austin, D. R.; Diveki, Z.; Hutchinson, S. E. E.; Siegel, T.; Ruberti, M.; Averbukh, V.; Miseikis, L.; Strüber, C. S.; Chipperfield, L.; Marangos, J. P.

    2016-08-01

    We present the first measurement of the vectorial response of strongly dressed helium atoms probed by an attosecond pulse train (APT) polarised either parallel or perpendicular to the dressing field polarisation. The transient absorption is probed as a function of delay between the APT and the linearly polarised 800 nm field of peak intensity 1.3× {10}14 {{W}} {{cm}}-2. The APT spans the photon energy range 16-42 eV, covering the first ionisation energy of helium (24.59 eV). With parallel polarised dressing and probing fields, we observe modulations with periods of one half and one quarter of the dressing field period. When the polarisation of the dressing field is altered from parallel to perpendicular with respect to the APT polarisation we observe a large suppression in the modulation depth of the above ionisation threshold absorption. In addition to this we present the intensity dependence of the harmonic modulation depth as a function of delay between the dressing and probe fields, with dressing field peak intensities ranging from 2 × 1012 to 2 × 1014 {{W}} {{cm}}-2. We compare our experimental results with a full-dimensional solution of the single-atom time-dependent (TD) Schrödinger equation obtained using the recently developed abinitio TD B-spline ADC method and find good qualitative agreement for the above threshold harmonics.

  6. Polarisation response of delay dependent absorption modulation in strong field dressed helium atoms probed near threshold

    NASA Astrophysics Data System (ADS)

    Simpson, E. R.; Sanchez-Gonzalez, A.; Austin, D. R.; Diveki, Z.; Hutchinson, S. E. E.; Siegel, T.; Ruberti, M.; Averbukh, V.; Miseikis, L.; Strüber, C. S.; Chipperfield, L.; Marangos, J. P.

    2016-08-01

    We present the first measurement of the vectorial response of strongly dressed helium atoms probed by an attosecond pulse train (APT) polarised either parallel or perpendicular to the dressing field polarisation. The transient absorption is probed as a function of delay between the APT and the linearly polarised 800 nm field of peak intensity 1.3× {10}14 {{W}} {{cm}}-2. The APT spans the photon energy range 16–42 eV, covering the first ionisation energy of helium (24.59 eV). With parallel polarised dressing and probing fields, we observe modulations with periods of one half and one quarter of the dressing field period. When the polarisation of the dressing field is altered from parallel to perpendicular with respect to the APT polarisation we observe a large suppression in the modulation depth of the above ionisation threshold absorption. In addition to this we present the intensity dependence of the harmonic modulation depth as a function of delay between the dressing and probe fields, with dressing field peak intensities ranging from 2 × 1012 to 2 × 1014 {{W}} {{cm}}-2. We compare our experimental results with a full-dimensional solution of the single-atom time-dependent (TD) Schrödinger equation obtained using the recently developed abinitio TD B-spline ADC method and find good qualitative agreement for the above threshold harmonics.

  7. L-type calcium channel β subunit modulates angiotensin II responses in cardiomyocytes.

    PubMed

    Hermosilla, Tamara; Moreno, Cristian; Itfinca, Mircea; Altier, Christophe; Armisén, Ricardo; Stutzin, Andres; Zamponi, Gerald W; Varela, Diego

    2011-01-01

    Angiotensin II regulation of L-type calcium currents in cardiac muscle is controversial and the underlying signaling events are not completely understood. Moreover, the possible role of auxiliary subunit composition of the channels in Angiotensin II modulation of L-type calcium channels has not yet been explored. In this work we study the role of Ca(v)β subunits and the intracellular signaling responsible for L-type calcium current modulation by Angiotensin II. In cardiomyocytes, Angiotensin II exposure induces rapid inhibition of L-type current with a magnitude that is correlated with the rate of current inactivation. Semi-quantitative PCR of cardiomyocytes at different days of culture reveals changes in the Ca(v)β subunits expression pattern that are correlated with the rate of current inactivation and with Angiotensin II effect. Over-expression of individual b subunits in heterologous systems reveals that the magnitude of Angiotensin II inhibition is dependent on the Ca(v)β subunit isoform, with Ca(v)β(1b) containing channels being more strongly regulated. Ca(v)β(2a) containing channels were insensitive to modulation and this effect was partially due to the N-terminal palmitoylation sites of this subunit. Moreover, PLC or diacylglycerol lipase inhibition prevents the Angiotensin II effect on L-type calcium channels, while PKC inhibition with chelerythrine does not, suggesting a role of arachidonic acid in this process. Finally, we show that in intact cardiomyocytes the magnitude of calcium transients on spontaneous beating cells is modulated by Angiotensin II in a Ca(v)β subunit-dependent manner. These data demonstrate that Ca(v)β subunits alter the magnitude of inhibition of L-type current by Angiotensin II. PMID:21525790

  8. Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia

    PubMed Central

    Kim, Francis Y.; Barnes, Elizabeth A.; Ying, Lihua; Chen, Chihhsin; Lee, Lori; Alvira, Cristina M.

    2014-01-01

    Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1 flox/flox mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1+/+ and ET-1−/− mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1−/− and SM22α-ET-1+/+ (control) littermates. After exposure to hypoxia (10% O2, 21–24 days), RVSP was and vascular remodeling were less in SM22α-ET-1−/− mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC

  9. Frequency-modulated impulse response photothermal detection through optical reflectance. 2: Experimental.

    PubMed

    Power, J F; Mandelis, A

    1988-08-15

    A fast thermoreflectance impulse response photothermal imager was assembled and tested with several solid materials [quartz, stainless steel, and polyvinylidene difluoride (PVDF)I. The instrument was found to yield quantitative data in agreement with Green's function theoretical models of time domain heat conduction. The FM chirp laser intensity modulation technique used in these experiments gave wide bandwidth photothermal signals and was found to be only limited by the FFT instrumentation frequency response (100 kHz). Thermal diffusivities were calculated, while thermal lensing and thermoelastic effects were further observed. The imager was thus shown to be capable of replacing pulsed laser devices for truly nondestructive applications with materials with low damage threshold to optical pulses.

  10. An evaluation of the response modulation hypothesis in relation to attention-deficit/hyperactivity disorder.

    PubMed

    Farmer, Richard F; Rucklidge, Julia J

    2006-08-01

    Several hypotheses related to Newman's (e.g., Patterson & Newman, 1993) response modulation hypothesis were examined among adolescents with attention-deficit/hyperactivity disorder (ADHD; n=18) and normal controls (n=23). Consistent with predictions, youth with ADHD committed more passive avoidance errors (PAEs) than controls during the latter trials of a computerized go/no go task with mixed incentives, and this effect remained significant or marginally significant even after common variance associated with variables that covary with ADHD (i.e., IQ, oppositional-defiant/conduct disorder [ODD/CD] symptoms, anxious/depressed mood) was removed. While a moderate inverse association was observed between PAE frequency and the amount of time spent viewing response feedback following punishment, both categorical (diagnostic) and dimensional analyses of ADHD symptomatology indicated that ADHD and reflection on punishment feedback are uniquely associated with PAE commission. Findings from this study are discussed in relation to models of disinhibition applicable to youth with ADHD.

  11. An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response

    PubMed Central

    Shi, Yuheng; Yuan, Bofeng; Qi, Nan; Zhu, Wenting; Su, Jingru; Li, Xiaoyan; Qi, Peipei; Zhang, Dan; Hou, Fajian

    2015-01-01

    In response to virus infection, RIG-I senses viral RNA and activates the adaptor protein MAVS, which then forms prion-like filaments and stimulates a specific signalling pathway leading to type I interferon production to restrict virus proliferation. However, the mechanisms by which MAVS activity is regulated remain elusive. Here we identify distinct regions of MAVS responsible for activation of transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These IRF3- and NF-κB-stimulating regions recruit preferential TNF receptor-associated factors (TRAFs) for downstream signalling. Strikingly, these regions' activities are inhibited by their respective adjacent regions in quiescent MAVS. Our data thus show that an autoinhibitory mechanism modulates MAVS activity in unstimulated cells and, on viral infection, individual regions of MAVS are released following MAVS filament formation to activate antiviral signalling cascades. PMID:26183716

  12. Frequency-modulated impulse response photothermal detection through optical reflectance. 2: Experimental.

    PubMed

    Power, J F; Mandelis, A

    1988-08-15

    A fast thermoreflectance impulse response photothermal imager was assembled and tested with several solid materials [quartz, stainless steel, and polyvinylidene difluoride (PVDF)I. The instrument was found to yield quantitative data in agreement with Green's function theoretical models of time domain heat conduction. The FM chirp laser intensity modulation technique used in these experiments gave wide bandwidth photothermal signals and was found to be only limited by the FFT instrumentation frequency response (100 kHz). Thermal diffusivities were calculated, while thermal lensing and thermoelastic effects were further observed. The imager was thus shown to be capable of replacing pulsed laser devices for truly nondestructive applications with materials with low damage threshold to optical pulses. PMID:20539390

  13. Modulation of cellular immune responses in mice with disseminated histoplasmosis by recombinant interleukin-2.

    PubMed Central

    Deepe, G S; Taylor, C L; Harris, J E; Bullock, W E

    1986-01-01

    Depression of the cellular immune responses in mice with disseminated histoplasmosis is associated with deficient production of interleukin-2 (IL-2) by splenocytes. Therefore, we examined whether a highly purified preparation of IL-2, recombinant human IL-2 (rIL-2), could modify the cellular immune responses in infected mice and whether this lymphokine could alter the severity of histoplasmosis in animals. Exogenous rIL-2, at concentrations of up to 1,000 U/ml, failed to augment the proliferative responses to concanavalin A by unfractionated splenocytes or splenic T cells from mice infected for 1 week. In addition, rIL-2 did not modulate the plaque-forming cell response to sheep erythrocytes by splenocytes from these same mice. However, at week 3, rIL-2 in concentrations ranging from 10 to 1,000 U/ml considerably augmented the proliferative response to concanavalin A and plaque-forming cell response to sheep erythrocytes by splenocytes from infected mice. Kinetics studies demonstrated that rIL-2 exerted maximal immunoregulatory activity when added on day 0 or 1 to cultures of splenocytes. In vivo administration of rIL-2, 200 to 20,000 U/day, for 10 days to normal and 3-week-infected mice did not alter the proliferative activity of splenocytes to concanavalin A; 200,000 U of rIL-2 per day actually depressed the proliferative responses of splenocytes from normal and infected mice. In vivo, rIL-2 did not modify delayed-type hypersensitivity responses to sheep erythrocytes or to histoplasmin by normal and infected mice. Moreover, treatment with rIL-2 in vivo did not reduce the number of Histoplasma CFU in spleens of mice. Thus, despite the immunoenhancing effect of rIL-2 in vitro, this lymphokine failed to exert similar effects in vivo. PMID:3487507

  14. Parathyroid hormone modulates the response of osteoblast-like cells to mechanical stimulation

    NASA Technical Reports Server (NTRS)

    Ryder, K. D.; Duncan, R. L.

    2000-01-01

    Mechanical loading stimulates many responses in bone and osteoblasts associated with osteogenesis. Since loading and parathyroid hormone (PTH) activate similar signaling pathways in osteoblasts, we postulate that PTH can potentiate the effects of mechanical stimulation. Using an in vitro four-point bending device, we found that expression of COX-2, the inducible isoform of cyclooxygenase, was dependent on fluid forces generated across the culture plate, but not physiologic levels of strain in MC3T3-E1 osteoblast-like cells. Addition of 50 nM PTH during loading increased COX-2 expression at both subthreshold and threshold levels of fluid forces compared with either stimuli alone. We also demonstrated that application of fluid shear to MC3T3-E1 cells induced a rapid increase in [Ca(2+)](i). Although PTH did not significantly change [Ca(2+)](i) levels, flow and PTH did produce a significantly greater [Ca(2+)](i) response and increased the number of responding cells than is found in fluid shear alone. The [Ca(2+)](i) response to these stimuli was significantly decreased when the mechanosensitive channel inhibitor, gadolinium, was present. These studies indicate that PTH increases the cellular responses of osteoblasts to mechanical loading. Furthermore, this response may be mediated by alterations in [Ca(2+)](i) by modulating the mechanosensitive channel.

  15. Mitochondrial and Chloroplast Stress Responses Are Modulated in Distinct Touch and Chemical Inhibition Phases1[OPEN

    PubMed Central

    Ivanova, Aneta; Millar, A. Harvey; Whelan, James

    2016-01-01

    Previous studies have identified a range of transcription factors that modulate retrograde regulation of mitochondrial and chloroplast functions in Arabidopsis (Arabidopsis thaliana). However, the relative importance of these regulators and whether they act downstream of separate or overlapping signaling cascades is still unclear. Here, we demonstrate that multiple stress-related signaling pathways, with distinct kinetic signatures, converge on overlapping gene sets involved in energy organelle function. The transcription factor ANAC017 is almost solely responsible for transcript induction of marker genes around 3 to 6 h after chemical inhibition of organelle function and is a key regulator of mitochondrial and specific types of chloroplast retrograde signaling. However, an independent and highly transient gene expression phase, initiated within 10 to 30 min after treatment, also targets energy organelle functions, and is related to touch and wounding responses. Metabolite analysis demonstrates that this early response is concurrent with rapid changes in tricarboxylic acid cycle intermediates and large changes in transcript abundance of genes encoding mitochondrial dicarboxylate carrier proteins. It was further demonstrated that transcription factors AtWRKY15 and AtWRKY40 have repressive regulatory roles in this touch-responsive gene expression. Together, our results show that several regulatory systems can independently affect energy organelle function in response to stress, providing different means to exert operational control. PMID:27208304

  16. Oxytocin modulates the racial bias in neural responses to others' suffering.

    PubMed

    Sheng, Feng; Liu, Yi; Zhou, Bin; Zhou, Wen; Han, Shihui

    2013-02-01

    The intergroup relationship between a perceiver and a target person influences empathic neural responses to others' suffering, which are increased for racial in-group members compared to out-group members. The current study investigated whether oxytocin (OT), a neuropeptide that has been linked to empathic concern and in-group favoritism, contributes to the racial bias in empathic neural responses. Event-related brain potentials were recorded in Chinese male adults during race judgments on Asian and Caucasian faces expressing pain or showing a neutral expression after intranasal self-administration of OT or placebo. A fronto-central positive activity at 128-188 ms (P2) was of larger amplitude in response to the pain expressions compared with the neutral expressions of racial in-group members but not of racial out-group members. OT treatment increased this racial in-group bias in neural responses and resulted in its correlation with a positive implicit attitude toward racial in-group members. Our findings suggest that OT interacts with the intergroup relationship to modulate empathic neural responses to others' suffering.

  17. Modulation of invariant natural killer T cell cytokine responses by indoleamine 2,3-dioxygenase

    PubMed Central

    Molano, Alberto; Illarionov, Petr A.; Besra, Gurdyal S.; Putterman, Chaim; Porcelli, Steven A.

    2008-01-01

    1. SUMMARY The intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which degrades the rare and essential aminoacid tryptophan and converts it into a series of biologically active catabolites, has been linked to the regulation of immune tolerance by specific dendritic cell subsets, and to the downmodulation of exacerbated immune responses. Although the immunoregulatory effects of IDO may be in part due to generalized suppression of cell proliferation caused by tryptophan starvation, there is also evidence that tryptophan catabolites could be directly responsible for some of the observed effects. In this report, we investigated the consequences of IDO activity, particularly with regard to the effects of tryptophan-derived catabolites, on the cytokine responses of activated invariant natural killer T (iNKT) cells, a specialized T cell subset known to have immunoregulatory properties. Our results showed that pharmacologic inhibition of IDO skewed cytokine responses of iNKT cells towards a Th1 profile. In contrast, the presence at low micromolar concentrations of the tryptophan catabolites L-kynurenine, 3-hydroxy-kynurenine, or 3-hydroxy-anthranilic acid shifted the cytokine balance towards a Th2 pattern. These findings have implications for our current understanding of immunoregulation, and the mechanisms by which iNKT cells participate in the modulation of immune responses. PMID:18272236

  18. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.

    PubMed

    Dekkers, Johanna F; Berkers, Gitte; Kruisselbrink, Evelien; Vonk, Annelotte; de Jonge, Hugo R; Janssens, Hettie M; Bronsveld, Inez; van de Graaf, Eduard A; Nieuwenhuis, Edward E S; Houwen, Roderick H J; Vleggaar, Frank P; Escher, Johanna C; de Rijke, Yolanda B; Majoor, Christof J; Heijerman, Harry G M; de Winter-de Groot, Karin M; Clevers, Hans; van der Ent, Cornelis K; Beekman, Jeffrey M

    2016-06-22

    Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation. PMID:27334259

  19. Spatial Attention and Temporal Expectation Under Timed Uncertainty Predictably Modulate Neuronal Responses in Monkey V1.

    PubMed

    Sharma, Jitendra; Sugihara, Hiroki; Katz, Yarden; Schummers, James; Tenenbaum, Joshua; Sur, Mriganka

    2015-09-01

    The brain uses attention and expectation as flexible devices for optimizing behavioral responses associated with expected but unpredictably timed events. The neural bases of attention and expectation are thought to engage higher cognitive loci; however, their influence at the level of primary visual cortex (V1) remains unknown. Here, we asked whether single-neuron responses in monkey V1 were influenced by an attention task of unpredictable duration. Monkeys covertly attended to a spot that remained unchanged for a fixed period and then abruptly disappeared at variable times, prompting a lever release for reward. We show that monkeys responded progressively faster and performed better as the trial duration increased. Neural responses also followed monkey's task engagement-there was an early, but short duration, response facilitation, followed by a late but sustained increase during the time monkeys expected the attention spot to disappear. This late attentional modulation was significantly and negatively correlated with the reaction time and was well explained by a modified hazard function. Such bimodal, time-dependent changes were, however, absent in a task that did not require explicit attentional engagement. Thus, V1 neurons carry reliable signals of attention and temporal expectation that correlate with predictable influences on monkeys' behavioral responses. PMID:24836689

  20. Copying competitors? Interdependency modulates stimulus-based retrieval of observed responses.

    PubMed

    Giesen, Carina; Herrmann, Johanna; Rothermund, Klaus

    2014-10-01

    We investigated whether stimuli are integrated with responses that are merely observed, but not executed by oneself, and examined the moderating role of mutual dependency between coactors on the binding and retrieval of stimuli and observed responses. A prime-probe paradigm was shared between 2 coactors who took the roles of actor and observer in turns. We also varied the interdependency between the pairs of participants (cooperation vs. competition vs. independence). Results of Experiment 1 indicated that prime observers showed stimulus-based retrieval of observed responses when it was their turn to act in the 2 interdependent conditions, whereas prime observers in the independent condition did not. Results of Experiment 2 excluded the possibility that the stronger retrieval effects in the interdependent conditions are due to social facilitation of retrieval processes in general, as interdependency did not modulate stimulus-based retrieval of self-generated responses. We conclude that binding and retrieval of stimuli and observed responses is a conditionally automatic process that is contingent on mutual dependency between actor and observer.

  1. Phototropin 1 and dim-blue light modulate the red light de-etiolation response.

    PubMed

    Wang, Yihai; M Folta, Kevin

    2014-01-01

    Light signals regulate seedling morphological changes during de-etiolation through the coordinated actions of multiple light-sensing pathways. Previously we have shown that red-light-induced hypocotyl growth inhibition can be reversed by addition of dim blue light through the action of phototropin 1 (phot1). Here we further examine the fluence-rate relationships of this blue light effect in short-term (hours) and long-term (days) hypocotyl growth assays. The red stem-growth inhibition and blue promotion is a low-fluence rate response, and blue light delays or attenuates both the red light and far-red light responses. These de-etiolation responses include blue light reversal of red or far-red induced apical hook opening. This response also requires phot1. Cryptochromes (cry1 and cry2) are activated by higher blue light fluence-rates and override phot1's influence on hypocotyl growth promotion. Exogenous application of auxin transport inhibitor naphthylphthalamic acid abolished the blue light stem growth promotion in both hypocotyl growth and hook opening. Results from the genetic tests of this blue light effect in auxin transporter mutants, as well as phytochrome kinase substrate mutants indicated that aux1 may play a role in blue light reversal of red light response. Together, the phot1-mediated adjustment of phytochrome-regulated photomorphogenic events is most robust in dim blue light conditions and is likely modulated by auxin transport through its transporters. PMID:25482790

  2. Copying competitors? Interdependency modulates stimulus-based retrieval of observed responses.

    PubMed

    Giesen, Carina; Herrmann, Johanna; Rothermund, Klaus

    2014-10-01

    We investigated whether stimuli are integrated with responses that are merely observed, but not executed by oneself, and examined the moderating role of mutual dependency between coactors on the binding and retrieval of stimuli and observed responses. A prime-probe paradigm was shared between 2 coactors who took the roles of actor and observer in turns. We also varied the interdependency between the pairs of participants (cooperation vs. competition vs. independence). Results of Experiment 1 indicated that prime observers showed stimulus-based retrieval of observed responses when it was their turn to act in the 2 interdependent conditions, whereas prime observers in the independent condition did not. Results of Experiment 2 excluded the possibility that the stronger retrieval effects in the interdependent conditions are due to social facilitation of retrieval processes in general, as interdependency did not modulate stimulus-based retrieval of self-generated responses. We conclude that binding and retrieval of stimuli and observed responses is a conditionally automatic process that is contingent on mutual dependency between actor and observer. PMID:25151104

  3. Ultrasensitivity in the Cofilin Signaling Module: A Mechanism for Tuning T Cell Responses

    PubMed Central

    Ramirez-Munoz, Rocio; Castro-Sánchez, Patricia; Roda-Navarro, Pedro

    2016-01-01

    Ultrasensitivity allows filtering weak activating signals and responding emphatically to small changes in stronger stimuli. In the presence of positive feedback loops, ultrasensitivity enables the existence of bistability, which convert graded stimuli into switch-like, sometimes irreversible, responses. In this perspective, we discuss mechanisms that can potentially generate a bistable response in the phosphorylation/dephosphorylation monocycle that regulates the activity of cofilin in dynamic actin networks. We pay particular attention to the phosphatase Slingshot-1 (SSH-1), which is involved in a reciprocal regulation and a positive feedback loop for cofilin activation. Based on these signaling properties and experimental evidences, we propose that bistability in the cofilin signaling module might be instrumental in T cell responses to antigenic stimulation. Initially, a switch-like response in the amount of active cofilin as a function of SSH-1 activation might assist in controlling the naïve T cell specificity and sensitivity. Second, high concentrations of active cofilin might endow antigen-experienced T cells with faster and more efficient responses. We discuss the cofilin function in the context of T cell receptor triggering and spatial regulation of plasma membrane signaling molecules. PMID:26925064

  4. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.

    PubMed

    Dekkers, Johanna F; Berkers, Gitte; Kruisselbrink, Evelien; Vonk, Annelotte; de Jonge, Hugo R; Janssens, Hettie M; Bronsveld, Inez; van de Graaf, Eduard A; Nieuwenhuis, Edward E S; Houwen, Roderick H J; Vleggaar, Frank P; Escher, Johanna C; de Rijke, Yolanda B; Majoor, Christof J; Heijerman, Harry G M; de Winter-de Groot, Karin M; Clevers, Hans; van der Ent, Cornelis K; Beekman, Jeffrey M

    2016-06-22

    Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.

  5. The amygdala modulates neuronal activation in the hippocampus in response to spatial novelty.

    PubMed

    Sheth, Archana; Berretta, Sabina; Lange, Nicholas; Eichenbaum, Howard

    2008-01-01

    Emerging evidence indicates that the amygdala and the hippocampus play an important role in the pathophysiology of major psychotic disorders. Consistent with this evidence, and with data indicating amygdala modulation of hippocampal activity, animal model investigations have shown that a disruption of amygdala activity induces neurochemical changes in the hippocampus that are similar to those detected in subjects with schizophrenia. With the present study, we used induction of the immediate early gene Fos, to test the hypothesis that the amygdala may affect neuronal activation of the hippocampus in response to different spatial environments (familiar, modified, and novel). Exploratory and anxiety related behaviors were also assessed. In vehicle-treated rats, exposure to a modified version of the familiar environment was associated with an increase of numerical densities of Fos-immunoreactive nuclei in sectors CA1 and CA2, while exposure to a completely novel environment was associated with an increase in sectors CA1, CA4, and DG, compared with the familiar environment. Pharmacological disruption of amygdala activity resulted in a failure to increase Fos induction in the hippocampus in response to these environments. Exploratory behavior in response to the different environments was not altered by manipulation of amygdala activity. These findings support the idea that the amygdala modulates spatial information processing in the hippocampus and may affect encoding of specific environmental features, while complex behavioral responses to environment may be the result of broader neural circuits. These findings also raise the possibility that amygdala abnormalities may contribute to impairments in cognitive information processing in subjects with major psychoses.

  6. Dimerization Controls Marburg Virus VP24-dependent Modulation of Host Antioxidative Stress Responses.

    PubMed

    Johnson, Britney; Li, Jing; Adhikari, Jagat; Edwards, Megan R; Zhang, Hao; Schwarz, Toni; Leung, Daisy W; Basler, Christopher F; Gross, Michael L; Amarasinghe, Gaya K

    2016-08-28

    Marburg virus (MARV), a member of the Filoviridae family that also includes Ebola virus (EBOV), causes lethal hemorrhagic fever with case fatality rates that have exceeded 50% in some outbreaks. Within an infected cell, there are numerous host-viral interactions that contribute to the outcome of infection. Recent studies identified MARV protein 24 (mVP24) as a modulator of the host antioxidative responses, but the molecular mechanism remains unclear. Using a combination of biochemical and mass spectrometry studies, we show that mVP24 is a dimer in solution that directly binds to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) to regulate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). This interaction between Keap1 and mVP24 occurs through the Kelch interaction loop (K-Loop) of mVP24 leading to upregulation of antioxidant response element transcription, which is distinct from other Kelch binders that regulate Nrf2 activity. N-terminal truncations disrupt mVP24 dimerization, allowing monomeric mVP24 to bind Kelch with higher affinity and stimulate higher antioxidative stress response element (ARE) reporter activity. Mass spectrometry-based mapping of the interface revealed overlapping binding sites on Kelch for mVP24 and the Nrf2 proteins. Substitution of conserved cysteines, C209 and C210, to alanine in the mVP24 K-Loop abrogates Kelch binding and ARE activation. Our studies identify a shift in the monomer-dimer equilibrium of MARV VP24, driven by its interaction with Keap1 Kelch domain, as a critical determinant that modulates host responses to pathogenic Marburg viral infections. PMID:27497688

  7. Targeting microRNAs as key modulators of tumor immune response.

    PubMed

    Paladini, Laura; Fabris, Linda; Bottai, Giulia; Raschioni, Carlotta; Calin, George A; Santarpia, Libero

    2016-06-27

    The role of immune response is emerging as a key factor in the complex multistep process of cancer. Tumor microenvironment contains different types of immune cells, which contribute to regulate the fine balance between anti and protumor signals. In this context, mechanisms of crosstalk between cancer and immune cells remain to be extensively elucidated. Interestingly, microRNAs (miRNAs) have been demonstrated to function as crucial regulators of immune response in both physiological and pathological conditions. Specifically, different miRNAs have been reported to have a role in controlling the development and the functions of tumor-associated immune cells. This review aims to describe the most important miRNAs acting as critical modulators of immune response in the context of different solid tumors. In particular, we discuss recent studies that have demonstrated the existence of miRNA-mediated mechanisms regulating the recruitment and the activation status of specific tumor-associated immune cells in the tumor microenvironment. Moreover, various miRNAs have been found to target key cancer-related immune pathways, which concur to mediate the secretion of immunosuppressive or immunostimulating factors by cancer or immune cells. Modalities of miRNA exchange and miRNA-based delivery strategies are also discussed. Based on these findings, the modulation of individual or multiple miRNAs has the potential to enhance or inhibit specific immune subpopulations supporting antitumor immune responses, thus contributing to negatively affect tumorigenesis. New miRNA-based strategies can be developed for more effective immunotherapeutic interventions in cancer.

  8. How Does Emotional Context Modulate Response Inhibition in Alexithymia: Electrophysiological Evidence from an ERP Study

    PubMed Central

    Yu, Fengqiong; Cao, Zhaolun; Zhu, Chunyan; Cai, Zhu; Hu, Panpan; Pu, Hui; Wang, Kai

    2012-01-01

    Background Alexithymia, characterized by difficulties in identifying and describing feelings, is highly indicative of a broad range of psychiatric disorders. Several studies have also discovered the response inhibition ability impairment in alexithymia. However, few studies on alexithymic individuals have specifically examined how emotional context modulates response inhibition procedure. In order to investigate emotion cognition interaction in alexithymia, we analyzed the spatiao-temporal features of such emotional response inhibition by the approaches of event-related potentials and neural source-localization. Method The study participants included 15 subjects with high alexithymia scores on the 20-item Toronto Alexithymia Scale (alexithymic group) and 15 matched subjects with low alexithymia scores (control group). Subjects were instructed to perform a modified emotional Go/Nogo task while their continuous electroencephalography activities were synchronously recorded. The task includes 3 categories of emotional contexts (positive, negative and neutral) and 2 letters (“M” and “W”) centered in the screen. Participants were told to complete go and nogo actions based on the letters. We tested the influence of alexithymia in this emotional Go/Nogo task both in behavioral level and related neural activities of N2 and P3 ERP components. Results We found that negatively valenced context elicited larger central P3 amplitudes of the Nogo–Go difference wave in the alexithymic group than in the control group. Furthermore, source-localization analyses implicated the anterior cingulate cortex (ACC) as the neural generator of the Nogo-P3. Conclusion These findings suggest that difficulties in identifying feelings, particularly in negative emotions, is a major feature of alexithymia, and the ACC plays a critical role in emotion-modulated response inhibition related to alexithymia. PMID:23227242

  9. The Effect of Nanotopography on Modulating Protein Adsorption and the Fibrotic Response

    PubMed Central

    Kam, Kimberly R.; Walsh, Laura A.; Bock, Suzanne M.; Ollerenshaw, Jeremy D.; Ross, Russell F.

    2014-01-01

    Understanding and modulating the cellular response to implanted biomaterials is crucial for the field of tissue engineering and regenerative medicine. Since cells typically reside in an extracellular matrix containing nanoscale architecture, identifying synthetic nanostructures that induce desirable cellular behaviors could greatly impact the field. Using nanoimprint lithography, nanostructured patterns were generated on thin film polymeric materials. The ability of these surfaces to influence protein adsorption, fibroblast proliferation and morphology, and fibrotic markers was investigated. Nanostructured features with aspect ratios greater than five allowed for less protein adsorption, resulting in decreased fibroblast proliferation and rounded cellular morphology. These nanofeatures also induced significantly lower gene expression of collagen 1α2, collagen 3α1, and growth factors such as connective tissue growth factor, integrin linked kinase, transforming growth factor β1 (TGF-β1), and epidermal growth factor, key factors associated with a fibrotic response. The results demonstrate that select nanostructured surfaces could be used to modulate the fibrotic behavior in cells and have the potential to be used as antifibrotic architecture for medical implants or tissue engineering scaffolds. PMID:23914986

  10. Methanothermobacter thermautotrophicus modulates its membrane lipids in response to hydrogen and nutrient availability

    PubMed Central

    Yoshinaga, Marcos Y.; Gagen, Emma J.; Wörmer, Lars; Broda, Nadine K.; Meador, Travis B.; Wendt, Jenny; Thomm, Michael; Hinrichs, Kai-Uwe

    2015-01-01

    Methanothermobacter thermautotrophicus strain ΔH is a model hydrogenotrophic methanogen, for which extensive biochemical information, including the complete genome sequence, is available. Nevertheless, at the cell membrane lipid level, little is known about the responses of this archaeon to environmental stimuli. In this study, the lipid composition of M. thermautotrophicus was characterized to verify how this archaeon modulates its cell membrane components during growth phases and in response to hydrogen depletion and nutrient limitation (potassium and phosphate). As opposed to the higher abundance of phospholipids in the stationary phase of control experiments, cell membranes under nutrient, and energy stress were dominated by glycolipids that likely provided a more effective barrier against ion leakage. We also identified particular lipid regulatory mechanisms in M. thermautotrophicus, which included the accumulation of polyprenols under hydrogen-limited conditions and an increased content of sodiated adducts of lipids in nutrient-limited cells. These findings suggest that M. thermautotrophicus intensely modulates its cell membrane lipid composition to cope with energy and nutrient availability in dynamic environments. PMID:25657645

  11. Pyroelectric PVDF sensor modeling of the temporal voltage response to arbitrarily modulated radiation.

    PubMed

    Capineri, L; Masotti, L; Mazzoni, M

    2000-01-01

    Our design of transducer arrays for custom pyroelectric sensors is mainly devoted to IR laser beam characterization and control. It benefits from some of the properties of PVDF film such as low cost, low weight, mechanical flexibility, chemical stability (inert), and compatibility of thick film interconnection technologies on metallized films. By using the temporal characteristics of the source intensity and starting from a standard equivalent one-dimensional model of a multilayer thick-film transducer in the frequency domain, we developed a computer model of the PVDF sensor that determines the temporal response to arbitrarily modulated radiation. The validation of the model accuracy has been carried out with a simulation procedure performed on a PVDF sensor designed for accurate beam alignment of low power laser beams. In this case, an iterative algorithm also was developed to estimate some thermal and physical properties of the front absorbing and the metallization layers that are generally barely known. We present a fitting procedure to determine these properties by using the temporal pyroelectric response to a square wave modulated laser diode that provides a reliable reference signal. PMID:18238686

  12. Self-esteem modulates amygdala-ventrolateral prefrontal cortex connectivity in response to mortality threats.

    PubMed

    Yanagisawa, Kuniaki; Abe, Nobuhito; Kashima, Emiko S; Nomura, Michio

    2016-03-01

    Reminders of death often elicit defensive responses in individuals, especially among those with low self-esteem. Although empirical evidence indicates that self-esteem serves as a buffer against mortality threats, the precise neural mechanism underlying this effect remains unknown. We used functional magnetic resonance imaging (fMRI) to test the hypothesis that self-esteem modulates neural responses to death-related stimuli, especially functional connectivity within the limbic-frontal circuitry, thereby affecting subsequent defensive reactions. As predicted, individuals with high self-esteem subjected to a mortality threat exhibited increased amygdala-ventrolateral prefrontal cortex (VLPFC) connectivity during the processing of death-related stimuli compared with individuals who have low self-esteem. Further analysis revealed that stronger functional connectivity between the amygdala and the VLPFC predicted a subsequent decline in responding defensively to those who threaten one's beliefs. These results suggest that the amygdala-VLPFC interaction, which is modulated by self-esteem, can reduce the defensiveness caused by death-related stimuli, thereby providing a neural explanation for why individuals with high self-esteem exhibit less defensive reactions to mortality threats.

  13. Endocannabinoid modulation of fear responses: learning and state-dependent performance effects.

    PubMed

    Reich, C G; Mohammadi, M H; Alger, B E

    2008-09-01

    Recently, disruption of the endogenous cannabinoid (endocannabinoid, eCB) system was found to impair extinction in delay and contextual fear conditioning models. However, conditioning procedures used in that work precluded investigation of possible eCB effects on acquisition of learned fear. We therefore examined the role of eCBs in modulating fear responses using multiple-trial versions of trace (hippocampal-dependent) and delay (amygdala-dependent) Pavlovian fear conditioning. By administering the CB1 receptor antagonist AM251 (5 mg/kg, i.p) to C57/Bl/6 mice at various times, we systematically identified the stages of learning and memory (i.e. acquisition, consolidation, recall and extinction) that are modulated by eCB signaling. During tone (CS) - footshock (US) conditioning, AM251 enhanced acquisition of freezing behavior for both trace- and delay-conditioning protocols. CB1 antagonism also enhanced generalized fear (baseline freezing) and cued (CS) freezing during memory recall tests in a state-dependent manner for both trace and delay conditioned animals. Furthermore, in trace-conditioned animals, AM251 impaired extinction performance of both cued and generalized fear. CB1 antagonism did not affect short-term memory (STM) or long-term memory (LTM) consolidation processes. Together, these results suggest that during acquisition and recall of aversive learning, eCBs prevent the expression and retention of inappropriate generalized and learned responses. These findings have important implications for the therapeutic use of CB1 antagonists.

  14. Risk for eating disorders modulates startle-responses to body words.

    PubMed

    Herbert, Cornelia; Kübler, Andrea; Vögele, Claus

    2013-01-01

    Body image disturbances are core symptoms of eating disorders (EDs). Recent evidence suggests that changes in body image may occur prior to ED onset and are not restricted to in-vivo exposure (e.g. mirror image), but also evident during presentation of abstract cues such as body shape and weight-related words. In the present study startle modulation, heart rate and subjective evaluations were examined during reading of body words and neutral words in 41 student female volunteers screened for risk of EDs. The aim was to determine if responses to body words are attributable to a general negativity bias regardless of ED risk or if activated, ED relevant negative body schemas facilitate priming of defensive responses. Heart rate and word ratings differed between body words and neutral words in the whole female sample, supporting a general processing bias for body weight and shape-related concepts in young women regardless of ED risk. Startle modulation was specifically related to eating disorder symptoms, as was indicated by significant positive correlations with self-reported body dissatisfaction. These results emphasize the relevance of examining body schema representations as a function of ED risk across different levels of responding. Peripheral-physiological measures such as the startle reflex could possibly be used as predictors of females' risk for developing EDs in the future.

  15. Prestimulus EEG Alpha Oscillations Modulate Task-Related fMRI BOLD Responses to Auditory Stimuli

    PubMed Central

    Walz, Jennifer M.; Goldman, Robin I.; Carapezza, Michael; Muraskin, Jordan; Brown, Truman R.; Sajda, Paul

    2015-01-01

    EEG alpha-band activity is generally thought to represent an inhibitory state related to decreased attention and play a role in suppression of task-irrelevant stimulus processing, but a competing hypothesis suggests an active role in processing task-relevant information – one in which phase dynamics are involved. Here we used simultaneous EEG-fMRI and a whole-brain analysis to investigate the effects of prestimulus alpha activity on the event-related BOLD response during an auditory oddball task. We separately investigated the effects of the posterior alpha rhythm’s power and phase on activity related to task-relevant stimulus processing and also investigated higher-level decision-related processing. We found stronger decision-related BOLD activity in areas late in the processing stream when subjects were in the high alpha power state prior to stimulus onset, but did not detect any effect in primary sensory regions. Our phase analysis revealed correlates in bilateral thalamus, providing support for a thalamo-cortical loop in attentional modulations and suggesting that the cortical alpha rhythm acts as a cyclic modulator of task-related responses very early in the processing stream. Our results help to reconcile the competing inhibition and active-processing hypotheses for ongoing alpha oscillations and begin to tease apart the distinct roles and mechanisms underlying their power and phase. PMID:25797833

  16. Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

    PubMed Central

    Maiya, Rajani; Zhou, Yan; Norris, Erin H.; Kreek, Mary Jeanne; Strickland, Sidney

    2009-01-01

    Cocaine exposure induces long-lasting molecular and structural adaptations in the brain. In this study, we show that tissue plasminogen activator (tPA), an extracellular protease involved in neuronal plasticity, modulates the biochemical and behavioral response to cocaine. When injected in the acute binge paradigm, cocaine enhanced tPA activity in the amygdala, which required activation of corticotropin-releasing factor type-1 (CRF-R1) receptors. Compared with WT mice, tPA−/− mice injected with cocaine displayed attenuated phosphorylation of ERK, cAMP response element binding protein (CREB), and dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and blunted induction of immediate early genes (IEGs) c-Fos, Egr-1, and Homer 1a in the amygdala and the nucleus accumbens (NAc). tPA−/− mice also displayed significantly higher basal preprodynorphin (ppDyn) mRNA levels in the NAc in comparison to WT mice, and cocaine decreased ppDyn mRNA levels in tPA−/− mice only. Cocaine-induced locomotor sensitization and conditioned place preference (CPP) were attenuated in tPA−/− mice. Cocaine exposure also had an anxiolytic effect in tPA−/− but not WT mice. These results identify tPA as an important and novel component of the signaling pathway that modulates cocaine-induced changes in neuroadaptation and behavior. PMID:19181855

  17. Culture modulates the brain response to human expressions of emotion: electrophysiological evidence.

    PubMed

    Liu, Pan; Rigoulot, Simon; Pell, Marc D

    2015-01-01

    To understand how culture modulates on-line neural responses to social information, this study compared how individuals from two distinct cultural groups, English-speaking North Americans and Chinese, process emotional meanings of multi-sensory stimuli as indexed by both behaviour (accuracy) and event-related potential (N400) measures. In an emotional Stroop-like task, participants were presented face-voice pairs expressing congruent or incongruent emotions in conditions where they judged the emotion of one modality while ignoring the other (face or voice focus task). Results indicated that while both groups were sensitive to emotional differences between channels (with lower accuracy and higher N400 amplitudes for incongruent face-voice pairs), there were marked group differences in how intruding facial or vocal cues affected accuracy and N400 amplitudes, with English participants showing greater interference from irrelevant faces than Chinese. Our data illuminate distinct biases in how adults from East Asian versus Western cultures process socio-emotional cues, supplying new evidence that cultural learning modulates not only behaviour, but the neurocognitive response to different features of multi-channel emotion expressions. PMID:25477081

  18. Is Dying Young Worse than Dying Old?

    ERIC Educational Resources Information Center

    Jecker, Nancy S.; Schneiderman, Lawrence J.

    1994-01-01

    Notes that, in contemporary Western society, people feel death of small child is greater injustice than death of older adult and experience correspondingly greater sorrow, anger, regret, or bitterness when very young person dies. Contrasts these attitudes with those of ancient Greece and shows relevance that different attitudes toward death have…

  19. Sesquiterpene lactones induce distinct forms of cell death that modulate human monocyte-derived macrophage responses.

    PubMed

    López-Antón, Nancy; Hermann, Corinna; Murillo, Renato; Merfort, Irmgard; Wanner, Gerhard; Vollmar, Angelika M; Dirsch, Verena M

    2007-01-01

    Sesquiterpene lactones (SQTLs) are shown to possess anti-inflammatory as well as cytotoxic activity. No study, however, links both activities. We, therefore, hypothesized that SQTL-treated, dying cells might induce an anti-inflammatory response in cocultured THP-1 macrophages. Here we show that SQTLs bearing either an alpha,beta-unsaturated cyclopentenone or an alpha-methylene-gamma-lactone induce different forms of cell death. Whereas the cyclopentenone SQTL induced typical apoptosis, the alpha-methylene-gamma-lactone SQTLs-induced cell death lacked partly classical signs of apoptosis, such as DNA fragmentation. All SQTLs, however, activated caspases and the nuclear morphology of cell death was dependent on caspase activation. Most interestingly, alpha-methylene-gamma-lactone SQTLs induced a more pronounced phosphatidylserine (PS) exposure than the cyclopentenone SQTL. Especially, 7-hydroxycostunolide (HC), with an alpha-methylene-gamma-lactone substituted with a hydroxyl group, showed a striking fast and pronounced PS translocation. This result was in agreement with a strong activation of phagocytosis in cocultured THP-1 macrophages. Interestingly, HC-treated Jurkat cells led to an early (3.5 h) but transient increase in TNF-alpha levels in macrophage coculture. Release of TGF-beta remained unaffected after 18 h. We propose that this type of SQTL may influence local inflammation by transiently activating the immune system and help to clear cells by inducing a form of cell death that promotes phagocytosis.

  20. Extrusion die and method

    DOEpatents

    Lipp, G. Daniel

    1994-05-03

    A method and die apparatus for manufacturing a honeycomb body of triangular cell cross-section and high cell density, the die having a combination of (i) feedholes feeding slot intersections and (ii) feedholes feeding slot segments not supplied from slot intersections, whereby a reduction in feedhole count is achieved while still retaining good extrusion efficiency and extrudate uniformity.

  1. Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages.

    PubMed

    Nazimek, Katarzyna; Kozlowski, Michael; Bryniarski, Pawel; Strobel, Spencer; Bryk, Agata; Myszka, Michal; Tyszka, Anna; Kuszmiersz, Piotr; Nowakowski, Jaroslaw; Filipczak-Bryniarska, Iwona

    2016-08-01

    Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive

  2. Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics

    PubMed Central

    Wu, Ann C.; Himes, Blanca E.; Lasky-Su, Jessica; Litonjua, Augusto; Peters, Stephen P.; Lima, John; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Qiu, Weiliang; Weiss, Scott T.; Tantisira, Kelan

    2013-01-01

    Background Single nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and β2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with bronchodilator response. Objective To assess whether, among asthma subjects, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids vs. those on placebo. Methods A genome-wide association analysis was conducted using 581 white subjects from the Childhood Asthma Management Program (CAMP). Using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier Or Corticosteroid or Corticosteroid-Salmeterol (LOCCS) Trial. Results The combined P-value for the CAMP and LOCCS populations was 4.81E-08 for rs3752120, which is located in the zinc finger protein gene ZNF432, and has unknown function. Conclusions Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma. Clinical Implications Clinicians who treat asthma patients with inhaled corticosteroids should be aware that the patient's genetic makeup likely influences response as measured in lung function. Capsule Summary Our study suggests that inhaled corticosteroids could influence the effect of multiple SNPs associated with bronchodilator response across the genome. PMID:24280104

  3. DELLA proteins modulate Arabidopsis defences induced in response to caterpillar herbivory.

    PubMed

    Lan, Zhiyi; Krosse, Sebastian; Achard, Patrick; van Dam, Nicole M; Bede, Jacqueline C

    2014-02-01

    Upon insect herbivory, many plant species change the direction of metabolic flux from growth into defence. Two key pathways modulating these processes are the gibberellin (GA)/DELLA pathway and the jasmonate pathway. In this study, the effect of caterpillar herbivory on plant-induced responses was compared between wild-type Arabidopsis thaliana (L.) Heynh. and quad-della mutants that have constitutively elevated GA responses. The labial saliva (LS) of caterpillars of the beet armyworm, Spodoptera exigua, is known to influence induced plant defence responses. To determine the role of this herbivore cue in determining metabolic shifts, plants were subject to herbivory by caterpillars with intact or impaired LS secretions. In both wild-type and quad-della plants, a jasmonate burst is an early response to caterpillar herbivory. Negative growth regulator DELLA proteins are required for the LS-mediated suppression of hormone levels. Jasmonate-dependent marker genes are induced in response to herbivory independently of LS, with the exception of AtPDF1.2 that showed LS-dependent expression in the quad-della mutant. Early expression of the salicylic acid (SA)-marker gene, AtPR1, was not affected by herbivory which also reflected SA hormone levels; however, this gene showed LS-dependent expression in the quad-della mutant. DELLA proteins may positively regulate glucosinolate levels and suppress laccase-like multicopper oxidase activity in response to herbivory. The present results show a link between DELLA proteins and early, induced plant defences in response to insect herbivory; in particular, these proteins are necessary for caterpillar LS-associated attenuation of defence hormones. PMID:24399173

  4. Responses of neurons in the rat's ventral nucleus of the lateral lemniscus to amplitude-modulated tones.

    PubMed

    Zhang, Huiming; Kelly, Jack B

    2006-12-01

    Recordings were made from single neurons in the rat's ventral nucleus of the lateral lemniscus (VNLL) to determine responses to amplitude-modulated (AM) tones. The neurons were first characterized on the basis of their response to tone bursts presented to the contralateral ear and a distinction was made between those with transient onset responses and those with sustained responses. Sinusoidal AM tones were then presented to the contralateral ear with a carrier that matched the neuron's characteristic frequency (CF). Modulation transfer functions were generated on the basis of firing rate (MTF(FR)) and vector strength (MTF(VS)). Ninety-two percent of onset neurons that responded continuously to AM tones had band-pass MTF(FR)s with best modulation frequencies from 10 to 300 Hz. Fifty-four percent of sustained neurons had band-pass MTF(FR)s with best modulation frequencies from 10 to 500 Hz; other neurons had band-suppressed, all-pass, low-pass, or high-pass functions. Most neurons showed either band-pass or low-pass MTF(VS). Responses were well synchronized to the modulation cycle with maximum vector strengths ranging from 0.37 to 0.98 for sustained neurons and 0.78 to 0.99 for onset neurons. The upper frequency limit for response synchrony was higher than that reported for inferior colliculus, but lower than that seen in more peripheral structures. Results suggest that VNLL neurons, especially those with onset responses to tone bursts, are sensitive to temporal features of sounds and narrowly tuned to different modulation rates. However, there was no evidence of a topographic relation between dorsoventral position along the length of VNLL and best modulation frequency as determined by either firing rate or vector strength. PMID:16928797

  5. Non-linear Membrane Properties in Entorhinal Cortical Stellate Cells Reduce Modulation of Input-Output Responses by Voltage Fluctuations

    PubMed Central

    Fernandez, Fernando R.; Malerba, Paola; White, John A.

    2015-01-01

    The presence of voltage fluctuations arising from synaptic activity is a critical component in models of gain control, neuronal output gating, and spike rate coding. The degree to which individual neuronal input-output functions are modulated by voltage fluctuations, however, is not well established across different cortical areas. Additionally, the extent and mechanisms of input-output modulation through fluctuations have been explored largely in simplified models of spike generation, and with limited consideration for the role of non-linear and voltage-dependent membrane properties. To address these issues, we studied fluctuation-based modulation of input-output responses in medial entorhinal cortical (MEC) stellate cells of rats, which express strong sub-threshold non-linear membrane properties. Using in vitro recordings, dynamic clamp and modeling, we show that the modulation of input-output responses by random voltage fluctuations in stellate cells is significantly limited. In stellate cells, a voltage-dependent increase in membrane resistance at sub-threshold voltages mediated by Na+ conductance activation limits the ability of fluctuations to elicit spikes. Similarly, in exponential leaky integrate-and-fire models using a shallow voltage-dependence for the exponential term that matches stellate cell membrane properties, a low degree of fluctuation-based modulation of input-output responses can be attained. These results demonstrate that fluctuation-based modulation of input-output responses is not a universal feature of neurons and can be significantly limited by subthreshold voltage-gated conductances. PMID:25909971

  6. Non-linear Membrane Properties in Entorhinal Cortical Stellate Cells Reduce Modulation of Input-Output Responses by Voltage Fluctuations.

    PubMed

    Fernandez, Fernando R; Malerba, Paola; White, John A

    2015-04-01

    The presence of voltage fluctuations arising from synaptic activity is a critical component in models of gain control, neuronal output gating, and spike rate coding. The degree to which individual neuronal input-output functions are modulated by voltage fluctuations, however, is not well established across different cortical areas. Additionally, the extent and mechanisms of input-output modulation through fluctuations have been explored largely in simplified models of spike generation, and with limited consideration for the role of non-linear and voltage-dependent membrane properties. To address these issues, we studied fluctuation-based modulation of input-output responses in medial entorhinal cortical (MEC) stellate cells of rats, which express strong sub-threshold non-linear membrane properties. Using in vitro recordings, dynamic clamp and modeling, we show that the modulation of input-output responses by random voltage fluctuations in stellate cells is significantly limited. In stellate cells, a voltage-dependent increase in membrane resistance at sub-threshold voltages mediated by Na+ conductance activation limits the ability of fluctuations to elicit spikes. Similarly, in exponential leaky integrate-and-fire models using a shallow voltage-dependence for the exponential term that matches stellate cell membrane properties, a low degree of fluctuation-based modulation of input-output responses can be attained. These results demonstrate that fluctuation-based modulation of input-output responses is not a universal feature of neurons and can be significantly limited by subthreshold voltage-gated conductances.

  7. Suppression of flicker response with increasing test illuminance: roles of temporal waveform, modulation depth, and frequency.

    PubMed

    Eisner, A

    1995-02-01

    This study examined the detectability of flicker for small foveal long-wavelength test stimuli centered within surrounding long-wavelength annular adaptation stimuli. Flicker threshold-versus-illuminance (tvi) curves were analyzed for four different test-stimulus waveforms--sine-wave, square-wave, and rapid-on sawtooth and rapid-off sawtooth flicker--at temporal frequencies ranging from 12 to 21 Hz and at temporal modulation depths ranging from approximately 50% to 100%. For all stimulus combinations that were examined involving temporal frequencies above 12 Hz, the resultant flicker tvi curves shared the following characteristic features: First, at operationally dim surround illuminances, there was always a single elevated threshold for detection of flicker. Second, some surround illuminance always could be found for which flicker threshold decreased abruptly, typically by approximately 1.5 log units within 0.1 log unit of surround illuminance increase. Third, when test illuminance was incremented above this lower flicker threshold, flicker always vanished; when test illuminance was incremented still further, flicker reappeared. Finally, at sufficiently bright surround illuminances flicker did not disappear with increasing test illuminance. Although these effects held for all waveforms, the abrupt decrease of flicker threshold occurred at brighter surround illuminances for sawtooth than for sine-wave flicker, and at brighter surround illuminances for sine-wave than for square-wave flicker, at least for fully modulated waveforms (of a given temporal frequency). Moreover, when modulation depth was adjusted so that any two different waveforms had the same first-harmonic contrast, the resultant flicker tvi curves became identical when plotted as first-harmonic amplitude versus surround illuminance. This identity held for any given temporal frequency, even though the flicker tvi curves for 12-Hz fully modulated sine-wave or square-wave flicker did not manifest flicker

  8. Brain stem adenosine receptors modulate centrally mediated hypotensive responses in conscious rats: A review.

    PubMed

    Nassar, Noha N; Abdel-Rahman, Abdel A

    2015-05-01

    Adenosine is implicated in the modulation of cardiovascular responses either at the peripheral or at central level in experimental animals. However, there are no dedicated reviews on the involvement of adenosine in mediating the hypotensive response of centrally administered clonidine in general and specifically in aortically barodenervated rats (ABD). The conscious ABD rat model exhibits surgically induced baroreflex dysfunction and exaggerated hypotensive response, compared with conscious sham-operated (SO) rats. The current review focuses on, the role of adenosine receptors in blood pressure (BP) regulation and their possible crosstalk with other receptors e.g. imidazoline (I1) and alpha (α2A) adrenergic receptor (AR). The former receptor is a molecular target for clonidine, whose hypotensive effect is enhanced approx. 3-fold in conscious ABD rats. We also discussed how the balance between the brain stem adenosine A1 and A2A receptors is regulated by baroreceptors and how such balance influences the centrally mediated hypotensive responses. The use of the ABD rat model yielded insight into the downstream signaling cascades following clonidine-evoked hypotension in a surgical model of baroreflex dysfunction. PMID:26257930

  9. Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.

    PubMed

    Verthelyi, Daniela; Wang, Vivian

    2010-12-22

    Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these products are frequent and can seriously impact their safety and efficacy. Of the many factors that can impact protein immunogenicity, this study focuses on the role of innate immune response modulating impurities (IIRMIs) that could be present despite product purification and whether these impurities can synergize to facilitate an immunogenic response to therapeutic proteins. Using lipopolysaccharide (LPS) and CpG ODN as IIRMIs we showed that trace levels of these impurities synergized to induce IgM, IFNγ, TNFα and IL-6 expression. In vivo, trace levels of these impurities synergized to increase antigen-specific IgG antibodies to ovalbumin. Further, whereas mice treated with human erythropoietin showed a transient increase in hematocrit, those that received human erythropoietin containing low levels of IIRMIs had reduced response to erythropoietin after the 1(st) dose and developed long-lasting anemia following subsequent doses. This suggests that the presence of IIRMIs facilitated a breach in tolerance to the endogenous mouse erythropoietin. Overall, these studies indicate that the risk of enhancing immunogenicity should be considered when establishing acceptance limits of IIRMIs for therapeutic proteins.

  10. BAS-drive trait modulates dorsomedial striatum activity during reward response-outcome associations.

    PubMed

    Costumero, Víctor; Barrós-Loscertales, Alfonso; Fuentes, Paola; Rosell-Negre, Patricia; Bustamante, Juan Carlos; Ávila, César

    2016-09-01

    According to the Reinforcement Sensitivity Theory, behavioral studies have found that individuals with stronger reward sensitivity easily detect cues of reward and establish faster associations between instrumental responses and reward. Neuroimaging studies have shown that processing anticipatory cues of reward is accompanied by stronger ventral striatum activity in individuals with stronger reward sensitivity. Even though establishing response-outcome contingencies has been consistently associated with dorsal striatum, individual differences in this process are poorly understood. Here, we aimed to study the relation between reward sensitivity and brain activity while processing response-reward contingencies. Forty-five participants completed the BIS/BAS questionnaire and performed a gambling task paradigm in which they received monetary rewards or punishments. Overall, our task replicated previous results that have related processing high reward outcomes with activation of striatum and medial frontal areas, whereas processing high punishment outcomes was associated with stronger activity in insula and middle cingulate. As expected, the individual differences in the activity of dorsomedial striatum correlated positively with BAS-Drive. Our results agree with previous studies that have related the dorsomedial striatum with instrumental performance, and suggest that the individual differences in this area may form part of the neural substrate responsible for modulating instrumental conditioning by reward sensitivity. PMID:26489979

  11. Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator).

    PubMed

    Isoda, Takayoshi; Paolocci, Nazareno; Haghighi, Kobra; Wang, Congrong; Wang, Yibin; Georgakopoulos, Dimitrios; Servillo, Giuseppe; Della Fazia, Maria Agnese; Kranias, Evangelia G; Depaoli-Roach, Anna A; Sassone-Corsi, Paolo; Kass, David A

    2003-02-01

    The cAMP response element modulator (CREM) plays pivotal roles in the hypothalamic-pituitary-gonadal axis. CREM mRNA is robustly expressed in human myocardium, and identified isoforms may suppress cAMP response element-mediated transcription. However, little is known about the physiological importance of CREM in intact hearts remains unknown. We studied CREM-null mice and age-matched control littermates by in vivo pressure-volume loops to analyze basal and reserve cardiac function. Basal systolic and diastolic function, echocardiographic morphology, and myocardial histology were normal in CREM-null animals. However functional reserve with increasing heart rate was markedly depressed, with less contractile augmentation (+22+/-9% CREM-/- vs.+62+/-11% controls, P<0.05) and relaxation shortening (5+/-5% CREM-/- vs. -18+/-3% controls; P<0.05) at faster rates. In contrast, isoproterenol dose-responses were similar, suggesting normal beta-adrenergic receptor-coupled signaling. Gene expression of calcium handling proteins (SERCA, phospholamban) and stress-response genes (e.g., alpha-skeletal actin, beta-myosin heavy chain, natriuretic peptides) were similar between groups. However, total and serine-phosphorylated phospholamban protein declined -38 and -64% respectively, and protein phosphatase-1 (PP1) activity increased 44% without increased protein levels (all P<0.01) in CREM-/- vs. controls. These results demonstrate novel involvement of CREM in regulation of PP1 activity and of PLB, likely resulting in a potent frequency-dependent influence on cardiac function.

  12. BAS-drive trait modulates dorsomedial striatum activity during reward response-outcome associations.

    PubMed

    Costumero, Víctor; Barrós-Loscertales, Alfonso; Fuentes, Paola; Rosell-Negre, Patricia; Bustamante, Juan Carlos; Ávila, César

    2016-09-01

    According to the Reinforcement Sensitivity Theory, behavioral studies have found that individuals with stronger reward sensitivity easily detect cues of reward and establish faster associations between instrumental responses and reward. Neuroimaging studies have shown that processing anticipatory cues of reward is accompanied by stronger ventral striatum activity in individuals with stronger reward sensitivity. Even though establishing response-outcome contingencies has been consistently associated with dorsal striatum, individual differences in this process are poorly understood. Here, we aimed to study the relation between reward sensitivity and brain activity while processing response-reward contingencies. Forty-five participants completed the BIS/BAS questionnaire and performed a gambling task paradigm in which they received monetary rewards or punishments. Overall, our task replicated previous results that have related processing high reward outcomes with activation of striatum and medial frontal areas, whereas processing high punishment outcomes was associated with stronger activity in insula and middle cingulate. As expected, the individual differences in the activity of dorsomedial striatum correlated positively with BAS-Drive. Our results agree with previous studies that have related the dorsomedial striatum with instrumental performance, and suggest that the individual differences in this area may form part of the neural substrate responsible for modulating instrumental conditioning by reward sensitivity.

  13. Modulation of PF10_0355 (MSPDBL2) Alters Plasmodium falciparum Response to Antimalarial Drugs

    PubMed Central

    Van Tyne, Daria; Uboldi, Alessandro D.; Healer, Julie; Cowman, Alan F.

    2013-01-01

    Malaria's ability to rapidly adapt to new drugs has allowed it to remain one of the most devastating infectious diseases of humans. Understanding and tracking the genetic basis of these adaptations are critical to the success of treatment and intervention strategies. The novel antimalarial resistance locus PF10_0355 (Pfmspdbl2) was previously associated with the parasite response to halofantrine, and functional validation confirmed that overexpression of this gene lowered parasite sensitivity to both halofantrine and the structurally related antimalarials mefloquine and lumefantrine, predominantly through copy number variation. Here we further characterize the role of Pfmspdbl2 in mediating the antimalarial drug response of Plasmodium falciparum. Knockout of Pfmspdbl2 increased parasite sensitivity to halofantrine, mefloquine, and lumefantrine but not to unrelated antimalarials, further suggesting that this gene mediates the parasite response to a specific class of antimalarial drugs. A single nucleotide polymorphism encoding a C591S mutation within Pfmspdbl2 had the strongest association with halofantrine sensitivity and showed a high derived allele frequency among Senegalese parasites. Transgenic parasites expressing the ancestral Pfmspdbl2 allele were more sensitive to halofantrine and structurally related antimalarials than were parasites expressing the derived allele, revealing an allele-specific effect on drug sensitivity in the absence of copy number effects. Finally, growth competition experiments showed that under drug pressure, parasites expressing the derived allele of Pfmspdbl2 outcompeted parasites expressing the ancestral allele within a few generations. Together, these experiments demonstrate that modulation of Pfmspdbl2 affects malaria parasite responses to antimalarial drugs. PMID:23587962

  14. Immune modulation of macrophage pro-inflammatory response by goldenseal and Astragalus extracts.

    PubMed

    Clement-Kruzel, Stacia; Hwang, Shen-An; Kruzel, Mark C; Dasgupta, Amitava; Actor, Jeffrey K

    2008-09-01

    Goldenseal (Hydrastis canadenisis) is a native American medicinal plant used as an immune stimulant. Astragalus (Astragalus membranaceus) is a widely used herbal product in China, other Asian countries, and the United States as an immune stimulant to be taken on first clinical signs of infection. In this study, the innate effects of goldenseal and Astragalus on pro-inflammatory cytokines produced by cultured macrophages were examined using two different commercial preparations of goldenseal and Astragalus. Both goldenseal and Astragalus were found to exhibit little to no direct effect on stimulation of mouse macrophages (J774A.1 cells), with only Astragalus able to affect production of tumor necrosis factor (TNF)-alpha when used in high concentrations. However, both goldenseal and Astragalus were able to modify responses from lipopolysaccharide-stimulated macrophages, with identified immunomodulatory effects to reduce production of TNF-alpha, interleukin (IL)-6, IL-10, and IL-12 in a dose-dependent manner. The results obtained indicate that both goldenseal and Astragalus exhibit abilities to modulate macrophage responses during stimulation. Therefore, it is hypothesized that their historical use as therapeutic agents may be due to reduction in the pro-inflammatory response that indirectly leads to limiting of clinical symptoms during infection. Both products differ in their immune stimulatory patterns, offering insight into differential use and therapeutic potential of these products to regulate macrophage immune responses and activation events.

  15. Vaccinia-Related Kinase 2 Modulates the Stress Response to Hypoxia Mediated by TAK1▿

    PubMed Central

    Blanco, Sandra; Santos, Claudio; Lazo, Pedro A.

    2007-01-01

    Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response. PMID:17709393

  16. FILAMENTOUS FLOWER Is a Direct Target of JAZ3 and Modulates Responses to Jasmonate.

    PubMed

    Boter, Marta; Golz, John F; Giménez-Ibañez, Selena; Fernandez-Barbero, Gemma; Franco-Zorrilla, José M; Solano, Roberto

    2015-11-01

    The plant hormone jasmonate (JA) plays an important role in regulating growth, development, and immunity. Activation of the JA-signaling pathway is based on the hormone-triggered ubiquitination and removal of transcriptional repressors (JASMONATE-ZIM DOMAIN [JAZ] proteins) by an SCF receptor complex (SCF(COI1)/JAZ). This removal allows the rapid activation of transcription factors (TFs) triggering a multitude of downstream responses. Identification of TFs bound by the JAZ proteins is essential to better understand how the JA-signaling pathway modulates and integrates different responses. In this study, we found that the JAZ3 repressor physically interacts with the YABBY (YAB) family transcription factor FILAMENTOUS FLOWER (FIL)/YAB1. In Arabidopsis thaliana, FIL regulates developmental processes such as axial patterning and growth of lateral organs, shoot apical meristem activity, and inflorescence phyllotaxy. Phenotypic analysis of JA-regulated responses in loss- and gain-of-function FIL lines suggested that YABs function as transcriptional activators of JA-triggered responses. Moreover, we show that MYB75, a component of the WD-repeat/bHLH/MYB complex regulating anthocyanin production, is a direct transcriptional target of FIL. We propose that JAZ3 interacts with YABs to attenuate their transcriptional function. Upon perception of JA signal, degradation of JAZ3 by the SCF(COI1) complex releases YABs to activate a subset of JA-regulated genes in leaves leading to anthocyanin accumulation, chlorophyll loss, and reduced bacterial defense. PMID:26530088

  17. The sweet side of inequality: how advantageous status modulates empathic response to others' gains and losses.

    PubMed

    Shen, Qiang; Jin, Jia; Ma, Qingguo

    2013-11-01

    In the past decade, considerable amounts of studies have explored the neural underpinnings of empathic response toward the positive and negative feelings of others, such as pain and social exclusion, in the field of neuroeconomics. In addition, empathic response of observing other's financial gains and losses have recently started to gain increasing attention in this interdisciplinary field. However, the effects of inequality-averse social preference on individuals' response toward other's gains and losses have not yet been clearly characterized. This work conducted an electrophysiological study with a simple gambling task to explore how inequality aversion matters in modulating neural temporal dynamics toward self and others' gains and losses using scalp-recorded event-related potentials (ERPs). The electrophysiological data demonstrated increased amplitude of P300 toward self's monetary gains and losses independent of advantageous and disadvantageous status. Intriguingly, subjects in the high pay group evoked more pronounced gain loss disparity of feedback-related negativity (FRN) amplitude toward others than themselves. Meanwhile, such a pattern was not observed among the subjects in the low pay group. Therefore, the current double dissociation results of FRN and P300 may indicate that advantageous status enhances subjects' empathic response toward others' pecuniary outcome, giving a direct electrophysiological evidence for the economic modeling on inequality aversion behavior. PMID:24004845

  18. The cell surface receptor Slamf6 modulates innate immune responses during Citrobacter rodentium-induced colitis.

    PubMed

    van Driel, Boaz; Wang, Guoxing; Liao, Gongxian; Halibozek, Peter J; Keszei, Marton; O'Keeffe, Michael S; Bhan, Atul K; Wang, Ninghai; Terhorst, Cox

    2015-09-01

    The homophilic cell surface receptors CD150 (Slamf1) and CD352 (Slamf6) are known to modulate adaptive immune responses. Although the Th17 response was enhanced in Slamf6(-/-) C57BL/6 mice upon oral infection with Citrobacter rodentium, the pathologic consequences are indistinguishable from an infection of wild-type C57BL/6 mice. Using a reporter-based binding assay, we show that Slamf6 can engage structures on the outer cell membrane of several Gram(-) bacteria. Therefore, we examined whether Slamf6, like Slamf1, is also involved in innate responses to bacteria and regulates peripheral inflammation by assessing the outcome of C. rodentium infections in Rag(-/-) mice. Surprisingly, the pathology and immune responses in the lamina propria of C. rodentium-infected Slamf6(-/-) Rag(-/-) mice were markedly reduced as compared with those of Rag(-/-) mice. Infiltration of inflammatory phagocytes into the lamina propria was consistently lower in Slamf6(-/-) Rag(-/-) mice than in Rag(-/-) animals. Concomitant with the reduced systemic translocation of the bacteria was an enhanced production of IL-22, suggesting that Slamf6 suppresses a mucosal protective program. Furthermore, administering a mAb (330) that inhibits bacterial interactions with Slamf6 to Rag(-/-) mice ameliorated the infection compared with a control antibody. We conclude that Slamf6-mediated interactions of colonic innate immune cells with specific Gram(-) bacteria reduce mucosal protection and enhance inflammation, contributing to lethal colitis that is caused by C. rodentium infections in Rag(-/-) mice.

  19. Grapevine Plasticity in Response to an Altered Microclimate: Sauvignon Blanc Modulates Specific Metabolites in Response to Increased Berry Exposure.

    PubMed

    Young, Philip R; Eyeghe-Bickong, Hans A; du Plessis, Kari; Alexandersson, Erik; Jacobson, Dan A; Coetzee, Zelmari; Deloire, Alain; Vivier, Melané A

    2016-03-01

    In this study, the metabolic and physiological impacts of an altered microclimate on quality-associated primary and secondary metabolites in grape (Vitis vinifera) 'Sauvignon Blanc' berries was determined in a high-altitude vineyard. The leaf and lateral shoot removal in the bunch zones altered the microclimate by increasing the exposure of the berries. The physical parameters (berry diameter and weight), primary metabolites (sugars and organic acids), as well as bunch temperature and leaf water potential were predominantly not affected by the treatment. The increased exposure led to higher levels of specific carotenoids and volatile terpenoids in the exposed berries, with earlier berry stages reacting distinctly from the later developmental stages. Plastic/nonplastic metabolite responses could be further classified to identify metabolites that were developmentally controlled and/or responded to the treatment in a predictable fashion (assessed over two consecutive vintages). The study demonstrates that grapevine berries exhibit a degree of plasticity within their secondary metabolites and respond physiologically to the increased exposure by increasing metabolites with potential antioxidant activity. Taken together, the data provide evidence that the underlying physiological responses relate to the maintenance of stress pathways by modulating antioxidant molecules in the berries. PMID:26628747

  20. Extracellular vesicles modulate host-microbe responses by altering TLR2 activity and phagocytosis.

    PubMed

    van Bergenhenegouwen, Jeroen; Kraneveld, Aletta D; Rutten, Lieke; Kettelarij, Nienke; Garssen, Johan; Vos, Arjan P

    2014-01-01

    Oral delivery of Gram positive bacteria, often derived from the genera Lactobacillus or Bifidobacterium, can modulate immune function. Although the exact mechanisms remain unclear, immunomodulatory effects may be elicited through the direct interaction of these bacteria with the intestinal epithelium or resident dendritic cell (DC) populations. We analyzed the immune activation properties of Lactobacilli and Bifidobacterium species and made the surprising observation that cellular responses in vitro were differentially influenced by the presence of serum, specifically the extracellular vesicle (EV) fraction. In contrast to the tested Lactobacilli species, tested Bifidobacterium species induce TLR2/6 activity which is inhibited by the presence of EVs. Using specific TLR ligands, EVs were found to enhance cellular TLR2/1 and TLR4 responses while TLR2/6 responses were suppressed. No effect could be observed on cellular TLR5 responses. We determined that EVs play a role in bacterial aggregation, suggesting that EVs interact with bacterial surfaces. EVs were found to slightly enhance DC phagocytosis of Bifidobacterium breve whereas phagocytosis of Lactobacillus rhamnosus was virtually absent upon serum EV depletion. DC uptake of a non-microbial substance (dextran) was not affected by the different serum fractions suggesting that EVs do not interfere with DC phagocytic capacity but rather modify the DC-microbe interaction. Depending on the microbe, combined effects of EVs on TLR activity and phagocytosis result in a differential proinflammatory DC cytokine release. Overall, these data suggest that EVs play a yet unrecognized role in host-microbe responses, not by interfering in recipient cellular responses but via attachment to, or scavenging of, microbe-associated molecular patterns. EVs can be found in any tissue or bodily fluid, therefore insights into EV-microbe interactions are important in understanding the mechanism of action of potential probiotics and gut immune

  1. Coinfection with Streptococcus pneumoniae Modulates the B Cell Response to Influenza Virus

    PubMed Central

    Wolf, Amaya I.; Strauman, Maura C.; Mozdzanowska, Krystyna; Whittle, James R. R.; Williams, Katie L.; Sharpe, Arlene H.; Weiser, Jeffrey N.; Caton, Andrew J.; Hensley, Scott E.

    2014-01-01

    ABSTRACT Pathogen-specific antibodies (Abs) protect against respiratory infection with influenza A virus (IAV) and Streptococcus pneumoniae and are the basis of effective vaccines. Sequential or overlapping coinfections with both pathogens are common, yet the impact of coinfection on the generation and maintenance of Ab responses is largely unknown. We report here that the B cell response to IAV is altered in mice coinfected with IAV and S. pneumoniae and that this response differs, depending on the order of pathogen exposure. In mice exposed to S. pneumoniae prior to IAV, the initial virus-specific germinal center (GC) B cell response is significantly enhanced in the lung-draining mediastinal lymph node and spleen, and there is an increase in CD4+ T follicular helper (TFH) cell numbers. In contrast, secondary S. pneumoniae infection exaggerates early antiviral antibody-secreting cell formation, and at later times, levels of GCs, TFH cells, and antiviral serum IgG are elevated. Mice exposed to S. pneumoniae prior to IAV do not maintain the initially robust GC response in secondary lymphoid organs and exhibit reduced antiviral serum IgG with diminished virus neutralization activity a month after infection. Our data suggest that the history of pathogen exposures can critically affect the generation of protective antiviral Abs and may partially explain the differential susceptibility to and disease outcomes from IAV infection in humans. IMPORTANCE Respiratory tract coinfections, specifically those involving influenza A viruses and Streptococcus pneumoniae, remain a top global health burden. We sought to determine how S. pneumoniae coinfection modulates the B cell immune response to influenza virus since antibodies are key mediators of protection. PMID:25100838

  2. Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design

    PubMed Central

    Brown, Aisling F.; Leech, John M.; Rogers, Thomas R.; McLoughlin, Rachel M.

    2014-01-01

    In apparent contrast to its invasive potential Staphylococcus aureus colonizes the anterior nares of 20–80% of the human population. The relationship between host and microbe appears particularly individualized and colonization status seems somehow predetermined. After decolonization, persistent carriers often become re-colonized with their prior S. aureus strain, whereas non-carriers resist experimental colonization. Efforts to identify factors facilitating colonization have thus far largely focused on the microorganism rather than on the human host. The host responds to S. aureus nasal colonization via local expression of anti-microbial peptides, lipids, and cytokines. Interplay with the co-existing microbiota also influences colonization and immune regulation. Transient or persistent S. aureus colonization induces specific systemic immune responses. Humoral responses are the most studied of these and little is known of cellular responses induced by colonization. Intriguingly, colonized patients who develop bacteremia may have a lower S. aureus-attributable mortality than their non-colonized counterparts. This could imply a staphylococcal-specific immune “priming” or immunomodulation occurring as a consequence of colonization and impacting on the outcome of infection. This has yet to be fully explored. An effective vaccine remains elusive. Anti-S. aureus vaccine strategies may need to drive both humoral and cellular immune responses to confer efficient protection. Understanding the influence of colonization on adaptive response is essential to intelligent vaccine design, and may determine the efficacy of vaccine-mediated immunity. Clinical trials should consider colonization status and the resulting impact of this on individual patient responses. We urgently need an increased appreciation of colonization and its modulation of host immunity. PMID:24409186

  3. Cycle training modulates satellite cell and transcriptional responses to a bout of resistance exercise.

    PubMed

    Murach, Kevin A; Walton, R Grace; Fry, Christopher S; Michaelis, Sami L; Groshong, Jason S; Finlin, Brian S; Kern, Philip A; Peterson, Charlotte A

    2016-09-01

    This investigation evaluated whether moderate-intensity cycle ergometer training affects satellite cell and molecular responses to acute maximal concentric/eccentric resistance exercise in middle-aged women. Baseline and 72 h postresistance exercise vastus lateralis biopsies were obtained from seven healthy middle-aged women (56 ± 5 years, BMI 26 ± 1, VO2max 27 ± 4) before and after 12 weeks of cycle training. Myosin heavy chain (MyHC) I- and II-associated satellite cell density and cross-sectional area was determined via immunohistochemistry. Expression of 93 genes representative of the muscle-remodeling environment was also measured via NanoString. Overall fiber size increased ~20% with cycle training (P = 0.052). MyHC I satellite cell density increased 29% in response to acute resistance exercise before endurance training and 50% with endurance training (P < 0.05). Following endurance training, MyHC I satellite cell density decreased by 13% in response to acute resistance exercise (acute resistance × training interaction, P < 0.05). Genes with an interaction effect tracked with satellite cell behavior, increasing in the untrained state and decreasing in the endurance trained state in response to resistance exercise. Similar satellite cell and gene expression response patterns indicate coordinated regulation of the muscle environment to promote adaptation. Moderate-intensity endurance cycle training modulates the response to acute resistance exercise, potentially conditioning the muscle for more intense concentric/eccentric activity. These results suggest that cycle training is an effective endurance exercise modality for promoting growth in middle-aged women, who are susceptible to muscle mass loss with progressing age. PMID:27650251

  4. Cycle training modulates satellite cell and transcriptional responses to a bout of resistance exercise.

    PubMed

    Murach, Kevin A; Walton, R Grace; Fry, Christopher S; Michaelis, Sami L; Groshong, Jason S; Finlin, Brian S; Kern, Philip A; Peterson, Charlotte A

    2016-09-01

    This investigation evaluated whether moderate-intensity cycle ergometer training affects satellite cell and molecular responses to acute maximal concentric/eccentric resistance exercise in middle-aged women. Baseline and 72 h postresistance exercise vastus lateralis biopsies were obtained from seven healthy middle-aged women (56 ± 5 years, BMI 26 ± 1, VO2max 27 ± 4) before and after 12 weeks of cycle training. Myosin heavy chain (MyHC) I- and II-associated satellite cell density and cross-sectional area was determined via immunohistochemistry. Expression of 93 genes representative of the muscle-remodeling environment was also measured via NanoString. Overall fiber size increased ~20% with cycle training (P = 0.052). MyHC I satellite cell density increased 29% in response to acute resistance exercise before endurance training and 50% with endurance training (P < 0.05). Following endurance training, MyHC I satellite cell density decreased by 13% in response to acute resistance exercise (acute resistance × training interaction, P < 0.05). Genes with an interaction effect tracked with satellite cell behavior, increasing in the untrained state and decreasing in the endurance trained state in response to resistance exercise. Similar satellite cell and gene expression response patterns indicate coordinated regulation of the muscle environment to promote adaptation. Moderate-intensity endurance cycle training modulates the response to acute resistance exercise, potentially conditioning the muscle for more intense concentric/eccentric activity. These results suggest that cycle training is an effective endurance exercise modality for promoting growth in middle-aged women, who are susceptible to muscle mass loss with progressing age.

  5. The role of ozone feedback in modulating the atmospheric response to the solar cycle forcing

    NASA Astrophysics Data System (ADS)

    Bednarz, Ewa; Maycock, Amanda; Braesicke, Peter; Telford, Paul; Abraham, Luke; Pyle, John

    2016-04-01

    in the seasonality of the dynamical response in the Northern Hemisphere high latitudes. All in all, our results highlight the importance of the solar-ozone feedback in modulating the atmospheric response to the solar cycle forcing and the importance of properly representing this for future model studies of the impact of the solar cycle forcing on climate.

  6. Polarization-independent and submillisecond response phase modulators using a 90° twisted dual-frequency liquid crystal

    NASA Astrophysics Data System (ADS)

    Huang, Yuhua; Wen, Chien-Hui; Wu, Shin-Tson

    2006-07-01

    A polarization-independent phase modulator using a 90° twisted dual-frequency liquid crystal (DFLC) is demonstrated. In addition to being polarization independent, such a phase modulator exhibits many other advantages such as being scattering-free and having large phase change, low operating voltage, and submillisecond response time. Using a 15μm transmissive DFLC cell, the phase shift achieves 1π at λ =633nm and the applied voltage is lower than 25Vrms. Potential applications of such a phase modulator for laser beam steering, tunable-focus lenses, and switchable two-dimensional/three-dimensional liquid crystal displays are foreseeable.

  7. Spatial Correlations in Natural Scenes Modulate Response Reliability in Mouse Visual Cortex

    PubMed Central

    Rikhye, Rajeev V.

    2015-01-01

    Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). Certain stimuli can suppress this intertrial variability to increase the reliability of neuronal responses. In particular, responses to natural scenes, which have broadband spatiotemporal statistics, are more reliable than responses to stimuli such as gratings. However, very little is known about which stimulus statistics modulate reliable coding and how this occurs at the neural ensemble level. Here, we sought to elucidate the role that spatial correlations in natural scenes play in reliable coding. We developed a novel noise-masking method to systematically alter spatial correlations in natural movies, without altering their edge structure. Using high-speed two-photon calcium imaging in vivo, we found that responses in mouse V1 were much less reliable at both the single neuron and population level when spatial correlations were removed from the image. This change in reliability was due to a reorganization of between-neuron correlations. Strongly correlated neurons formed ensembles that reliably and accurately encoded visual stimuli, whereas reducing spatial correlations reduced the activation of these ensembles, leading to an unreliable code. Together with an ensemble-specific normalization model, these results suggest that the coordinated activation of specific subsets of neurons underlies the reliable coding of natural scenes. SIGNIFICANCE STATEMENT The natural environment is rich with information. To process this information with high fidelity, V1 neurons have to be robust to noise and, consequentially, must generate responses that are reliable from trial to trial. While several studies have hinted that both stimulus attributes and population coding may reduce noise, the details remain unclear. Specifically, what features of natural scenes are important and how do they modulate reliability? This study is the first to investigate the role of spatial

  8. Hormonal modulation of extinction responses induced by sexual steroid hormones in rats.

    PubMed

    Rivas-Arancibia, S; Vazquez-Pereyra, F

    1994-01-01

    A functional interrelation between the nervous and endocrine systems has been established. However, few studies have dealt with the effects of sexual steroids on learning and memory. The aim of this work was to determine whether sexual steroid hormones could modulate the extinction response of a passive avoidance conditioning in rats. Male Wistar rats, randomly assigned to five groups, two controls and three experimental groups, were submitted to a one-trial passive avoidance conditioning and tested for their retention 24 hr after and during 10 weeks. One control group received no treatment at all, the other received vegetable oil, and the three experimental received 20 mg of testosterone enanthate, 0.8 mg estradiol valerate, or 4 mg nandrolone decanoate, respectively. All substances were applied in a 0.3 ml volume, 24 hours before training and before testing for retention each week during 10 weeks. Results indicate that the extinction process is modulated by these hormones, since testosterone and estradiol facilitate extinction, whereas the anabolic androgen produced a resistance to the extinction process.

  9. Viewing photos and reading nouns of natural graspable objects similarly modulate motor responses.

    PubMed

    Marino, Barbara F M; Sirianni, Miriam; Volta, Riccardo Dalla; Magliocco, Fabio; Silipo, Francesco; Quattrone, Aldo; Buccino, Giovanni

    2014-01-01

    It is well known that the observation of graspable objects recruits the same motor representations involved in their actual manipulation. Recent evidence suggests that the presentation of nouns referring to graspable objects may exert similar effects. So far, however, it is not clear to what extent the modulation of the motor system during object observation overlaps with that related to noun processing. To address this issue, 2 behavioral experiments were carried out using a go-no go paradigm. Healthy participants were presented with photos and nouns of graspable and non-graspable natural objects. Also scrambled images and pseudowords obtained from the original stimuli were used. At a go-signal onset (150 ms after stimulus presentation) participants had to press a key when the stimulus referred to a real object, using their right (Experiment 1) or left (Experiment 2) hand, and refrain from responding when a scrambled image or a pseudoword was presented. Slower responses were found for both photos and nouns of graspable objects as compared to non-graspable objects, independent of the responding hand. These findings suggest that processing seen graspable objects and written nouns referring to graspable objects similarly modulates the motor system. PMID:25538596

  10. Simulation of the ATLAS SCT barrel module response to LHC beam loss scenarios

    NASA Astrophysics Data System (ADS)

    Rose, P.; Grillo, A. A.; Fadeyev, V.; Spencer, E.; Wilder, M.; Domingo, M.

    2014-03-01

    In the event of beam loss at the LHC, ATLAS Inner Detector components nearest the beam line may be subjected to unusually large amounts of radiation. Understanding their behavior in such an event is important in determining whether they would still function properly. We built a SPICE model of the silicon strip module electrical system to determine the behavior of its elements during a realistic beam loss scenario. We found that the power supply and bias filter characteristics strongly affect the module response in such scenarios. In particular, the following self-limiting phenomena were observed: there is a finite amount of charge initially available on the bias filter capacitors for collection by the strips; the power supply current limit reduces the rate at which the bias filter capacitors' charge can be replenished; the reduced bias voltage leads to a smaller depletion depth in the sensors which results in less collected charge. These effects provide a larger measure of safety during beam loss events than was previously assumed. In particular, the voltage across the coupling capacitor stays below the specifications limit for a wide range of beam loss rates. The current into the ABCD channels exceeds the limit only for very high rates of beam loss.

  11. Water flow modulates the response of coral reef communities to ocean acidification.

    PubMed

    Comeau, S; Edmunds, P J; Lantz, C A; Carpenter, R C

    2014-10-20

    By the end of the century coral reefs likely will be affected negatively by ocean acidification (OA), but both the effects of OA on coral communities and the crossed effects of OA with other physical environmental variables are lacking. One of the least considered physical parameters is water flow, which is surprising considering its strong role in modulating the physiology of reef organisms and communities. In the present study, the effects of flow were tested on coral reef communities maintained in outdoor flumes under ambient pCO2 and high pCO2 (1300 μatm). Net calcification of coral communities, including sediments, was affected by both flow and pCO2 with calcification correlated positively with flow under both pCO2 treatments. The effect of flow was less evident for sediments where dissolution exceeded precipitation of calcium carbonate under all flow speeds at high pCO2. For corals and calcifying algae there was a strong flow effect, particularly at high pCO2 where positive net calcification was maintained at night in the high flow treatment. Our results demonstrate the importance of water flow in modulating the coral reef community response to OA and highlight the need to consider this parameter when assessing the effects of OA on coral reefs.

  12. Viewing photos and reading nouns of natural graspable objects similarly modulate motor responses

    PubMed Central

    Marino, Barbara F. M.; Sirianni, Miriam; Volta, Riccardo Dalla; Magliocco, Fabio; Silipo, Francesco; Quattrone, Aldo; Buccino, Giovanni

    2014-01-01

    It is well known that the observation of graspable objects recruits the same motor representations involved in their actual manipulation. Recent evidence suggests that the presentation of nouns referring to graspable objects may exert similar effects. So far, however, it is not clear to what extent the modulation of the motor system during object observation overlaps with that related to noun processing. To address this issue, 2 behavioral experiments were carried out using a go-no go paradigm. Healthy participants were presented with photos and nouns of graspable and non-graspable natural objects. Also scrambled images and pseudowords obtained from the original stimuli were used. At a go-signal onset (150 ms after stimulus presentation) participants had to press a key when the stimulus referred to a real object, using their right (Experiment 1) or left (Experiment 2) hand, and refrain from responding when a scrambled image or a pseudoword was presented. Slower responses were found for both photos and nouns of graspable objects as compared to non-graspable objects, independent of the responding hand. These findings suggest that processing seen graspable objects and written nouns referring to graspable objects similarly modulates the motor system. PMID:25538596

  13. Serotonin transporter gene polymorphism modulates inflammatory cytokine responses during acute stress

    PubMed Central

    Yamakawa, Kaori; Matsunaga, Masahiro; Isowa, Tokiko; Ohira, Hideki

    2015-01-01

    Cytokines are important mediators of various stress-related modulations of immune function. A major genetic factor determining inter-individual differences in stress reactivity is polymorphisms of the serotonin (5-hydroxytryptamine, 5HT) transporter (5HTT) gene. A short (S) variant, compared with a long (L) variant, of the promoter region of the 5HTT gene-linked polymorphic region (5HTTLPR) has been related to emotional and stress hyper-reactivity. The present study examined whether the 5HTTLPR can modulate responses of inflammatory cytokines under acute stress. Nine Japanese male participants carrying two copies of the S alleles and nine Japanese males carrying S and L alleles underwent the Trier Social Stress Test (TSST). Inflammatory cytokines, endocrine parameters, heart rate and subjective stress were measured before, during and after the task. The participants carrying the SS alleles, but not those carrying the SL alleles, showed a significant increase of IL-1β immediately after TSST. This hyper-reactivity to acute stress in individuals with the SS alleles was also observed in their heart rate and cortisol levels. These results suggest that the S allele of the 5HTTLPR is consistently associated with stress reactivity in multi-level stress-related biological systems. PMID:26349674

  14. Transcriptional modulation of enterotoxigenic Escherichia coli virulence genes in response to epithelial cell interactions.

    PubMed

    Kansal, Rita; Rasko, David A; Sahl, Jason W; Munson, George P; Roy, Koushik; Luo, Qingwei; Sheikh, Alaullah; Kuhne, Kurt J; Fleckenstein, James M

    2013-01-01

    Enterotoxigenic Escherichia coli (ETEC) strains are a leading cause of morbidity and mortality due to diarrheal illness in developing countries. There is currently no effective vaccine against these important pathogens. Because genes modulated by pathogen-host interactions potentially encode putative vaccine targets, we investigated changes in gene expression and surface morphology of ETEC upon interaction with intestinal epithelial cells in vitro. Pan-genome microarrays, quantitative reverse transcriptase PCR (qRT-PCR), and transcriptional reporter fusions of selected promoters were used to study changes in ETEC transcriptomes. Flow cytometry, immunofluorescence microscopy, and scanning electron microscopy were used to investigate alterations in surface antigen expression and morphology following pathogen-host interactions. Following host cell contact, genes for motility, adhesion, toxin production, immunodominant peptides, and key regulatory molecules, including cyclic AMP (cAMP) receptor protein (CRP) and c-di-GMP, were substantially modulated. These changes were accompanied by visible changes in both ETEC architecture and the expression of surface antigens, including a novel highly conserved adhesin molecule, EaeH. The studies reported here suggest that pathogen-host interactions are finely orchestrated by ETEC and are characterized by coordinated responses involving the sequential deployment of multiple virulence molecules. Elucidation of the molecular details of these interactions could highlight novel strategies for development of vaccines for these important pathogens. PMID:23115039

  15. SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response

    PubMed Central

    Mund, Andreas; Schubert, Tobias; Staege, Hannah; Kinkley, Sarah; Reumann, Kerstin; Kriegs, Malte; Fritsch, Lauriane; Battisti, Valentine; Ait-Si-Ali, Slimane; Hoffbeck, Anne-Sophie; Soutoglou, Evi; Will, Hans

    2012-01-01

    Survival time-associated plant homeodomain (PHD) finger protein in Ovarian Cancer 1 (SPOC1, also known as PHF13) is known to modulate chromatin structure and is essential for testicular stem-cell differentiation. Here we show that SPOC1 is recruited to DNA double-strand breaks (DSBs) in an ATM-dependent manner. Moreover, SPOC1 localizes at endogenous repair foci, including OPT domains and accumulates at large DSB repair foci characteristic for delayed repair at heterochromatic sites. SPOC1 depletion enhances the kinetics of ionizing radiation-induced foci (IRIF) formation after γ-irradiation (γ-IR), non-homologous end-joining (NHEJ) repair activity, and cellular radioresistance, but impairs homologous recombination (HR) repair. Conversely, SPOC1 overexpression delays IRIF formation and γH2AX expansion, reduces NHEJ repair activity and enhances cellular radiosensitivity. SPOC1 mediates dose-dependent changes in chromatin association of DNA compaction factors KAP-1, HP1-α and H3K9 methyltransferases (KMT) GLP, G9A and SETDB1. In addition, SPOC1 interacts with KAP-1 and H3K9 KMTs, inhibits KAP-1 phosphorylation and enhances H3K9 trimethylation. These findings provide the first evidence for a function of SPOC1 in DNA damage response (DDR) and repair. SPOC1 acts as a modulator of repair kinetics and choice of pathways. This involves its dose-dependent effects on DNA damage sensors, repair mediators and key regulators of chromatin structure. PMID:23034801

  16. Correlation of neural responses in the cochlear nucleus with low-frequency noise amplitude modulation of a tonal signal

    NASA Astrophysics Data System (ADS)

    Bibikov, N. G.

    2014-09-01

    The responses of single neurons of the cochlear nucleus of a grass frog to long tonal signals amplitude-modulated by repeat intervals of low-frequency noise have been studied. The carrier frequency always corresponded to the characteristic frequency of the studied cell (a range of 0.2 kHz-2 kHz); the modulated signal was noise in the ranges 0-15 Hz, 0-50 Hz, or 0-150 Hz. We obtained the correlation functions of the cyclic histogram reflecting the change in probability of a neuron pulse discharge (spike) during the modulation period with the shape of the signal envelope in the same period. The form of the obtained correlation functions usually does not change qualitatively with a change in carrier level or modulation depth; however, this could essentially depend of the frequency component of the modulating function. In the majority of cases, comparison of the cyclic histogram of the reaction with only the current amplitude value does not adequately reveal the signal's time features that determine the reaction of a neuron. The response is also determined by the other sound features, primarily by the rate of the change in amplitude. The studied neurons differed among themselves, both in preference toward a certain range of modulated frequencies and in the features of the envelope that caused the cell's response.

  17. Transcranial modulation of brain oscillatory responses: A concurrent tDCS-MEG investigation.

    PubMed

    Hanley, Claire J; Singh, Krish D; McGonigle, David J

    2016-10-15

    Despite the increasing use of transcranial direct current stimulation (tDCS), the physiological mechanisms underlying its effects are still largely unknown. One approach to directly investigate the effects of the neuromodulation technique on the brain is to integrate tDCS with non-invasive neuroimaging in humans. To provide new insight into the neurobiology of the method, DC stimulation (1mA, 600s) was applied concurrently with Magnetoencephalography (MEG), while participants engaged in a visuomotor task before, during and after a period of tDCS. Responses in the motor beta band (15-30Hz) and visual gamma band (30-80Hz) were localised using Synthetic Aperture Magnetometry (SAM). The resulting induced and evoked oscillatory responses were subsequently analysed. A statistically significant reduction of average power in the visual gamma band was observed for anodal compared to sham stimulation. The magnitude of motor evoked responses was also found to be significantly modulated by anodal stimulation. These results demonstrate that MEG can be used to derive inferences on the cortical mechanisms of tDCS.

  18. Ethylene positively regulates cold tolerance in grapevine by modulating the expression of ETHYLENE RESPONSE FACTOR 057

    PubMed Central

    Sun, Xiaoming; Zhao, Tingting; Gan, Shuheng; Ren, Xiaodie; Fang, Linchuan; Karungo, Sospeter Karanja; Wang, Yi; Chen, Liang; Li, Shaohua; Xin, Haiping

    2016-01-01

    Ethylene (ET) is a gaseous plant hormone that plays essential roles in biotic and abiotic stress responses in plants. However, the role of ET in cold tolerance varies in different species. This study revealed that low temperature promotes the release of ET in grapevine. The treatment of exogenous 1-aminocyclopropane-1-carboxylate increased the cold tolerance of grapevine. By contrast, the application of the ET biosynthesis inhibitor aminoethoxyvinylglycine reduced the cold tolerance of grapevine. This finding suggested that ET positively affected cold stress responses in grapevine. The expression of VaERF057, an ET signaling downstream gene, was strongly induced by low temperature. The overexpression of VaERF057 also enhanced the cold tolerance of Arabidopsis. Under cold treatment, malondialdehyde content was lower and superoxide dismutase, peroxidase, and catalase activities were higher in transgenic lines than in wild-type plants. RNA-Seq results showed that 32 stress-related genes, such as CBF1-3, were upregulated in VaERF057-overexpressing transgenic line. Yeast one-hybrid results further demonstrated that VaERF057 specifically binds to GCC-box and DRE motifs. Thus, VaERF057 may directly regulate the expression of its target stress-responsive genes by interacting with a GCC-box or a DRE element. Our work confirmed that ET positively regulates cold tolerance in grapevine by modulating the expression of VaERF057. PMID:27039848

  19. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation

    SciTech Connect

    Okumura, Atsushi; Alce, Tim; Lubyova, Barbora; Ezelle, Heather; Strebel, Klaus; Pitha, Paula M.

    2008-03-30

    The activation of IRF-3 during the early stages of viral infection is critical for the initiation of the antiviral response; however the activation of IRF-3 in HIV-1 infected cells has not yet been characterized. We demonstrate that the early steps of HIV-1 infection do not lead to the activation and nuclear translocation of IRF-3; instead, the relative levels of IRF-3 protein are decreased due to the ubiquitin-associated proteosome degradation. Addressing the molecular mechanism of this effect we show that the degradation is independent of HIV-1 replication and that virion-associated accessory proteins Vif and Vpr can independently degrade IRF-3. The null mutation of these two genes reduced the capacity of the HIV-1 virus to down modulate IRF-3 levels. The degradation was associated with Vif- and Vpr-mediated ubiquitination of IRF-3 and was independent of the activation of IRF-3. N-terminal lysine residues were shown to play a critical role in the Vif- and Vpr-mediated degradation of IRF-3. These data implicate Vif and Vpr in the disruption of the initial antiviral response and point to the need of HIV-1 to circumvent the antiviral response during the very early phase of replication.

  20. Habituation of Auditory Steady State Responses Evoked by Amplitude-Modulated Acoustic Signals in Rats

    PubMed Central

    Prado-Gutierrez, Pavel; Castro-Fariñas, Anisleidy; Morgado-Rodriguez, Lisbet; Velarde-Reyes, Ernesto; Martínez, Agustín D.; Martínez-Montes, Eduardo

    2015-01-01

    Generation of the auditory steady state responses (ASSR) is commonly explained by the linear combination of random background noise activity and the stationary response. Based on this model, the decrease of amplitude that occurs over the sequential averaging of epochs of the raw data has been exclusively linked to the cancelation of noise. Nevertheless, this behavior might also reflect the non-stationary response of the ASSR generators. We tested this hypothesis by characterizing the ASSR time course in rats with different auditory maturational stages. ASSR were evoked by 8-kHz tones of different supra-threshold intensities, modulated in amplitude at 115 Hz. Results show that the ASSR amplitude habituated to the sustained stimulation and that dishabituation occurred when deviant stimuli were presented. ASSR habituation increased as animals became adults, suggesting that the ability to filter acoustic stimuli with no-relevant temporal information increased with age. Results are discussed in terms of the current model of the ASSR generation and analysis procedures. They might have implications for audiometric tests designed to assess hearing in subjects who cannot provide reliable results in the psychophysical trials. PMID:26557360

  1. Molecular force modulation spectroscopy revealing the dynamic response of single bacteriorhodopsins.

    PubMed

    Janovjak, Harald; Müller, Daniel J; Humphris, Andrew D L

    2005-02-01

    Recent advances in atomic force microscopy allowed globular and membrane proteins to be mechanically unfolded on a single-molecule level. Presented is an extension to the existing force spectroscopy experiments. While unfolding single bacteriorhodopsins from native purple membranes, small oscillation amplitudes (6-9 nm) were supplied to the vertical displacement of the cantilever at a frequency of 3 kHz. The phase and amplitude response of the cantilever-protein system was converted to reveal the elastic (conservative) and viscous (dissipative) contributions to the unfolding process. The elastic response (stiffness) of the extended parts of the protein were in the range of a few tens pN/nm and could be well described by the derivative of the wormlike chain model. Discrete events in the viscous response coincided with the unfolding of single secondary structure elements and were in the range of 1 microNs/m. In addition, these force modulation spectroscopy experiments revealed novel mechanical unfolding intermediates of bacteriorhodopsin. We found that kinks result in a loss of unfolding cooperativity in transmembrane helices. Reconstructing force-distance spectra by the integration of amplitude-distance spectra verified their position, offering a novel approach to detect intermediates during the forced unfolding of single proteins. PMID:15574708

  2. Serotonin modulates worker responsiveness to trail pheromone in the ant Pheidole dentata.

    PubMed

    Muscedere, Mario L; Johnson, Natalie; Gillis, Brendan C; Kamhi, J Frances; Traniello, James F A

    2012-03-01

    As social insect workers mature, outside-nest tasks associated with foraging and defense are typically performed at higher frequencies. Foraging in ants is often a pheromonally mediated collective action performed by mature workers; age-dependent differences in olfactory response thresholds may therefore proximately regulate task repertoire development. In the ant Pheidole dentata, foraging activity increases with chronological age in minor workers, and is chemically controlled. The onset of foraging in minor workers is accompanied by marked neuroanatomical and neurochemical changes, including synaptic remodeling in olfactory regions of the brain, proliferation of serotonergic neurons, and increased brain titers of monoamines, notably serotonin. We examined the linkage of serotonin and olfactory responsiveness by assaying trail-following performance in mature P. dentata minor workers with normal serotonin levels, or serotonin levels experimentally lowered by oral administration of the serotonin synthesis inhibitor α-methyltryptophan (AMTP). By assessing responsiveness to standardized pheromone trails, we demonstrate that trail-following behaviors are significantly reduced in serotonin-depleted workers. AMTP-treated individuals were less likely to initiate trail following, and oriented along pheromone trails for significantly shorter distances than untreated, similar-age workers. These results demonstrate for the first time that serotonin modulates olfactory processes and/or motor functions associated with cooperative foraging in ants. PMID:22134381

  3. Ethylene positively regulates cold tolerance in grapevine by modulating the expression of ETHYLENE RESPONSE FACTOR 057.

    PubMed

    Sun, Xiaoming; Zhao, Tingting; Gan, Shuheng; Ren, Xiaodie; Fang, Linchuan; Karungo, Sospeter Karanja; Wang, Yi; Chen, Liang; Li, Shaohua; Xin, Haiping

    2016-01-01

    Ethylene (ET) is a gaseous plant hormone that plays essential roles in biotic and abiotic stress responses in plants. However, the role of ET in cold tolerance varies in different species. This study revealed that low temperature promotes the release of ET in grapevine. The treatment of exogenous 1-aminocyclopropane-1-carboxylate increased the cold tolerance of grapevine. By contrast, the application of the ET biosynthesis inhibitor aminoethoxyvinylglycine reduced the cold tolerance of grapevine. This finding suggested that ET positively affected cold stress responses in grapevine. The expression of VaERF057, an ET signaling downstream gene, was strongly induced by low temperature. The overexpression of VaERF057 also enhanced the cold tolerance of Arabidopsis. Under cold treatment, malondialdehyde content was lower and superoxide dismutase, peroxidase, and catalase activities were higher in transgenic lines than in wild-type plants. RNA-Seq results showed that 32 stress-related genes, such as CBF1-3, were upregulated in VaERF057-overexpressing transgenic line. Yeast one-hybrid results further demonstrated that VaERF057 specifically binds to GCC-box and DRE motifs. Thus, VaERF057 may directly regulate the expression of its target stress-responsive genes by interacting with a GCC-box or a DRE element. Our work confirmed that ET positively regulates cold tolerance in grapevine by modulating the expression of VaERF057. PMID:27039848

  4. Reproducibility of exercise-induced modulation of cardiovascular responses to cold stress.

    PubMed

    Rashed, H M; Leventhal, G; Madu, E C; Reddy, R; Cardoso, S

    1997-04-01

    The modulation of cardiovascular responses to the cold pressor test (CPT) as produced by exercise was studied in 13 volunteers. The reproducibility of the measurements selected for the study, i.e. heart rate (HR), blood pressure (BP), blood flow (BF) and skin temperature (ST), was investigated through repeat experiments in the fall of 1994 and the winter of 1995. HR was monitored before, during and after a 10-min period of bicycling at 70% of reserve HR. BP, cutaneous BF and ST were measured before and after exercise. Two CPTs (hand into ice-cold water for 1 min) were performed: one preceding exercise and another at 3 min after exercise. The results obtained allow us to conclude that in non-hypertensive volunteers (1) the pronounced cardiovascular responses (ST, BF and BP) induced by CPT are reproducible (p > 0.2) when compared to basal level values and (2) cardiovascular responses to cold stress are significantly attenuated by exercise (p < 0.03). Our study, therefore, supports and validates the use of our coupled exercise-CPT method in ongoing epidemiological studies attempting to identify individuals at risk for the development of hypertension as well as those most likely to benefit from preventative exercise programs.

  5. 'I love Rock 'n' Roll'--music genre preference modulates brain responses to music.

    PubMed

    Istók, Eva; Brattico, Elvira; Jacobsen, Thomas; Ritter, Aileen; Tervaniemi, M

    2013-02-01

    The present study examined the effect of participants' music genre preference on the neural processes underlying evaluative and cognitive judgements of music using the event-related potential technique. To this aim, two participant groups differing in their preference for Latin American and Heavy Metal music performed a liking judgement and a genre classification task on a variety of excerpts of either music genre. A late positive potential (LPP) was elicited in all conditions between 600 and 900 ms after stimulus onset. During the genre classification task, an early negativity was elicited by the preferred compared to the non-preferred music at around 230-370 ms whereas the non-preferred genre was characterized by a larger LPP. The findings suggest that evaluative and cognitive judgements of music are accompanied by affective responses and that the valence of music may spontaneously modulate early processes of music categorization even when no overt liking judgement is required. PMID:23201033

  6. Carbon monoxide and mitochondria—modulation of cell metabolism, redox response and cell death

    PubMed Central

    Almeida, Ana S.; Figueiredo-Pereira, Cláudia; Vieira, Helena L. A.

    2015-01-01

    Carbon monoxide (CO) is an endogenously produced gasotransmitter, which is associated with cytoprotection and cellular homeostasis in several distinct cell types and tissues. CO mainly targets mitochondria because: (i) mitochondrial heme-proteins are the main potential candidates for CO to bind, (ii) many CO's biological actions are dependent on mitochondrial ROS signaling and (iii) heme is generated in the mitochondrial compartment. Mitochondria are the key cell energy factory, producing ATP through oxidative phosphorylation and regulating cell metabolism. These organelles are also implicated in many cell signaling pathways and the production of reactive oxygen species (ROS). Finally, mitochondria contain several factors activating programmed cell death pathways, which are released from the mitochondrial inter-membrane space upon mitochondrial membrane permeabilization. Therefore, disclosing CO mode of action at mitochondria opens avenues for deeper understanding CO's biological properties. Herein, it is discussed how CO affects the three main aspects of mitochondrial modulation of cell function: metabolism, redox response and cell death. PMID:25709582

  7. Color of scents: chromatic stimuli modulate odor responses in the human brain.

    PubMed

    Osterbauer, Robert A; Matthews, Paul M; Jenkinson, Mark; Beckmann, Christian F; Hansen, Peter C; Calvert, Gemma A

    2005-06-01

    Color has a profound effect on the perception of odors. For example, strawberry-flavored drinks smell more pleasant when colored red than green and descriptions of the "nose" of a wine are dramatically influenced by its color. Using functional magnetic resonance imaging, we demonstrate a neurophysiological correlate of these cross-modal visual influences on olfactory perception. Subjects were scanned while exposed either to odors or colors in isolation or to color-odor combinations that were rated on the basis of how well they were perceived to match. Activity in caudal regions of the orbitofrontal cortex and in the insular cortex increased progressively with the perceived congruency of the odor-color pairs. These findings demonstrate the neuronal correlates of olfactory response modulation by color cues in brain areas previously identified as encoding the hedonic value of smells. PMID:15689393

  8. Experience Modulates the Reproductive Response to Heat Stress in C. elegans via Multiple Physiological Processes

    PubMed Central

    Gouvêa, Devin Y.; Aprison, Erin Z.; Ruvinsky, Ilya

    2015-01-01

    Natural environments are considerably more variable than laboratory settings and often involve transient exposure to stressful conditions. To fully understand how organisms have evolved to respond to any given stress, prior experience must therefore be considered. We investigated the effects of individual and ancestral experience on C. elegans reproduction. We documented ways in which cultivation at 15°C or 25°C affects developmental time, lifetime fecundity, and reproductive performance after severe heat stress that exceeds the fertile range of the organism but is compatible with survival and future fecundity. We found that experience modulates multiple aspects of reproductive physiology, including the male and female germ lines and the interaction between them. These responses vary in their environmental sensitivity, suggesting the existence of complex mechanisms for coping with unpredictable and stressful environments. PMID:26713620

  9. 'I love Rock 'n' Roll'--music genre preference modulates brain responses to music.

    PubMed

    Istók, Eva; Brattico, Elvira; Jacobsen, Thomas; Ritter, Aileen; Tervaniemi, M

    2013-02-01

    The present study examined the effect of participants' music genre preference on the neural processes underlying evaluative and cognitive judgements of music using the event-related potential technique. To this aim, two participant groups differing in their preference for Latin American and Heavy Metal music performed a liking judgement and a genre classification task on a variety of excerpts of either music genre. A late positive potential (LPP) was elicited in all conditions between 600 and 900 ms after stimulus onset. During the genre classification task, an early negativity was elicited by the preferred compared to the non-preferred music at around 230-370 ms whereas the non-preferred genre was characterized by a larger LPP. The findings suggest that evaluative and cognitive judgements of music are accompanied by affective responses and that the valence of music may spontaneously modulate early processes of music categorization even when no overt liking judgement is required.

  10. Nonlocal nonlinear response of thermal Rydberg atoms and modulational instability in an absorptive nonlinear medium

    NASA Astrophysics Data System (ADS)

    Zhang, Lida; Evers, Jörg

    2016-09-01

    Nonlinear and nonlocal effects are discussed in the interaction of laser fields with thermal Rydberg atoms in an electromagnetically induced transparency configuration. We assume that the system's steady state adiabatically follows the time variation in the dipole-dipole interactions due to the atomic motion and use a continuum description for the atomic medium. Based on these approximations, we obtain an analytical form for the nonlocal nonlinear atomic response of the thermal medium and study it for different parameter cases. We further propose a generalized model to describe the modulational instability (MI) in absorptive nonlinear media, in order to understand the propagation dynamics in the thermal Rydberg medium. Interestingly, this model predicts that at short propagation distances, each wave component exhibits the MI effect in absorptive nonlinear media, unlike in the purely dispersive case.

  11. The Role of Environmental Factors in Modulating Immune Responses in Early Life

    PubMed Central

    MacGillivray, Duncan M.; Kollmann, Tobias R.

    2014-01-01

    The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved. PMID:25309535

  12. Selective estrogen receptor modulators differentially alter the immune response of gilthead seabream juveniles.

    PubMed

    Rodenas, M C; Cabas, I; García-Alcázar, A; Meseguer, J; Mulero, V; García-Ayala, A

    2016-05-01

    17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives and hormone replacement therapy, tamoxifen (Tmx), a selective estrogen-receptor modulator used in hormone replacement therapy, and G1, a G protein-coupled estrogen receptor (GPER) selective agonist, differentially increased the hepatic vitellogenin (vtg) gene expression and altered the immune response in adult gilthead seabream (Sparus aurata L.) males. However, no information exists on the effects of these compounds on the immune response of juveniles. This study aims, for the first time, to investigate the effects of the dietary intake of EE2, Tmx or G1 on the immune response of gilthead seabream juveniles and the capacity of the immune system of the specimens to recover its functionality after ceasing exposures (recovery period). The specimens were immunized with hemocyanin in the presence of aluminium adjuvant 1 (group A) or 120 (group B) days after the treatments ceased (dpt). The results indicate that EE2 and Tmx, but not G1, differentially promoted a transient alteration in hepatic vtg gene expression. Although all three compounds did not affect the production of reactive oxygen intermediates, they inhibited the induction of interleukin-1β (il1b) gene expression after priming. Interestingly, although Tmx increased the percentage of IgM-positive cells in both head kidney and spleen during the recovery period, the antibody response of vaccinated fish varied depending on the compound used and when the immunization was administered. Taken together, our results suggest that these compounds differentially alter the capacity of fish to respond to infection during ontogeny and, more interestingly, that the adaptive immune response remained altered to an extent that depends on the compound. PMID:27012396

  13. Selective estrogen receptor modulators differentially alter the immune response of gilthead seabream juveniles.

    PubMed

    Rodenas, M C; Cabas, I; García-Alcázar, A; Meseguer, J; Mulero, V; García-Ayala, A

    2016-05-01

    17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives and hormone replacement therapy, tamoxifen (Tmx), a selective estrogen-receptor modulator used in hormone replacement therapy, and G1, a G protein-coupled estrogen receptor (GPER) selective agonist, differentially increased the hepatic vitellogenin (vtg) gene expression and altered the immune response in adult gilthead seabream (Sparus aurata L.) males. However, no information exists on the effects of these compounds on the immune response of juveniles. This study aims, for the first time, to investigate the effects of the dietary intake of EE2, Tmx or G1 on the immune response of gilthead seabream juveniles and the capacity of the immune system of the specimens to recover its functionality after ceasing exposures (recovery period). The specimens were immunized with hemocyanin in the presence of aluminium adjuvant 1 (group A) or 120 (group B) days after the treatments ceased (dpt). The results indicate that EE2 and Tmx, but not G1, differentially promoted a transient alteration in hepatic vtg gene expression. Although all three compounds did not affect the production of reactive oxygen intermediates, they inhibited the induction of interleukin-1β (il1b) gene expression after priming. Interestingly, although Tmx increased the percentage of IgM-positive cells in both head kidney and spleen during the recovery period, the antibody response of vaccinated fish varied depending on the compound used and when the immunization was administered. Taken together, our results suggest that these compounds differentially alter the capacity of fish to respond to infection during ontogeny and, more interestingly, that the adaptive immune response remained altered to an extent that depends on the compound.

  14. Light touch modulates balance recovery following perturbation: from fast response to stance restabilization.

    PubMed

    Martinelli, Alessandra Rezende; Coelho, Daniel Boari; Magalhães, Fernando Henrique; Kohn, André Fabio; Teixeira, Luis Augusto

    2015-05-01

    Light fingertip touch of a static bar generates extra somatosensory information used by the postural control system to reduce body sway. While the effect of light touch has been studied in quiet stance, less attention has been given to its potential benefit for reactive postural responses. In the present study, we tested the effect of light fingertip touch of a stable surface on recovery of postural stability from a mechanical perturbation. Participants stood upright on a force plate touching a static rigid bar while being pulled backward by a load. Unpredictable release of the load induced fast anterior body sway, requiring a reactive response to recover balance. Effect of light touch on postural responses was assessed as a function of vision and malleability of the support surface, analyzing different epochs ranging from the pre-perturbation period to recovery of a relatively stable quiet stance. Results showed that light touch induced lower magnitude of muscular activation in all epochs. Center of pressure (CoP) displacement/sway was affected by interaction of light touch with manipulation of the other sensory information. For the periods associated with quiet stance, light touch led to decreased CoP sway in the malleable surface in the pre-perturbation epoch, and in the condition combining no vision and malleable surface in the balance restabilization and follow-up quiet stance epochs. For the fast reactive response epoch, light touch induced smaller amplitude of CoP displacement across conditions, and lower CoP maximum velocity in the condition combining no vision and rigid surface. These results showed that light touch modulates postural responses in all epochs associated with an unanticipated mechanical perturbation, with a more noticeable effect in conditions manipulating sensory information relevant for balance control.

  15. Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD

    PubMed Central

    Hoffmann, Roland F.; Durham, Andrew L.; Marwick, John A.; Brandenburg, Simone M.; de Bruin, Harold G.; Jonker, Marnix R.; Rossios, Christos; Tsitsiou, Eleni; Caramori, Gaetano; Contoli, Marco; Casolari, Paolo; Monaco, Francesco; Andò, Filippo; Speciale, Giuseppe; Kilty, Iain; Chung, Kian F.; Papi, Alberto; Lindsay, Mark A.; ten Hacken, Nick H. T.; van den Berge, Maarten; Timens, Wim; Barnes, Peter J.; van Oosterhout, Antoon J.; Kirkham, Paul A.; Heijink, Irene H.

    2015-01-01

    In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3β-Ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3β-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress-induced activation of the MEK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub. PMID:26320152

  16. Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD.

    PubMed

    Ngkelo, Anta; Hoffmann, Roland F; Durham, Andrew L; Marwick, John A; Brandenburg, Simone M; de Bruin, Harold G; Jonker, Marnix R; Rossios, Christos; Tsitsiou, Eleni; Caramori, Gaetano; Contoli, Marco; Casolari, Paolo; Monaco, Francesco; Andò, Filippo; Speciale, Giuseppe; Kilty, Iain; Chung, Kian F; Papi, Alberto; Lindsay, Mark A; Ten Hacken, Nick H T; van den Berge, Maarten; Timens, Wim; Barnes, Peter J; van Oosterhout, Antoon J; Adcock, Ian M; Kirkham, Paul A; Heijink, Irene H

    2015-11-15

    In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3β-Ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3β-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress-induced activation of the MEK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub. PMID:26320152

  17. Sensory input from the osphradium modulates the response to memory-enhancing stressors in Lymnaea stagnalis.

    PubMed

    Karnik, Vikram; Braun, Marvin; Dalesman, Sarah; Lukowiak, Ken

    2012-02-01

    In the freshwater environment species often rely on chemosensory information to modulate behavior. The pond snail, Lymnaea stagnalis, is a model species used to characterize the causal mechanisms of long-term memory (LTM) formation. Chemical stressors including crayfish kairomones and KCl enhance LTM formation (≥24 h) in Lymnaea; however, how these stressors are sensed and the mechanism by which they affect the electrophysiological properties of neurons necessary for memory formation are poorly understood. Here, we assessed whether the osphradium, a primary chemosensory organ in Lymnaea, modulates LTM enhancement. To test this we severed the osphradial nerve proximal to the osphradium, using sham-operated animals as controls, and assessed the behavioral and electrophysiological response to crayfish kairomones and KCl. We operantly conditioned aerial respiratory behavior in intact, sham and osphradially cut animals, and tested for enhanced memory formation after exposure to the chemical stressors. Sham-operated animals displayed the same memory enhancement as intact animals but snails with a severed osphradial nerve did not show LTM enhancement. Extracellular recordings made from the osphradial nerve demonstrate that these stressors evoked afferent sensory activity. Intracellular recordings from right pedal dorsal 1 (RPeD1), a neuron necessary for LTM formation, demonstrate that its electrophysiological activity is altered by input from the osphradium following exposure to crayfish kairomones or KCl in sham and intact animals but no response is seen in RPeD1 in osphradially cut animals. Therefore, sensory input from the osphradium is necessary for LTM enhancement following exposure to these chemical stressors.

  18. The velocity of light intensity increase modulates the photoprotective response in coastal diatoms.

    PubMed

    Giovagnetti, Vasco; Flori, Serena; Tramontano, Ferdinando; Lavaud, Johann; Brunet, Christophe

    2014-01-01

    In aquatic ecosystems, the superimposition of mixing events to the light diel cycle exposes phytoplankton to changes in the velocity of light intensity increase, from diurnal variations to faster mixing-related ones. This is particularly true in coastal waters, where diatoms are dominant. This study aims to investigate if coastal diatoms differently activate the photoprotective responses, xanthophyll cycle (XC) and non-photochemical fluorescence quenching (NPQ), to cope with predictable light diel cycle and unpredictable mixing-related light variations. We compared the effect of two fast light intensity increases (simulating mixing events) with that of a slower increase (corresponding to the light diel cycle) on the modulation of XC and NPQ in the planktonic coastal diatom Pseudo-nitzschia multistriata. During each light treatment, the photon flux density (PFD) progressively increased from darkness to five peaks, ranging from 100 to 650 µmol photons m-2 s-1. Our results show that the diel cycle-related PFD increase strongly activates XC through the enhancement of the carotenoid biosynthesis and induces a moderate and gradual NPQ formation over the light gradient. In contrast, during mixing-related PFD increases, XC is less activated, while higher NPQ rapidly develops at moderate PFD. We observe that together with the light intensity and its increase velocity, the saturation light for photosynthesis (Ek) is a key parameter in modulating photoprotection. We propose that the capacity to adequately regulate and actuate alternative photoprotective 'safety valves' in response to changing velocity of light intensity increase further enhances the photophysiological flexibility of diatoms. This might be an evolutionary outcome of diatom adaptation to turbulent marine ecosystems characterized by unpredictable mixing-related light changes over the light diel cycle.

  19. Modulating protein behaviors on responsive surface by external electric fields: A molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Xie, Yun; Pan, Yufang; Zhang, Rong; Liang, Ying; Li, Zhanchao

    2015-01-01

    Molecular dynamics simulations were employed to investigate the modulation of protein behaviors on the electrically responsive zwitterionic phosphorylcholine self-assembled monolayers (PC-SAMs). Results show that PC-SAMs could sensitively respond to the applied electric fields and exhibit three states with different charge distributions, namely both the negatively charged phosphate groups and the positively charged choline groups are exposed to the solution in the absence of electric fields (state 1), phosphate groups exposed in the presence of positive electric fields (state 2), and choline groups exposed in the presence of negative electric fields (state 3). Under state 1, the adsorption of Cyt c on the PC-SAM is reversible and the orientations of Cyt c are randomly distributed. Under state 2, the adsorption of Cyt c is enhanced due to the electrostatic attractions between the exposed phosphate groups and the positively charged protein; when adsorbed on the PC-SAMs, Cyt c tends to adopt the orientation with the heme plane perpendicular to the surface plane, and the percentage of this orientation increases as the field strength rises up. Under state 3, the adsorption of Cyt c is retarded because of the electrostatic repulsions between the exposed choline groups and the protein; however, if the gaps between PC chains are large enough, Cyt c could insert into the PC-SAM and access the phosphate groups after overcoming a slight energy barrier. Under three states, the basic backbone structures of Cyt c are well kept within the simulation time since the conformation of Cyt c is mainly affected by the surface-generated electric fields, whose strengths are modulated by the external electric fields and are not strong enough to deform protein. The results indicate the possibility of regulating protein behaviors, including promoting or retarding protein adsorption and regulating protein orientations, on responsive surfaces by applying electric fields on the surfaces without

  20. When Somebody Dies

    MedlinePlus

    ... alguien muere All living things — including bugs and fish and people — die. It's difficult, even for grownups, ... kind of death for families and friends to deal with because it happens so fast. There is ...

  1. Age-Related Differences in Auditory Processing as Assessed by Amplitude-Modulation Following Responses in Quiet and in Noise

    PubMed Central

    Parthasarathy, Aravindakshan; Cunningham, Paul A.; Bartlett, Edward L.

    2010-01-01

    Our knowledge of age-related changes in auditory processing in the central auditory system is limited, unlike the changes in the peripheral hearing organs which are more extensively studied. This study aims to further understanding of temporal processing in aging using non-invasive electrophysiological measurements in a rat model system. Amplitude modulation following responses (AMFRs) were assessed using sinusoidally amplitude modulated (SAM) tones presented to aged (92- to 95-weeks old) and young (9- to 12-weeks old) Fischer-344 rats. The modulation frequency and sound level were systematically varied, and the SAM stimuli were also presented simultaneously with wideband background noise at various levels. The overall shapes and cutoff frequencies of the AMFR temporal modulation transfer functions (tMTFs) were similar between young and aged animals. The fast Fourier transform (FFT) amplitudes of the aged animals were similar to the young in the 181–512 Hz modulation frequency range, but were significantly lower at most modulation frequencies above and below. There were no significant age-related differences in the nature of growth or FFT amplitudes with change in sound level at 256 and 1024 Hz modulation frequencies. The AMFR amplitudes were also not correlated with the ABR wave I or wave III amplitudes elicited for broadband click stimuli presented at the same sound level suggesting that sustained AMFR provide complementary information to phasic ABR responses. The FFT amplitudes varied significantly between young and aged animals for SAM stimuli in the presence of background noise, depending on the modulation frequency used and signal to noise ratio. The results show that the representation of temporally modulated stimuli is similar between young and aged animals in quiet listening conditions, but diverges substantially with the addition of background noise. This is consistent with a decrease in inhibition causing altered temporal processing with age. PMID

  2. Responses of neurons in chinchilla auditory cortex to frequency-modulated tones.

    PubMed

    Brown, Trecia A; Harrison, Robert V

    2009-04-01

    Frequency-modulated (FM) stimuli have been used to explore the behavior of neurons in the auditory cortex of several animal models; however, the properties of FM-sensitive auditory cortical neurons in the chinchilla are still unknown. Single-unit responses to FM stimulation were obtained from the auditory cortex of anesthetized adult chinchillas (Chinchilla laniger). Upward and downward linear FM sweeps spanning frequencies from 0.1 to 20 kHz were presented at speeds of 0.05 to 0.82 kHz/ms. Results indicated that >90% of sampled neurons were responsive to FM sweeps. The population preference was for upward FM sweeps and for medium to fast speeds (> or =0.3 kHz/ms). Few units (3%) were selective for downward FM sweeps, whereas <22% of units preferred slow speeds (< or =0.1 kHz/ms). Velocity preference and direction sensitivity were positively correlated for upward sweeps only (r = 0.40, P = 0.0021, t-test). Three types of firing rate patterns were observed in the FM response peristimulus time histograms: a single peak at sweep onset/offset ("onset") and a single peak ("late") or multiple peaks ("burst") during the sweep. "Late" units expressed the highest mean values for direction sensitivity and speed selectivity; "onset" units were selective only for direction and "burst" units were not selective for either direction or speed. The robust responsiveness of these neurons to FM sweeps suggests a functional role for FM detection such as the identification of FM sweeps present in vocalizations of other organisms within the chinchilla's natural environment. PMID:19211659

  3. Post-error action control is neurobehaviorally modulated under conditions of constant speeded response

    PubMed Central

    Soshi, Takahiro; Ando, Kumiko; Noda, Takamasa; Nakazawa, Kanako; Tsumura, Hideki; Okada, Takayuki

    2015-01-01

    Post-error slowing (PES) is an error recovery strategy that contributes to action control, and occurs after errors in order to prevent future behavioral flaws. Error recovery often malfunctions in clinical populations, but the relationship between behavioral traits and recovery from error is unclear in healthy populations. The present study investigated the relationship between impulsivity and error recovery by simulating a speeded response situation using a Go/No-go paradigm that forced the participants to constantly make accelerated responses prior to stimuli disappearance (stimulus duration: 250 ms). Neural correlates of post-error processing were examined using event-related potentials (ERPs). Impulsivity traits were measured with self-report questionnaires (BIS-11, BIS/BAS). Behavioral results demonstrated that the commission error for No-go trials was 15%, but PES did not take place immediately. Delayed PES was negatively correlated with error rates and impulsivity traits, showing that response slowing was associated with reduced error rates and changed with impulsivity. Response-locked error ERPs were clearly observed for the error trials. Contrary to previous studies, error ERPs were not significantly related to PES. Stimulus-locked N2 was negatively correlated with PES and positively correlated with impulsivity traits at the second post-error Go trial: larger N2 activity was associated with greater PES and less impulsivity. In summary, under constant speeded conditions, error monitoring was dissociated from post-error action control, and PES did not occur quickly. Furthermore, PES and its neural correlate (N2) were modulated by impulsivity traits. These findings suggest that there may be clinical and practical efficacy of maintaining cognitive control of actions during error recovery under common daily environments that frequently evoke impulsive behaviors. PMID:25674058

  4. Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats

    PubMed Central

    2013-01-01

    Background Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult. Methods In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines. Results Prenatally, FA induced acute downregulation in IL-1β, TNF-α and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls. Conclusions FA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy. PMID:23351591

  5. Effect of reduced attention on auditory amplitude-modulation following responses: a study with chirp-evoked potentials.

    PubMed

    Alegre, Manuel; Barbosa, Carla; Valencia, Miguel; Pérez-Alcázar, Marta; Iriarte, Jorge; Artieda, Julio

    2008-02-01

    The amplitude of the auditory amplitude-modulation following responses (AMFR) is variable, depending on the modulation rate. Although 40-Hz responses have higher amplitudes in adults, the AMFR in the 80- to 120-Hz range are less influenced by sleep and more consistent in children. The effect of attention on 40-Hz responses has been addressed in some studies; however, no study to our knowledge has investigated the effect of attention on other stimulation rates. Our aim was to test the effect of attention on the AMFR to different frequencies of stimulation, using a chirp-modulated tone as stimulus. We recorded chirp-evoked responses in 12 subjects while attending to the sound (first condition) and reading a novel (second condition), in a randomly determined sequence. The energy of the response and the intertrial coherence (ITC) were measured by means of time-frequency transforms. The frequency range of response was similar in both conditions. No significant differences were found in the ITC values in the 40-Hz and the 80- to 120-Hz ranges, nor in the energy of the 40-Hz response. The only statistically significant difference found was the lower energy of the response in the 80- to 120-Hz range in the reading condition. Our results suggest that attention may affect auditory steady-state clinical testing using amplitude values. Phase measures may be preferable in this context.

  6. Response properties and location of neurons selective for sinusoidal frequency modulations in the inferior colliculus of the big brown bat.

    PubMed

    Yue, Qi; Casseday, John H; Covey, Ellen

    2007-09-01

    Most animal vocalizations, including echolocation signals used by bats, contain frequency-modulated (FM) components. Previous studies have described a class of neurons in the inferior colliculus (IC) of the big brown bat that respond exclusively to sinusoidally frequency modulated (SFM) signals and fail to respond to pure tones, noise, amplitude-modulated tones, or single FM sweeps. The aims of this study were to further characterize these neurons' response properties and to determine whether they are localized within a specific area of the IC. We recorded extracellularly from 214 neurons throughout the IC. Of these, 47 (22%) responded exclusively to SFM. SFM-selective cells were tuned to relatively low carrier frequencies (9-50 kHz), low modulation rates (20-210 Hz), and shallow modulation depths (3-10 kHz). Most had extremely low thresholds, with an average of 16.5 +/- 7.6 dB SPL, and 89% had upper thresholds and closed response areas. For SFM-selective cells with spontaneous activity, the spontaneous activity was eliminated when sound amplitude exceeded their upper threshold and resumed after the stimulus was over. These findings suggest that SFM-selective cells receive low-threshold excitatory inputs and high-threshold inhibitory inputs. SFM-selective cells were clustered in the rostrodorsal part of the IC. Within this area, best modulation rate appeared to be correlated with best carrier frequency and depth within the IC.

  7. Breaking down seasonality: androgen modulation and stress response in a highly stable environment.

    PubMed

    González-Gómez, Paulina L; Merrill, Loren; Ellis, Vincenzo A; Venegas, Cristobal; Pantoja, Javiera I; Vasquez, Rodrigo A; Wingfield, John C

    2013-09-15

    Previous studies show that most birds inhabiting temperate regions have well defined life history stages, and they modulate the production of testosterone (T) and corticosterone (CORT) in response to changes in seasonality. In this study we aimed to examine baseline and stress-induced levels of CORT and circulating T in relation with life history stages in the rufous-collared sparrow, Zonotrichia capensis. We carried out this study for a year in a population inhabiting riparian habitats in the Atacama Desert in Chile, one of the most climatically stable and driest places in the world. This environment shows minimal yearly change in average temperature and precipitation is virtually zero. We found individuals breeding, molting and overlapping breeding and molt year round, although most individuals were molting during March and in breeding condition during October. T levels were not related to individual breeding condition, and at population level they were not significantly different across sampling months. Baseline levels of CORT did not vary across the year. Stress-induced levels of CORT were suppressed during March when most of the birds were molting. This phenomenon was also observed in birds not molting during this period suggesting a mechanism other than molt in determining the stress-response suppression. Our results strongly suggest that in this study site, long-term extremely stable conditions could have relaxed the selective pressures over the timing of life history stages which was evidenced by the breeding and molt schedules, its overlap and endocrine profiles. PMID:23707496

  8. Individual Differences in Valence Modulation of Face-Selective M170 Response

    PubMed Central

    Japee, Shruti; Crocker, Laura; Carver, Frederick; Pessoa, Luiz; Ungerleider, Leslie G.

    2009-01-01

    Magnetoencephalography was used to examine the effect of individual differences on the temporal dynamics of emotional face processing by grouping subjects based on their ability to detect masked valence-laden stimuli. Receiver operating characteristic curves and a nonparametric sensitivity measure were used to categorize subjects into those that could and could not reliably detect briefly presented fearful faces that were backward-masked by neutral faces. Results showed that, in a cluster of face-responsive sensors, the strength of the M170 response was modulated by valence only when subjects could reliably detect the masked fearful faces. Source localization of the M170 peak using synthetic aperture magnetometry identified sources in face processing areas such as right middle occipital gyrus and left fusiform gyrus that showed the valence effect for those target durations at which subjects were sensitive to the fearful stimulus. Subjects who were better able to detect fearful faces also showed higher trait anxiety levels. These results suggest that individual differences between subjects, such as trait anxiety levels and sensitivity to fearful stimuli, may be an important factor to consider when studying emotion processing. PMID:19186917

  9. (Still) longing for food: insulin reactivity modulates response to food pictures.

    PubMed

    Kroemer, Nils B; Krebs, Lena; Kobiella, Andrea; Grimm, Oliver; Vollstädt-Klein, Sabine; Wolfensteller, Uta; Kling, Ricarda; Bidlingmaier, Martin; Zimmermann, Ulrich S; Smolka, Michael N

    2013-10-01

    Overweight and obesity pose serious challenges to public health and are promoted by our food-rich environment. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to food cues after overnight fasting and following a standardized caloric intake (i.e., a 75 g oral glucose tolerance test, OGTT) in 26 participants (body mass index, BMI between 18.5 and 24.9 kg m(-2)). They viewed pictures of palatable food and low-level control stimuli in a block design and rated their current appetite after each block. Compared to control pictures, food pictures activated a large bilateral network typically involved in homeostatically and hedonically motivated food processing. Glucose ingestion was followed by decreased activation in the basal ganglia and paralimbic regions and increased activation in parietal and occipital regions. Plasma level increases in insulin correlated with cue-induced appetite at the neural and behavioral level. High insulin increases were associated with reduced activation in various bilateral regions including the fusiform gyrus, the superior temporal gyrus, the medial frontal gyrus, and the limbic system in the right hemisphere. In addition, they were accompanied by lower subjective appetite ratings following food pictures and modulated the neural response associated with it (e.g., in the fusiform gyrus). We conclude that individual insulin reactivity is critical to reduce food-cue responsivity after an initial energy intake and thereby may help to counteract overeating.

  10. Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.

    PubMed

    Porter, Shaina N; Cluster, Andrew S; Signer, Robert A J; Voigtmann, Jenna; Monlish, Darlene A; Schuettpelz, Laura G; Magee, Jeffrey A

    2016-06-14

    Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). Pten has been proposed to regulate HSCs cell autonomously and non-cell autonomously, but the relative importance of each mechanism has not been directly tested. Furthermore, the cytokines that activate the PI3K pathway upstream of Pten are not well defined. We sought to clarify whether Pten cell autonomously or non-cell autonomously regulates HSC mobilization. We also tested whether Pten deficiency affects the HSC response to granulocyte colony-stimulating factor (G-CSF) and interferon-α (IFNα) since these cytokines induce HSC mobilization or proliferation, respectively. We show that Pten regulates HSC mobilization and expansion in the spleen primarily via cell-autonomous mechanisms. Pten-deficient HSCs do not require G-CSF to mobilize, although they are hyper-sensitized to even low doses of exogenous G-CSF. Pten-deficient HSCs are similarly sensitized to IFNα. Pten therefore modulates the HSC response to inflammatory cytokines.

  11. The shopping brain: math anxiety modulates brain responses to buying decisions.

    PubMed

    Jones, William J; Childers, Terry L; Jiang, Yang

    2012-01-01

    Metacognitive theories propose that consumers track fluency feelings when buying, which may have biological underpinnings. We explored this using event-related potential (ERP) measures as twenty high-math anxiety (High MA) and nineteen low-math anxiety (Low MA) consumers made buying decisions for promoted (e.g., 15% discount) and non-promoted products. When evaluating prices, ERP correlates of higher perceptual and conceptual fluency were associated with buys, however only for High MA females under no promotions. In contrast, High MA females and Low MA males demonstrated greater FN400 amplitude, associated with enhanced conceptual processing, to prices of buys relative to non-buys under promotions. Concurrent late positive component (LPC) differences under no promotions suggest discrepant retrieval processes during price evaluations between consumer groups. When making decisions to buy or not, larger (smaller) P3, sensitive to outcome responses in the brain, was associated with buying for High MA females (Low MA females) under promotions, an effect also present for males under no promotions. Thus, P3 indexed decisions to buy differently between anxiety groups, but only for promoted items among females and for no promotions among males. Our findings indicate that perceptual and conceptual processes interact with anxiety and gender to modulate brain responses during consumer choices.

  12. Binding Dynamics of Targeted Microbubbles in Response to Modulated Acoustic Radiation Force

    PubMed Central

    Wang, Shiying; Hossack, John A; Klibanov, Alexander L; Mauldin, F William

    2014-01-01

    Detection of molecular targeted microbubbles plays a foundational role in ultrasound-based molecular imaging and targeted gene or drug delivery. In this paper, an empirical model describing the binding dynamics of targeted microbubbles in response to modulated acoustic radiation forces in large vessels is presented and experimentally verified using tissue-mimicking flow phantoms. Higher flow velocity and microbubble concentration led to faster detaching rates for specifically bound microbubbles (p < 0.001). Higher time-averaged acoustic radiation force intensity led to faster attaching rates and a higher saturation level of specifically bound microbubbles (p < 0.05). The level of residual microbubble signal in targeted experiments after cessation of radiation forces was the only response parameter that was reliably different between targeted and control experiments (p < 0.05). A related parameter, the ratio of residual-to-saturated microbubble signal (Rresid), is proposed as a measurement that is independent of absolute acoustic signal magnitude and therefore able to reliably detect targeted adhesion independently of control measurements (p < 0.01). These findings suggest the possibility of enhanced detection of specifically bound microbubbles in real-time, using relatively short imaging protocols (approximately 3 min), without waiting for free microbubble clearance. PMID:24374866

  13. Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.

    PubMed

    Porter, Shaina N; Cluster, Andrew S; Signer, Robert A J; Voigtmann, Jenna; Monlish, Darlene A; Schuettpelz, Laura G; Magee, Jeffrey A

    2016-06-14

    Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). Pten has been proposed to regulate HSCs cell autonomously and non-cell autonomously, but the relative importance of each mechanism has not been directly tested. Furthermore, the cytokines that activate the PI3K pathway upstream of Pten are not well defined. We sought to clarify whether Pten cell autonomously or non-cell autonomously regulates HSC mobilization. We also tested whether Pten deficiency affects the HSC response to granulocyte colony-stimulating factor (G-CSF) and interferon-α (IFNα) since these cytokines induce HSC mobilization or proliferation, respectively. We show that Pten regulates HSC mobilization and expansion in the spleen primarily via cell-autonomous mechanisms. Pten-deficient HSCs do not require G-CSF to mobilize, although they are hyper-sensitized to even low doses of exogenous G-CSF. Pten-deficient HSCs are similarly sensitized to IFNα. Pten therefore modulates the HSC response to inflammatory cytokines. PMID:27185281

  14. Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers.

    PubMed

    Bermudez-Brito, Miriam; Faas, Marijke M; de Vos, Paul

    2016-01-01

    Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis. PMID:27452116

  15. Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics

    PubMed Central

    LaBarge, Mark A; Parvin, Bahram; Lorens, James B

    2014-01-01

    The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments has revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes, and in a number of cases has revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery. PMID:24582543

  16. Modulation of the immune response by infection with Cryptosporidium spp. in children with allergic diseases.

    PubMed

    Guangorena-Gómez, J O; Maravilla-Domínguez, A; García-Arenas, G; Cervantes-Flores, M; Meza-Velázquez, R; Rivera-Guillén, M; Acosta-Saavedra, L C; Goytia-Acevedo, R C

    2016-08-01

    It has been demonstrated that the allergic response can be ameliorated by the administration of pathogen derivatives that activate Toll-like receptors and induce a Th1-type immune response (IR). Cryptosporidium is a parasite that promotes an IR via Toll-like receptors and elicits the production of Th1-type cytokines, which limit cryptosporidiosis. The aim of this study was to investigate allergy-related immune markers in children naturally infected with Cryptosporidium. In a cross-sectional study, 49 children with or without clinical diagnosis of allergies, oocysts of Cryptosporidium spp. in the faeces were screened microscopically. We microscopically screened for leucocytes, examined T and B cells for allergy-related activation markers using flow cytometry and evaluated serum for total IgE using chemiluminescence. Children with allergies and Cryptosporidium in the faeces had significantly lower levels of total IgE, B cells, CD19(+) CD23(+) and CD19(+) CD124(+) cells as well as a greater percentage of interferon-gamma (IFN-γ(+) ) and IL-4(+) CD4(+) cells than children with allergies without Cryptosporidium. This is the first description of the modulation of the IR in children with allergic diseases in the setting of natural Cryptosporidium infection. Our findings suggest the involvement of CD4(+) cells producing IL-4 and IFN-γ in the IR to Cryptosporidium in naturally infected children. PMID:27150641

  17. Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers

    PubMed Central

    Bermudez-Brito, Miriam; Faas, Marijke M; de Vos, Paul

    2016-01-01

    Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis. PMID:27452116

  18. Like or dislike? Affective preference modulates neural response to others' gains and losses.

    PubMed

    Wang, Yang; Qu, Chen; Luo, Qiuling; Qu, Lulu; Li, Xuebing

    2014-01-01

    Previous studies have demonstrated that the brain responds differentially to others' gains and losses relative to one's own, moderated by social context factors such as competition and interpersonal relationships. In the current study, we tested the hypothesis that the neural response to others' outcomes could be modulated by a short-term induced affective preference. We engaged 17 men and 18 women in a social-exchange game, in which two confederates played fairly or unfairly. Both men and women rated the fair player as likable and the unfair players as unlikable. Afterwards, ERPs were recorded while participants observed each confederates playing a gambling game individually. This study examines feedback related negativity (FRN), an ERP component sensitive to negative feedback. ANOVA showed a significant interaction in which females but not males displayed stronger FRNs when observing likable players' outcomes compared to unlikable ones'. However, males did not respond differently under either circumstance. These findings suggest that, at least in females, the neural response is influenced by a short-term induced affective preference. PMID:25171075

  19. Dopamine D₂ receptor modulation of human response inhibition and error awareness.

    PubMed

    Nandam, L Sanjay; Hester, Robert; Wagner, Joe; Dean, Angela J; Messer, Cassandra; Honeysett, Asha; Nathan, Pradeep J; Bellgrove, Mark A

    2013-04-01

    Response inhibition, comprising action cancellation and action restraint, and error awareness are executive functions of considerable clinical relevance to neuropsychiatric disorders. Nevertheless, our understanding of their underlying catecholamine mechanisms, particularly regarding dopamine, is limited. Here, we used the dopamine D2 agonist cabergoline to study its ability to improve inhibitory control and modulate awareness of performance errors. A randomized, double-blind, placebo-controlled, crossover design with a single dose of cabergoline (1.25 mg) and placebo (dextrose) was employed in 25 healthy participants. They each performed the stop-signal task, a well-validated measure of action cancellation, and the Error Awareness Task, a go/no-go measure of action restraint and error awareness, under each drug condition. Cabergoline was able to selectively reduce stop-signal RT, compared with placebo, indicative of enhanced action cancellation (p < .05). This enhancement occurred without concomitant changes in overall response speed or RT variability and was not seen for errors of commission on the Error Awareness Task. Awareness of performance errors on the go/no-go task was, however, significantly improved by cabergoline compared with placebo (p < .05). Our results contribute to growing evidence for the dopaminergic control of distinct aspects of human executive ability, namely, action cancellation and error awareness. The findings may aid the development of new, or the repurposing of existing, pharmacotherapy that targets the cognitive dysfunction of psychiatric and neurological disorders. They also provide further evidence that specific cognitive paradigms have correspondingly specific neurochemical bases. PMID:23163418

  20. Dynamical response of the North Pacific Ocean to the tropical variability and its decadal modulation

    NASA Astrophysics Data System (ADS)

    Nonaka, M.; Taguchi, B.; Schneider, N.

    2015-12-01

    While teleconnections from the tropical Pacific to the North Pacific sea surface temperature are well known, the dynamical response of the North Pacific Ocean to the tropical atmosphere-ocean variability is not well investigated. Based on observed and reanalysis data, we investigate this link through a correlation analysis using the indices of Nino3, Nino3.4, and El Nino Modoki Index (EMI). The simultaneous correlation maps of the wind-stress curl indicate that the signal associated with EMI in the eastern North Pacific is stronger than the counterparts with Nino3 and Nino3.4. Responding to these signals in wind-stress curl, sea surface height (SSH) anomalies develop following EMI, but almost no SSH responses are found to Nino3 and Nino3.4. As El Nino Modoki lasts for a longer period than canonical El Nino, the stronger wind-stress curl signal to EMI drives the ocean more persistently, and induces substantial SSH signals. The induced SSH signals propagate westward to the western boundary region around 35N, affecting variability in the Kuroshio Extension, which might further exert feedback on the atmosphere aloft. The teleconnection from EMI to the North Pacific, however, was not found before the 1990s, indicating its clear decadal modulation.

  1. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response.

    PubMed

    Yan, Qingsheng; Dutt, Shilpee; Xu, Rong; Graves, Katherine; Juszczynski, Przemyslaw; Manis, John P; Shipp, Margaret A

    2009-10-01

    Although the BBAP E3 ligase and its binding partner BAL are overexpressed in chemotherapy-resistant lymphomas, the role of these proteins in DNA damage responses remains undefined. Because BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. Because 53BP1 localizes to DNA damage sites, in part, via an interaction with dimethyl H4K20, these data directly implicate BBAP in the monoubiquitylation and additional posttranslational modification of histone H4 and an associated DNA damage response. PMID:19818714

  2. Emotion processing fails to modulate putative mirror neuron response to trained visuomotor associations.

    PubMed

    Fitzgibbon, Bernadette M; Kirkovski, Melissa; Fornito, Alex; Paton, Bryan; Fitzgerald, Paul B; Enticott, Peter G

    2016-04-01

    Recent neuroimaging studies have demonstrated that activation of the putative human mirror neuron system (MNS) can be elicited via visuomotor training. This is generally interpreted as supporting an associative learning account of the mirror neuron system (MNS) that argues against the ontogeny of the MNS to be an evolutionary adaptation for social cognition. The current study assessed whether a central component of social cognition, emotion processing, would influence the MNS activity to trained visuomotor associations, which could support a broader role of the MNS in social cognition. Using functional magnetic resonance imaging (fMRI), we assessed repetition suppression to the presentation of stimulus pairs involving a simple hand action and a geometric shape that was either congruent or incongruent with earlier association training. Each pair was preceded by an image of positive, negative, or neutral emotionality. In support of an associative learning account of the MNS, repetition suppression was greater for trained pairs compared with untrained pairs in several regions, primarily supplementary motor area (SMA) and right inferior frontal gyrus (rIFG). This response, however, was not modulated by the valence of the emotional images. These findings argue against a fundamental role of emotion processing in the mirror neuron response, and are inconsistent with theoretical accounts linking mirror neurons to social cognition.

  3. Opioid modulation of facial itch- and pain-related responses and grooming behavior in rats.

    PubMed

    Spradley, Jessica M; Davoodi, Auva; Carstens, Mirela Iodi; Carstens, Earl

    2012-09-01

    Intradermal facial injections of pruritogens or algogens elicit distinct behavioral hindlimb scratch or forelimb wiping responses in rodents. We systematically investigated the parameters and opioid modulation of these evoked behaviors and spontaneous facial grooming in rats. Serotonin (5-HT) elicited hindlimb scratch bouts with few wipes. Scratching was attenuated by the µ-opiate antagonist naltrexone but not morphine. In contrast, cheek injection of mustard oil (allyl-isothiocyanate (AITC)) elicited ipsilateral forelimb wipes but little hindlimb scratching. AITC-evoked wiping was significantly attenuated by morphine but not naltrexone. Spontaneous facial grooming by the forepaws was attenuated by naltrexone, whereas morphine did not affect grooming behavior before or after cheek injections of 5-HT or AITC. These data validate that the rodent "cheek" model discriminates between itch- and pain-related behaviors. Naltrexone sensitivity of facial grooming and 5-HT-evoked scratch-ing suggests a common functionality. Forelimb wipes may represent a nocifensive response akin to rubbing an injury to relieve pain.

  4. Steady-state BOLD Response to Higher-order Cognition Modulates Low-Frequency Neural Oscillations.

    PubMed

    Wang, Yi-Feng; Dai, Gang-Shu; Liu, Feng; Long, Zhi-Liang; Yan, Jin H; Chen, Hua-Fu

    2015-12-01

    Steady-state responses (SSRs) reflect the synchronous neural oscillations evoked by noninvasive and consistently repeated stimuli at the fundamental or harmonic frequencies. The steady-state evoked potentials (SSEPs; the representative form of the SSRs) have been widely used in the cognitive and clinical neurosciences and brain-computer interface research. However, the steady-state evoked potentials have limitations in examining high-frequency neural oscillations and basic cognition. In addition, synchronous neural oscillations in the low frequency range (<1 Hz) and in higher-order cognition have received a little attention. Therefore, we examined the SSRs in the low frequency range using a new index, the steady-state BOLD responses (SSBRs) evoked by semantic stimuli. Our results revealed that the significant SSBRs were induced at the fundamental frequency of stimuli and the first harmonic in task-related regions, suggesting the enhanced variability of neural oscillations entrained by exogenous stimuli. The SSBRs were independent of neurovascular coupling and characterized by sensorimotor bias, an indication of regional-dependent neuroplasticity. Furthermore, the amplitude of SSBRs may predict behavioral performance and show the psychophysiological relevance. Our findings provide valuable insights into the understanding of the SSRs evoked by higher-order cognition and how the SSRs modulate low-frequency neural oscillations. PMID:26284992

  5. Antipsychotic dose modulates behavioral and neural responses to feedback during reinforcement learning in schizophrenia.

    PubMed

    Insel, Catherine; Reinen, Jenna; Weber, Jochen; Wager, Tor D; Jarskog, L Fredrik; Shohamy, Daphna; Smith, Edward E

    2014-03-01

    Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.

  6. Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics.

    PubMed

    Labarge, Mark A; Parvin, Bahram; Lorens, James B

    2014-04-01

    The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments have revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes and in a number of cases have revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus, introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery.

  7. Calpain A modulates Toll responses by limited Cactus/IκB proteolysis

    PubMed Central

    Fontenele, Marcio; Lim, Bomyi; Oliveira, Danielle; Buffolo, Márcio; Perlman, David H.; Schupbach, Trudi; Araujo, Helena

    2013-01-01

    Calcium-dependent cysteine proteases of the calpain family are modulatory proteases that cleave their substrates in a limited manner. Among their substrates, calpains target vertebrate and invertebrate IκB proteins. Because proteolysis by calpains potentially generates novel protein functions, it is important to understand how this affects NFκB activity. We investigate the action of Calpain A (CalpA) on the Drosophila melanogaster IκB homologue Cactus in vivo. CalpA alters the absolute amounts of Cactus protein. Our data indicate, however, that CalpA uses additional mechanisms to regulate NFκB function. We provide evidence that CalpA interacts physically with Cactus, recognizing a Cactus pool that is not bound to Dorsal, a fly NFκB/Rel homologue. We show that proteolytic cleavage by CalpA generates Cactus fragments lacking an N-terminal region required for Toll responsiveness. These fragments are generated in vivo and display properties distinct from those of full-length Cactus. We propose that CalpA targets free Cactus, which is incorporated into and modulates Toll-responsive complexes in the embryo and immune system. PMID:23864715

  8. Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers.

    PubMed

    Bermudez-Brito, Miriam; Faas, Marijke M; de Vos, Paul

    2016-07-25

    Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis.

  9. Psychopathic traits modulate brain responses to drug cues in incarcerated offenders

    PubMed Central

    Cope, Lora M.; Vincent, Gina M.; Jobelius, Justin L.; Nyalakanti, Prashanth K.; Calhoun, Vince D.; Kiehl, Kent A.

    2014-01-01

    Recent neuroscientific evidence indicates that psychopathy is associated with abnormal function and structure in limbic and paralimbic areas. Psychopathy and substance use disorders are highly comorbid, but clinical experience suggests that psychopaths abuse drugs for different reasons than non-psychopaths, and that psychopaths do not typically experience withdrawal and craving upon becoming incarcerated. These neurobiological abnormalities may be related to psychopaths' different motivations for—and symptoms of—drug use. This study examined the modulatory effect of psychopathic traits on the neurobiological craving response to pictorial drug stimuli. Drug-related pictures and neutral pictures were presented and rated by participants while hemodynamic activity was monitored using functional magnetic resonance imaging. These data were collected at two correctional facilities in New Mexico using the Mind Research Network mobile magnetic resonance imaging system. The sample comprised 137 incarcerated adult males and females (93 females) with histories of substance dependence. The outcome of interest was the relation between psychopathy scores (using the Hare Psychopathy Checklist-Revised) and hemodynamic activity associated with viewing drug-related pictures vs. neutral pictures. There was a negative association between psychopathy scores and hemodynamic activity for viewing drug-related cues in the anterior cingulate, posterior cingulate, hippocampus, amygdala, caudate, globus pallidus, and parts of the prefrontal cortex. Psychopathic traits modulate the neurobiological craving response and suggest that individual differences are important for understanding and treating substance abuse. PMID:24605095

  10. Alarmin’ Immunologists: IL-33 as a Putative Target for Modulating T Cell-Dependent Responses

    PubMed Central

    Gajardo Carrasco, Tania; Morales, Rodrigo A.; Pérez, Francisco; Terraza, Claudia; Yáñez, Luz; Campos-Mora, Mauricio; Pino-Lagos, Karina

    2015-01-01

    IL-33 is a known member of the IL-1 cytokine superfamily classically named “atypical” due to its diverse functions. The receptor for this cytokine is the ST2 chain (or IL-1RL1), part of the IL-1R family, and the accessory chain IL-1R. ST2 can be found as both soluble and membrane-bound forms, property that explains, at least in part, its wide range of functions. IL-33 has increasingly gained our attention as a potential target to modulate immune responses. At the beginning, it was known as one of the participants during the development of allergic states and other Th2-mediated responses and it is now accepted that IL-33 contributes to Th1-driven pathologies as demonstrated in animal models of experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis, and trinitrobenzene sulfonic acid-induced experimental colitis, among others. Interestingly, current data are placing IL-33 as a novel regulator of immune tolerance by affecting regulatory T cells (Tregs); although the mechanism is not fully understood, it seems that dendritic cells and myeloid suppressor-derived cells may be cooperating in the generation and/or establishment of IL-33-mediated tolerance. Here, we review the most updated literature on IL-33, its role on T cell biology, and its impact in immune tolerance. PMID:26082774

  11. Coding the Meaning of Sounds: Contextual Modulation of Auditory Responses in the Basolateral Amygdala

    PubMed Central

    Grimsley, Jasmine M. S.; Hazlett, Emily G.

    2013-01-01

    Female mice emit a low-frequency harmonic (LFH) call in association with distinct behavioral contexts: mating and physical threat or pain. Here we report the results of acoustic, behavioral, and neurophysiological studies of the contextual analysis of these calls in CBA/CaJ mice. We first show that the acoustical features of the LFH call do not differ between contexts. We then show that male mice avoid the LFH call in the presence of a predator cue (cat fur) but are more attracted to the same exemplar of the call in the presence of a mating cue (female urine). The males thus use nonauditory cues to determine the meaning of the LFH call, but these cues do not generalize to noncommunication sounds, such as noise bursts. We then characterized neural correlates of contextual meaning of the LFH call in responses of basolateral amygdala (BLA) neurons from awake, freely moving mice. There were two major findings. First, BLA neurons typically displayed early excitation to all tested behaviorally aversive stimuli. Second, the nonauditory context modulates the BLA population response to the LFH call but not to the noncommunication sound. These results suggest that the meaning of communication calls is reflected in the spike discharge patterns of BLA neurons. PMID:24174686

  12. Female Lincoln's sparrows modulate their behavior in response to variation in male song quality

    PubMed Central

    Sewall, Kendra B.; Salvante, Katrina G.

    2010-01-01

    Sexually reproducing organisms should mate with the highest quality individuals that they can. When female songbirds choose a mate, they are thought to use several aspects of male song that reflect his quality. Under resource-limited environmental conditions, male Lincoln's sparrows (Melospiza lincolnii) vary among one another in several aspects of song quality, including song length, song complexity, and trill performance. In a 2-pronged approach, we tested whether variation in song quality of male Lincoln's sparrows influences the behavior of females that are in a reproductive-like state. Over two trials, we exposed females to songs from the high and low ends of the distribution of naturally occurring song quality variation and found a higher level of behavioral activity in females exposed to high-quality songs, especially when they had first been exposed to low-quality songs. We also examined female phonotaxis toward antiphonally played songs with experimentally elevated and reduced trill performance and found that females moved preferentially toward the songs with elevated trill performance. Contrary to most studies investigating the behavioral responses of wild, female songbirds to variation in male song, we obtained our results without administering exogenous estradiol, which can artificially perturb the female's physiology. Our results demonstrate that the behavior of female Lincoln's sparrows is modulated by the quality of male songs to which they are exposed and that trill performance plays a significant role in this behavioral modulation. Furthermore, as the order of song quality presentation matters, it appears that recent song experience also influences female behavior. PMID:22476505

  13. Gedunin, a natural tetranortriterpenoid, modulates T lymphocyte responses and ameliorates allergic inflammation.

    PubMed

    Ferraris, Fausto K; Moret, Katelim Hottz; Figueiredo, Alexandre Bezerra Conde; Penido, Carmen; Henriques, Maria das Graças M O

    2012-09-01

    T lymphocytes are critical cells involved in allergy. Here, we report that the natural tetranortriterpenoid gedunin impaired allergic responses primarily by modulating T lymphocyte functions. The intraperitoneal (i.p.) administration of gedunin inhibited pleural leukocyte accumulation triggered by intra-pleural (i.pl.) challenge with ovalbumin (OVA) in previously sensitized C57BL/6 mice; this inhibition was primarily due to the impairment of eosinophil and T lymphocyte influx. Likewise, i.pl. pre-treatment with gedunin inhibited eosinophil and T lymphocyte migration into mouse lungs 24 h after OVA intra-nasal (i.n.) instillation. Pre-treatment with gedunin diminished the levels of CCL2, CCL3, CCL5, CCL11, Interleukin-5 and leukotriene B(4) at the allergic site. In vitro pre-treatment with gedunin failed to inhibit T lymphocyte adhesion and chemotaxis towards pleural washes recovered from OVA-challenged mice, suggesting that gedunin inhibits T lymphocyte migration in vivo via the inhibition of chemotactic mediators in situ. In vivo pre-treatment with gedunin reduced the numbers of CD69(+) and CD25(+) T lymphocytes in the pleura and CD25(+) cells in the thoracic lymph nodes 24 h after OVA i.pl. challenge. In accordance, in vitro treatment of T lymphocytes with gedunin inhibited α-CD3 mAb-induced expression of CD69 and CD25, proliferation, Interleukin-2 production and nuclear translocation of NFκB and NFAT. Notably, post-treatment of mice with gedunin reverted OVA-induced lung allergic inflammation by decreasing the T lymphocyte and eosinophil counts and the levels of eosinophilotactic mediators in bronchoalveolar lavage fluid. Our results demonstrate a remarkable anti-allergic effect of gedunin due to its capability to modulate T cell activation and trafficking into the airways. PMID:22709475

  14. Equine herpesvirus type 1 modulates inflammatory host immune response genes in equine endothelial cells.

    PubMed

    Johnstone, Stephanie; Barsova, Jekaterina; Campos, Isabel; Frampton, Arthur R

    2016-08-30

    Equine herpesvirus myeloencephalopathy (EHM), a disease caused by equine herpesvirus type 1 (EHV-1), is characterized by severe inflammation, thrombosis, and hypoxia in central nervous system (CNS) endothelial cells, which can result in a spectrum of clinical signs including urinary incontinence, ataxia, and paralysis. Strains of EHV-1 that contain a single point mutation within the viral DNA polymerase (nucleotide A2254>G2254: amino acid N752→D752) are isolated from EHM afflicted horses at higher frequencies than EHV-1 strains that do not harbor this mutation. Due to the correlation between the DNA Pol mutation and EHM disease, EHV-1 strains that contain the mutation have been designated as neurologic. In this study, we measured virus replication, cell to cell spread efficacy, and host inflammatory responses in equine endothelial cells infected with 12 different strains of EHV-1. Two strains, T953 (Ohio 2003) (neurologic) and Kentucky A (KyA) (non-neurologic), have well described disease phenotypes while the remaining strains used in this study are classified as neurologic or non-neurologic based solely on the presence or absence of the DNA pol mutation, respectively. Results show that the neurologic strains do not replicate better or spread more efficiently in endothelial cells. Also, the majority of the host inflammatory genes were modulated similarly regardless of EHV-1 genotype. Analyses of host gene expression showed that a subset of pro-inflammatory cytokines, including the CXCR3 ligands CXCL9, CXCL10, and CXCL11, as well as CCL5, IL-6 and TNF-α were consistently up-regulated in endothelial cells infected with each EHV-1 strain. The identification of specific pro-inflammatory cytokines in endothelial cells that are modulated by EHV-1 provides further insight into the factors that contribute to the immunopathology observed after infection and may also reveal new targets for disease intervention. PMID:27527764

  15. Neuroticism Modulates the Effects of Intranasal Vasopressin Treatment on the Neural Response to Positive and Negative Social Interactions

    PubMed Central

    Feng, Chunliang; DeMarco, Ashley C.; Haroon, Ebrahim; Rilling, James K.

    2015-01-01

    Neuroticism is a fundamental personality trait associated with proneness to feel negative affect. Here we ask how Neuroticism influences the neural response to positive and negative social interactions and how Neuroticism modulates the effect of intranasal oxytocin (OT) and vasopressin (AVP) on the neural response to social interactions. In a double-blind, placebo-controlled study, 153 male participants were randomized to receive 24 IU intranasal OT, 20 IU AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game. On a different day, subjects completed the NEO personality inventory to measure Neuroticism. Neuroticism was positively correlated with the neural response to negative social interactions in the anterior cingulate cortex/medial prefrontal cortex and with the neural response to positive social interactions in the insula, indicating that Neuroticism modulates neuropsychological processing of both negative and positive social interactions. Neuroticism did not modulate the effect of intranasal OT treatment on the neural response to either positive or negative social interactions. On the other hand, AVP treatment significantly interacted with Neuroticism to modulate the BOLD response to both positive and negative social interactions. Specifically, AVP increased anterior cingulate cortex/medial prefrontal cortex and lateral temporal lobe responses to negative social interactions to a greater extent in participants scoring high rather than low on Neuroticism. AVP also increased the insula response to positive social interactions to a greater extent in participants scoring high rather than low on Neuroticism. These results imply that AVP may increase emotion regulation in response to negative social interactions and the salience of positive social interactions to a greater extent in individuals high compared to low in Neuroticism. The current findings urge caution against uniform clinical application of

  16. Genetic and environmental modulation of neurotrophic and anabolic stress response: Counterbalancing forces.

    PubMed

    Taylor, Marcus K; Carpenter, Jennifer; Stone, Michael; Hernandez, Lisa M; Rauh, Mitchell J; Laurent, Heidemarie K; Granger, Douglas A

    2015-11-01

    The serotonin transporter genetic variant 5HTTLPR influences activation and feedback control of the hypothalamic-pituitary-adrenal axis, and has been shown to influence the effect of stressful life events on behavioral health. We recently reported that 5HTTLPR modulates cortisol response in healthy military men exposed to intense stress. Less is known of its combined effects with environmental factors in this context, or of its effect on neuroprotective stress responses. In this follow-up study, we examined the unique and combined effects of 5HTTLPR and prior trauma exposure on neuroprotective (salivary nerve growth factor [sNGF]), anabolic (dehydroepiandrosterone sulfate [DHEAS] and testosterone), and catabolic (cortisol) stress responses. Ninety-three healthy, active-duty military men were studied before, during, and 24h after a stressful 12-day survival course. Distinct and interactive effects of 5HTTLPR long allele carriage [L] versus homozygous short allele carriage [SS]) and prior trauma exposure (low versus high) were evaluated, after which a priori group comparisons were performed between hypothesized high resilience (L/low) and low resilience (SS/high) groups. For sNGF, L/low produced the greatest sNGF throughout stress exposure while SS/high demonstrated the smallest; L/high and SS/low bisected these two extremes and were nearly identical to each other (i.e., SS/high < SS/low = L/high < L/low). Thus, 5HTTLPR and prior trauma exposure demonstrated counterbalancing (additive) forces. Similar patterns were found for DHEAS. To our knowledge, this study is the first to report counterbalancing genetic and environmental effects on novel biomarkers related to resilience in humans exposed to real-world stress. These findings have profound implications for health, performance and training in high-stress occupational settings.

  17. Lipreading and covert speech production similarly modulate human auditory-cortex responses to pure tones

    PubMed Central

    Kauramäki, Jaakko; Jääskeläinen, Iiro P.; Hari, Riitta; Möttönen, Riikka; Rauschecker, Josef P.; Sams, Mikko

    2010-01-01

    Watching the lips of a speaker enhances speech perception. At the same time, the 100-ms response to speech sounds is suppressed in the observer’s auditory cortex. Here, we used whole-scalp 306-channel magnetoencephalography (MEG) to study whether lipreading modulates human auditory processing already at the level of the most elementary sound features, i.e., pure tones. We further envisioned the temporal dynamics of the suppression to tell whether the effect is driven by top-down influences. Nineteen subjects were presented with 50-ms tones spanning six octaves (125–8000 Hz) (1) during “lipreading”, i.e. when they watched video clips of silent articulations of Finnish vowels /a/, /i/, /o/, /y/, and reacted to vowels presented twice in a row, (2) during a visual control task, (3) during a still-face passive control condition, and, in a separate experiment with a subset of nine subjects, (4) during covert production of the same vowels. Auditory-cortex 100-ms responses (N100m) were equally suppressed in the lipreading and covert speech-production tasks compared with the visual control and baseline tasks; the effects involved all frequencies and were most prominent in the left hemisphere. Responses to tones presented at different times with respect to the onset of the visual articulation showed significantly increased N100m suppression immediately after the articulatory gesture. These findings suggest that the lipreading-related suppression in the auditory cortex is caused by top-down influences, possibly by an efference copy from the speech-production system, generated during both own speech and lipreading. PMID:20107058

  18. Glucocorticoids and protein kinase A coordinately modulate transcription factor recruitment at a glucocorticoid-responsive unit.

    PubMed Central

    Espinás, M L; Roux, J; Pictet, R; Grange, T

    1995-01-01

    The rat tyrosine aminotransferase gene is a model system to study transcriptional regulation by glucocorticoid hormones. We analyzed transcription factor binding to the tyrosine aminotransferase gene glucocorticoid-responsive unit (GRU) at kb -2.5, using in vivo footprinting studies with both dimethyl sulfate and DNase I. At this GRU, glucocorticoid activation triggers a disruption of the nucleosomal structure. We show here that various regulatory pathways affect transcription factor binding to this GRU. The binding differs in two closely related glucocorticoid-responsive hepatoma cell lines. In line H4II, glucocorticoid induction promotes the recruitment of hepatocyte nuclear factor 3 (HNF3), presumably through the nucleosomal disruption. However, the footprint of the glucocorticoid receptor (GR) is not visible, even though a regular but transient interaction of the GR is necessary to maintain HNF3 binding. In contrast, in line FTO2B, HNF3 binds to the GRU in the absence of glucocorticoids and nucleosomal disruption, showing that a "closed" chromatin conformation does not repress the binding of certain transcription factors in a uniform manner. In FTO2B cells, the footprint of the GR is detectable, but this requires the activation of protein kinase A. In addition, protein kinase A stimulation also improves the recruitment of HNF3 independently of glucocorticoids and enhances the glucocorticoid response mediated by this GRU in an HNF3-dependent manner. In conclusion, the differences in the behavior of this regulatory sequence in the two cell lines show that various regulatory pathways are integrated at this GRU through modulation of interrelated events: transcription factor binding to DNA and nucleosomal disruption. PMID:7565684

  19. MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression

    PubMed Central

    Wang, Yemin; Huang, Jen-Wei; Li, Ming; Cavenee, Webster K.; Mitchell, Patrick S.; Zhou, Xiaofeng; Tewari, Muneesh; Furnari, Frank B.; Taniguchi, Toshiyasu

    2011-01-01

    Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs are short, non-protein-encoding RNA molecules, which post-transcriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How microRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay utilizing ionizing radiation-induced γH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human microRNA mimics, we identified several microRNAs that inhibited γH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3′-UTR, reduced histone H2AX expression and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA damaging agents (cisplatin, camptothecin, and ionizing radiation). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138-mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA damaging agents. PMID:21693595

  20. ISG12 is a critical modulator of innate immune responses in murine models of sepsis.

    PubMed

    Uhrin, P; Perkmann, T; Binder, B; Schabbauer, G

    2013-09-01

    Sepsis is still a major burden for our society with high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. Recently the role of nuclear receptors (NRs) became a major topic of interest in transcriptional regulation of inflammatory processes. Nuclear receptors, such as the peroxisome proliferators-activated receptors (PPARs), have been demonstrated to exert anti-inflammatory properties by interfering with the NFκB pathway. We identified the nuclear envelope protein, interferon stimulated gene 12 (ISG12), which directly interacts with NRs. ISG12 is a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. To examine the role of ISG12 in acute inflammatory processes we used recently generated ISG12 deficient mice. We can clearly demonstrate that lack of ISG12 prolongs survival in experimental sepsis and endotoxemia. Furthermore we can show that several acute inflammatory parameters, such as systemic IL6 cytokine levels, are downregulated in septic ISG12-/- animals. Consistently, similar results were obtained in in vitro experiments in peritoneal macrophages derived from ISG12 deficient mice. In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response, and showed a significantly higher mortality after lethal endotoxemic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1.

  1. ISG12 is a critical modulator of innate immune responses in murine models of sepsis☆

    PubMed Central

    Uhrin, P.; Perkmann, T.; Binder, B.; Schabbauer, G.

    2013-01-01

    Sepsis is still a major burden for our society with high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. Recently the role of nuclear receptors (NRs) became a major topic of interest in transcriptional regulation of inflammatory processes. Nuclear receptors, such as the peroxisome proliferators-activated receptors (PPARs), have been demonstrated to exert anti-inflammatory properties by interfering with the NFκB pathway. We identified the nuclear envelope protein, interferon stimulated gene 12 (ISG12), which directly interacts with NRs. ISG12 is a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. To examine the role of ISG12 in acute inflammatory processes we used recently generated ISG12 deficient mice. We can clearly demonstrate that lack of ISG12 prolongs survival in experimental sepsis and endotoxemia. Furthermore we can show that several acute inflammatory parameters, such as systemic IL6 cytokine levels, are downregulated in septic ISG12−/− animals. Consistently, similar results were obtained in in vitro experiments in peritoneal macrophages derived from ISG12 deficient mice. In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response, and showed a significantly higher mortality after lethal endotoxemic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1. PMID:23747037

  2. Social stress modulates the cortisol response to an acute stressor in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Jeffrey, J D; Gollock, M J; Gilmour, K M

    2014-01-15

    In rainbow trout (Oncorhynchus mykiss) of subordinate social status, circulating cortisol concentrations were elevated under resting conditions but the plasma cortisol and glucose responses to an acute stressor (confinement in a net) were attenuated relative to those of dominant trout. An in vitro head kidney preparation, and analysis of the expression of key genes in the stress axis prior to and following confinement in a net were then used to examine the mechanisms underlying suppression of the acute cortisol stress response in trout experiencing chronic social stress. With porcine adrenocorticotropic hormone (ACTH) as the secretagogue, ACTH-stimulated cortisol production was significantly lower for head kidney preparations from subordinate trout than for those from dominant trout. Dominant and subordinate fish did not, however, differ in the relative mRNA abundance of melanocortin-2 receptor (MC2R), steroidogenic acute regulatory protein (StAR) or cytochrome P450 side chain cleavage enzyme (P450scc) within the head kidney, although the relative mRNA abundance of these genes was significantly higher in both dominant and subordinate fish than in sham trout (trout that did not experience social interactions but were otherwise treated identically to the dominant and subordinate fish). The relative mRNA abundance of all three genes was significantly higher in trout exposed to an acute net stressor than under control conditions. Upstream of cortisol production in the stress axis, plasma ACTH concentrations were not affected by social stress, nor was the relative mRNA abundance of the binding protein for corticotropin releasing factor (CRF-BP). The relative mRNA abundance of CRF in the pre-optic area of subordinate fish was significantly higher than that of dominant or sham fish 1h after exposure to the stressor. Collectively, the results indicate that chronic social stress modulates cortisol production at the level of the interrenal cells, resulting in an attenuated

  3. Wettability and osteoblast cell response modulation through UV laser processing of nylon 6,6

    NASA Astrophysics Data System (ADS)

    Waugh, D. G.; Lawrence, J.

    2011-08-01

    With an ageing population the demand for cheap, efficient implants is ever increasing. Laser surface treatment offers a unique means of varying biomimetic properties to determine generic parameters to predict cell responses. This paper details how a KrF excimer laser can be employed for both laser-induced patterning and whole area irradiative processing to modulate the wettability characteristics and osteoblast cell response following 24 h and 4 day incubation. Through white light interferometry (WLI) it was found that the surface roughness had considerably increased by up to 1.5 μm for the laser-induced patterned samples and remained somewhat constant at around 0.1 μm for the whole area irradiative processed samples. A sessile drop device determined that the wettability characteristics differed between the surface treatments. For the patterned samples the contact angle, θ, increased by up to 25° which can be attributed to a mixed-state wetting regime. For the whole area irradiative processed samples θ decreased owed to an increase in polar component, γP. For all samples θ was a decreasing function of the surface energy. The laser whole area irradiative processed samples gave rise to a distinct correlative trend between the cell response, θ and γP. However, no strong relationship was determined for the laser-induced patterned samples due to the mixed-state wetting regime. As a result, owed to the relationships and evidence of cell differentiation one can deduce that laser whole area irradiative processing is an attractive technology for employment within regenerative medicine to meet the demands of an ageing population.

  4. Genetic and environmental modulation of neurotrophic and anabolic stress response: Counterbalancing forces.

    PubMed

    Taylor, Marcus K; Carpenter, Jennifer; Stone, Michael; Hernandez, Lisa M; Rauh, Mitchell J; Laurent, Heidemarie K; Granger, Douglas A

    2015-11-01

    The serotonin transporter genetic variant 5HTTLPR influences activation and feedback control of the hypothalamic-pituitary-adrenal axis, and has been shown to influence the effect of stressful life events on behavioral health. We recently reported that 5HTTLPR modulates cortisol response in healthy military men exposed to intense stress. Less is known of its combined effects with environmental factors in this context, or of its effect on neuroprotective stress responses. In this follow-up study, we examined the unique and combined effects of 5HTTLPR and prior trauma exposure on neuroprotective (salivary nerve growth factor [sNGF]), anabolic (dehydroepiandrosterone sulfate [DHEAS] and testosterone), and catabolic (cortisol) stress responses. Ninety-three healthy, active-duty military men were studied before, during, and 24h after a stressful 12-day survival course. Distinct and interactive effects of 5HTTLPR long allele carriage [L] versus homozygous short allele carriage [SS]) and prior trauma exposure (low versus high) were evaluated, after which a priori group comparisons were performed between hypothesized high resilience (L/low) and low resilience (SS/high) groups. For sNGF, L/low produced the greatest sNGF throughout stress exposure while SS/high demonstrated the smallest; L/high and SS/low bisected these two extremes and were nearly identical to each other (i.e., SS/high < SS/low = L/high < L/low). Thus, 5HTTLPR and prior trauma exposure demonstrated counterbalancing (additive) forces. Similar patterns were found for DHEAS. To our knowledge, this study is the first to report counterbalancing genetic and environmental effects on novel biomarkers related to resilience in humans exposed to real-world stress. These findings have profound implications for health, performance and training in high-stress occupational settings. PMID:26136163

  5. Lipreading and covert speech production similarly modulate human auditory-cortex responses to pure tones.

    PubMed

    Kauramäki, Jaakko; Jääskeläinen, Iiro P; Hari, Riitta; Möttönen, Riikka; Rauschecker, Josef P; Sams, Mikko

    2010-01-27

    Watching the lips of a speaker enhances speech perception. At the same time, the 100 ms response to speech sounds is suppressed in the observer's auditory cortex. Here, we used whole-scalp 306-channel magnetoencephalography (MEG) to study whether lipreading modulates human auditory processing already at the level of the most elementary sound features, i.e., pure tones. We further envisioned the temporal dynamics of the suppression to tell whether the effect is driven by top-down influences. Nineteen subjects were presented with 50 ms tones spanning six octaves (125-8000 Hz) (1) during "lipreading," i.e., when they watched video clips of silent articulations of Finnish vowels /a/, /i/, /o/, and /y/, and reacted to vowels presented twice in a row; (2) during a visual control task; (3) during a still-face passive control condition; and (4) in a separate experiment with a subset of nine subjects, during covert production of the same vowels. Auditory-cortex 100 ms responses (N100m) were equally suppressed in the lipreading and covert-speech-production tasks compared with the visual control and baseline tasks; the effects involved all frequencies and were most prominent in the left hemisphere. Responses to tones presented at different times with respect to the onset of the visual articulation showed significantly increased N100m suppression immediately after the articulatory gesture. These findings suggest that the lipreading-related suppression in the auditory cortex is caused by top-down influences, possibly by an efference copy from the speech-production system, generated during both own speech and lipreading. PMID:20107058

  6. Balancing bilateral sensory activity: callosal processing modulates sensory transmission through the contralateral thalamus by altering the response threshold.

    PubMed

    Li, Lu; Ebner, Ford F

    2006-07-01

    Rats tactually explore a nearly spherical space field around their heads with their whiskers. The information sampled by the two sets of whiskers is integrated bilaterally at the cortical level in an activity dependent manner via the corpus callosum. We have recently shown that sensory activity in one barrel field cortex (BFC) modulates the processing of incoming sensory information to the other BFC. Whether interhemispheric integration is dynamically linked with corticothalamic modulation of incoming sensory activity is an important hypothesis to test, since subcortical relay neurons are directly modulated by cortical neurons through top-down processes. In the present study, we compared the direct sensory responses of single thalamic relay neurons under urethane anesthesia before and after inactivating the BFC contralateral to a thalamic neuron. The data show that silencing one BFC reduces response magnitude in contralateral thalamic relay neurons, significantly and reversibly, in response to test stimuli applied to the principal whisker at two times response threshold (2T) intensity for each unit. Neurons in the ventral posterior medial (VPM) nucleus and the medial division of the posterior nucleus (POm) react in a similar manner, although POm neurons are more profoundly depressed by inactivation of the contralateral BFC than VPM neurons. The results support the novel idea that the subcortical relay of sensory information to one hemisphere is strongly modulated by activity levels in the contralateral as well as in the ipsilateral SI cortex. The mechanism of the modulation appears to be based on shifting the stimulus-response curves of thalamic neurons, thereby rendering them more or less sensitive to sensory stimuli. We conclude that global sensory processing is created by combining activity in each cerebral hemisphere and continually balancing the flow of information to cortex by adjusting the responsiveness of ascending sensory pathways.

  7. TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)

    EPA Science Inventory

    TITLE:
    TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

  8. Effects of GABA[subscript A] Modulators on the Repeated Acquisition of Response Sequences in Squirrel Monkeys

    ERIC Educational Resources Information Center

    Campbell, Una C.; Winsauer, Peter J.; Stevenson, Michael W.; Moerschbaecher, Joseph M.

    2004-01-01

    The present study investigated the effects of positive and negative GABA[subscript A] modulators under three different baselines of repeated acquisition in squirrel monkeys in which the monkeys acquired a three-response sequence on three keys under a second-order fixed-ratio (FR) schedule of food reinforcement. In two of these baselines, the…

  9. Intramuscular administration of a synthetic CpG-oligodeoxynucleotide modulates functional responses of neutrophils of neonatal foals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neutrophils play an important role in protecting against infection. Foals have age-dependent deficiencies in neutrophil function that may contribute to their predisposition to infection. Thus, we investigated the ability of a CpG-ODN formulated with Emulsigen® to modulate functional responses of ne...

  10. The arabidopsis polyamine transporter LHRI/AtPUT3 modulates heat responsive gene expression by regulating mRNA stability

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polyamines (PA) involve in the gene regulation by interacting with various anionic macromolecules such as DNA, RNA and proteins and modulating their structure and function. Previous studies have showed that changing in polyamine biosynthesis alters plant response to different abiotic stresses. Here,...

  11. Experiences of the dying.

    PubMed

    Schoenbeck, Susan L

    2011-01-01

    It is often a mystery to us how we have come to know and believe in certain things. Beliefs are like guests who come up to a door. They come in only if the host opens it and invites them in. Otherwise they are turned away, unable to enter. LPNs/LVNs are invited to reflect on their experiences and expand their knowledge and beliefs. There is growing recognition that bedside talks of the dying, spirit travel and near-death events are real events for the people who experience them. LPNs/ LVNs are encouraged to expand their knowledge and beliefs about dying.

  12. [Human dying has changed].

    PubMed

    Llano Escobar, A

    1990-01-01

    In the modern era, the act of dying, at least in the West, presents a series of new characteristics resulting from scientific and technological progress and social changes. More and more frequently, humans die in the strange surroundings of medical establishments without the support of their loved ones and without the opportunity of taking part in decisions related to their own deaths. In the light of the serious personal and social problems caused by this transformation of human death, bioethics emerges as an attempt to uncover options that are more humane.

  13. Uropathogenic Escherichia coli Modulates Innate Immunity To Suppress Th1-Mediated Inflammatory Responses during Infectious Epididymitis

    PubMed Central

    Lang, Tali; Hudemann, Christoph; Tchatalbachev, Svetlin; Stammler, Angelika; Michel, Vera; Aslani, Ferial; Bhushan, Sudhanshu; Chakraborty, Trinad; Renz, Harald

    2014-01-01

    Infectious epididymitis in men, a frequent entity in urological outpatient settings, is commonly caused by bacteria originating from the anal region ascending the genitourinary tract. One of the most prevalent pathogens associated with epididymitis is Escherichia coli. In our previous study, we showed that semen quality is compromised in men following epididymitis associated with specific E. coli pathovars. Thus, our aim was to investigate possible differences in immune responses elicited during epididymitis following infection with the uropathogenic E. coli (UPEC) strain CFT073 and the nonpathogenic enteric E. coli (NPEC) strain 470. Employing an in vivo experimental epididymitis model, C57BL/6 mice were infected with UPEC CFT073, NPEC 470, or phosphate-buffered saline (PBS) as a sham control for up to 7 days. After infection with NPEC 470, the expression of proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha in the epididymis was significantly increased. Conversely, UPEC CFT073-challenged mice displayed inflammatory gene expression at levels comparable to sham PBS-treated animals. Moreover, by day 7 only NPEC-infected animals showed activation of adaptive immunity evident by a substantial influx of CD3+ and F4/80+ cells in the epididymal interstitium. This correlated with enhanced production of Th1-associated cytokines IL-2 and gamma interferon (IFN-γ). Furthermore, splenocytes isolated from UPEC-infected mice exhibited diminished T-cell responses with significantly reduced secretion of IL-2 and IFN-γ in contrast to NPEC-infected animals. Overall, these findings provide new insights into understanding pathogen-specific modulation of host immunity during acute phases of epididymitis, which may influence severity of disease and clinical outcomes. PMID:24366252

  14. Adenosine modulates light responses of rat retinal ganglion cell photoreceptors througha cAMP-mediated pathway

    PubMed Central

    Sodhi, Puneet; Hartwick, Andrew T E

    2014-01-01

    Adenosine is an established neuromodulator in the mammalian retina, with A1 adenosine receptors being especially prevalent in the innermost ganglion cell layer. Activation of A1 receptors causes inhibition of adenylate cyclase, decreases in intracellular cyclic AMP (cAMP) levels and inhibition of protein kinase A (PKA). In this work, our aim was to characterize the effects of adenosine on the light responses of intrinsically photosensitive retinal ganglion cells (ipRGCs) and to determine whether these photoreceptors are subject to neuromodulation through intracellular cAMP-related signalling pathways. Using multielectrode array recordings from postnatal and adult rat retinas, we demonstrated that adenosine significantly shortened the duration of ipRGC photoresponses and reduced the number of light-evoked spikes fired by these neurons. The effects were A1 adenosine receptor-mediated, and the expression of this receptor on melanopsin-containing ipRGCs was confirmed by calcium imaging experiments on isolated cells in purified cultures. While inhibition of the cAMP/PKA pathway by adenosine shortened ipRGC light responses, stimulation of this pathway with compounds such as forskolin had the opposite effect and lengthened the duration of ipRGC spiking. Our findings reveal that the modification of ipRGC photoresponses through a cAMP/PKA pathway is a general feature of rat ganglion cell photoreceptors, and this pathway can be inhibited through activation of A1 receptors by adenosine. As adenosine levels in the retina rise at night, adenosinergic modulation of ipRGCs may serve as an internal regulatory mechanism to limit transmission of nocturnal photic signals by ipRGCs to the brain. Targeting retinal A1 adenosine receptors for ipRGC inhibition represents a potential therapeutic target for sleep disorders and migraine-associated photophobia. PMID:25038240

  15. G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress.

    PubMed

    Boortz, Kayla A; Syring, Kristen E; Dai, Chunhua; Pound, Lynley D; Oeser, James K; Jacobson, David A; Wang, Jen-Chywan; McGuinness, Owen P; Powers, Alvin C; O'Brien, Richard M

    2016-08-01

    The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress. PMID:27300767

  16. Iron oxide nanoparticles modulate lipopolysaccharide-induced inflammatory responses in primary human monocytes

    PubMed Central

    Grosse, Susann; Stenvik, Jørgen; Nilsen, Asbjørn M

    2016-01-01

    Co-stimulation of the immune system to more than one agent concomitantly is very common in real life, and considering the increasing use of engineered nanoparticles and nanomaterials, it is highly relevant to assess the ability of these materials to modulate key innate immune responses, which has not yet been studied in detail. We investigated the immunomodulatory effects of 10 nm and 30 nm iron oxide nanoparticles (IONPs) on primary human monocytes in the presence and absence of Toll-like receptor 4 agonist lipopolysaccharide (LPS). Prior to the cell studies, we characterized the physicochemical properties of the nanoparticles in cell culture medium and ensured that the nanoparticles were free from biological contamination. Cellular uptake of the IONPs in monocytes was assessed using transmission electron microscopy. Using enzyme-linked immunosorbent assay, we found that the IONPs per se did not induce the production of proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. However, the IONPs had the ability to suppress LPS-induced nuclear factor kappa B activation and production of proinflammatory cytokines in primary human monocytes in an LPS and a particle dose-dependent manner. Using confocal microscopy and fluorescently labeled LPS, we showed that the effects correlated with impaired LPS internalization by monocytes in the presence of IONPs, which could be partly explained by LPS adsorption onto the nanoparticle surface. Additionally, the results from particle pretreatment experiments indicate that other cellular mechanisms might also play a role in the observed effects, which warrants further studies to elucidate the additional mechanisms underlying the capacity of IONPs to alter the reactivity of monocytes to LPS and to mount an appropriate cellular response. PMID:27695322

  17. Pregnane X Receptor Modulates the Inflammatory Response in Primary Cultures of Hepatocytes

    PubMed Central

    Sun, Mengxi; Cui, Wenqi; Woody, Sarah K.

    2015-01-01

    Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS-inducible expression of the key inflammatory mediators interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1β when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine. PMID:25527709

  18. Iron oxide nanoparticles modulate lipopolysaccharide-induced inflammatory responses in primary human monocytes

    PubMed Central

    Grosse, Susann; Stenvik, Jørgen; Nilsen, Asbjørn M

    2016-01-01

    Co-stimulation of the immune system to more than one agent concomitantly is very common in real life, and considering the increasing use of engineered nanoparticles and nanomaterials, it is highly relevant to assess the ability of these materials to modulate key innate immune responses, which has not yet been studied in detail. We investigated the immunomodulatory effects of 10 nm and 30 nm iron oxide nanoparticles (IONPs) on primary human monocytes in the presence and absence of Toll-like receptor 4 agonist lipopolysaccharide (LPS). Prior to the cell studies, we characterized the physicochemical properties of the nanoparticles in cell culture medium and ensured that the nanoparticles were free from biological contamination. Cellular uptake of the IONPs in monocytes was assessed using transmission electron microscopy. Using enzyme-linked immunosorbent assay, we found that the IONPs per se did not induce the production of proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. However, the IONPs had the ability to suppress LPS-induced nuclear factor kappa B activation and production of proinflammatory cytokines in primary human monocytes in an LPS and a particle dose-dependent manner. Using confocal microscopy and fluorescently labeled LPS, we showed that the effects correlated with impaired LPS internalization by monocytes in the presence of IONPs, which could be partly explained by LPS adsorption onto the nanoparticle surface. Additionally, the results from particle pretreatment experiments indicate that other cellular mechanisms might also play a role in the observed effects, which warrants further studies to elucidate the additional mechanisms underlying the capacity of IONPs to alter the reactivity of monocytes to LPS and to mount an appropriate cellular response.

  19. Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress.

    PubMed

    Yao, Yu; Rabodzey, Aleksandr; Dewey, C Forbes

    2007-08-01

    Flow-induced mechanotransduction in vascular endothelial cells has been studied over the years with a major focus on putative connections between disturbed flow and atherosclerosis. Recent studies have brought in a new perspective that the glycocalyx, a structure decorating the luminal surface of vascular endothelium, may play an important role in the mechanotransduction. This study reports that modifying the amount of the glycocalyx affects both short-term and long-term shear responses significantly. It is well established that after 24 h of laminar flow, endothelial cells align in the direction of flow and their proliferation is suppressed. We report here that by removing the glycocalyx by using the specific enzyme heparinase III, endothelial cells no longer align under flow after 24 h and they proliferate as if there were no flow present. In addition, confluent endothelial cells respond rapidly to flow by decreasing their migration speed by 40% and increasing the amount of vascular endothelial cadherin in the cell-cell junctions. These responses are not observed in the cells treated with heparinase III. Heparan sulfate proteoglycans (a major component of the glycocalyx) redistribute after 24 h of flow application from a uniform surface profile to a distinct peripheral pattern with most molecules detected above cell-cell junctions. We conclude that the presence of the glycocalyx is necessary for the endothelial cells to respond to fluid shear, and the glycocalyx itself is modulated by the flow. The redistribution of the glycocalyx also appears to serve as a cell-adaptive mechanism by reducing the shear gradients that the cell surface experiences.

  20. Modulation of Hsp60 in response to coral brown band disease.

    PubMed

    Seveso, Davide; Montano, Simone; Reggente, Melissa Amanda; Orlandi, Ivan; Galli, Paolo; Vai, Marina

    2015-06-29

    Brown band disease (BrB), a virulent coral disease characterized by a dense concentration of ciliates ingesting coral tissue, is responsible for ongoing coral losses on Indo-Pacific reefs. Although several efforts have been made to identify the microbial communities associated with BrB and study the disease ecology, less attention has been given to the effect of ciliate presence on coral physiology. Levels of the mitochondrial heat shock protein 60-kDa (Hsp60, a biomarker indicative of cellular stress) were analyzed in apparently healthy coral polyps located at different distances along the advancing front of infection in Acropora muricata colonies affected by BrB in a Maldivian reef. Different Hsp60 levels were found in different parts of the same colony. Starting from a basal protein level in the healthy control colonies, a down-regulation of Hsp60 expression was detected near the ciliate band, indicating that the Hsp60 defense activity was probably already compromised due to the rapid progression rate of the BrB ciliate on the diseased branches and/or to the etiology of the disease. Moving away from the band, the Hsp60 levels gradually returned to a state comparable to that found in the control, showing that cellular damage was confined to areas near the infection. In conclusion, we propose the analysis of Hsp60 modulation as a useful tool for examining physiological variations that are not detected at the morphological level in corals subjected to epizootic diseases, while providing new insights into the immune response of corals.

  1. Fibrinogen modulates leukocyte recruitment in vivo during the acute inflammatory response.

    PubMed

    Vitorino de Almeida, V; Silva-Herdade, A; Calado, A; Rosário, H S; Saldanha, C

    2015-01-01

    Besides playing an important role in blood hemostases, fibrinogen also regulates leukocyte function in inflammation. Our previous in vitro studies showed that the adhesive behaviour of the neutrophil is modulated by soluble fibrinogen when present at a physiological concentration. This led us to propose that this plasma glycoprotein might further influence leukocyte recruitment in vivo and thus contribute to the inflammatory response. To address this in vivo, leukocyte recruitment was here investigated under acute inflammatory conditions in the absence of soluble fibrinogen in the blood circulation. For such, intravital microscopy on mesentery post-capillary venules was performed on homozygous fibrinogen α chain-deficient mice ((α-/-) mice). Acute inflammatory states were induced by perfusing platelet activating factor (PAF) over the exposed tissue. As control animals, two groups of mice expressing soluble fibrinogen in circulation were used, namely, C57BL/6 wild type animals and heterozygous fibrinogen α chain-deficient mice ((α+/-) mice). Under acute inflammatory conditions, an abnormal pattern of recruitment was observed for leukocytes in homozygous (α-/-) mice in comparison to both control groups. In fact, the former exhibited a significantly decreased number of rolling leukocytes that nevertheless, migrated with increased rolling velocities when compared to leukocytes from control animals. Consistently, homozygous mice further displayed a diminished number of adherent leukocytes than the other groups. Altogether our observations led us to conclude that leukocyte recruitment in homozygous (α-/-) mice is compromised what strongly suggests a role for soluble fibrinogen in leukocyte recruitment in inflammation.

  2. An anti-infective peptide that selectively modulates the innate immune response.

    PubMed

    Scott, Monisha G; Dullaghan, Edie; Mookherjee, Neeloffer; Glavas, Natalie; Waldbrook, Matthew; Thompson, Annick; Wang, Aikun; Lee, Ken; Doria, Silvana; Hamill, Pam; Yu, Jie Jessie; Li, Yuexin; Donini, Oreola; Guarna, M Marta; Finlay, B Brett; North, John R; Hancock, Robert E W

    2007-04-01

    We show that an innate defense-regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.

  3. Noradrenergic and cholinergic modulation of late ERP responses to deviant stimuli.

    PubMed

    Brown, Stephen B R E; van der Wee, Nic J A; van Noorden, Martijn S; Giltay, Erik J; Nieuwenhuis, Sander

    2015-12-01

    Researchers have proposed several hypotheses about the neuromodulator systems involved in generating P3 components of the ERP. To test some of these hypotheses, we conducted a randomized placebo-controlled crossover study in which we investigated how the late positive ERP response to deviant stimuli is modulated by (a) clonidine, an α2 agonist that attenuates baseline noradrenergic activity; and (b) scopolamine, a muscarinic antagonist of acetylcholine receptors. We collected EEG data from 18 healthy volunteers during the performance of an auditory oddball task with several active and passive task conditions. We then used temporospatial principal component analysis (PCA) to decompose the ERP waveforms. The PCA revealed two distinct late positive ERP components: the classic parietal P300 and the frontal novelty P3. Statistical analysis of the temporospatial factor scores indicated that in most conditions the amplitude of the classic P300 was increased by clonidine and scopolamine. In contrast, the amplitude of the novelty P3 was decreased by both drugs. The similar pattern of results for clonidine and scopolamine probably reflects the strong interactions between the noradrenergic and cholinergic systems. The results, in combination with previous pharmacological studies, suggest a critical role for both neuromodulator systems in the generation of the P300 and the novelty P3.

  4. Dbo/Henji Modulates Synaptic dPAK to Gate Glutamate Receptor Abundance and Postsynaptic Response

    PubMed Central

    Wang, Manyu; Chen, Pei-Yi; Wang, Chien-Hsiang; Lai, Tzu-Ting; Tsai, Pei-I; Cheng, Ying-Ju; Kao, Hsiu-Hua; Chien, Cheng-Ting

    2016-01-01

    In response to environmental and physiological changes, the synapse manifests plasticity while simultaneously maintains homeostasis. Here, we analyzed mutant synapses of henji, also known as dbo, at the Drosophila neuromuscular junction (NMJ). In henji mutants, NMJ growth is defective with appearance of satellite boutons. Transmission electron microscopy analysis indicates that the synaptic membrane region is expanded. The postsynaptic density (PSD) houses glutamate receptors GluRIIA and GluRIIB, which have distinct transmission properties. In henji mutants, GluRIIA abundance is upregulated but that of GluRIIB is not. Electrophysiological results also support a GluR compositional shift towards a higher IIA/IIB ratio at henji NMJs. Strikingly, dPAK, a positive regulator for GluRIIA synaptic localization, accumulates at the henji PSD. Reducing the dpak gene dosage suppresses satellite boutons and GluRIIA accumulation at henji NMJs. In addition, dPAK associated with Henji through the Kelch repeats which is the domain essential for Henji localization and function at postsynapses. We propose that Henji acts at postsynapses to restrict both presynaptic bouton growth and postsynaptic GluRIIA abundance by modulating dPAK. PMID:27736876

  5. Perceptual load modulates anterior cingulate cortex response to threat distractors in generalized social anxiety disorder.

    PubMed

    Wheaton, Michael G; Fitzgerald, Daniel A; Phan, K Luan; Klumpp, Heide

    2014-09-01

    Generalized social anxiety disorder (gSAD) is associated with impoverished anterior cingulate cortex (ACC) engagement during attentional control. Attentional Control Theory proposes such deficiencies may be offset when demands on resources are increased to execute goals. To test the hypothesis attentional demands affect ACC response 23 patients with gSAD and 24 matched controls performed an fMRI task involving a target letter in a string of identical targets (low load) or a target letter in a mixed letter string (high load) superimposed on fearful, angry, and neutral face distractors. Regardless of load condition, groups were similar in accuracy and reaction time. Under low load gSAD patients showed deficient rostral ACC recruitment to fearful (vs. neutral) distractors. For high load, increased activation to fearful (vs. neutral) distractors was observed in gSAD suggesting a compensatory function. Results remained after controlling for group differences in depression level. Findings indicate perceptual demand modulates ACC in gSAD. PMID:24978315

  6. The response of the hypothalamic-pituitary-gonadal axis to fasting is modulated by leptin.

    PubMed

    Steiner, J; LaPaglia, N; Kirsteins, L; Emanuele, M; Emanuele, N

    2003-05-01

    Reproductive function is intimately related to caloric consumption. During fasting states, the hormones regulating reproduction, those of the hypothalamic-pituitary-gonadal axis, in particular, are severely altered. With the exciting observations that the obese (ob) gene product leptin, may also modulate neuroendocrine functions, we examined leptin's ability to prevent the consequences of fasting on reproductive hormones. Two groups of male rats, aged 65 days old, were either fasted and saline-injected or fasted and leptin-treated for approximately three days. Another group was given free access to rat chow. Leptin was able to prevent the fasting-induced fall of serum testosterone. Similar to testosterones dependence on leptin, leptin concentrations were somewhat dependent on testosterone. Castration accelerated the normal, age-related increase in serum leptin. Leptin also prevented the fasting-induced fall in luteinizing hormone (LH). The increase of beta-LH mRNA seen in the fasting state was prevented by leptin. There were no differences noted in luteinizing hormone releasing hormone (LHRH) mRNA among any of the groups. While neither fasting nor fasting plus leptin caused