Altered Balance of Receptive Field Excitation and Suppression in Visual Cortex of Amblyopic Macaque Monkeys.

PubMed

Hallum, Luke E; Shooner, Christopher; Kumbhani, Romesh D; Kelly, Jenna G; García-Marín, Virginia; Majaj, Najib J; Movshon, J Anthony; Kiorpes, Lynne

2017-08-23

In amblyopia, a visual disorder caused by abnormal visual experience during development, the amblyopic eye (AE) loses visual sensitivity whereas the fellow eye (FE) is largely unaffected. Binocular vision in amblyopes is often disrupted by interocular suppression. We used 96-electrode arrays to record neurons and neuronal groups in areas V1 and V2 of six female macaque monkeys ( Macaca nemestrina ) made amblyopic by artificial strabismus or anisometropia in early life, as well as two visually normal female controls. To measure suppressive binocular interactions directly, we recorded neuronal responses to dichoptic stimulation. We stimulated both eyes simultaneously with large sinusoidal gratings, controlling their contrast independently with raised-cosine modulators of different orientations and spatial frequencies. We modeled each eye's receptive field at each cortical site using a difference of Gaussian envelopes and derived estimates of the strength of central excitation and surround suppression. We used these estimates to calculate ocular dominance separately for excitation and suppression. Excitatory drive from the FE dominated amblyopic visual cortex, especially in more severe amblyopes, but suppression from both the FE and AEs was prevalent in all animals. This imbalance created strong interocular suppression in deep amblyopes: increasing contrast in the AE decreased responses at binocular cortical sites. These response patterns reveal mechanisms that likely contribute to the interocular suppression that disrupts vision in amblyopes. SIGNIFICANCE STATEMENT Amblyopia is a developmental visual disorder that alters both monocular vision and binocular interaction. Using microelectrode arrays, we examined binocular interaction in primary visual cortex and V2 of six amblyopic macaque monkeys ( Macaca nemestrina ) and two visually normal controls. By stimulating the eyes dichoptically, we showed that, in amblyopic cortex, the binocular combination of signals is altered. The excitatory influence of the two eyes is imbalanced to a degree that can be predicted from the severity of amblyopia, whereas suppression from both eyes is prevalent in all animals. This altered balance of excitation and suppression reflects mechanisms that may contribute to the interocular perceptual suppression that disrupts vision in amblyopes. Copyright © 2017 the authors 0270-6474/17/378216-11$15.00/0.

Cross-orientation masking in human color vision: application of a two-stage model to assess dichoptic and monocular sources of suppression.

PubMed

Kim, Yeon Jin; Gheiratmand, Mina; Mullen, Kathy T

2013-05-28

Cross-orientation masking (XOM) occurs when the detection of a test grating is masked by a superimposed grating at an orthogonal orientation, and is thought to reveal the suppressive effects mediating contrast normalization. Medina and Mullen (2009) reported that XOM was greater for chromatic than achromatic stimuli at equivalent spatial and temporal frequencies. Here we address whether the greater suppression found in binocular color vision originates from a monocular or interocular site, or both. We measure monocular and dichoptic masking functions for red-green color contrast and achromatic contrast at three different spatial frequencies (0.375, 0.75, and 1.5 cpd, 2 Hz). We fit these functions with a modified two-stage masking model (Meese & Baker, 2009) to extract the monocular and interocular weights of suppression. We find that the weight of monocular suppression is significantly higher for color than achromatic contrast, whereas dichoptic suppression is similar for both. These effects are invariant across spatial frequency. We then apply the model to the binocular masking data using the measured values of the monocular and interocular sources of suppression and show that these are sufficient to account for color binocular masking. We conclude that the greater strength of chromatic XOM has a monocular origin that transfers through to the binocular site.

Interocular suppression in normal and amblyopic vision: spatio-temporal properties.

PubMed

Huang, Pi-Chun; Baker, Daniel H; Hess, Robert F

2012-10-31

We measured the properties of interocular suppression in strabismic amblyopes and compared these to dichoptic masking in binocularly normal observers. We used a dichoptic version of the well-established probed-sinewave paradigm that measured sensitivity to a brief target stimulus (one of four letters to be discriminated) in the amblyopic eye at different times relative to a suppression-inducing mask in the fixing eye. This was done using both sinusoidal steady state and transient approaches. The suppression-inducing masks were either modulations of luminance or contrast (full field, just overlaying the target, or just surrounding the target). Our results were interpreted using a descriptive model that included contrast gain control and spatio-temporal filtering prior to excitatory binocular combination. The suppression we measured, other than in magnitude, was not fundamentally different from normal dichoptic masking: lowpass spatio-temporal properties with similar contributions from both surround and overlay suppression.

Breaking continuous flash suppression: competing for consciousness on the pre-semantic battlefield

PubMed Central

Gayet, Surya; Van der Stigchel, Stefan; Paffen, Chris L. E.

2014-01-01

Traditionally, interocular suppression is believed to disrupt high-level (i.e., semantic or conceptual) processing of the suppressed visual input. The development of a new experimental paradigm, breaking continuous flash suppression (b-CFS), has caused a resurgence of studies demonstrating high-level processing of visual information in the absence of visual awareness. In this method the time it takes for interocularly suppressed stimuli to breach the threshold of visibility, is regarded as a measure of access to awareness. The aim of the current review is twofold. First, we provide an overview of the literature using this b-CFS method, while making a distinction between two types of studies: those in which suppression durations are compared between different stimulus classes (such as upright faces versus inverted faces), and those in which suppression durations are compared for stimuli that either match or mismatch concurrently available information (such as a colored target that either matches or mismatches a color retained in working memory). Second, we aim at dissociating high-level processing from low-level (i.e., crude visual) processing of the suppressed stimuli. For this purpose, we include a thorough review of the control conditions that are used in these experiments. Additionally, we provide recommendations for proper control conditions that we deem crucial for disentangling high-level from low-level effects. Based on this review, we argue that crude visual processing suffices for explaining differences in breakthrough times reported using b-CFS. As such, we conclude that there is as yet no reason to assume that interocularly suppressed stimuli receive full semantic analysis. PMID:24904476

Transient improvements in fixational stability in strabismic amblyopes following bifoveal fixation and reduced interocular suppression.

PubMed

Raveendran, Rajkumar Nallour; Babu, Raiju J; Hess, Robert F; Bobier, William R

2014-03-01

To test the hypothesis that fixational stability of the amblyopic eye in strabismics will improve when viewing provides both bifoveal fixation and reduced inter-ocular suppression by reducing the contrast to the fellow eye. Seven strabismic amblyopes (Age: 29.2 ± 9 years; five esotropes and two exotropes) showing clinical characteristics of central suppression were recruited. Interocular suppression was measured by a global motion task. For each participant, a balance point was determined which defined contrast levels for each eye where binocular combination was optimal (interocular suppression minimal). When the balance point could not be determined, this participant was excluded. Bifoveal fixation was established by ocular alignment using a haploscope. Participants dichoptically viewed similar targets (a cross of 2.3° surrounded by a square of 11.3°) at 40 cm. Target contrasts presented to each eye were either high contrast (100% to both eyes) or balanced contrast (attenuated contrast in the fellow fixing eye). Fixation stability was measured over a 5 min period and quantified using bivariate contour ellipse areas in four different binocular conditions; unaligned/high contrast, unaligned/balance point, aligned/high contrast and aligned/balance point. Fixation stability was also measured in six control subjects (Age: 25.3 ± 4 years). Bifoveal fixation in the strabismics was transient (58.15 ± 15.7 s). Accordingly, fixational stability was analysed over the first 30 s using repeated measures anova. Post hoc analysis revealed that for the amblyopic subjects, the fixational stability of the amblyopic eye was significantly improved in aligned/high contrast (p = 0.01) and aligned/balance point (p < 0.01) conditions. Fixational stability of the fellow fixing eye was not different statistically across conditions. Bivariate contour ellipse areas of the amblyopic and fellow fixing eyes were therefore averaged for each amblyope in the four conditions and compared with normals. This averaged bivariate contour ellipse area was significantly greater (reduced fixational stability, p = 0.04) in amblyopes compared to controls except in the case of aligned and balanced contrast (aligned/balance point, p = 0.19). Fixation stability in the amblyopic eye appears to improve with bifoveal fixation and reduced interocular suppression. However, once initiated, bifoveal fixation is transient with the strabismic eye drifting away from foveal alignment, thereby increasing the angle of strabismus. © 2014 The Authors Ophthalmic & Physiological Optics © 2014 The College of Optometrists.

The Relationship Between Fusion, Suppression, and Diplopia in Normal and Amblyopic Vision.

PubMed

Spiegel, Daniel P; Baldwin, Alex S; Hess, Robert F

2016-10-01

Single vision occurs through a combination of fusion and suppression. When neither mechanism takes place, we experience diplopia. Under normal viewing conditions, the perceptual state depends on the spatial scale and interocular disparity. The purpose of this study was to examine the three perceptual states in human participants with normal and amblyopic vision. Participants viewed two dichoptically separated horizontal blurred edges with an opposite tilt (2.35°) and indicated their binocular percept: "one flat edge," "one tilted edge," or "two edges." The edges varied with scale (fine 4 min arc and coarse 32 min arc), disparity, and interocular contrast. We investigated how the binocular interactions vary in amblyopic (visual acuity [VA] > 0.2 logMAR, n = 4) and normal vision (VA ≤ 0 logMAR, n = 4) under interocular variations in stimulus contrast and luminance. In amblyopia, despite the established sensory dominance of the fellow eye, fusion prevails at the coarse scale and small disparities (75%). We also show that increasing the relative contrast to the amblyopic eye enhances the probability of fusion at the fine scale (from 18% to 38%), and leads to a reversal of the sensory dominance at coarse scale. In normal vision we found that interocular luminance imbalances disturbed binocular combination only at the fine scale in a way similar to that seen in amblyopia. Our results build upon the growing evidence that the amblyopic visual system is binocular and further show that the suppressive mechanisms rendering the amblyopic system functionally monocular are scale dependent.

The role of suppression in amblyopia.

PubMed

Li, Jingrong; Thompson, Benjamin; Lam, Carly S Y; Deng, Daming; Chan, Lily Y L; Maehara, Goro; Woo, George C; Yu, Minbin; Hess, Robert F

2011-06-13

This study had three main goals: to assess the degree of suppression in patients with strabismic, anisometropic, and mixed amblyopia; to establish the relationship between suppression and the degree of amblyopia; and to compare the degree of suppression across the clinical subgroups within the sample. Using both standard measures of suppression (Bagolini lenses and neutral density [ND] filters, Worth 4-Dot test) and a new approach involving the measurement of dichoptic motion thresholds under conditions of variable interocular contrast, the degree of suppression in 43 amblyopic patients with strabismus, anisometropia, or a combination of both was quantified. There was good agreement between the quantitative measures of suppression made with the new dichoptic motion threshold technique and measurements made with standard clinical techniques (Bagolini lenses and ND filters, Worth 4-Dot test). The degree of suppression was found to correlate directly with the degree of amblyopia within our clinical sample, whereby stronger suppression was associated with a greater difference in interocular acuity and poorer stereoacuity. Suppression was not related to the type or angle of strabismus when this was present or the previous treatment history. These results suggest that suppression may have a primary role in the amblyopia syndrome and therefore have implications for the treatment of amblyopia.

Measuring colour rivalry suppression in amblyopia.

PubMed

Hofeldt, T S; Hofeldt, A J

1999-11-01

To determine if the colour rivalry suppression is an index of the visual impairment in amblyopia and if the stereopsis and fusion evaluator (SAFE) instrument is a reliable indicator of the difference in visual input from the two eyes. To test the accuracy of the SAFE instrument for measuring the visual input from the two eyes, colour rivalry suppression was measured in six normal subjects. A test neutral density filter (NDF) was placed before one eye to induce a temporary relative afferent defect and the subject selected the NDF before the fellow eye to neutralise the test NDF. In a non-paediatric private practice, 24 consecutive patients diagnosed with unilateral amblyopia were tested with the SAFE. Of the 24 amblyopes, 14 qualified for the study because they were able to fuse images and had no comorbid disease. The relation between depth of colour rivalry suppression, stereoacuity, and interocular difference in logMAR acuity was analysed. In normal subjects, the SAFE instrument reversed temporary defects of 0.3 to 1. 8 log units to within 0.6 log units. In amblyopes, the NDF to reverse colour rivalry suppression was positively related to interocular difference in logMAR acuity (beta=1.21, p<0.0001), and negatively related to stereoacuity (beta=-0.16, p=0.019). The interocular difference in logMAR acuity was negatively related to stereoacuity (beta=-0.13, p=0.009). Colour rivalry suppression as measured with the SAFE was found to agree closely with the degree of visual acuity impairment in non-paediatric patients with amblyopia.

Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression.

PubMed

Bossi, Manuela; Tailor, Vijay K; Anderson, Elaine J; Bex, Peter J; Greenwood, John A; Dahlmann-Noor, Annegret; Dakin, Steven C

2017-06-01

Amblyopia is a common developmental visual impairment characterized by a substantial difference in acuity between the two eyes. Current monocular treatments, which promote use of the affected eye by occluding or blurring the fellow eye, improve acuity, but are hindered by poor compliance. Recently developed binocular treatments can produce rapid gains in visual function, thought to be as a result of reduced interocular suppression. We set out to develop an effective home-based binocular treatment system for amblyopia that would engage high levels of compliance but that would also allow us to assess the role of suppression in children's response to binocular treatment. Balanced binocular viewing therapy (BBV) involves daily viewing of dichoptic movies (with "visibility" matched across the two eyes) and gameplay (to monitor compliance and suppression). Twenty-two children (3-11 years) with anisometropic (n = 7; group 1) and strabismic or combined mechanism amblyopia (group 2; n = 6 and 9, respectively) completed the study. Groups 1 and 2 were treated for a maximum of 8 or 24 weeks, respectively. The treatment elicited high levels of compliance (on average, 89.4% ± 24.2% of daily dose in 68.23% ± 12.2% of days on treatment) and led to a mean improvement in acuity of 0.27 logMAR (SD 0.22) for the amblyopic eye. Importantly, acuity gains were not correlated with a reduction in suppression. BBV is a binocular treatment for amblyopia that can be self-administered at home (with remote monitoring), producing rapid and substantial benefits that cannot be solely mediated by a reduction in interocular suppression.

The neural basis of suppression and amblyopia in strabismus.

PubMed

Sengpiel, F; Blakemore, C

1996-01-01

The neurophysiological consequences of artificial strabismus in cats and monkeys have been studied for 30 years. However, until very recently no clear picture has emerged of neural deficits that might account for the powerful interocular suppression that strabismic humans experience, nor for the severe amblyopia that is often associated with convergent strabismus. Here we review the effects of squint on the integrative capacities of the primary visual cortex and propose a hypothesis about the relationship between suppression and amblyopia. Most neurons in the visual cortex of normal cats and monkeys can be excited through either eye and show strong facilitation during binocular stimulation with contours of similar orientation in the two eyes. But in strabismic animals, cortical neurons tend to fall into two populations of monocularly excitable cells and exhibit suppressive binocular interactions that share key properties with perceptual suppression in strabismic humans. Such interocular suppression, if prolonged and asymmetric (with input from the squinting eye habitually suppressed by that from the fixating eye), might lead to neural defects in the representation of the deviating eye and hence to amblyopia.

Continuous Flash Suppression: Stimulus Fractionation rather than Integration.

PubMed

Moors, Pieter; Hesselmann, Guido; Wagemans, Johan; van Ee, Raymond

2017-10-01

Recent studies using continuous flash suppression suggest that invisible stimuli are processed as integrated, semantic entities. We challenge the viability of this account, given recent findings on the neural basis of interocular suppression and replication failures of high-profile CFS studies. We conclude that CFS reveals stimulus fractionation in visual cortex. Copyright © 2017 Elsevier Ltd. All rights reserved.

Binocular contrast-gain control for natural scenes: Image structure and phase alignment.

PubMed

Huang, Pi-Chun; Dai, Yu-Ming

2018-05-01

In the context of natural scenes, we applied the pattern-masking paradigm to investigate how image structure and phase alignment affect contrast-gain control in binocular vision. We measured the discrimination thresholds of bandpass-filtered natural-scene images (targets) under various types of pedestals. Our first experiment had four pedestal types: bandpass-filtered pedestals, unfiltered pedestals, notch-filtered pedestals (which enabled removal of the spatial frequency), and misaligned pedestals (which involved rotation of unfiltered pedestals). Our second experiment featured six types of pedestals: bandpass-filtered, unfiltered, and notch-filtered pedestals, and the corresponding phase-scrambled pedestals. The thresholds were compared for monocular, binocular, and dichoptic viewing configurations. The bandpass-filtered pedestal and unfiltered pedestals showed classic dipper shapes; the dipper shapes of the notch-filtered, misaligned, and phase-scrambled pedestals were weak. We adopted a two-stage binocular contrast-gain control model to describe our results. We deduced that the phase-alignment information influenced the contrast-gain control mechanism before the binocular summation stage and that the phase-alignment information and structural misalignment information caused relatively strong divisive inhibition in the monocular and interocular suppression stages. When the pedestals were phase-scrambled, the elimination of the interocular suppression processing was the most convincing explanation of the results. Thus, our results indicated that both phase-alignment information and similar image structures cause strong interocular suppression. Copyright © 2018 Elsevier Ltd. All rights reserved.

Importance of phase alignment for interocular suppression.

PubMed

Maehara, Goro; Huang, Pi-Chun; Hess, Robert F

2009-07-01

We measured contrast thresholds for Gabor targets in the presence of maskers which had higher or lower spatial frequencies than the targets. A high-pass fractal masker elevated target contrast thresholds at low and intermediate pedestal contrasts in both monocular and dichoptic modes of presentation, suggesting that the masking occurs after a monocular processing stage. Moreover we found that a high-pass checkerboard masker elevated thresholds at the low and intermediate pedestal contrasts and that most of this threshold elevation disappeared when the phase of the masker's spatial components were scrambled. This masking was effective only in the dichoptic presentation, not in the monocular presentation. These results indicate that phase alignment of the high spatial frequency components plays a crucial role for interocular suppression. We speculate that phase alignments signal the existence of a luminance contour in the monocular image and that this signal suppresses processing of information in the other eye when there is no corresponding signal in that eye.

Scene Integration Without Awareness: No Conclusive Evidence for Processing Scene Congruency During Continuous Flash Suppression.

PubMed

Moors, Pieter; Boelens, David; van Overwalle, Jaana; Wagemans, Johan

2016-07-01

A recent study showed that scenes with an object-background relationship that is semantically incongruent break interocular suppression faster than scenes with a semantically congruent relationship. These results implied that semantic relations between the objects and the background of a scene could be extracted in the absence of visual awareness of the stimulus. In the current study, we assessed the replicability of this finding and tried to rule out an alternative explanation dependent on low-level differences between the stimuli. Furthermore, we used a Bayesian analysis to quantify the evidence in favor of the presence or absence of a scene-congruency effect. Across three experiments, we found no convincing evidence for a scene-congruency effect or a modulation of scene congruency by scene inversion. These findings question the generalizability of previous observations and cast doubt on whether genuine semantic processing of object-background relationships in scenes can manifest during interocular suppression. © The Author(s) 2016.

Affect of the unconscious: visually suppressed angry faces modulate our decisions.

PubMed

Almeida, Jorge; Pajtas, Petra E; Mahon, Bradford Z; Nakayama, Ken; Caramazza, Alfonso

2013-03-01

Emotional and affective processing imposes itself over cognitive processes and modulates our perception of the surrounding environment. In two experiments, we addressed the issue of whether nonconscious processing of affect can take place even under deep states of unawareness, such as those induced by interocular suppression techniques, and can elicit an affective response that can influence our understanding of the surrounding environment. In Experiment 1, participants judged the likeability of an unfamiliar item--a Chinese character--that was preceded by a face expressing a particular emotion (either happy or angry). The face was rendered invisible through an interocular suppression technique (continuous flash suppression; CFS). In Experiment 2, backward masking (BM), a less robust masking technique, was used to render the facial expressions invisible. We found that despite equivalent phenomenological suppression of the visual primes under CFS and BM, different patterns of affective processing were obtained with the two masking techniques. Under BM, nonconscious affective priming was obtained for both happy and angry invisible facial expressions. However, under CFS, nonconscious affective priming was obtained only for angry facial expressions. We discuss an interpretation of this dissociation between affective processing and visual masking techniques in terms of distinct routes from the retina to the amygdala.

Deconstructing continuous flash suppression

PubMed Central

Yang, Eunice; Blake, Randolph

2012-01-01

In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular “Mondrian” CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS. PMID:22408039

Deconstructing continuous flash suppression.

PubMed

Yang, Eunice; Blake, Randolph

2012-03-08

In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular "Mondrian" CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS.

Affect of the unconscious: Visually suppressed angry faces modulate our decisions

PubMed Central

Pajtas, Petra E.; Mahon, Bradford Z.; Nakayama, Ken; Caramazza, Alfonso

2016-01-01

Emotional and affective processing imposes itself over cognitive processes and modulates our perception of the surrounding environment. In two experiments, we addressed the issue of whether nonconscious processing of affect can take place even under deep states of unawareness, such as those induced by interocular suppression techniques, and can elicit an affective response that can influence our understanding of the surrounding environment. In Experiment 1, participants judged the likeability of an unfamiliar item—a Chinese character—that was preceded by a face expressing a particular emotion (either happy or angry). The face was rendered invisible through an interocular suppression technique (continuous flash suppression; CFS). In Experiment 2, backward masking (BM), a less robust masking technique, was used to render the facial expressions invisible. We found that despite equivalent phenomenological suppression of the visual primes under CFS and BM, different patterns of affective processing were obtained with the two masking techniques. Under BM, nonconscious affective priming was obtained for both happy and angry invisible facial expressions. However, under CFS, nonconscious affective priming was obtained only for angry facial expressions. We discuss an interpretation of this dissociation between affective processing and visual masking techniques in terms of distinct routes from the retina to the amygdala. PMID:23224765

Non-conscious processing of motion coherence can boost conscious access.

PubMed

Kaunitz, Lisandro; Fracasso, Alessio; Lingnau, Angelika; Melcher, David

2013-01-01

Research on the scope and limits of non-conscious vision can advance our understanding of the functional and neural underpinnings of visual awareness. Here we investigated whether distributed local features can be bound, outside of awareness, into coherent patterns. We used continuous flash suppression (CFS) to create interocular suppression, and thus lack of awareness, for a moving dot stimulus that varied in terms of coherence with an overall pattern (radial flow). Our results demonstrate that for radial motion, coherence favors the detection of patterns of moving dots even under interocular suppression. Coherence caused dots to break through the masks more often: this indicates that the visual system was able to integrate low-level motion signals into a coherent pattern outside of visual awareness. In contrast, in an experiment using meaningful or scrambled biological motion we did not observe any increase in the sensitivity of detection for meaningful patterns. Overall, our results are in agreement with previous studies on face processing and with the hypothesis that certain features are spatiotemporally bound into coherent patterns even outside of attention or awareness.

The perceptual consequences of interocular suppression in amblyopia.

PubMed

Maehara, Goro; Thompson, Benjamin; Mansouri, Behzad; Farivar, Reza; Hess, Robert F

2011-11-21

It is known that information from an amblyopic eye can be strongly suppressed when both eyes are open. The authors investigated the way in which suppression influences the relative perception of suprathreshold contrast and luminance between a person's eyes under dichoptic viewing conditions. Stimuli consisted of four patches of luminance or four patches containing gratings. Two patches were presented to each eye. Ten amblyopes with mild suppression (six strabismic, three anisometropic and strabismic, and one deprivation; mean age, 34.5 years) and three control observers with normal vision (mean age, 33.0 years) matched the appearance of the stimuli presented to each eye. The match involved manipulation of either luminance or contrast. Amblyopes with mild suppression decreased stimulus luminance in the fellow fixing eye or increased luminance in the amblyopic eye to achieve a match (mean matching luminance, 21.1 and 39.6 cd/m(2) for the fellow fixing eye and the amblyopic eye, respectively; standard luminance, 30 cd/m(2)). This interocular mismatch was also observed when luminance was variable and contrast was kept constant (mean matching luminance, 22.8 cd/m(2) for the fellow fixing eye). On the other hand, the amblyopic eye showed no loss of perceived contrast. There was little or no mismatch between the two eyes of control participants with normal binocular vision. Amblyopes have monocular deficits in contrast perception but dichoptic deficits in luminance perception, suggesting that suppression in its mild form involves luminance processing.

Monocular Perceptual Deprivation from Interocular Suppression Temporarily Imbalances Ocular Dominance.

PubMed

Kim, Hyun-Woong; Kim, Chai-Youn; Blake, Randolph

2017-03-20

Early visual experience sculpts neural mechanisms that regulate the balance of influence exerted by the two eyes on cortical mechanisms underlying binocular vision [1, 2], and experience's impact on this neural balancing act continues into adulthood [3-5]. One recently described, compelling example of adult neural plasticity is the effect of patching one eye for a relatively short period of time: contrary to intuition, monocular visual deprivation actually improves the deprived eye's competitive advantage during a subsequent period of binocular rivalry [6-8], the robust form of visual competition prompted by dissimilar stimulation of the two eyes [9, 10]. Neural concomitants of this improvement in monocular dominance are reflected in measurements of brain responsiveness following eye patching [11, 12]. Here we report that patching an eye is unnecessary for producing this paradoxical deprivation effect: interocular suppression of an ordinarily visible stimulus being viewed by one eye is sufficient to produce shifts in subsequent predominance of that eye to an extent comparable to that produced by patching the eye. Moreover, this imbalance in eye dominance can also be induced by prior, extended viewing of two monocular images differing only in contrast. Regardless of how shifts in eye dominance are induced, the effect decays once the two eyes view stimuli equal in strength. These novel findings implicate the operation of interocular neural gain control that dynamically adjusts the relative balance of activity between the two eyes [13, 14]. Copyright © 2017 Elsevier Ltd. All rights reserved.

Autosomal Dominant Cataract: Intrafamilial Phenotypic Variability, Interocular Asymmetry, and Variable Progression in Four Chilean Families

PubMed Central

Shafie, Suraiya M.; Barria von-Bischhoffshausen, Fernando R.; Bateman, J. Bronwyn

2006-01-01

PURPOSE To document intrafamilial and interocular phenotypic variability of autosomal dominant cataract (ADC). DESIGN Prospective observational case series. METHODS We performed ophthalmologic examination in four Chilean ADC families. RESULTS The families exhibited variability with respect to morphology, location with the lens, color and density of cataracts among affected members. We documented asymmetry between eyes in the morphology, location within the lens, color and density of cataracts, and a variable rate of progression. CONCLUSIONS The cataracts in these families exhibit wide intrafamilial and interocular phenotypic variability, supporting the premise that the mutated genes are expressed differentially in individuals and between eyes; other genes or environmental factors may be the bases for this variability. Marked progression among some family members underscores the variable clinical course of a common mutation within a family. Like retinitis pigmentosa, classification of ADC will be most useful if based on the gene and specific mutation. PMID:16564818

Latent binocular function in amblyopia.

PubMed

Chadnova, Eva; Reynaud, Alexandre; Clavagnier, Simon; Hess, Robert F

2017-11-01

Recently, psychophysical studies have shown that humans with amblyopia do have binocular function that is not normally revealed due to dominant suppressive interactions under normal viewing conditions. Here we use magnetoencephalography (MEG) combined with dichoptic visual stimulation to investigate the underlying binocular function in humans with amblyopia for stimuli that, because of their temporal properties, would be expected to bypass suppressive effects and to reveal any underlying binocular function. We recorded contrast response functions in visual cortical area V1 of amblyopes and normal observers using a steady state visually evoked responses (SSVER) protocol. We used stimuli that were frequency-tagged at 4Hz and 6Hz that allowed identification of the responses from each eye and were of a sufficiently high temporal frequency (>3Hz) to bypass suppression. To characterize binocular function, we compared dichoptic masking between the two eyes in normal and amblyopic participants as well as interocular phase differences in the two groups. We observed that the primary visual cortex responds less to the stimulation of the amblyopic eye compared to the fellow eye. The pattern of interaction in the amblyopic visual system however was not significantly different between the amblyopic and fellow eyes. However, the amblyopic suppressive interactions were lower than those observed in the binocular system of our normal observers. Furthermore, we identified an interocular processing delay of approximately 20ms in our amblyopic group. To conclude, when suppression is greatly reduced, such as the case with our stimulation above 3Hz, the amblyopic visual system exhibits a lack of binocular interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Relating binocular and monocular vision in strabismic and anisometropic amblyopia.

PubMed

Agrawal, Ritwick; Conner, Ian P; Odom, J V; Schwartz, Terry L; Mendola, Janine D

2006-06-01

To examine deficits in monocular and binocular vision in adults with amblyopia and to test the following 2 hypotheses: (1) Regardless of clinical subtype, the degree of impairment in binocular integration predicts the pattern of monocular acuity deficits. (2) Subjects who lack binocular integration exhibit the most severe interocular suppression. Seven subjects with anisometropia, 6 subjects with strabismus, and 7 control subjects were tested. Monocular tests included Snellen acuity, grating acuity, Vernier acuity, and contrast sensitivity. Binocular tests included Titmus stereo test, binocular motion integration, and dichoptic contrast masking. As expected, both groups showed deficits in monocular acuity, with subjects with strabismus showing greater deficits in Vernier acuity. Both amblyopic groups were then characterized according to the degree of residual stereoacuity and binocular motion integration ability, and 67% of subjects with strabismus compared with 29% of subjects with anisometropia were classified as having "nonbinocular" vision according to our criterion. For this nonbinocular group, Vernier acuity is most impaired. In addition, the nonbinocular group showed the most dichoptic contrast masking of the amblyopic eye and the least dichoptic contrast masking of the fellow eye. The degree of residual binocularity and interocular suppression predicts monocular acuity and may be a significant etiological mechanism of vision loss.

Is Suppression Just Normal Dichoptic Masking? Suprathreshold Considerations.

PubMed

Reynaud, Alexandre; Hess, Robert F

2016-10-01

Amblyopic patients have a deficit in visual acuity and contrast sensitivity in their amblyopic eye as well as suppression of the amblyopic eye input under binocular viewing conditions. In this study we wanted to assess the origin of the amblyopic suppression by studying the contrast perception of the amblyopic eye at suprathreshold levels under binocular and monocular viewing. Using a suprathreshold contrast matching task in which the reference and target stimuli were presented to different eyes either simultaneously or successively, we measured interocular contrast matching in 10 controls and 11 amblyopes (mean age 35 ± 15; 5 strabismics; 3 anisometropes; 3 mixed). This was then used as an index of the binocular balance across spatial frequency and compared against the contrast sensitivity ratio measured with the same stimuli. We observed that binocular matching becomes more imbalanced at high spatial frequency for amblyopes, compared with controls; that this imbalance did not depend in either group on whether the stimuli were presented simultaneously or successively; and that for both modes of presentation the matching balance correlates well with the interocular contrast sensitivity ratio (mean correlation coefficient of the slopes R = 0.7125). The results from our amblyopes show comparable losses of contrast perception at and above threshold under these binocular viewing conditions across a wide spatial frequency range, much stronger than that observed for our controls. This occurs under conditions in which there should be no dichoptic masking. Furthermore, the matching contrast could be well predicted by the monocular contrast sensitivity. Altogether, this suggests that amblyopic suppression cannot be explained by normal dichoptic masking but rather an attenuation of the input.

Evaluation of Interocular Retinal Nerve Fiber Layer Thickness Symmetry as a Diagnostic Modality for Glaucoma.

PubMed

Hong, Seung Woo; Lee, Seung Bum; Jee, Dong-Hyun; Ahn, Myung Douk

2016-09-01

The purpose of study was to measure the diagnostic utility of interocular retinal nerve fiber layer (RNFL) symmetry and interocular RNFL thickness comparison. Both eyes of 103 normal subjects and 106 glaucoma patients (31 patients with early glaucoma and 75 patients with moderate to severe glaucoma) received comprehensive ophthalmologic evaluation including visual field testing and optic disc scanning using optical coherence tomography. RNFL thickness values for 256 measurement points were rearranged according to a new reference line connecting the optic disc center and the foveola. The interocular RNFL thickness symmetry value and absolute and fractional interocular difference in RNFL thickness were calculated and compared between groups. Area under the receiver operating characteristic curves (AUROCs) were calculated and compared. Among the parameters reflecting whole RNFL status, the corrected interocular RNFL thickness symmetry exhibited the largest AUROCs at all glaucoma stages. RNFL thickness and absolute and fractional interocular difference in RNFL thickness exhibited largest AUROC in the inferotemporal area, regardless of glaucoma stage. In the early glaucoma group, absolute and fractional interocular RNFL thickness differences in the temporal and superotemporal areas exhibited equal to or larger AUROCs than RNFL thickness. The AUROCs for RNFL thickness were greater than those for absolute and fractional interocular RNFL thickness differences in the moderate to severe glaucoma group except in the nasal and temporal area. The corrected interocular RNFL thickness symmetry value is an effective diagnostic tool for glaucoma. Interocular comparison of RNFL thickness has good diagnostic performance and gives information about the RNFL beyond just the RNFL thickness itself.

Interocular asymmetry of the visual field defects in newly diagnosed normal-tension glaucoma, primary open-angle glaucoma, and chronic angle-closure glaucoma.

PubMed

Huang, Ping; Shi, Yan; Wang, Xin; Liu, Mugen; Zhang, Chun

2014-09-01

To compare the interocular asymmetry of visual field loss in newly diagnosed normal-tension glaucoma (NTG), primary open-angle glaucoma (POAG), and chronic angle-closure glaucoma (CACG) patients. Visual field results of 117 newly diagnosed, treatment-naive glaucoma patients (42 NTG, 38 POAG, and 37 CACG) were studied retrospectively. The following 3 visual field defect parameters were used to evaluate the interocular asymmetry: (1) global indices; (2) local mean deviations (MDs) of 6 predefined visual field areas; and (3) stage designated by glaucoma staging system 2. The differences of the above parameters between the trial eye (the eye with greater MDs) and the fellow eye in each subject were defined as interocular asymmetry scores. Interocular asymmetry of visual field loss was presented in all the 3 groups (all P<0.05). CACG group had greater total MD interocular asymmetry score compared with the NTG and POAG groups (among groups, P=0.008; NTG vs. CACG, P=0.005; POAG vs. CACG, P=0.009). CACG also presented with significantly higher local MD interocular asymmetry scores at central, inferior, and temporal areas compared with those of the POAG group and at inferior area compared with that of NTG group. No significant difference in either total or local MDs was detected between NTG and POAG (all P>0.05). Interocular asymmetry scores of glaucoma staging system 2 had no significant difference among the 3 groups (P=0.068). All CACG, POAG, and NTG groups presented with interocular asymmetric visual field loss at the time of diagnosis. CACG had greater interocular asymmetry compared with NTG and POAG. No significant interocular asymmetry difference was observed between NTG and POAG.

Binocular combination in abnormal binocular vision

PubMed Central

Ding, Jian; Klein, Stanley A.; Levi, Dennis M.

2013-01-01

We investigated suprathreshold binocular combination in humans with abnormal binocular visual experience early in life. In the first experiment we presented the two eyes with equal but opposite phase shifted sine waves and measured the perceived phase of the cyclopean sine wave. Normal observers have balanced vision between the two eyes when the two eyes' images have equal contrast (i.e., both eyes contribute equally to the perceived image and perceived phase = 0°). However, in observers with strabismus and/or amblyopia, balanced vision requires a higher contrast image in the nondominant eye (NDE) than the dominant eye (DE). This asymmetry between the two eyes is larger than predicted from the contrast sensitivities or monocular perceived contrast of the two eyes and is dependent on contrast and spatial frequency: more asymmetric with higher contrast and/or spatial frequency. Our results also revealed a surprising NDE-to-DE enhancement in some of our abnormal observers. This enhancement is not evident in normal vision because it is normally masked by interocular suppression. However, in these abnormal observers the NDE-to-DE suppression was weak or absent. In the second experiment, we used the identical stimuli to measure the perceived contrast of a cyclopean grating by matching the binocular combined contrast to a standard contrast presented to the DE. These measures provide strong constraints for model fitting. We found asymmetric interocular interactions in binocular contrast perception, which was dependent on both contrast and spatial frequency in the same way as in phase perception. By introducing asymmetric parameters to the modified Ding-Sperling model including interocular contrast gain enhancement, we succeeded in accounting for both binocular combined phase and contrast simultaneously. Adding binocular contrast gain control to the modified Ding-Sperling model enabled us to predict the results of dichoptic and binocular contrast discrimination experiments and provides new insights into the mechanisms of abnormal binocular vision. PMID:23397039

Binocular combination in abnormal binocular vision.

PubMed

Ding, Jian; Klein, Stanley A; Levi, Dennis M

2013-02-08

We investigated suprathreshold binocular combination in humans with abnormal binocular visual experience early in life. In the first experiment we presented the two eyes with equal but opposite phase shifted sine waves and measured the perceived phase of the cyclopean sine wave. Normal observers have balanced vision between the two eyes when the two eyes' images have equal contrast (i.e., both eyes contribute equally to the perceived image and perceived phase = 0°). However, in observers with strabismus and/or amblyopia, balanced vision requires a higher contrast image in the nondominant eye (NDE) than the dominant eye (DE). This asymmetry between the two eyes is larger than predicted from the contrast sensitivities or monocular perceived contrast of the two eyes and is dependent on contrast and spatial frequency: more asymmetric with higher contrast and/or spatial frequency. Our results also revealed a surprising NDE-to-DE enhancement in some of our abnormal observers. This enhancement is not evident in normal vision because it is normally masked by interocular suppression. However, in these abnormal observers the NDE-to-DE suppression was weak or absent. In the second experiment, we used the identical stimuli to measure the perceived contrast of a cyclopean grating by matching the binocular combined contrast to a standard contrast presented to the DE. These measures provide strong constraints for model fitting. We found asymmetric interocular interactions in binocular contrast perception, which was dependent on both contrast and spatial frequency in the same way as in phase perception. By introducing asymmetric parameters to the modified Ding-Sperling model including interocular contrast gain enhancement, we succeeded in accounting for both binocular combined phase and contrast simultaneously. Adding binocular contrast gain control to the modified Ding-Sperling model enabled us to predict the results of dichoptic and binocular contrast discrimination experiments and provides new insights into the mechanisms of abnormal binocular vision.

Probing the influence of unconscious fear-conditioned visual stimuli on eye movements.

PubMed

Madipakkam, Apoorva Rajiv; Rothkirch, Marcus; Wilbertz, Gregor; Sterzer, Philipp

2016-11-01

Efficient threat detection from the environment is critical for survival. Accordingly, fear-conditioned stimuli receive prioritized processing and capture overt and covert attention. However, it is unknown whether eye movements are influenced by unconscious fear-conditioned stimuli. We performed a classical fear-conditioning procedure and subsequently recorded participants' eye movements while they were exposed to fear-conditioned stimuli that were rendered invisible using interocular suppression. Chance-level performance in a forced-choice-task demonstrated unawareness of the stimuli. Differential skin conductance responses and a change in participants' fearfulness ratings of the stimuli indicated the effectiveness of conditioning. However, eye movements were not biased towards the fear-conditioned stimulus. Preliminary evidence suggests a relation between the strength of conditioning and the saccadic bias to the fear-conditioned stimulus. Our findings provide no strong evidence for a saccadic bias towards unconscious fear-conditioned stimuli but tentative evidence suggests that such an effect may depend on the strength of the conditioned response. Copyright © 2016 Elsevier Inc. All rights reserved.

Dynamics of processing invisible faces in the brain: automatic neural encoding of facial expression information.

PubMed

Jiang, Yi; Shannon, Robert W; Vizueta, Nathalie; Bernat, Edward M; Patrick, Christopher J; He, Sheng

2009-02-01

The fusiform face area (FFA) and the superior temporal sulcus (STS) are suggested to process facial identity and facial expression information respectively. We recently demonstrated a functional dissociation between the FFA and the STS as well as correlated sensitivity of the STS and the amygdala to facial expressions using an interocular suppression paradigm [Jiang, Y., He, S., 2006. Cortical responses to invisible faces: dissociating subsystems for facial-information processing. Curr. Biol. 16, 2023-2029.]. In the current event-related brain potential (ERP) study, we investigated the temporal dynamics of facial information processing. Observers viewed neutral, fearful, and scrambled face stimuli, either visibly or rendered invisible through interocular suppression. Relative to scrambled face stimuli, intact visible faces elicited larger positive P1 (110-130 ms) and larger negative N1 or N170 (160-180 ms) potentials at posterior occipital and bilateral occipito-temporal regions respectively, with the N170 amplitude significantly greater for fearful than neutral faces. Invisible intact faces generated a stronger signal than scrambled faces at 140-200 ms over posterior occipital areas whereas invisible fearful faces (compared to neutral and scrambled faces) elicited a significantly larger negative deflection starting at 220 ms along the STS. These results provide further evidence for cortical processing of facial information without awareness and elucidate the temporal sequence of automatic facial expression information extraction.

A gender- and sexual orientation-dependent spatial attentional effect of invisible images.

PubMed

Jiang, Yi; Costello, Patricia; Fang, Fang; Huang, Miner; He, Sheng

2006-11-07

Human observers are constantly bombarded with a vast amount of information. Selective attention helps us to quickly process what is important while ignoring the irrelevant. In this study, we demonstrate that information that has not entered observers' consciousness, such as interocularly suppressed (invisible) erotic pictures, can direct the distribution of spatial attention. Furthermore, invisible erotic information can either attract or repel observers' spatial attention depending on their gender and sexual orientation. While unaware of the suppressed pictures, heterosexual males' attention was attracted to invisible female nudes, heterosexual females' attention was attracted to invisible male nudes, gay males behaved similarly to heterosexual females, and gay/bisexual females performed in-between heterosexual males and females.

A gender- and sexual orientation-dependent spatial attentional effect of invisible images

PubMed Central

Jiang, Yi; Costello, Patricia; Fang, Fang; Huang, Miner; He, Sheng

2006-01-01

Human observers are constantly bombarded with a vast amount of information. Selective attention helps us to quickly process what is important while ignoring the irrelevant. In this study, we demonstrate that information that has not entered observers' consciousness, such as interocularly suppressed (invisible) erotic pictures, can direct the distribution of spatial attention. Furthermore, invisible erotic information can either attract or repel observers' spatial attention depending on their gender and sexual orientation. While unaware of the suppressed pictures, heterosexual males' attention was attracted to invisible female nudes, heterosexual females' attention was attracted to invisible male nudes, gay males behaved similarly to heterosexual females, and gay/bisexual females performed in-between heterosexual males and females. PMID:17075055

Interocular transfer of depth discrimination in intact and in DSO-sectioned pigeons.

PubMed

Musumeci, D; Lemeignan, M; Bloch, S

1991-07-22

Interocular transfer (IOT) of a depth discrimination task was studied in intact pigeons and with a section of the supraoptic decussation (DSO). Animals were trained to respond to the nearer of two small light emitting diodes placed at different depths in the left and right compartments of a black tunnel. The near stimulus (at 10.5 cm from the eyes) and the far one (at 21 cm) could only be seen one at a time. Though the task was difficult to learn monocularly, intact as well as lesioned animals had good transfer scores with the untrained eye. Success in transfer may be related to the presentation of the discriminanda which assured that their images impinged upon the retinal 'red field'. DSO-transection did not affect IOT possibly because differential oculomotor adjustments needed for focusing near or far targets provide central bilateral and/or binocular information which is not conveyed by the DSO.

On the use of continuous flash suppression for the study of visual processing outside of awareness

PubMed Central

Yang, Eunice; Brascamp, Jan; Kang, Min-Suk; Blake, Randolph

2014-01-01

The interocular suppression technique termed continuous flash suppression (CFS) has become an immensely popular tool for investigating visual processing outside of awareness. The emerging picture from studies using CFS is that extensive processing of a visual stimulus, including its semantic and affective content, occurs despite suppression from awareness of that stimulus by CFS. However, the current implementation of CFS in many studies examining processing outside of awareness has several drawbacks that may be improved upon for future studies using CFS. In this paper, we address some of those shortcomings, particularly ones that affect the assessment of unawareness during CFS, and ones to do with the use of “visible” conditions that are often included as a comparison to a CFS condition. We also discuss potential biases in stimulus processing as a result of spatial attention and feature-selective suppression. We suggest practical guidelines that minimize the effects of those limitations in using CFS to study visual processing outside of awareness. PMID:25071685

Advantage of hole stimulus in rivalry competition.

PubMed

Meng, Qianli; Cui, Ding; Zhou, Ke; Chen, Lin; Ma, Yuanye

2012-01-01

Mounting psychophysical evidence suggests that early visual computations are sensitive to the topological properties of stimuli, such as the determination of whether the object has a hole or not. Previous studies have demonstrated that the hole feature took some advantages during conscious perception. In this study, we investigate whether there exists a privileged processing for hole stimuli during unconscious perception. By applying a continuous flash suppression paradigm, the target was gradually introduced to one eye to compete against a flashed full contrast Mondrian pattern which was presented to the other eye. This method ensured that the target image was suppressed during the initial perceptual period. We compared the initial suppressed duration between the stimuli with and without the hole feature and found that hole stimuli required less time than no-hole stimuli to gain dominance against the identical suppression noise. These results suggest the hole feature could be processed in the absence of awareness, and there exists a privileged detection of hole stimuli during suppressed phase in the interocular rivalry.

Deficient Binocular Combination Reveals Mechanisms of Anisometropic Amblyopia: Signal Attenuation and Interocular Inhibition

PubMed Central

Huang, Chang-Bing; Zhou, Jiawei; Lu, Zhong-Lin; Zhou, Yifeng

2012-01-01

Amblyopia is a developmental disorder that results in deficits of monocular and binocular vision. It's presently unclear whether these deficits result from attenuation of signals in the amblyopic eye, inhibition by signals in the fellow eye, or both. In this study, we characterize the mechanisms underlying anisometropic amblyopia using a binocular phase and contrast combination paradigm and a contrast-gain control model. Subjects dichoptically viewed two slightly different images and reported the perceived contrast and phase of the resulting cyclopean percept. We found that the properties of binocular combination were abnormal in many aspects, which is explained by a combination of (1) attenuated monocular signal in the amblyopic eye, (2) stronger interocular contrast-gain control from the fellow eye to the signal in amblyopic eye (direct interocular inhibition), and (3) stronger interocular contrast-gain control from the fellow eye to the contrast gain control signal from the amblyopic eye (indirect interocular inhibition). We conclude that anisometropic amblyopia led to both monocular and interocular deficits. A complete understanding of the mechanisms underlying amblyopia requires studies of both monocular deficits and binocular interactions. PMID:21546609

Chromatic interocular-switch rivalry.

PubMed

Christiansen, Jens H; D'Antona, Anthony D; Shevell, Steven K

2017-05-01

Interocular-switch rivalry (also known as stimulus rivalry) is a kind of binocular rivalry in which two rivalrous images are swapped between the eyes several times a second. The result is stable periods of one image and then the other, with stable intervals that span many eye swaps (Logothetis, Leopold, & Sheinberg, 1996). Previous work used this close kin of binocular rivalry with rivalrous forms. Experiments here test whether chromatic interocular-switch rivalry, in which the swapped stimuli differ in only chromaticity, results in slow alternation between two colors. Swapping equiluminant rivalrous chromaticities at 3.75 Hz resulted in slow perceptual color alternation, with one or the other color often continuously visible for two seconds or longer (during which there were 15+ eye swaps). A well-known theory for sustained percepts from interocular-switch rivalry with form is inhibitory competition between binocular neurons driven by monocular neurons with matched orientation tuning in each eye; such binocular neurons would produce a stable response when a given orientation is swapped between the eyes. A similar model can account for the percepts here from chromatic interocular-switch rivalry and is underpinned by the neurophysiological finding that color-preferring binocular neurons are driven by monocular neurons from each eye with well-matched chromatic selectivity (Peirce, Solomon, Forte, & Lennie, 2008). In contrast to chromatic interocular-switch rivalry, luminance interocular-switch rivalry with swapped stimuli that differ in only luminance did not result in slowly alternating percepts of different brightnesses.

Characterization of Visual Function, Interocular Variability and Progression Using Static Perimetry-Derived Metrics in RPGR-Associated Retinopathy.

PubMed

Tee, James J L; Yang, Yesa; Kalitzeos, Angelos; Webster, Andrew; Bainbridge, James; Weleber, Richard G; Michaelides, Michel

2018-05-01

To characterize bilateral visual function, interocular variability and progression by using static perimetry-derived volumetric and pointwise metrics in subjects with retinitis pigmentosa associated with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. This was a prospective longitudinal observational study of 47 genetically confirmed subjects. Visual function was assessed with ETDRS and Pelli-Robson charts; and Octopus 900 static perimetry using a customized, radially oriented 185-point grid. Three-dimensional hill-of-vision topographic models were produced and interrogated with the Visual Field Modeling and Analysis software to obtain three volumetric metrics: VTotal, V30, and V5. These were analyzed together with Octopus mean sensitivity values. Interocular differences were assessed with the Bland-Altman method. Metric-specific exponential decline rates were calculated. Baseline symmetry was demonstrated by relative interocular difference values of 1% for VTotal and 8% with V30. Degree of symmetry varied between subjects and was quantified with the subject percentage interocular difference (SPID). SPID was 16% for VTotal and 17% for V30. Interocular symmetry in progression was greatest when quantified by VTotal and V30, with 73% and 64% of subjects possessing interocular rate differences smaller in magnitude than respective annual progression rates. Functional decline was evident with increasing age. An overall annual exponential decline of 6% was evident with both VTotal and V30. In general, good interocular symmetry exists; however, there was both variation between subjects and with the use of various metrics. Our findings will guide patient selection and design of RPGR treatment trials, and provide clinicians with specific prognostic information to offer patients affected by this condition.

Does partial occlusion promote normal binocular function?

PubMed

Li, Jingrong; Thompson, Benjamin; Ding, Zhaofeng; Chan, Lily Y L; Chen, Xiang; Yu, Minbin; Deng, Daming; Hess, Robert F

2012-10-03

There is growing evidence that abnormal binocular interactions play a key role in the amblyopia syndrome and represent a viable target for treatment interventions. In this context the use of partial occlusion using optical devices such as Bangerter filters as an alternative to complete occlusion is of particular interest. The aims of this study were to understand why Bangerter filters do not result in improved binocular outcomes compared to complete occlusion, and to compare the effects of Bangerter filters, optical blur and neutral density (ND) filters on normal binocular function. The effects of four strengths of Bangerter filters (0.8, 0.6, 0.4, 0.2) on letter and vernier acuity, contrast sensitivity, stereoacuity, and interocular suppression were measured in 21 observers with normal vision. In a subset of 14 observers, the partial occlusion effects of Bangerter filters, ND filters and plus lenses on stereopsis and interocular suppression were compared. Bangerter filters did not have graded effect on vision and induced significant disruption to binocular function. This disruption was greater than that of monocular defocus but weaker than that of ND filters. The effect of the Bangerter filters on stereopsis was more pronounced than their effect on monocular acuity, and the induced monocular acuity deficits did not predict the induced deficits in stereopsis. Bangerter filters appear to be particularly disruptive to binocular function. Other interventions, such as optical defocus and those employing computer generated dichoptic stimulus presentation, may be more appropriate than partial occlusion for targeting binocular function during amblyopia treatment.

Dissociations of subliminal and supraliminal self-face from other-face processing: behavioral and ERP evidence.

PubMed

Geng, Haiyan; Zhang, Shen; Li, Qi; Tao, Ran; Xu, Shan

2012-10-01

Self-related information has been found to be processed more quickly and accurately in studies with supraliminal self-stimuli and traditional paradigms such as masked priming. We conducted two experiments to investigate whether subliminal self-face processing enjoys this advantage and the neural correlates of processing self-faces at both subliminal and supraliminal levels. We found that self-faces were quicker than famous-other faces to gain dominance against dynamic noise patterns during prolonged interocular suppression to enter awareness (Experiment 1). Meanwhile, subliminal contrast of self- and famous-other face processing was reflected in a reduced early vertex positive potential (VPP) component, whereas supraliminal self-other face differentiation was reflected in an enhanced N170, as well as a more positive late component (300-580ms, Experiment 2) to the self-face. The clear dissociations of self- and other-face processing found across our two experiments validate the self advantage. Our findings also contribute to understandings of the mechanisms underlying self-face processing at different levels of awareness. Copyright © 2012 Elsevier Ltd. All rights reserved.

Chromatic interocular-switch rivalry

PubMed Central

Christiansen, Jens H.; D'Antona, Anthony D.; Shevell, Steven K.

2017-01-01

Interocular-switch rivalry (also known as stimulus rivalry) is a kind of binocular rivalry in which two rivalrous images are swapped between the eyes several times a second. The result is stable periods of one image and then the other, with stable intervals that span many eye swaps (Logothetis, Leopold, & Sheinberg, 1996). Previous work used this close kin of binocular rivalry with rivalrous forms. Experiments here test whether chromatic interocular-switch rivalry, in which the swapped stimuli differ in only chromaticity, results in slow alternation between two colors. Swapping equiluminant rivalrous chromaticities at 3.75 Hz resulted in slow perceptual color alternation, with one or the other color often continuously visible for two seconds or longer (during which there were 15+ eye swaps). A well-known theory for sustained percepts from interocular-switch rivalry with form is inhibitory competition between binocular neurons driven by monocular neurons with matched orientation tuning in each eye; such binocular neurons would produce a stable response when a given orientation is swapped between the eyes. A similar model can account for the percepts here from chromatic interocular-switch rivalry and is underpinned by the neurophysiological finding that color-preferring binocular neurons are driven by monocular neurons from each eye with well-matched chromatic selectivity (Peirce, Solomon, Forte, & Lennie, 2008). In contrast to chromatic interocular-switch rivalry, luminance interocular-switch rivalry with swapped stimuli that differ in only luminance did not result in slowly alternating percepts of different brightnesses. PMID:28510624

Clinical vision characteristics of the congenital achromatopsias. I. Visual acuity, refractive error, and binocular status.

PubMed

Haegerstrom-Portnoy, G; Schneck, M E; Verdon, W A; Hewlett, S E

1996-07-01

Visual acuity, refractive error, and binocular status were determined in 43 autosomal recessive (AR) and 15 X-linked (XL) congenital achromats. The achromats were classified by color matching and spectral sensitivity data. Large interindividual variation in refractive error and visual acuity was present within each achromat group (complete AR, incomplete AR, and XL). However, the number of individuals with significant interocular acuity differences is very small. Most XLs are myopic; ARs show a wide range of refractive error from high myopia to high hyperopia. Acuity of the AR and XL groups was very similar. With-the-rule astigmatism of large amount is very common in achromats, particularly ARs. There is a close association between strabismus and interocular acuity differences in the ARs, with the fixating eye having better than average acuity. The large overlap of acuity and refractive error of XL and AR achromats suggests that these measures are less useful for differential diagnosis than generally indicated by the clinical literature.

Binocular rivalry from invisible patterns

PubMed Central

Zou, Jinyou; He, Sheng; Zhang, Peng

2016-01-01

Binocular rivalry arises when incompatible images are presented to the two eyes. If the two eyes’ conflicting features are invisible, leading to identical perceptual interpretations, does rivalry competition still occur? Here we investigated whether binocular rivalry can be induced from conflicting but invisible spatial patterns. A chromatic grating counterphase flickering at 30 Hz appeared uniform, but produced significant tilt aftereffect and orientation-selective adaptation. The invisible pattern also generated significant BOLD activities in the early visual cortex, with minimal response in the parietal and frontal cortical areas. Compared with perceptually matched uniform stimuli, a monocularly presented invisible chromatic grating enhanced the rivalry competition with a low-contrast visible grating presented to the other eye. Furthermore, switching from a uniform field to a perceptually matched invisible chromatic grating produced interocular suppression at approximately 200 ms after onset of the invisible grating. Experiments using briefly presented monocular probes revealed evidence for sustained rivalry competition between two invisible gratings during continuous dichoptic presentations. These findings indicate that even without visible interocular conflict, and with minimal engagement of frontoparietal cortex and consciousness related top-down feedback, perceptually identical patterns with invisible conflict features produce rivalry competition in the early visual cortex. PMID:27354535

Contrast masking in strabismic amblyopia: attenuation, noise, interocular suppression and binocular summation.

PubMed

Baker, Daniel H; Meese, Tim S; Hess, Robert F

2008-07-01

To investigate amblyopic contrast vision at threshold and above we performed pedestal-masking (contrast discrimination) experiments with a group of eight strabismic amblyopes using horizontal sinusoidal gratings (mainly 3c/deg) in monocular, binocular and dichoptic configurations balanced across eye (i.e. five conditions). With some exceptions in some observers, the four main results were as follows. (1) For the monocular and dichoptic conditions, sensitivity was less in the amblyopic eye than in the good eye at all mask contrasts. (2) Binocular and monocular dipper functions superimposed in the good eye. (3) Monocular masking functions had a normal dipper shape in the good eye, but facilitation was diminished in the amblyopic eye. (4) A less consistent result was normal facilitation in dichoptic masking when testing the good eye, but a loss of this when testing the amblyopic eye. This pattern of amblyopic results was replicated in a normal observer by placing a neutral density filter in front of one eye. The two-stage model of binocular contrast gain control [Meese, T.S., Georgeson, M.A. & Baker, D.H. (2006). Binocular contrast vision at and above threshold. Journal of Vision 6, 1224-1243.] was 'lesioned' in several ways to assess the form of the amblyopic deficit. The most successful model involves attenuation of signal and an increase in noise in the amblyopic eye, and intact stages of interocular suppression and binocular summation. This implies a behavioural influence from monocular noise in the amblyopic visual system as well as in normal observers with an ND filter over one eye.

Spatial attention can modulate unconscious orientation processing.

PubMed

Bahrami, Bahador; Carmel, David; Walsh, Vincent; Rees, Geraint; Lavie, Nilli

2008-01-01

It has recently been suggested that visual spatial attention can only affect consciously perceived events. We measured the effects of sustained spatial attention on orientation-selective adaptation to gratings, rendered invisible by prolonged interocular suppression. Spatial attention augmented the orientation-selective adaptation to invisible adaptor orientation. The effect of attention was clearest for test stimuli at peri-threshold, intermediate contrast levels, suggesting that previous negative results were due to assessing orientation discrimination at maximum contrast. On the basis of these findings we propose a constrained hypothesis for the difference between neuronal mechanisms of spatial attention in the presence versus absence of awareness.

Interocular difference and duration for doubling of the minimal angle of visual resolution in patients with Stargardt disease.

PubMed

Hajali, Manal; Fishman, Gerald A; Anderson, Robert J; McAnany, J Jason

2009-07-01

To determine the extent of interocular difference in visual acuity (VA) and the time to at least double the minimal angle of resolution (MAR) in a cohort of patients with Stargardt disease. One hundred fifty patients with Stargardt disease who were examined at least four times over a minimum period of 3 years were identified and their VA and age at each visit recorded. The maximum interocular difference of VA was determined by whether the MAR between the two eyes differed by less than a factor of 2 or by a factor of 2 or greater. Differences in maximum VA between the two eyes were also examined according to a Bland-Altman-type approach. One hundred thirty-one eyes from 76 patients were subjected to survival analysis to determine whether the time to at least double the MAR was dependent on age at baseline or starting VA. Of the 150 patients, 48% had interocular MAR that differed maximally by a factor of less than 2. Thirty-five percent showed a maximum interocular difference in their Snellen VA of less than one line. The Bland-Altman- type analysis showed that maximum interocular acuity difference was dependent on the mean acuity of the two eyes. The hazard for at least doubling the MAR was related to baseline vision and patient age. This information has clinical significance for patient counseling and for monitoring possible benefits and patient selection in future treatment trials.

CFS MATLAB toolbox: An experiment builder for continuous flash suppression (CFS) task.

PubMed

Nuutinen, Mikko; Mustonen, Terhi; Häkkinen, Jukka

2017-09-15

CFS toolbox is an open-source collection of MATLAB functions that utilizes PsychToolbox-3 (PTB-3). It is designed to allow a researcher to create and run continuous flash suppression experiments using a variety of experimental parameters (i.e., stimulus types and locations, noise characteristics, and experiment window settings). In a CFS experiment, one of the eyes at a time is presented with a dynamically changing noise pattern, while the other eye is concurrently presented with a static target stimulus, such as a Gabor patch. Due to the strong interocular suppression created by the dominant noise pattern mask, the target stimulus is rendered invisible for an extended duration. Very little knowledge of MATLAB is required for using the toolbox; experiments are generated by modifying csv files with the required parameters, and result data are output to text files for further analysis. The open-source code is available on the project page under a Creative Commons License ( http://www.mikkonuutinen.arkku.net/CFS_toolbox/ and https://bitbucket.org/mikkonuutinen/cfs_toolbox ).

Measurement of suprathreshold binocular interactions in amblyopia.

PubMed

Mansouri, B; Thompson, B; Hess, R F

2008-12-01

It has been established that in amblyopia, information from the amblyopic eye (AME) is not combined with that from the fellow fixing eye (FFE) under conditions of binocular viewing. However, recent evidence suggests that mechanisms that combine information between the eyes are intact in amblyopia. The lack of binocular function is most likely due to the imbalanced inputs from the two eyes under binocular conditions [Baker, D. H., Meese, T. S., Mansouri, B., & Hess, R. F. (2007b). Binocular summation of contrast remains intact in strabismic amblyopia. Investigative Ophthalmology & Visual Science, 48(11), 5332-5338]. We have measured the extent to which the information presented to each eye needs to differ for binocular combination to occur and in doing so we quantify the influence of interocular suppression. We quantify these suppressive effects for suprathreshold processing of global stimuli for both motion and spatial tasks. The results confirm the general importance of these suppressive effects in rendering the structurally binocular visual system of a strabismic amblyope, functionally monocular.

Mechanisms of recovery of visual function in adult amblyopia through a tailored action video game.

PubMed

Vedamurthy, Indu; Nahum, Mor; Bavelier, Daphne; Levi, Dennis M

2015-02-26

Amblyopia is a deficit in vision that arises from abnormal visual experience early in life. It was long thought to develop into a permanent deficit, unless properly treated before the end of the sensitive period for visual recovery. However, a number of studies now suggest that adults with long-standing amblyopia may at least partially recover visual acuity and stereopsis following perceptual training. Eliminating or reducing interocular suppression has been hypothesized to be at the root of these changes. Here we show that playing a novel dichoptic video game indeed results in reduced suppression, improved visual acuity and, in some cases, improved stereopsis. Our relatively large cohort of adults with amblyopia, allowed us, for the first time, to assess the link between visual function recovery and reduction in suppression. Surprisingly, no significant correlation was found between decreased suppression and improved visual function. This finding challenges the prevailing view and suggests that while dichoptic training improves visual acuity and stereopsis in adult amblyopia, reduced suppression is unlikely to be at the root of visual recovery. These results are discussed in the context of their implication on recovery of amblyopia in adults.

Mechanisms of recovery of visual function in adult amblyopia through a tailored action video game

PubMed Central

Vedamurthy, Indu; Nahum, Mor; Bavelier, Daphne; Levi, Dennis M.

2015-01-01

Amblyopia is a deficit in vision that arises from abnormal visual experience early in life. It was long thought to develop into a permanent deficit, unless properly treated before the end of the sensitive period for visual recovery. However, a number of studies now suggest that adults with long-standing amblyopia may at least partially recover visual acuity and stereopsis following perceptual training. Eliminating or reducing interocular suppression has been hypothesized to be at the root of these changes. Here we show that playing a novel dichoptic video game indeed results in reduced suppression, improved visual acuity and, in some cases, improved stereopsis. Our relatively large cohort of adults with amblyopia, allowed us, for the first time, to assess the link between visual function recovery and reduction in suppression. Surprisingly, no significant correlation was found between decreased suppression and improved visual function. This finding challenges the prevailing view and suggests that while dichoptic training improves visual acuity and stereopsis in adult amblyopia, reduced suppression is unlikely to be at the root of visual recovery. These results are discussed in the context of their implication on recovery of amblyopia in adults. PMID:25719537

Dichoptic movie viewing treats childhood amblyopia.

PubMed

Li, Simone L; Reynaud, Alexandre; Hess, Robert F; Wang, Yi-Zhong; Jost, Reed M; Morale, Sarah E; De La Cruz, Angie; Dao, Lori; Stager, David; Birch, Eileen E

2015-10-01

Contrast-balanced dichoptic experience with perceptual-learning tasks or simple games has been shown to improve visual acuity significantly in amblyopia. However, these tasks are intensive and repetitive, and up to 40% of unsupervised patients are noncompliant. We investigated the efficacy of a potentially more engaging movie method to provide contrast-balanced binocular experience via complementary dichoptic stimulation. Eight amblyopic children 4-10 years of age were enrolled in a prospective cohort study to watch 3 dichoptic movies per week for 2 weeks on a passive 3D display. Dichoptic versions of 18 popular animated feature films were created. A patterned image mask of irregularly shaped blobs was multiplied with the movie images seen by the amblyopic eye and an inverse mask was multiplied with the images seen by the fellow eye. Fellow-eye contrast was initially set at a reduced level that allowed binocular vision and was then incremented by 10% at each visit. Best-corrected visual acuity, random dot stereoacuity, and interocular suppression were measured at baseline and 2 weeks. Mean amblyopic eye visual acuity (with standard error of the mean) improved from a logarithm of minimum angle of resolution of 0.72 ± 0.08 at baseline to 0.52 ± 0.09 (P = 0.003); that is, 2.0 lines of improvement at the 2-week outcome visit. No significant change in interocular suppression or stereoacuity was found. Passive viewing of dichoptic feature films is feasible and could be a promising new treatment for childhood amblyopia. The maximum improvement that may be achieved by watching dichoptic movies remains to be determined. No known side effects are associated with this new treatment. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

Dichoptic movie viewing treats childhood amblyopia

PubMed Central

Li, Simone L.; Reynaud, Alexandre; Hess, Robert F.; Wang, Yi-Zhong; Jost, Reed M.; Morale, Sarah E.; De La Cruz, Angie; Dao, Lori; Stager, David; Birch, Eileen E.

2015-01-01

Background Contrast-balanced dichoptic experience with perceptual-learning tasks or simple games has been shown to improve visual acuity significantly in amblyopia. However, these tasks are intensive and repetitive, and up to 40% of unsupervised patients are noncompliant. We investigated the efficacy of a potentially more engaging movie method to provide contrast-balanced binocular experience via complementary dichoptic stimulation. Methods Eight amblyopic children 4–10 years of age were enrolled in a prospective cohort study to watch 3 dichoptic movies per week for 2 weeks on a passive 3D display. Dichoptic versions of 18 popular animated feature films were created. A patterned image mask of irregularly shaped blobs was multiplied with the movie images seen by the amblyopic eye and an inverse mask was multiplied with the images seen by the fellow eye. Fellow-eye contrast was initially set at a reduced level that allowed binocular vision and was then incremented by 10% at each visit. Best-corrected visual acuity, random dot stereoacuity, and interocular suppression were measured at baseline and 2 weeks. Results Mean amblyopic eye visual acuity (with standard error of the mean) improved from a logarithm of minimum angle of resolution of 0.72 ± 0.08 at baseline to 0.52 ± 0.09 (P = 0.003); that is, 2.0 lines of improvement at the 2-week outcome visit. No significant change in interocular suppression or stereoacuity was found. Conclusions Passive viewing of dichoptic feature films is feasible and could be a promising new treatment for childhood amblyopia. The maximum improvement that may be achieved by watching dichoptic movies remains to be determined. No known side effects are associated with this new treatment. PMID:26486019

Interocular symmetry in macular choroidal thickness in children.

PubMed

Al-Haddad, Christiane; El Chaar, Lama; Antonios, Rafic; El-Dairi, Mays; Noureddin, Baha'

2014-01-01

Objective. To report interocular differences in choroidal thickness in children using spectral domain optical coherence tomography (SD-OCT) and correlate findings with biometric data. Methods. This observational cross-sectional study included 91 (182 eyes) healthy children aged 6 to 17 years with no ocular abnormality except refractive error. After a comprehensive eye exam and axial length measurement, high definition macular scans were performed using SD-OCT. Two observers manually measured the choroidal thickness at the foveal center and at 1500 µm nasally, temporally, inferiorly, and superiorly. Interocular differences were computed; correlations with age, gender, refractive error, and axial length were performed. Results. Mean age was 10.40 ± 3.17 years; mean axial length and refractive error values were similar between fellow eyes. There was excellent correlation between the two observers' measurements. No significant interocular differences were observed at any location. There was only a trend for right eyes to have higher values in all thicknesses, except the superior thickness. Most of the choroidal thickness measurements correlated positively with spherical equivalent but not with axial length, age, or gender. Conclusion. Choroidal thickness measurements in children as performed using SD-OCT revealed a high level of interobserver agreement and consistent interocular symmetry. Values correlated positively with spherical equivalent refraction.

Interocular suppression in strabismic amblyopia results in an attenuated and delayed hemodynamic response function in early visual cortex.

PubMed

Farivar, Reza; Thompson, Benjamin; Mansouri, Behzad; Hess, Robert F

2011-12-20

Factors such as strabismus or anisometropia during infancy can disrupt normal visual development and result in amblyopia, characterized by reduced visual function in an otherwise healthy eye and often associated with persistent suppression of inputs from the amblyopic eye by those from the dominant eye. It has become evident from fMRI studies that the cortical response to stimulation of the amblyopic eye is also affected. We were interested to compare the hemodynamic response function (HRF) of early visual cortex to amblyopic vs. dominant eye stimulation. In the first experiment, we found that stimulation of the amblyopic eye resulted in a signal that was both attenuated and delayed in its time to peak. We postulated that this delay may be due to suppressive effects of the dominant eye and, in our second experiment, measured the cortical response of amblyopic eye stimulation under two conditions--where the dominant eye was open and seeing a static pattern (high suppression) or where the dominant eye was patched and closed (low suppression). We found that the HRF in response to amblyopic eye stimulation depended on whether the dominant eye was open. This effect was manifested as both a delayed HRF under the suppressed condition and an amplitude reduction.

Myopic refractive shift represents dense nuclear sclerosis and thin lens in lenticular myopia.

PubMed

Cho, Yang Kyung; Huang, Wei; Nishimura, Eiichi

2013-09-01

It is not rare to meet unilateral nuclear sclerotic cataracts with myopic refractive changes (lenticular myopia) compared with the fellow eye in the ophthalmic examination of patients with decreased visual acuity. To determine the relationship between the myopic refractive changes and interocular differences of parameters, we investigated the interocular differences of ocular parameters between a lenticular myopic eye and the fellow eye. This retrospective study included 68 eyes of 34 patients, who showed unilateral lenticular myopia. We compared the dimensions of ocular component, such as anterior chamber depth, anterior chamber volume, lens thickness, vitreous chamber depth, lens position, lens density of nuclear sclerosis, anterior lens curvature and myopic refractive changes (spherical equivalent refraction) between the lenticular myopic eye and the myopic refractive change were examined. Statistically significant differences were found between the lenticular myopic eye and the fellow eye for anterior chamber depth (p = 0.015) anterior chamber volume (p = 0.031), lens thickness (p < 0.001), lens density of the nuclear sclerosis (p < 0.001) and the spherical equivalent myopic refractive changes (p < 0.001). Based on univariate analysis, the interocular difference in spherical equivalent refraction was significantly correlated with interocular differences of the density of the nuclear sclerosis (r = 0.79, p < 0.001), lens thickness (r = -0.70, p < 0.001) and vitreous chamber depth (r = 0.43, p = 0.012). Based on multiple regression analysis, the interocular difference in spherical equivalent refraction was significantly correlated with interocular differences of density of nuclear sclerosis (p < 0.001) and lens thickness (p = 0.007). The difference in myopic spherical change reflects the differences in the severity of nuclear sclerosis and lens thickness between the lenticular myopic eye and the fellow eye. © 2013 The Authors. Clinical and Experimental Optometry © 2013 Optometrists Association Australia.

Unconscious processing of facial attractiveness: invisible attractive faces orient visual attention

PubMed Central

Hung, Shao-Min; Nieh, Chih-Hsuan; Hsieh, Po-Jang

2016-01-01

Past research has proven human’s extraordinary ability to extract information from a face in the blink of an eye, including its emotion, gaze direction, and attractiveness. However, it remains elusive whether facial attractiveness can be processed and influences our behaviors in the complete absence of conscious awareness. Here we demonstrate unconscious processing of facial attractiveness with three distinct approaches. In Experiment 1, the time taken for faces to break interocular suppression was measured. The results showed that attractive faces enjoyed the privilege of breaking suppression and reaching consciousness earlier. In Experiment 2, we further showed that attractive faces had lower visibility thresholds, again suggesting that facial attractiveness could be processed more easily to reach consciousness. Crucially, in Experiment 3, a significant decrease of accuracy on an orientation discrimination task subsequent to an invisible attractive face showed that attractive faces, albeit suppressed and invisible, still exerted an effect by orienting attention. Taken together, for the first time, we show that facial attractiveness can be processed in the complete absence of consciousness, and an unconscious attractive face is still capable of directing our attention. PMID:27848992

Unconscious processing of facial attractiveness: invisible attractive faces orient visual attention.

PubMed

Hung, Shao-Min; Nieh, Chih-Hsuan; Hsieh, Po-Jang

2016-11-16

Past research has proven human's extraordinary ability to extract information from a face in the blink of an eye, including its emotion, gaze direction, and attractiveness. However, it remains elusive whether facial attractiveness can be processed and influences our behaviors in the complete absence of conscious awareness. Here we demonstrate unconscious processing of facial attractiveness with three distinct approaches. In Experiment 1, the time taken for faces to break interocular suppression was measured. The results showed that attractive faces enjoyed the privilege of breaking suppression and reaching consciousness earlier. In Experiment 2, we further showed that attractive faces had lower visibility thresholds, again suggesting that facial attractiveness could be processed more easily to reach consciousness. Crucially, in Experiment 3, a significant decrease of accuracy on an orientation discrimination task subsequent to an invisible attractive face showed that attractive faces, albeit suppressed and invisible, still exerted an effect by orienting attention. Taken together, for the first time, we show that facial attractiveness can be processed in the complete absence of consciousness, and an unconscious attractive face is still capable of directing our attention.

Depth of suppression in anisometropic amblyopia (with or without microtropia).

PubMed

Firth, Alison Y; Stevenson, Clare

2012-01-01

There are conflicting reports concerning the relationship between depth of suppression and level of amblyopia in strabismics. Little attention has been given to anisometropes. This study examines the density of suppression in anisometropic amblyopes, with or without microtropia, and investigates whether there is a relationship with level of amblyopia. Patients with anisometropia (defined as a difference of 1D or 0.5 D cyl), binocular single vision and a difference in corrected visual acuity of at least 0.1 logMAR between eyes were recalled. The degree of amblyopia was expressed as the interocular difference using the Bailey-Lovie logMAR chart. Stereoacuity (Titmus test), binocular alignment and fixation were recorded. The depth of suppression was measured using the neutral density filter bar together with the Worth four dot test at 4.5m (subtending an angle of 0.5 degrees). Best spherical equivalent (BSE) was calculated to represent anisometropia. Thirteen participants aged 8.3 years to 12.1 years (mean 9.7 years) completed the study. No significant correlation was present (r=0.10, p=0.74) between the depth of suppression and degree of amblyopia. However, there was a correlation between depth of suppression and level of stereoacuity (r=0.59, p=0.03). Six participants had microtropia and showed stronger suppression (p=0.03) and worse stereoacuity (p=0.001) than the pure anisometropes. No evidence was found of a relationship between density of suppression and amblyopia in this cohort of anisometropic amblyopes.

Regional Extent of Peripheral Suppression in Amblyopia.

PubMed

Babu, Raiju J; Clavagnier, Simon; Bobier, William R; Thompson, Benjamin; Hess, Robert F

2017-04-01

Previously, we have mapped amblyopic eye suppression within the central 20° of the visual field and observed a gradient of suppression that is strongest in central vision and weakens with increasing eccentricity. In this study, using a large dichoptic display, we extend our novel suppression mapping approach further into the periphery (from 20°-60°) to assess whether suppression continues to decline with eccentricity or plateaus. Sixteen participants with amblyopia (10 with strabismus, 6 with anisometropia without strabismus; mean age: 37.9 ± 11 years) and six normal observers (mean age: 28.3 ± 5 years) took part. The visual stimulus (60° diameter), viewed from 57 cm, was composed of four concentric annuli (5° radius) with alternate contrast polarities starting from an eccentricity of 10°. Each annulus was divided into eight sectors subtending 45° of visual angle. Participants adjusted the contrast of a single sector presented to the fellow eye to match the perceived contrast of the remaining stimulus elements that were presented to the amblyopic eye. A matching contrast that was lower in the fellow eye than the amblyopic eye indicated suppression. Patients with strabismus exhibited significantly stronger interocular suppression than controls across all eccentricities (P = 0.01). Patients with anisometropia did not differ from controls (P = 0.58). Suppression varied significantly with eccentricity (P = 0.005) but this effect did not differ between patient groups (P = 0.217). In amblyopia, suppression is present beyond the central 10° in patients with strabismus. Suppression becomes weaker at greater eccentricities and this may enable peripheral fusion that could be used by binocular treatment methods.

Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia.

PubMed

Kelly, Krista R; Jost, Reed M; Wang, Yi-Zhong; Dao, Lori; Beauchamp, Cynthia L; Leffler, Joel N; Birch, Eileen E

2018-03-01

Childhood amblyopia can be treated with binocular games or movies that rebalance contrast between the eyes, which is thought to reduce depth of interocular suppression so the child can experience binocular vision. While visual acuity gains have been reported following binocular treatment, studies rarely report gains in binocular outcomes (i.e., stereoacuity, suppression) in amblyopic children. Here, we evaluated binocular outcomes in children who had received binocular treatment for childhood amblyopia. Data for amblyopic children enrolled in two ongoing studies were pooled. The sample included 41 amblyopic children (6 strabismic, 21 anisometropic, 14 combined; age 4-10 years; ≤4 prism diopters [PD]) who received binocular treatment (20 game, 21 movies; prescribed 9-10 hours treatment). Amblyopic eye visual acuity and binocular outcomes (Randot Preschool Stereoacuity, extent of suppression, and depth of suppression) were assessed at baseline and at 2 weeks. Mean amblyopic eye visual acuity (P < 0.001) and mean stereoacuity improved (P = 0.045), and mean extent (P = 0.005) and depth of suppression (P = 0.003) were reduced from baseline at the 2-week visit (87% game adherence, 100% movie adherence). Depth of suppression was reduced more in children aged <8 years than in those aged ≥8 years (P = 0.004). Worse baseline depth of suppression was correlated with a larger depth of suppression reduction at 2 weeks (P = 0.001). After 2 weeks, binocular treatment in amblyopic children improved visual acuity and binocular outcomes, reducing the extent and depth of suppression and improving stereoacuity. Binocular treatments that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia.

Moving stimuli are less effectively masked using traditional continuous flash suppression (CFS) compared to a moving Mondrian mask (MMM): a test case for feature-selective suppression and retinotopic adaptation.

PubMed

Moors, Pieter; Wagemans, Johan; de-Wit, Lee

2014-01-01

Continuous flash suppression (CFS) is a powerful interocular suppression technique, which is often described as an effective means to reliably suppress stimuli from visual awareness. Suppression through CFS has been assumed to depend upon a reduction in (retinotopically specific) neural adaptation caused by the continual updating of the contents of the visual input to one eye. In this study, we started from the observation that suppressing a moving stimulus through CFS appeared to be more effective when using a mask that was actually more prone to retinotopically specific neural adaptation, but in which the properties of the mask were more similar to those of the to-be-suppressed stimulus. In two experiments, we find that using a moving Mondrian mask (i.e., one that includes motion) is more effective in suppressing a moving stimulus than a regular CFS mask. The observed pattern of results cannot be explained by a simple simulation that computes the degree of retinotopically specific neural adaptation over time, suggesting that this kind of neural adaptation does not play a large role in predicting the differences between conditions in this context. We also find some evidence consistent with the idea that the most effective CFS mask is the one that matches the properties (speed) of the suppressed stimulus. These results question the general importance of retinotopically specific neural adaptation in CFS, and potentially help to explain an implicit trend in the literature to adapt one's CFS mask to match one's to-be-suppressed stimuli. Finally, the results should help to guide the methodological development of future research where continuous suppression of moving stimuli is desired.

Effect of Interocular Delay on Disparity-Selective V1 Neurons: Relationship to Stereoacuity and the Pulfrich Effect

PubMed Central

Read, Jenny C. A.; Cumming, Bruce G.

2006-01-01

The temporal properties of disparity-sensitive neurons place important temporal constraints on stereo matching. We examined these constraints by measuring the responses of disparity-selective neurons in striate cortex of awake behaving monkeys to random-dot stereograms that contained interocular delays. Disparity selectivity was gradually abolished by increasing interocular delay (when the delay exceeds the integration time, the inputs from the 2 eyes become uncorrelated). The amplitude of the disparity-selective response was a Gaussian function of interocular delay, with a mean of 16 ms (±5 ms, SD). Psychophysical measures of stereoacuity, in both monkey and human observers, showed a closely similar dependency on time, suggesting that temporal integration in V1 neurons is what determines psychophysical matching constraints over time. There was a slight but consistent asymmetry in the neuronal responses, as if the optimum stimulus is one in which the right stimulus leads by about 4 ms. Because all recordings were made in the left hemisphere, this probably reflects nasotemporal differences in conduction times; psychophysical data are compatible with this interpretation. In only a few neurons (5/72), interocular delay caused a change in the preferred disparity. Such tilted disparity/delay profiles have been invoked previously to explain depth perception in the stroboscopic version of the Pulfrich effect (and other variants). However, the great majority of the neurons did not show tilted disparity/delay profiles. This suggests that either the activity of these neurons is ignored when viewing Pulfrich stimuli, or that current theories relating neuronal properties to perception in the Pulfrich effect need to be reevaluated. PMID:15788521

Visual functions and interocular interactions in anisometropic children with and without amblyopia.

PubMed

Lai, Xin Jie; Alexander, Jack; He, Mingguang; Yang, Zhikuan; Suttle, Catherine

2011-08-29

In uncorrected anisometropia, protracted dichoptic stimulation may result in interocular inhibition, which may be a contributing factor in amblyopia development. This study investigates the relationship between interocular interactions and anisometropic amblyopia. Three visual functions (low-contrast acuity, contrast sensitivity, and alignment sensitivity) were measured in the nondominant eye of 44 children aged 5 to 11 years: 10 with normal vision, 17 with anisometropia without amblyopia, and 17 with anisometropic amblyopia. The dominant eye was either fully or partially occluded. The difference in nondominant eye visual function between the full-and partial-occlusion conditions was termed the interaction index. The index of each visual function was compared between subject groups. A higher index indicates stronger inhibition of nondominant eye function with partial occlusion of the dominant eye. Amblyopic children had 6 months of therapy (refractive correction and occlusion), and the reduction in interocular difference in high-contrast acuity was regarded as the treatment outcome. The relationships of the interaction index with the degree of anisometropia, the severity of amblyopia, and the treatment outcomes were examined. The acuity interaction index was significantly higher in anisometropic children with amblyopia than in those without (P = 0.003). It was positively correlated with the degree of anisometropia (r(s) = 0.35, P = 0.042) and the amblyopic treatment outcomes (r(s) = 0.54, P = 0.038). No such difference or association was found between the contrast sensitivity or alignment sensitivity interaction index and anisometropic amblyopia. Interocular interactions are associated with amblyopia, the degree of anisometropia, and amblyopia treatment outcomes, but these associations are visual function dependent.

Contrast-balanced binocular treatment in children with deprivation amblyopia.

PubMed

Hamm, Lisa M; Chen, Zidong; Li, Jinrong; Dai, Shuan; Black, Joanna; Yuan, Junpeng; Yu, Minbin; Thompson, Benjamin

2017-11-28

Children with deprivation amblyopia due to childhood cataract have been excluded from much of the emerging research into amblyopia treatment. An investigation was conducted to determine whether contrast-balanced binocular treatment - a strategy currently being explored for children with anisometropic and strabismic amblyopia - may be effective in children with deprivation amblyopia. An unmasked, case-series design intended to assess proof of principle was employed. Eighteen children with deprivation amblyopia due to childhood cataracts (early bilateral n = 7, early unilateral n = 7, developmental n = 4), as well as 10 children with anisometropic (n = 8) or mixed anisometropic and strabismic amblyopia (n = 2) were prescribed one hour a day of treatment over a six-week period. Supervised treatment was available. Visual acuity, contrast sensitivity, global motion perception and interocular suppression were measured pre- and post-treatment. Visual acuity improvements occurred in the anisometropic/strabismic group (0.15 ± 0.05 logMAR, p = 0.014), but contrast sensitivity did not change. As a group, children with deprivation amblyopia had a smaller but statistically significant improvement in weaker eye visual acuity (0.09 ± 0.03 logMAR, p = 0.004), as well a significant improvement in weaker eye contrast sensitivity (p = 0.004). Subgroup analysis suggested that the children with early bilateral deprivation had the largest improvements, while children with early unilateral cataract did not improve. Interestingly, binocular contrast sensitivity also improved in children with early bilateral deprivation. Global motion perception improved for both subgroups with early visual deprivation, as well as children with anisometropic or mixed anisometropic/strabismic amblyopia. Interocular suppression improved for all subgroups except children with early unilateral deprivation. These data suggest that supervised contrast-balanced binocular treatment should be further investigated as a treatment option for children with deprivation amblyopia. However, for children with more severe deprivation amblyopia due to early unilateral cataracts, supplementary or alternative options should also be explored. © 2017 Optometry Australia.

Anisometropia of ocular refractive and biometric measures among 66- to 79-year-old female twins.

PubMed

Pärssinen, Olavi; Kauppinen, Markku; Kaprio, Jaakko; Rantanen, Taina

2016-12-01

To examine the prevalence of anisometropia of spherical refraction (AnisoSR), astigmatism (AnisoAST) and spherical equivalent (AnisoSE) and their associations with spherical refraction (SR), refractive astigmatism (AST), spherical equivalent (SE) and interocular differences of ocular biometric parameters among elderly female twins. Refraction of 117 monozygotic (MZ) and 116 dizygotic (DZ) female twin subjects aged 66-79 years was assessed with an auto-refractor (Topcon AT) and controlled by subjective refraction. Corneal refraction, anterior chamber depth and axial length were measured with a Zeiss IOL Master. Participants with eyes operated for cataract or glaucoma were excluded, but the grade of nuclear opacity was not recorded. The associations between the absolute values of AnisoSR, AnisoAST and AnisoSE with SR, AST, SE, corneal refractive power (CR), corneal astigmatism (CAST), anterior chamber depth (ACD) and axial length (AL) and with their interocular differences were calculated. When calculating the interdependencies of the differences, the real and absolute differences between the right and left eye were used. Means ± standard deviations for AnisoSR, AnisoAST and AnisoSE were 0.67 ± 0.92 D, 0.42 ± 0.41 D and 0.65 ± 0.71 D, respectively. AnisoSR, AnisoAST and AnisoSE >1.0 D were present in 14.7%, 4.2% and 17.7% of cases, respectively. Anisometropia of spherical refraction (AnisoSR), AnisoAST and AnisoSE were higher the more negative the values of SR or SE. Hyperopic ametropia did not increase these anisometropia values. The correlations of AnisoSR and AnisoSE with the absolute values of interocular differences in CR and AL were non-significant. Using the real values of the interocular differences, the respective correlations were significant. The correlation between the real interocular differences in CR and AL was negative (r = -0.258, p < 0.001). Thus, the combined effect of the real interocular differences in CR and AL was a decrease in AnisoSR and AnisoSE (emmetropization). Higher AnisoSR and AnisoSE were associated with more myopic refraction and longer AL. Higher AnisoAST was associated with more negative SR and higher AST and CAST. The negative correlation between real interocular differences in CR and AL indicated their influence of emmetropization in AnisoSR and AnisoSE. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia

PubMed Central

Kelly, Krista R.; Jost, Reed M.; Wang, Yi-Zhong; Dao, Lori; Beauchamp, Cynthia L.; Leffler, Joel N.; Birch, Eileen E.

2018-01-01

Purpose Childhood amblyopia can be treated with binocular games or movies that rebalance contrast between the eyes, which is thought to reduce depth of interocular suppression so the child can experience binocular vision. While visual acuity gains have been reported following binocular treatment, studies rarely report gains in binocular outcomes (i.e., stereoacuity, suppression) in amblyopic children. Here, we evaluated binocular outcomes in children who had received binocular treatment for childhood amblyopia. Methods Data for amblyopic children enrolled in two ongoing studies were pooled. The sample included 41 amblyopic children (6 strabismic, 21 anisometropic, 14 combined; age 4–10 years; ≤4 prism diopters [PD]) who received binocular treatment (20 game, 21 movies; prescribed 9–10 hours treatment). Amblyopic eye visual acuity and binocular outcomes (Randot Preschool Stereoacuity, extent of suppression, and depth of suppression) were assessed at baseline and at 2 weeks. Results Mean amblyopic eye visual acuity (P < 0.001) and mean stereoacuity improved (P = 0.045), and mean extent (P = 0.005) and depth of suppression (P = 0.003) were reduced from baseline at the 2-week visit (87% game adherence, 100% movie adherence). Depth of suppression was reduced more in children aged <8 years than in those aged ≥8 years (P = 0.004). Worse baseline depth of suppression was correlated with a larger depth of suppression reduction at 2 weeks (P = 0.001). Conclusions After 2 weeks, binocular treatment in amblyopic children improved visual acuity and binocular outcomes, reducing the extent and depth of suppression and improving stereoacuity. Binocular treatments that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia. PMID:29625442

Neuronal responses in visual area V2 (V2) of macaque monkeys with strabismic amblyopia.

PubMed

Bi, H; Zhang, B; Tao, X; Harwerth, R S; Smith, E L; Chino, Y M

2011-09-01

Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia.

Neuronal Responses in Visual Area V2 (V2) of Macaque Monkeys with Strabismic Amblyopia

PubMed Central

Bi, H.; Zhang, B.; Tao, X.; Harwerth, R. S.; Smith, E. L.

2011-01-01

Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia. PMID:21263036

Activity in early visual areas predicts interindividual differences in binocular rivalry dynamics

PubMed Central

Yamashiro, Hiroyuki; Mano, Hiroaki; Umeda, Masahiro; Higuchi, Toshihiro; Saiki, Jun

2013-01-01

When dissimilar images are presented to the two eyes, binocular rivalry (BR) occurs, and perception alternates spontaneously between the images. Although neural correlates of the oscillating perception during BR have been found in multiple sites along the visual pathway, the source of BR dynamics is unclear. Psychophysical and modeling studies suggest that both low- and high-level cortical processes underlie BR dynamics. Previous neuroimaging studies have demonstrated the involvement of high-level regions by showing that frontal and parietal cortices responded time locked to spontaneous perceptual alternation in BR. However, a potential contribution of early visual areas to BR dynamics has been overlooked, because these areas also responded to the physical stimulus alternation mimicking BR. In the present study, instead of focusing on activity during perceptual switches, we highlighted brain activity during suppression periods to investigate a potential link between activity in human early visual areas and BR dynamics. We used a strong interocular suppression paradigm called continuous flash suppression to suppress and fluctuate the visibility of a probe stimulus and measured retinotopic responses to the onset of the invisible probe using functional MRI. There were ∼130-fold differences in the median suppression durations across 12 subjects. The individual differences in suppression durations could be predicted by the amplitudes of the retinotopic activity in extrastriate visual areas (V3 and V4v) evoked by the invisible probe. Weaker responses were associated with longer suppression durations. These results demonstrate that retinotopic representations in early visual areas play a role in the dynamics of perceptual alternations during BR. PMID:24353304

Alterations in audiovisual simultaneity perception in amblyopia

PubMed Central

2017-01-01

Amblyopia is a developmental visual impairment that is increasingly recognized to affect higher-level perceptual and multisensory processes. To further investigate the audiovisual (AV) perceptual impairments associated with this condition, we characterized the temporal interval in which asynchronous auditory and visual stimuli are perceived as simultaneous 50% of the time (i.e., the AV simultaneity window). Adults with unilateral amblyopia (n = 17) and visually normal controls (n = 17) judged the simultaneity of a flash and a click presented with both eyes viewing. The signal onset asynchrony (SOA) varied from 0 ms to 450 ms for auditory-lead and visual-lead conditions. A subset of participants with amblyopia (n = 6) was tested monocularly. Compared to the control group, the auditory-lead side of the AV simultaneity window was widened by 48 ms (36%; p = 0.002), whereas that of the visual-lead side was widened by 86 ms (37%; p = 0.02). The overall mean window width was 500 ms, compared to 366 ms among controls (37% wider; p = 0.002). Among participants with amblyopia, the simultaneity window parameters were unchanged by viewing condition, but subgroup analysis revealed differential effects on the parameters by amblyopia severity, etiology, and foveal suppression status. Possible mechanisms to explain these findings include visual temporal uncertainty, interocular perceptual latency asymmetry, and disruption of normal developmental tuning of sensitivity to audiovisual asynchrony. PMID:28598996

Alterations in audiovisual simultaneity perception in amblyopia.

PubMed

Richards, Michael D; Goltz, Herbert C; Wong, Agnes M F

2017-01-01

Amblyopia is a developmental visual impairment that is increasingly recognized to affect higher-level perceptual and multisensory processes. To further investigate the audiovisual (AV) perceptual impairments associated with this condition, we characterized the temporal interval in which asynchronous auditory and visual stimuli are perceived as simultaneous 50% of the time (i.e., the AV simultaneity window). Adults with unilateral amblyopia (n = 17) and visually normal controls (n = 17) judged the simultaneity of a flash and a click presented with both eyes viewing. The signal onset asynchrony (SOA) varied from 0 ms to 450 ms for auditory-lead and visual-lead conditions. A subset of participants with amblyopia (n = 6) was tested monocularly. Compared to the control group, the auditory-lead side of the AV simultaneity window was widened by 48 ms (36%; p = 0.002), whereas that of the visual-lead side was widened by 86 ms (37%; p = 0.02). The overall mean window width was 500 ms, compared to 366 ms among controls (37% wider; p = 0.002). Among participants with amblyopia, the simultaneity window parameters were unchanged by viewing condition, but subgroup analysis revealed differential effects on the parameters by amblyopia severity, etiology, and foveal suppression status. Possible mechanisms to explain these findings include visual temporal uncertainty, interocular perceptual latency asymmetry, and disruption of normal developmental tuning of sensitivity to audiovisual asynchrony.

Interocular high-order corneal wavefront aberration symmetry

NASA Astrophysics Data System (ADS)

Lombardo, Marco; Lombardo, Giuseppe; Serrao, Sebastiano

2006-04-01

The interocular symmetry of the high-order corneal wavefront aberration (WA) in a population of myopic eyes was analyzed before and after photorefractive keratectomy (PRK). The preoperative and one-year postoperative corneal aberration data (from third to seventh Zernike orders) for 4- and 7-mm pupils from right and left eyes were averaged after correcting for the effects of enantiomorphism to test for mirror symmetry. Also, the mean corneal point-spread function (PSF) for right and left eyes was calculated. Preoperatively, a moderate and high degree of correlation in the high-order corneal WA between eyes was found for 4- and 7-mm pupils, respectively. Myopic PRK did not significantly change the interocular symmetry of corneal high-order aberrations. No discernible differences in the orientation PSF between eyes were observed one year after surgery in comparison with the preoperative state over the two analyzed pupils.

A compact clinical instrument for quantifying suppression.

PubMed

Black, Joanne M; Thompson, Benjamin; Maehara, Goro; Hess, Robert F

2011-02-01

We describe a compact and convenient clinical apparatus for the measurement of suppression based on a previously reported laboratory-based approach. In addition, we report and validate a novel, rapid psychophysical method for measuring suppression using this apparatus, which makes the technique more applicable to clinical practice. By using a Z800 dual pro head-mounted display driven by a MAC laptop, we provide dichoptic stimulation. Global motion stimuli composed of arrays of moving dots are presented to each eye. One set of dots move in a coherent direction (termed signal) whereas another set of dots move in a random direction (termed noise). To quantify performance, we measure the signal/noise ratio corresponding to a direction-discrimination threshold. Suppression is quantified by assessing the extent to which it matters which eye sees the signal and which eye sees the noise. A space-saving, head-mounted display using current video technology offers an ideal solution for clinical practice. In addition, our optimized psychophysical method provided results that were in agreement with those produced using the original technique. We made measures of suppression on a group of nine adult amblyopic participants using this apparatus with both the original and new psychophysical paradigms. All participants had measurable suppression ranging from mild to severe. The two different psychophysical methods gave a strong correlation for the strength of suppression (rho = -0.83, p = 0.006). Combining the new apparatus and new psychophysical method creates a convenient and rapid technique for parametric measurement of interocular suppression. In addition, this apparatus constitutes the ideal platform for suppressors to combine information between their eyes in a similar way to binocularly normal people. This provides a convenient way for clinicians to implement the newly proposed binocular treatment of amblyopia that is based on antisuppression training.

Psychophysical "blinding" methods reveal a functional hierarchy of unconscious visual processing.

PubMed

Breitmeyer, Bruno G

2015-09-01

Numerous non-invasive experimental "blinding" methods exist for suppressing the phenomenal awareness of visual stimuli. Not all of these suppressive methods occur at, and thus index, the same level of unconscious visual processing. This suggests that a functional hierarchy of unconscious visual processing can in principle be established. The empirical results of extant studies that have used a number of different methods and additional reasonable theoretical considerations suggest the following tentative hierarchy. At the highest levels in this hierarchy is unconscious processing indexed by object-substitution masking. The functional levels indexed by crowding, the attentional blink (and other attentional blinding methods), backward pattern masking, metacontrast masking, continuous flash suppression, sandwich masking, and single-flash interocular suppression, fall at progressively lower levels, while unconscious processing at the lowest levels is indexed by eye-based binocular-rivalry suppression. Although unconscious processing levels indexed by additional blinding methods is yet to be determined, a tentative placement at lower levels in the hierarchy is also given for unconscious processing indexed by Troxler fading and adaptation-induced blindness, and at higher levels in the hierarchy indexed by attentional blinding effects in addition to the level indexed by the attentional blink. The full mapping of levels in the functional hierarchy onto cortical activation sites and levels is yet to be determined. The existence of such a hierarchy bears importantly on the search for, and the distinctions between, neural correlates of conscious and unconscious vision. Copyright © 2015 Elsevier Inc. All rights reserved.

Frequency-doubling technology perimetry and multifocal visual evoked potential in glaucoma, suspected glaucoma, and control patients

PubMed Central

Kanadani, Fabio N; Mello, Paulo AA; Dorairaj, Syril K; Kanadani, Tereza CM

2014-01-01

Introduction The gold standard in functional glaucoma evaluation is standard automated perimetry (SAP). However, SAP depends on the reliability of the patients’ responses and other external factors; therefore, other technologies have been developed for earlier detection of visual field changes in glaucoma patients. The frequency-doubling perimetry (FDT) is believed to detect glaucoma earlier than SAP. The multifocal visual evoked potential (mfVEP) is an objective test for functional evaluation. Objective To evaluate the sensitivity and specificity of FDT and mfVEP tests in normal, suspect, and glaucomatous eyes and compare the monocular and interocular mfVEP. Methods Ninety-five eyes from 95 individuals (23 controls, 33 glaucoma suspects, 39 glaucomatous) were enrolled. All participants underwent a full ophthalmic examination, followed by SAP, FDT, and mfVEP tests. Results The area under the curve for mean deviation and pattern standard deviation were 0.756 and 0.761, respectively, for FDT, 0.564 and 0.512 for signal and alpha for interocular mfVEP, and 0.568 and 0.538 for signal and alpha for monocular mfVEP. This difference between monocular and interocular mfVEP was not significant. Conclusion The FDT Matrix was superior to mfVEP in glaucoma detection. The difference between monocular and interocular mfVEP in the diagnosis of glaucoma was not significant. PMID:25075173

Differential effects of black currant anthocyanins on diffuser- or negative lens-induced ocular elongation in chicks.

PubMed

Iida, Hiroyuki; Nakamura, Yuko; Matsumoto, Hitoshi; Kawahata, Keiko; Koga, Jinichiro; Katsumi, Osamu

2013-01-01

To compare the inhibitory effects of 4 different types of black currant anthocyanins (BCAs) on ocular elongation in 2 different chick myopia models. In the first model, diffusers were used to induce form vision deprivation. In the second model, negative (-8D) spherical lenses were used to create a defocused retinal image. Either the diffusers or the -8D lenses were placed on the right eyes of 8-day-old chicks for 4 days. Ocular biometric components were measured using an A-scan ultrasound instrument on the third day after application of either the diffusers or -8D lenses. Interocular differences (globe component dimensions of the right diffuser or eyes covered with -8D lenses minus those of the open left eyes) were considered to evaluate the effect of BCAs. The BCAs used were cyanidin-3-glucoside (C3G), cyanidin-3-rutinoside (C3R), delphinidin-3-rutinoside (D3R), and delphinidin-3-glucoside (D3G). Each anthocyanin was administered intravenously at a dose of 0.027 μmol/kg once a day for 3 days. Compared to the vehicle treatment, C3G and C3R treatments significantly reduced both differential increases (positive values of interocular differences) of the ocular axial length induced by diffusers or -8D lenses (diffusers; C3G, C3R, and control: 0.32±0.051 mm, P<0.05; 0.25±0.034 mm, P<0.01; and 0.52±0.047 mm, -8D lenses; C3G, C3R, and control: 0.25±0.049 mm, P<0.01; 0.17±0.049 mm, P<0.001; and 0.50±0.056 mm). In contrast, compared to vehicle treatment, D3R treatment significantly decreased the differential increases in the ocular axial length only in chicks with myopia induced by -8D lenses (D3R and control: 0.17±0.049 mm and 0.50±0.056 mm, P<0.001). D3G did not inhibit the differential increase in the ocular axial length induced by either diffusers or -8D lenses. This study showed that the 4 tested BCAs had different effects on the 2 different experimental models of myopia.

Anisometropia of spherical equivalent and astigmatism among myopes: a 23-year follow-up study of prevalence and changes from childhood to adulthood.

PubMed

Pärssinen, Olavi; Kauppinen, Markku

2017-08-01

To study anisometropia of spherical equivalent and astigmatism from the onset of myopia at school age to adulthood. A total of 240 myopic schoolchildren (mean age 10.9 years), with no previous spectacles, were recruited during 1983-1984 to a randomized 3-year clinical trial of bifocal treatment of myopia. Examinations with subjective cyclopedic refraction were repeated 3 years later (follow-up 1) for 238 subjects and thereafter at the mean ages of 23.2 (follow-up 2) and 33.9 years (follow-up 3) for 178 and 134 subjects. After exclusions, the 102 subjects who attended all three follow-ups were included in the analyses. Corneal refractive power and astigmatism and anterior chamber depth was measured with Pentacam topography and axial length with IOL master at study end. Prevalence and changes in anisometropia of spherical equivalent (AnisoSE) and astigmatism (AnisoAST) and their relationships with refractive and axial measures were studied. Mean (±SD) of spherical equivalent (SE), AnisoSE and AnisoAST increased from baseline to follow-up end from -1.44 ± 0.57 D to -5.11 ± 2.23 D, from 0.28 ± 0.30 D to 0.68 ± 0.69 D and from 0.14 ± 0.18 D to 0.37 ± 0.36 D, respectively. Prevalence of AnioSE, ≥1 D, increased from 5% to 22.6% throughout follow-up. Higher AnisoSE was associated with SE in the less myopic eye at baseline and at follow-up 1, and with SE in the more myopic eye in follow-ups 2 and 3 in adulthood. At study end, AnisoSE was associated with the interocular difference in axial length (AL) (r = 0.612, p < 0.001) but not with the interocular difference in corneal refraction (CR) (r = -0.122, p = 0.266). In cases of low AnisoSE(≤1.00 D), the negative correlation between the real interocular differences (value of right eye minus value of left eye) in CR and AL (r = -0.427, p < 0.001) decreased the influence of the interocular difference in AL on AnisoSE, causing emmetropization in AnisoSE. The interocular difference in corneal astigmatism was the main factor associated with AnisoAST (r = 0.231, p = 0.020). No significant relationship was found between AnisoAST and level of SE. Anisometropia of the spherical equivalent (AnisoSE) increased along with the myopic progression and at study end was mainly associated with the interocular difference in AL. AnisoAST was mainly explained by the interocular difference in corneal astigmatism. In cases with low AnisoSE (≤1.0 D), the interrelationship between CR and AL decreased AnisoSE causing emmetropization in AnisoSE. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

More superimposition for contrast-modulated than luminance-modulated stimuli during binocular rivalry.

PubMed

Skerswetat, Jan; Formankiewicz, Monika A; Waugh, Sarah J

2018-01-01

Luminance-modulated noise (LM) and contrast-modulated noise (CM) gratings were presented with interocularly correlated, uncorrelated and anti-correlated binary noise to investigate their contributions to mixed percepts, specifically piecemeal and superimposition, during binocular rivalry. Stimuli were sine-wave gratings of 2 c/deg presented within 2 deg circular apertures. The LM stimulus contrast was 0.1 and the CM stimulus modulation depth was 1.0, equating to approximately 5 and 7 times detection threshold, respectively. Twelve 45 s trials, per noise configuration, were carried out. Fifteen participants with normal vision indicated via button presses whether an exclusive, piecemeal or superimposed percept was seen. For all noise conditions LM stimuli generated more exclusive visibility, and lower proportions of superimposition. CM stimuli led to greater proportions and longer periods of superimposition. For both stimulus types, correlated interocular noise generated more superimposition than did anti- or uncorrelated interocular noise. No significant effect of stimulus type (LM vs CM) or noise configuration (correlated, uncorrelated, anti-correlated) on piecemeal perception was found. Exclusive visibility was greater in proportion, and perceptual changes more numerous, during binocular rivalry for CM stimuli when interocular noise was not correlated. This suggests that mutual inhibition, initiated by non-correlated noise CM gratings, occurs between neurons processing luminance noise (first-order component), as well as those processing gratings (second-order component). Therefore, first- and second-order components can contribute to overall binocular rivalry responses. We suggest the addition of a new well to the current energy landscape model for binocular rivalry that takes superimposition into account. Copyright © 2017 Elsevier Ltd. All rights reserved.

Monocular deprivation of Fourier phase information boosts the deprived eye's dominance during interocular competition but not interocular phase combination.

PubMed

Bai, Jianying; Dong, Xue; He, Sheng; Bao, Min

2017-06-03

Ocular dominance has been extensively studied, often with the goal to understand neuroplasticity, which is a key characteristic within the critical period. Recent work on monocular deprivation, however, demonstrates residual neuroplasticity in the adult visual cortex. After deprivation of patterned inputs by monocular patching, the patched eye becomes more dominant. Since patching blocks both the Fourier amplitude and phase information of the input image, it remains unclear whether deprivation of the Fourier phase information alone is able to reshape eye dominance. Here, for the first time, we show that removing of the phase regularity without changing the amplitude spectra of the input image induced a shift of eye dominance toward the deprived eye, but only if the eye dominance was measured with a binocular rivalry task rather than an interocular phase combination task. These different results indicate that the two measurements are supported by different mechanisms. Phase integration requires the fusion of monocular images. The fused percept highly relies on the weights of the phase-sensitive monocular neurons that respond to the two monocular images. However, binocular rivalry reflects the result of direct interocular competition that strongly weights the contour information transmitted along each monocular pathway. Monocular phase deprivation may not change the weights in the integration (fusion) mechanism much, but alters the balance in the rivalry (competition) mechanism. Our work suggests that ocular dominance plasticity may occur at different stages of visual processing, and that homeostatic compensation also occurs for the lack of phase regularity in natural scenes. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Latent stereopsis for motion in depth in strabismic amblyopia.

PubMed

Hess, Robert F; Mansouri, Behzad; Thompson, Benjamin; Gheorghiu, Elena

2009-10-01

To investigate the residual stereo function of a group of 15 patients with strabismic amblyopia, by using motion-in-depth stimuli that allow discrimination of contributions from local disparity as opposed to those from local velocity mechanisms as a function of the rate of depth change. The stereo performance (percentage correct) was measured as a function of the rate of depth change for dynamic random dot stimuli that were either temporally correlated or uncorrelated. Residual stereoscopic function was demonstrated for motion in depth based on local disparity information in 2 of the 15 observers with strabismic amblyopia. The use of a neutral-density (ND) filter in front of the fixing eye enhanced motion-in-depth performance in four subjects randomly selected from the group that originally displayed only chance performance. This finding was true across temporal rate and for correlated and uncorrelated stimuli, suggesting that it was disparity based. The opposite occurred in a group of normal subjects. In a separate experiment, the hypothesis was that the beneficial effect of the ND filter is due to its contrast and/or mean luminance-reducing effects rather than any interocular time delay that it may introduce and that it is specific to motion-in-depth performance, as similar improvements were not found for static stereopsis. A small proportion of observers with strabismic amblyopia exhibit residual performance for motion in depth, and it is disparity based. Furthermore, some observers with strabismic amblyopia who do not display any significant stereo performance for motion in depth under normal binocular viewing may display above-chance stereo performance if the degree of interocular suppression is reduced. The authors term this phenomenon latent stereopsis.

Brightness discrimination and contrast sensitivity in chronic glaucoma--a clinical study.

PubMed

Teoh, S L; Allan, D; Dutton, G N; Foulds, W S

1990-04-01

The visual acuity, the difference in sensitivity of the two eyes to light (brightness ratio), and contrast sensitivity were assessed in 28 patients with chronic open angle glaucoma and compared with those of 41 normal controls of similar ages and visual acuity. The results obtained were related to the results of Tübingen visual field analysis in patients with glaucoma. Twenty-four of the 28 glaucoma patients (86%) had a significant disparity in brightness ratio between the two eyes. This was found to match the frequency of visual field loss. Moreover, there was a significant relationship between the interocular differences in brightness sense and the difference in the degree of visual field loss between the two eyes. Of the glaucoma patients 39% had sum contrast sensitivities outside the normal range for age-matched normal controls. No significant correlation was found between the interocular difference in brightness sense and the visual acuity or the interocular difference in sum contrast sensitivity. It is concluded that, in the presence of a normal visual acuity, the brightness ratio test warrants evaluation as a potential screening test for chronic open angle glaucoma.

Decreased cortical activation in response to a motion stimulus in anisometropic amblyopic eyes using functional magnetic resonance imaging.

PubMed

Bonhomme, Gabrielle R; Liu, Grant T; Miki, Atsushi; Francis, Ellie; Dobre, M-C; Modestino, Edward J; Aleman, David O; Haselgrove, John C

2006-12-01

Motion perception abnormalities and extrastriate abnormalities have been suggested in amblyopia. Functional MRI (fMRI) and motion stimuli were used to study whether interocular differences in activation are detectable in motion-sensitive cortical areas in patients with anisometropic amblyopia. We performed fMRI at 1.5 T 4 control subjects (20/20 OU), 1 with monocular suppression (20/25), and 2 with anisometropic amblyopia (20/60, 20/800). Monocular suppression was thought to be form fruste of amblyopia. The experimental stimulus consisted of expanding and contracting concentric rings, whereas the control condition consisted of stationary concentric rings. Activation was determined by contrasting the 2 conditions for each eye. Significant fMRI activation and comparable right and left eye activation was found in V3a and V5 in all control subjects (Average z-values in L vs R contrast 0.42, 0.43) and in the subject with monocular suppression (z = 0.19). The anisometropes exhibited decreased extrastriate activation in their amblyopic eyes compared with the fellow eyes (zs = 2.12, 2.76). Our data suggest motion-sensitive cortical structures may be less active when anisometropic amblyopic eyes are stimulated with moving rings. These results support the hypothesis that extrastriate cortex is affected in anisometropic amblyopia. Although suggestive of a magnocellular defect, the exact mechanism is unclear.

Emotion colors time perception unconsciously.

PubMed

Yamada, Yuki; Kawabe, Takahiro

2011-12-01

Emotion modulates our time perception. So far, the relationship between emotion and time perception has been examined with visible emotional stimuli. The present study investigated whether invisible emotional stimuli affected time perception. Using continuous flash suppression, which is a kind of dynamic interocular masking, supra-threshold emotional pictures were masked or unmasked depending on whether the retinal position of continuous flashes on one eye was consistent with that of the pictures on the other eye. Observers were asked to reproduce the perceived duration of a frame stimulus that was concurrently presented with a masked or unmasked emotional picture. As a result, negative emotional stimuli elongated the perceived duration of the frame stimulus in comparison with positive and neutral emotional stimuli, regardless of the visibility of emotional pictures. These results suggest that negative emotion unconsciously accelerates an internal clock, altering time perception. Copyright © 2011 Elsevier Inc. All rights reserved.

Time course of dichoptic masking in normals and suppression in amblyopes.

PubMed

Zhou, Jiawei; McNeal, Suzanne; Babu, Raiju J; Baker, Daniel H; Bobier, William R; Hess, Robert F

2014-04-17

To better understand the relationship between dichoptic masking in normal vision and suppression in amblyopia we address three questions: First, what is the time course of dichoptic masking in normals and amblyopes? Second, is interocular suppression low-pass or band-pass in its spatial dependence? And third, in the above two regards, is dichoptic masking in normals different from amblyopic suppression? We measured the dependence of dichoptic masking in normal controls and amblyopes on the temporal duration of presentation under three conditions; monocular (the nontested eye-i.e., dominant eye of normals or nonamblyopic eye of amblyopes, being patched), dichoptic-luminance (the nontested eye seeing a mean luminance-i.e., a DC component) and dichoptic-contrast (the nontested eye seeing high-contrast visual noise). The subject had to detect a letter in the other eye, the contrast of which was varied. We found that threshold elevation relative to the patched condition occurred in both normals and amblyopes when the nontested eye saw either 1/f or band-pass filtered noise, but not just mean luminance (i.e., there was no masking from the DC component that corresponds to a channel responsive to a spatial frequency of 0 cyc/deg); longer presentation of the target (corresponding to lower temporal frequencies) produced greater threshold elevation. Dichoptic masking exhibits similar properties in both subject groups, being low-pass temporally and band-pass spatially, so that masking was greatest at the longest presentation durations and was not greatly affected by mean luminance in the nontested eye. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Interocular transfer of spatial adaptation is weak at low spatial frequencies.

PubMed

Baker, Daniel H; Meese, Tim S

2012-06-15

Adapting one eye to a high contrast grating reduces sensitivity to similar target gratings shown to the same eye, and also to those shown to the opposite eye. According to the textbook account, interocular transfer (IOT) of adaptation is around 60% of the within-eye effect. However, most previous studies on this were limited to using high spatial frequencies, sustained presentation, and criterion-dependent methods for assessing threshold. Here, we measure IOT across a wide range of spatiotemporal frequencies, using a criterion-free 2AFC method. We find little or no IOT at low spatial frequencies, consistent with other recent observations. At higher spatial frequencies, IOT was present, but weaker than previously reported (around 35%, on average, at 8c/deg). Across all conditions, monocular adaptation raised thresholds by around a factor of 2, and observers showed normal binocular summation, demonstrating that they were not binocularly compromised. These findings prompt a reassessment of our understanding of the binocular architecture implied by interocular adaptation. In particular, the output of monocular channels may be available to perceptual decision making at low spatial frequencies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Brightness discrimination and contrast sensitivity in chronic glaucoma--a clinical study.

PubMed Central

Teoh, S L; Allan, D; Dutton, G N; Foulds, W S

1990-01-01

The visual acuity, the difference in sensitivity of the two eyes to light (brightness ratio), and contrast sensitivity were assessed in 28 patients with chronic open angle glaucoma and compared with those of 41 normal controls of similar ages and visual acuity. The results obtained were related to the results of Tübingen visual field analysis in patients with glaucoma. Twenty-four of the 28 glaucoma patients (86%) had a significant disparity in brightness ratio between the two eyes. This was found to match the frequency of visual field loss. Moreover, there was a significant relationship between the interocular differences in brightness sense and the difference in the degree of visual field loss between the two eyes. Of the glaucoma patients 39% had sum contrast sensitivities outside the normal range for age-matched normal controls. No significant correlation was found between the interocular difference in brightness sense and the visual acuity or the interocular difference in sum contrast sensitivity. It is concluded that, in the presence of a normal visual acuity, the brightness ratio test warrants evaluation as a potential screening test for chronic open angle glaucoma. PMID:2186795

Effects of unilateral topical atropine on binocular pupil responses and eye growth in mice.

PubMed

Barathi, V A; Beuerman, Roger W; Schaeffel, Frank

2009-02-01

Studies on drugs selected to target myopia development often use the vehicle-treated fellow eye as a control. However, it is not clear how much of the drug reaches the fellow eye, rendering it a potentially invalid control. Therefore, in this study, pupil responses were used to probe the effects of atropine in both eyes in mice, after unilateral topical application. In a second experiment, interocular differences in refractive development and axial eye growth were studied while atropine was applied daily to one eye. In 20 C57BL/6 (B6) wildtype mice, a single drop of 1% atropine solution was instilled into one eye. Mice were gently restrained by holding their necks while video image processing software detected the pupil and measured its diameter at a sampling rate of 30 Hz. A bright green LED, attached to the photoretinoscope of the video camera, was flashed. Pupil responses were quantified daily over a period of 2 weeks. In another group of 24 mice, one drop of 1% atropine was applied daily for 28 days. Axial length was measured pre- and post-treatment, using low coherence interferometry (the Zeiss AC-Master). Refractive development was measured by infrared photorefraction. Similar to previous findings with the same device, untreated eyes displayed a pupil constriction of 24.84+/-1.73% upon stimulation with the green LED. A single drop of 1% atropine caused complete suppression with no significant recovery over the whole observation period of two weeks. The responses in the fellow eye were temporarily reduced to about 75% and then recovered towards baseline. After daily atropine application, there was significant reduction in axial length of the eyes, relative to the saline-treated fellow eyes (3.234+/-0.186 versus 3.378+/-0.176 mm, n=24, p<0.01, paired t-test) and the refractions became more hyperopic/less myopic (+13.46+/-2.15 D versus +10.06+/-2.02 D, n=24, p<0.01). In line with previous findings, one drop of atropine solution caused a long lasting suppression of pupil responses in the mouse eye. New data show that the transfer to the fellow eye was limited, making interocular comparisons feasible. It is also new that topical atropine reduced axial eye growth even when mice had largely normal vision.

Biased recognition of facial affect in patients with major depressive disorder reflects clinical state.

PubMed

Münkler, Paula; Rothkirch, Marcus; Dalati, Yasmin; Schmack, Katharina; Sterzer, Philipp

2015-01-01

Cognitive theories of depression posit that perception is negatively biased in depressive disorder. Previous studies have provided empirical evidence for this notion, but left open the question whether the negative perceptual bias reflects a stable trait or the current depressive state. Here we investigated the stability of negatively biased perception over time. Emotion perception was examined in patients with major depressive disorder (MDD) and healthy control participants in two experiments. In the first experiment subjective biases in the recognition of facial emotional expressions were assessed. Participants were presented with faces that were morphed between sad and neutral and happy expressions and had to decide whether the face was sad or happy. The second experiment assessed automatic emotion processing by measuring the potency of emotional faces to gain access to awareness using interocular suppression. A follow-up investigation using the same tests was performed three months later. In the emotion recognition task, patients with major depression showed a shift in the criterion for the differentiation between sad and happy faces: In comparison to healthy controls, patients with MDD required a greater intensity of the happy expression to recognize a face as happy. After three months, this negative perceptual bias was reduced in comparison to the control group. The reduction in negative perceptual bias correlated with the reduction of depressive symptoms. In contrast to previous work, we found no evidence for preferential access to awareness of sad vs. happy faces. Taken together, our results indicate that MDD-related perceptual biases in emotion recognition reflect the current clinical state rather than a stable depressive trait.

Suppression of metabolic activity caused by infantile strabismus and strabismic amblyopia in striate visual cortex of macaque monkeys.

PubMed

Wong, Agnes M F; Burkhalter, Andreas; Tychsen, Lawrence

2005-02-01

Suppression is a major sensorial abnormality in humans and monkeys with infantile strabismus. We previously reported evidence of metabolic suppression in the visual cortex of strabismic macaques, using the mitochondrial enzyme cytochrome oxidase as an anatomic label. The purpose of this study was to further elucidate alterations in cortical metabolic activity, with or without amblyopia. Six macaque monkeys were used in the experiments (four strabismic and two control). Three of the strabismic monkeys had naturally occurring, infantile strabismus (two esotropic, one exotropic). The fourth strabismic monkey had infantile microesotropia induced by alternating monocular occlusion in the first months of life. Ocular motor behaviors and visual acuity were tested after infancy in each animal, and development of stereopsis was recorded during infancy in one strabismic and one control monkey. Ocular dominance columns (ODCs) of the striate visual cortex (area V1) were labeled using cytochrome oxidase (CO) histochemistry alone, or CO in conjunction with an anterograde tracer ([H 3 ]proline or WGA-HRP) injected into one eye. Each of the strabismic monkeys showed inequalities of metabolic activity in ODCs of opposite ocularity, visible as rows of lighter CO staining, corresponding to ODCs of lower metabolic activity, alternating with rows of darker CO staining, corresponding to ODCs of higher metabolic activity. In monkeys who had infantile strabismus and unilateral amblyopia, lower metabolic activity was found in (suppressed) ODCs driven by the nondominant eye in each hemisphere. In monkeys who had infantile esotropia and alternating fixation (no amblyopia), metabolic activity was lower in ODCs driven by the ipsilateral eye in each hemisphere. The suppression included a monocular core zone at the center of ODCs and binocular border zones at the boundaries of ODCs. This suppression was not evident in the monocular lamina of the LGN, indicating an intracortical rather than subcortical mechanism. Suppression of metabolic activity in ODCs of V1 differs depending upon whether infantile strabismus is alternating or occurs in conjunction with unilateral amblyopia. Our findings reinforce the principle that unrepaired strabismus promotes abnormal competition in V1, observable as interocular suppression of ODCs.

Maturation of Binocular, Monocular Grating Acuity and of the Visual Interocular Difference in the First 2 Years of Life.

PubMed

Costa, Marcelo Fernandes; de Cássia Rodrigues Matos França, Valtenice; Barboni, Mirella Teles Salgueiro; Ventura, Dora Fix

2018-05-01

The sweep visual evoked potential method (sVEP) is a powerful tool for measurement of visual acuity in infants. Despite the applicability and reliability of the technique in measuring visual functions the understanding of sVEP acuity maturation and how interocular difference of acuity develops in early infancy, as well as the availability of normality ranges, are rare in the literature. We measured binocular and monocular sVEPS acuities in 481 healthy infants aged from birth to 24 months without ophthalmological diseases. Binocular sVEP acuity was significantly higher than monocular visual acuities for almost all ages. Maturation of monocular sVEP acuity showed 2 longer critical periods while binocular acuity showed three maturation periods in the same age range. We found a systematic variation of the mean interocular acuity difference (IAD) range according to age from 1.45 cpd at birth to 0.31 cpd at 24 months. An additional contribution was the determination of sVEP acuity norms for the entire age range. We conclude that binocular and monocular sVEP acuities have distinct growth curves reflecting different maturation profiles for each function. Differences in IAD range shorten according to age and they should be considered in using the sVEP acuity measurements for clinical diagnosis as amblyopia.

Clinical Assessment of Stereoacuity and 3-D Stereoscopic Entertainment

PubMed Central

Tidbury, Laurence P.; Black, Robert H.; O’Connor, Anna R.

2015-01-01

Abstract Background/Aims: The perception of compelling depth is often reported in individuals where no clinically measurable stereoacuity is apparent. We aim to investigate the potential cause of this finding by varying the amount of stereopsis available to the subject, and assessing their perception of depth viewing 3-D video clips and a Nintendo 3DS. Methods: Monocular blur was used to vary interocular VA difference, consequently creating 4 levels of measurable binocular deficit from normal stereoacuity to suppression. Stereoacuity was assessed at each level using the TNO, Preschool Randot®, Frisby, the FD2, and Distance Randot®. Subjects also completed an object depth identification task using the Nintendo 3DS, a static 3DTV stereoacuity test, and a 3-D perception rating task of 6 video clips. Results: As intraocular VA differences increased, stereoacuity of the 57 subjects (aged 16–62 years) decreased (eg, 110”, 280”, 340”, and suppression). The ability to correctly identify depth on the Nintendo 3DS remained at 100% until suppression of one eye occurred. The perception of a compelling 3-D effect when viewing the video clips was rated high until suppression of one eye occurred, where the 3-D effect was still reported as fairly evident. Conclusion: If an individual has any level of measurable stereoacuity, the perception of 3-D when viewing stereoscopic entertainment is present. The presence of motion in stereoscopic video appears to provide cues to depth, where static cues are not sufficient. This suggests there is a need for a dynamic test of stereoacuity to be developed, to allow fully informed patient management decisions to be made. PMID:26669421

Multifocal visual evoked responses to dichoptic stimulation using virtual reality goggles: Multifocal VER to dichoptic stimulation.

PubMed

Arvind, Hemamalini; Klistorner, Alexander; Graham, Stuart L; Grigg, John R

2006-05-01

Multifocal visual evoked potentials (mfVEPs) have demonstrated good diagnostic capabilities in glaucoma and optic neuritis. This study aimed at evaluating the possibility of simultaneously recording mfVEP for both eyes with dichoptic stimulation using virtual reality goggles and also to determine the stimulus characteristics that yield maximum amplitude. ten healthy volunteers were recruited and temporally sparse pattern pulse stimuli were presented dichoptically using virtual reality goggles. Experiment 1 involved recording responses to dichoptically presented checkerboard stimuli and also confirming true topographic representation by switching off specific segments. Experiment 2 involved monocular stimulation and comparison of amplitude with Experiment 1. In Experiment 3, orthogonally oriented gratings were dichoptically presented. Experiment 4 involved dichoptic presentation of checkerboard stimuli at different levels of sparseness (5.0 times/s, 2.5 times/s, 1.66 times/s and 1.25 times/s), where stimulation of corresponding segments of two eyes were separated by 16.7, 66.7,116.7 & 166.7 ms respectively. Experiment 1 demonstrated good traces in all regions and confirmed topographic representation. However, there was suppression of amplitude of responses to dichoptic stimulation by 17.9+/-5.4% compared to monocular stimulation. Experiment 3 demonstrated similar suppression between orthogonal and checkerboard stimuli (p = 0.08). Experiment 4 demonstrated maximum amplitude and least suppression (4.8%) with stimulation at 1.25 times/s with 166.7 ms separation between eyes. It is possible to record mfVEP for both eyes during dichoptic stimulation using virtual reality goggles, which present binocular simultaneous patterns driven by independent sequences. Interocular suppression can be almost eliminated by using a temporally sparse stimulus of 1.25 times/s with a separation of 166.7 ms between stimulation of corresponding segments of the two eyes.

[Examinations with the Cardiff Acuity Test].

PubMed

Gräf, M; Becker, R; Neff, A; Kaufmann, H

1996-08-01

Recently, a new preferential looking (PL) test has been presented for measuring visual acuity in infants and young children (Cardiff Acuity Test, CAT). The PL target is a schematic vanishing picture composed of isoluminant lines with different spatial orientations. Fifty-three healthy children (4-34 months, group 1), 28 (4-35 months) children at risk for amblyopia due to strabismus (group 2), 19 healthy subjects, and 157 patients (group 3) were tested with the CAT. In group 2 the CAT was compared with the fixation preference test. In group 3 the CAT was compared with a recognition test (Landolt C test). In group 1 the interocular difference of the CAT data was a maximum of 1 dB (70% 0 dB, 30% 1 dB, 1/3 so-called octave). Thus, an interocular difference of > 1 dB was considered to be suggestive of monocular or asymmetrical visual impairment. The maximum value 6/6 was frequently achieved (RE 44%, LE 36%, > 18 months RE 57%, LE 46%). In group 2 only 20% of the monolateral strabismic children showed an interocular difference > 1 dB in the CAT. In group 3 we found significant correlations between the CAT and Landolt acuity. A ratio of about 1.7/1 between CAT and Landolt acuity remained constant in cataract eyes as compared to healthy eyes. In amblyopic eyes due to strabismus this ratio was 3.7/1. Thus, amblyopia was underestimated with the CAT. Without limiting the examination distance, interocular differences > 1 dB in the CAT occurred in 52% of the strabismic amblyopic patients (potential sensitivity). At a distance of 1 m this rate decreased to 22% (real sensitivity). In conclusion, the CAT definitely lacks sensitivity for strabismic amblyopia. The data suggest that the real sensitivity could be improved by using higher spatial frequencies. The use of familiar shapes instead of gratings such as PL targets affects cooperation favorably in 12- to 36-month-old children.

Push-pull training reduces foveal sensory eye dominance within the early visual channels

PubMed Central

Xu, Jingping P.; He, Zijiang J.; Ooi, Teng Leng

2011-01-01

A push-pull training protocol is applied to reduce sensory eye dominance in the foveal region. The training protocol consists of cueing the weak eye to force it to become dominant while the strong eye is suppressed when a pair of dichoptic orthogonal grating stimulus is subsequently presented to it (Ooi and He, 1999). We trained with four pairs of dichoptic orthogonal gratings (0°/90°, 90°/0°, 45°/135° and 135°/45° at 3 cpd) to affect the interocular inhibitory interaction tuned to the four trained orientations (0°, 45°, 90° and 135°). After a 10-day training session, we found a significant learning effect (reduced sensory eye dominance) at the trained orientations as well as at two other untrained orientations (22.5° and 67.5°). This suggests that the four pairs of oriented training stimuli are sufficient to produce a learning effect at any other orientation. The nearly complete transfer of the learning effect across orientation is attributed to the fact that the trained and untrained orientations are close enough to fall in the same orientation tuning function of the early visual cortical neurons (~37.5°). Applying the same notion of transfer of learning within the same feature channel, we also found a large transfer effect to an untrained spatial frequency (6 cpd), which is 1 octave higher than the trained spatial frequency (3 cpd). Furthermore, we found that stereopsis is improved, as is the competitive ability between the two eyes, after the push-pull training. Our data analysis suggests that these improvements are correlated with the reduced sensory eye dominance after the training, i.e., due to a more balanced interocular inhibition. We also found that the learning effect (reduced SED and stereo threshold) can be retained for more than a year after the termination of the push-pull training. PMID:21689673

Inherited congenital bilateral atresia of the external auditory canal, congenital bilateral vertical talus and increased interocular distance.

PubMed

Rasmussen, N; Johnsen, N J; Thomsen, J

1979-01-01

Six out of twenty descendants of a reportedly affected grandfather have congenital bilateral symmetrical and isolated subtotal atresia of the external auditory canal. Four of the six affected descendants have bilateral foot anomalies--two affected cousins having congenital vertical talus. All of the three affected boys in the third generation have increased interocular distance. Short fifth fingers, bilateral single transverse palmar creases, pyloric stenosis and congenital exotropia were found infrequently and are considered coincidental features. Apart from the atresia, oto-rhinolaryngologic examination, mental function, dermatoglyphics, IgA, kidney function and heart function of the affected descendants were all normal. The karyotype of four affected descendants examined was normal. An autosomal dominant inheritance with variable expressivity is suggested.

Crowding, visual awareness, and their respective neural loci

PubMed Central

Shin, Kilho; Chung, Susana T. L.; Tjan, Bosco S.

2017-01-01

In peripheral vision, object identification can be impeded when a target object is flanked by other objects. This phenomenon of crowding has been attributed to basic processes associated with image encoding by the visual system, but the neural origin of crowding is not known. Determining whether crowding depends on subjective awareness of the flankers can provide information on the neural origin of crowding. However, recent studies that manipulated flanker awareness have yielded conflicting results. In the current study, we suppressed flanker awareness with two methods: interocular suppression (IOS) and adaptation-induced blindness (AIB). We tested two different types of stimuli: gratings and letters. With IOS, we found that the magnitude of crowding increased as the number of physical flankers increased, even when the observers did not report seeing any of the flankers. In contrast, when flanker awareness was manipulated with AIB, the magnitude of crowding increased with the number of perceived flankers. Our results show that whether crowding is contingent on awareness of the flankers depends on the method used to suppress awareness. In addition, our results imply that the locus of crowding is upstream from the neural locus of IOS and close to or downstream from that of AIB. Neurophysiology and neuroimaging studies jointly implicate mid-to-high level visual processing stages for IOS, while direct evidence regarding the neural locus of AIB is limited. The most consistent interpretation of our empirical findings is to place the neural locus of crowding at an early cortical site, such as V1 or V2. PMID:28549353

Asymmetric Dichoptic Masking in Visual Cortex of Amblyopic Macaque Monkeys

PubMed Central

Shooner, Christopher; Hallum, Luke E.; García-Marín, Virginia; Kiorpes, Lynne

2017-01-01

In amblyopia, abnormal visual experience leads to an extreme form of eye dominance, in which vision through the nondominant eye is degraded. A key aspect of this disorder is perceptual suppression: the image seen by the stronger eye often dominates during binocular viewing, blocking the image of the weaker eye from reaching awareness. Interocular suppression is the focus of ongoing work aimed at understanding and treating amblyopia, yet its physiological basis remains unknown. We measured binocular interactions in visual cortex of anesthetized amblyopic monkeys (female Macaca nemestrina), using 96-channel “Utah” arrays to record from populations of neurons in V1 and V2. In an experiment reported recently (Hallum et al., 2017), we found that reduced excitatory input from the amblyopic eye (AE) revealed a form of balanced binocular suppression that is unaltered in amblyopia. Here, we report on the modulation of the gain of excitatory signals from the AE by signals from its dominant fellow eye (FE). Using a dichoptic masking technique, we found that AE responses to grating stimuli were attenuated by the presentation of a noise mask to the FE, as in a normal control animal. Responses to FE stimuli, by contrast, could not be masked from the AE. We conclude that a weakened ability of the amblyopic eye to modulate cortical response gain creates an imbalance of suppression that favors the dominant eye. SIGNIFICANCE STATEMENT In amblyopia, vision in one eye is impaired as a result of abnormal early visual experience. Behavioral observations in humans with amblyopia suggest that much of their visual loss is due to active suppression of their amblyopic eye. Here we describe experiments in which we studied binocular interactions in macaques with experimentally induced amblyopia. In normal monkeys, the gain of neuronal response to stimulation of one eye is modulated by contrast in the other eye, but in monkeys with amblyopia the balance of gain modulation is altered so that the weaker, amblyopic eye has little effect while the stronger fellow eye has a strong effect. This asymmetric suppression may be a key component of the perceptual losses in amblyopia. PMID:28760867

Asymmetric Dichoptic Masking in Visual Cortex of Amblyopic Macaque Monkeys.

PubMed

Shooner, Christopher; Hallum, Luke E; Kumbhani, Romesh D; García-Marín, Virginia; Kelly, Jenna G; Majaj, Najib J; Movshon, J Anthony; Kiorpes, Lynne

2017-09-06

In amblyopia, abnormal visual experience leads to an extreme form of eye dominance, in which vision through the nondominant eye is degraded. A key aspect of this disorder is perceptual suppression: the image seen by the stronger eye often dominates during binocular viewing, blocking the image of the weaker eye from reaching awareness. Interocular suppression is the focus of ongoing work aimed at understanding and treating amblyopia, yet its physiological basis remains unknown. We measured binocular interactions in visual cortex of anesthetized amblyopic monkeys (female Macaca nemestrina ), using 96-channel "Utah" arrays to record from populations of neurons in V1 and V2. In an experiment reported recently (Hallum et al., 2017), we found that reduced excitatory input from the amblyopic eye (AE) revealed a form of balanced binocular suppression that is unaltered in amblyopia. Here, we report on the modulation of the gain of excitatory signals from the AE by signals from its dominant fellow eye (FE). Using a dichoptic masking technique, we found that AE responses to grating stimuli were attenuated by the presentation of a noise mask to the FE, as in a normal control animal. Responses to FE stimuli, by contrast, could not be masked from the AE. We conclude that a weakened ability of the amblyopic eye to modulate cortical response gain creates an imbalance of suppression that favors the dominant eye. SIGNIFICANCE STATEMENT In amblyopia, vision in one eye is impaired as a result of abnormal early visual experience. Behavioral observations in humans with amblyopia suggest that much of their visual loss is due to active suppression of their amblyopic eye. Here we describe experiments in which we studied binocular interactions in macaques with experimentally induced amblyopia. In normal monkeys, the gain of neuronal response to stimulation of one eye is modulated by contrast in the other eye, but in monkeys with amblyopia the balance of gain modulation is altered so that the weaker, amblyopic eye has little effect while the stronger fellow eye has a strong effect. This asymmetric suppression may be a key component of the perceptual losses in amblyopia. Copyright © 2017 the authors 0270-6474/17/378734-08$15.00/0.

Estimating a just-noticeable difference for ocular comfort in contact lens wearers.

PubMed

Papas, Eric B; Keay, Lisa; Golebiowski, Blanka

2011-06-21

To estimate the just-noticeable difference (JND) in ocular comfort rating by human, contact lens-wearing subjects using 1 to 100 numerical scales. Ostensibly identical, new contact lenses were worn simultaneously in both eyes by 40 subjects who made individual comfort ratings for each eye using a 100-point numerical ratings scale (NRS). Concurrently, interocular preference was indicated on a five-point Likert scale (1 to 5: strongly prefer right, slightly prefer right, no preference, slightly prefer left, strongly prefer left, respectively). Differences in NRS comfort score (ΔC) between the right and left eyes were determined for each Likert scale preference criteria. The distribution of group ΔC scores was examined relative to alternative definitions of JND as a means of estimating its value. For Likert scores indicating the presence of a slight interocular preference, absolute ΔC ranged from 1 to 30 units with a mean of 7.4 ± 1.3 (95% confidence interval) across all lenses and trials. When there was no Likert scale preference expressed between the eyes, absolute ΔC did not exceed 5 units. For ratings of comfort using a 100-point numerical rating scale, the inter-ocular JND is unlikely to be less than 5 units. The estimate for the average value in the population was approximately 7 to 8 units. These numbers indicate the lowest level at which changes in comfort measured with such scales are likely to be clinically significant.

A method to detect progression of glaucoma using the multifocal visual evoked potential technique

PubMed Central

Wangsupadilok, Boonchai; Kanadani, Fabio N.; Grippo, Tomas M.; Liebmann, Jeffrey M.; Ritch, Robert; Hood, Donald C.

2010-01-01

Purpose To describe a method for monitoring progression of glaucoma using the multifocal visual evoked potential (mfVEP) technique. Methods Eighty-seven patients diagnosed with open-angle glaucoma were divided into two groups. Group I, comprised 43 patients who had a repeat mfVEP test within 50 days (mean 0.9 ± 0.5 months), and group II, 44 patients who had a repeat test after at least 6 months (mean 20.7 ± 9.7 months). Monocular mfVEPs were obtained using a 60-sector pattern reversal dartboard display. Monocular and interocular analyses were performed. Data from the two visits were compared. The total number of abnormal test points with P < 5% within the visual field (total scores) and number of abnormal test points within a cluster (cluster size) were calculated. Data for group I provided a measure of test–retest variability independent of disease progression. Data for group II provided a possible measure of progression. Results The difference in the total scores for group II between visit 1 and visit 2 for the interocular and monocular comparison was significant (P < 0.05) as was the difference in cluster size for the interocular comparison (P < 0.05). Group I did not show a significant change in either total score or cluster size. Conclusion The change in the total score and cluster size over time provides a possible method for assessing progression of glaucoma with the mfVEP technique. PMID:18830654

Progressive Recombination Suppression and Differentiation in Recently Evolved Neo-sex Chromosomes

PubMed Central

Natri, Heini M.; Shikano, Takahito; Merilä, Juha

2013-01-01

Recombination suppression leads to the structural and functional differentiation of sex chromosomes and is thus a crucial step in the process of sex chromosome evolution. Despite extensive theoretical work, the exact processes and mechanisms of recombination suppression and differentiation are not well understood. In threespine sticklebacks (Gasterosteus aculeatus), a different sex chromosome system has recently evolved by a fusion between the Y chromosome and an autosome in the Japan Sea lineage, which diverged from the ancestor of other lineages approximately 2 Ma. We investigated the evolutionary dynamics and differentiation processes of sex chromosomes based on comparative analyses of these divergent lineages using 63 microsatellite loci. Both chromosome-wide differentiation patterns and phylogenetic inferences with X and Y alleles indicated that the ancestral sex chromosomes were extensively differentiated before the divergence of these lineages. In contrast, genetic differentiation appeared to have proceeded only in a small region of the neo-sex chromosomes. The recombination maps constructed for the Japan Sea lineage indicated that recombination has been suppressed or reduced over a large region spanning the ancestral and neo-sex chromosomes. Chromosomal regions exhibiting genetic differentiation and suppressed or reduced recombination were detected continuously and sequentially in the neo-sex chromosomes, suggesting that differentiation has gradually spread from the fusion point following the extension of recombination suppression. Our study illustrates an ongoing process of sex chromosome differentiation, providing empirical support for the theoretical model postulating that recombination suppression and differentiation proceed in a gradual manner in the very early stage of sex chromosome evolution. PMID:23436913

Degree of Suppression of Mouse Myoblast Cell Line C₂C12 Differentiation Varies According to Chondroitin Sulfate Subtype.

PubMed

Warita, Katsuhiko; Oshima, Nana; Takeda-Okuda, Naoko; Tamura, Jun-Ichi; Hosaka, Yoshinao Z

2016-10-21

Chondroitin sulfate (CS), a type of glycosaminoglycan (GAG), is a factor involved in the suppression of myogenic differentiation. CS comprises two repeating sugars and has different subtypes depending on the position and number of bonded sulfate groups. However, the effect of each subtype on myogenic differentiation remains unclear. In this study, we spiked cultures of C₂C 12 myoblasts, cells which are capable of undergoing skeletal muscle differentiation, with one of five types of CS (CS-A, -B, -C, -D, or -E) and induced differentiation over a fixed time. After immunostaining of the formed myotubes with an anti-MHC antibody, we counted the number of nuclei in the myotubes and then calculated the fusion index (FI) as a measure of myotube differentiation. The FI values of all the CS-treated groups were lower than the FI value of the control group, especially the group treated with CS-E, which displayed notable suppression of myotube formation. To confirm that the sugar chain in CS-E is important in the suppression of differentiation, chondroitinase ABC (ChABC), which catabolizes CS, was added to the media. The addition of ChABC led to the degradation of CS-E, and neutralized the suppression of myotube formation by CS-E. Collectively, it can be concluded that the degree of suppression of differentiation depends on the subtype of CS and that CS-E strongly suppresses myogenic differentiation. We conclude that the CS sugar chain has inhibitory action against myoblast cell fusion.

Experience-driven plasticity in binocular vision

PubMed Central

Klink, P. Christiaan; Brascamp, Jan W.; Blake, Randolph; van Wezel, Richard J.A.

2010-01-01

Summary Experience-driven neuronal plasticity allows the brain to adapt its functional connectivity to recent sensory input. Here we use binocular rivalry [1], an experimental paradigm where conflicting images are presented to the individual eyes, to demonstrate plasticity in the neuronal mechanisms that convert visual information from two separated retinas into single perceptual experiences. Perception during binocular rivalry tended to initially consist of alternations between exclusive representations of monocularly defined images, but upon prolonged exposure, mixture percepts became more prevalent. The completeness of suppression, reflected in the incidence of mixture percepts, plausibly reflects the strength of inhibition that likely plays a role in binocular rivalry [2]. Recovery of exclusivity was possible, but required highly specific binocular stimulation. Documenting the prerequisites for these observed changes in perceptual exclusivity, our experiments suggest experience-driven plasticity at interocular inhibitory synapses, driven by the (lack of) correlated activity of neurons representing the conflicting stimuli. This form of plasticity is consistent with a previously proposed, but largely untested, anti-Hebbian learning mechanism for inhibitory synapses in vision [3, 4]. Our results implicate experience-driven plasticity as one governing principle in the neuronal organization of binocular vision. PMID:20674360

Visuospatial asymmetries and interocular transfer in the split-brain rat.

PubMed

Adelstein, A; Crowne, D P

1991-06-01

Interocular transfer (IOT), hemispheric superiority, and cerebral dominance were examined in split-brain female albino rats. Callosum-sectioned and intact animals were monocularly trained in the Morris water maze and tested in IOT and reversal phases. In the IOT phase, split-brain rats entered more nontarget quadrants and headed less accurately toward the platform than did controls. For both split-brain animals and controls, right-eye training resulted in shorter latencies and fewer nontarget entries than did left-eye training. Analyses of cerebral dominance showed shorter latencies and smaller heading errors over all 3 phases in rats that were trained with the nondominant eye. Right-eye dominant controls were less affected by platform reversal. Split-brain rats were inferior to controls in latency to find the platform and in target quadrant entries. This finding establishes a spatial cognitive deficit from callosum section.

Is adaptation to perceived interocular differences in height explained by vertical fusional eye movements?

PubMed

Maier, Felix M; Schaeffel, Frank

2013-07-24

To find out whether adaptation to a vertical prism involves more than fusional vertical eye movements. Adaptation to a vertical base-up 3 prism diopter prism was measured in a custom-programmed Maddox test in nine visually normal emmetropic subjects (mean age 27.0 ± 2.8 years). Vertical eye movements were binocularly measured in six of the subjects with a custom-programmed binocular video eye tracker. In the Maddox test, some subjects adjusted the perceived height as expected from the power of the prism while others appeared to ignore the prism. After 15 minutes of adaptation, the interocular difference in perceived height was reduced by on average 51% (from 0.86°-0.44°). The larger the initially perceived difference in height in a subject, the larger the amplitude of adaptation was. Eye tracking showed that the prism generated divergent vertical eye movements of 1.2° on average, which was less than expected from its power. Differences in eye elevation were maintained as long as the prism was in place. Small angles of lateral head tilt generated large interocular differences in eye elevation, much larger than the effects introduced by the prism. Vertical differences in retinal image height were compensated by vertical fusional eye movements but some subjects responded poorly to a vertical prism in both experiments; fusional eye movements were generally too small to realign both foveae with the fixation target; and the prism adaptation in the Maddox test was fully explained by the changes in vertical eye position, suggesting that no further adaptational mechanism may be involved.

Capturing age-related changes in functional contrast sensitivity with decreasing light levels in monocular and binocular vision.

PubMed

Gillespie-Gallery, Hanna; Konstantakopoulou, Evgenia; Harlow, Jonathan A; Barbur, John L

2013-09-09

It is challenging to separate the effects of normal aging of the retina and visual pathways independently from optical factors, decreased retinal illuminance, and early stage disease. This study determined limits to describe the effect of light level on normal, age-related changes in monocular and binocular functional contrast sensitivity. We recruited 95 participants aged 20 to 85 years. Contrast thresholds for correct orientation discrimination of the gap in a Landolt C optotype were measured using a 4-alternative, forced-choice (4AFC) procedure at screen luminances from 34 to 0.12 cd/m(2) at the fovea and parafovea (0° and ±4°). Pupil size was measured continuously. The Health of the Retina index (HRindex) was computed to capture the loss of contrast sensitivity with decreasing light level. Participants were excluded if they exhibited performance outside the normal limits of interocular differences or HRindex values, or signs of ocular disease. Parafoveal contrast thresholds showed a steeper decline and higher correlation with age at the parafovea than the fovea. Of participants with clinical signs of ocular disease, 83% had HRindex values outside the normal limits. Binocular summation of contrast signals declined with age, independent of interocular differences. The HRindex worsens more rapidly with age at the parafovea, consistent with histologic findings of rod loss and its link to age-related degenerative disease of the retina. The HRindex and interocular differences could be used to screen for and separate the earliest stages of subclinical disease from changes caused by normal aging.

Discriminating anisometropic amblyopia from myopia based on interocular inhibition

PubMed Central

Jia, Wuli; Zhou, Jiawei; Lu, Zhong-Lin; Lesmes, Luis A.; Huang, Chang-Bing

2016-01-01

Amblyopia screening during childhood is critical for early detection and successful treatment. In the current study, we develop and evaluate a screening method that exploits the imbalanced interocular inhibition between amblyopic and fellow eyes. In nineteen subjects with anisometropic amblyopia and twenty-two age-matched subjects with myopia, we measured the area under the contrast sensitivity functions (AUCSFs) in eight monocular conditions defined by tested eye (left, right), patching of the untested eye (translucent, opaque), and refractive status (corrected, uncorrected). For each test eye, we defined the inhibition index as the ratio between AUCSF values obtained in the translucent and opaque patching conditions of the untested eye. To evaluate the screening potential of the inhibition index, we compared results from patients with amblyopia and myopia. With and without optical correction, the index was significantly lower in the amblyopic eye than in the fellow eye of the amblyopic subjects and both eyes of the myopic subjects. No significant difference was found among the two eyes of the myopic subjects and the fellow eyes of the amblyopic subjects. With the inhibition index as the predictor, a logistic regression model successfully discriminated amblyopic eyes from myopic eyes with 100% accuracy in the uncorrected condition. In the corrected condition, with the inhibition index and interocular visual acuity difference as predictors, amblyopic eyes were likewise discriminated from myopic eyes with 100% accuracy. This pattern of CSF changes, caused by the different patching modes of the untested eye, provides a potential CSF signature to discriminate anisometropic amblyopia from myopia. PMID:25701741

Evaluation of multifocal visual evoked potentials in patients with Graves' orbitopathy and subclinical optic nerve involvement.

PubMed

Pérez-Rico, Consuelo; Rodríguez-González, Natividad; Arévalo-Serrano, Juan; Blanco, Román

2012-08-01

Dysthyroid optic neuropathy is the most serious, although infrequent (8-10 %) complication in Graves' orbitopathy (GO). It is known that early stages of compressive optic neuropathy may produce reversible visual field defects, suggesting axoplasmic stasis rather than ganglion cell death. This observational, cross-sectional, case-control study assessed 34 consecutive patients (65 eyes) with Graves' hyperthyroidism and longstanding GO and 31 age-matched control subjects. The patients' multifocal visual evoked potentials (mfVEP) were compared to their clinical and psychophysical (standard automated perimetry [SAP]) and structural (optic coherence tomography [OCT]) diagnostic test data. Abnormal cluster defects were found in 12.3 % and 3.1 % of eyes on the interocular and monocular amplitude analysis mfVEP probability plots, respectively. As well, mfVEP latencies delays were found in 13.8 and 20 % of eyes on the interocular and monocular analysis probability plots, respectively. Interestingly, 19 % of patients with GO had ocular hypertension, and a strong correlation between intraocular pressure measured at upgaze and mfVEP latency was found. MfVEP amplitudes and visual acuity were significantly related to each other (P < 0.05), but not with the latencies delays. However, relationships between the interocular or monocular mfVEP amplitudes and latencies analysis and SAP indices or OCT data were not statistically significant. One-third of our patients with GO showed changes in the mfVEP, indicating significant subclinical optic nerve dysfunction. In this sense, the mfVEP may be a useful diagnostic tool in the clinic for early diagnosis and monitoring of optic nerve function abnormalities in patients with GO.

Binocular combination of luminance profiles

PubMed Central

Ding, Jian; Levi, Dennis M.

2017-01-01

We develop and test a new two-dimensional model for binocular combination of the two eyes' luminance profiles. For first-order stimuli, the model assumes that one eye's luminance profile first goes through a luminance compressor, receives gain-control and gain-enhancement from the other eye, and then linearly combines the other eye's output profile. For second-order stimuli, rectification is added in the signal path of the model before the binocular combination site. Both the total contrast and luminance energies, weighted sums over both the space and spatial-frequency domains, were used in the interocular gain-control, while only the total contrast energy was used in the interocular gain-enhancement. To challenge the model, we performed a binocular brightness matching experiment over a large range of background and target luminances. The target stimulus was a dichoptic disc with a sharp edge that has an increment or decrement luminance from its background. The disk's interocular luminance ratio varied from trial to trial. To refine the model we tested three luminance compressors, five nested binocular combination models (including the Ding–Sperling and the DSKL models), and examined the presence or absence of total luminance energy in the model. We found that (1) installing a luminance compressor, either a logarithmic luminance function or luminance gain-control, (2) including both contrast and luminance energies, and (3) adding interocular gain-enhancement (the DSKL model) to a combined model significantly improved its performance. The combined model provides a systematic account of binocular luminance summation over a large range of luminance input levels. It gives a unified explanation of Fechner's paradox observed on a dark background, and a winner-take-all phenomenon observed on a light background. To further test the model, we conducted two additional experiments: luminance summation of discs with asymmetric contour information (Experiment 2), similar to Levelt (1965) and binocular combination of second-order contrast-modulated gratings (Experiment 3). We used the model obtained in Experiment 1 to predict the results of Experiments 2 and 3 and the results of our previous studies. Model simulations further refined the contrast space weight and contrast sensitivity functions that are installed in the model, and provide a reasonable account for rebalancing of imbalanced binocular vision by reducing the mean luminance in the dominant eye. PMID:29098293

Degraded attentional modulation of cortical neural populations in strabismic amblyopia

PubMed Central

Hou, Chuan; Kim, Yee-Joon; Lai, Xin Jie; Verghese, Preeti

2016-01-01

Behavioral studies have reported reduced spatial attention in amblyopia, a developmental disorder of spatial vision. However, the neural populations in the visual cortex linked with these behavioral spatial attention deficits have not been identified. Here, we use functional MRI–informed electroencephalography source imaging to measure the effect of attention on neural population activity in the visual cortex of human adult strabismic amblyopes who were stereoblind. We show that compared with controls, the modulatory effects of selective visual attention on the input from the amblyopic eye are substantially reduced in the primary visual cortex (V1) as well as in extrastriate visual areas hV4 and hMT+. Degraded attentional modulation is also found in the normal-acuity fellow eye in areas hV4 and hMT+ but not in V1. These results provide electrophysiological evidence that abnormal binocular input during a developmental critical period may impact cortical connections between the visual cortex and higher level cortices beyond the known amblyopic losses in V1 and V2, suggesting that a deficit of attentional modulation in the visual cortex is an important component of the functional impairment in amblyopia. Furthermore, we find that degraded attentional modulation in V1 is correlated with the magnitude of interocular suppression and the depth of amblyopia. These results support the view that the visual suppression often seen in strabismic amblyopia might be a form of attentional neglect of the visual input to the amblyopic eye. PMID:26885628

Degraded attentional modulation of cortical neural populations in strabismic amblyopia.

PubMed

Hou, Chuan; Kim, Yee-Joon; Lai, Xin Jie; Verghese, Preeti

2016-01-01

Behavioral studies have reported reduced spatial attention in amblyopia, a developmental disorder of spatial vision. However, the neural populations in the visual cortex linked with these behavioral spatial attention deficits have not been identified. Here, we use functional MRI-informed electroencephalography source imaging to measure the effect of attention on neural population activity in the visual cortex of human adult strabismic amblyopes who were stereoblind. We show that compared with controls, the modulatory effects of selective visual attention on the input from the amblyopic eye are substantially reduced in the primary visual cortex (V1) as well as in extrastriate visual areas hV4 and hMT+. Degraded attentional modulation is also found in the normal-acuity fellow eye in areas hV4 and hMT+ but not in V1. These results provide electrophysiological evidence that abnormal binocular input during a developmental critical period may impact cortical connections between the visual cortex and higher level cortices beyond the known amblyopic losses in V1 and V2, suggesting that a deficit of attentional modulation in the visual cortex is an important component of the functional impairment in amblyopia. Furthermore, we find that degraded attentional modulation in V1 is correlated with the magnitude of interocular suppression and the depth of amblyopia. These results support the view that the visual suppression often seen in strabismic amblyopia might be a form of attentional neglect of the visual input to the amblyopic eye.

Binocular combination of phase and contrast explained by a gain-control and gain-enhancement model

PubMed Central

Ding, Jian; Klein, Stanley A.; Levi, Dennis M.

2013-01-01

We investigated suprathreshold binocular combination, measuring both the perceived phase and perceived contrast of a cyclopean sine wave. We used a paradigm adapted from Ding and Sperling (2006, 2007) to measure the perceived phase by indicating the apparent location (phase) of the dark trough in the horizontal cyclopean sine wave relative to a black horizontal reference line, and we used the same stimuli to measure perceived contrast by matching the binocular combined contrast to a standard contrast presented to one eye. We found that under normal viewing conditions (high contrast and long stimulus duration), perceived contrast is constant, independent of the interocular contrast ratio and the interocular phase difference, while the perceived phase shifts smoothly from one eye to the other eye depending on the contrast ratios. However, at low contrasts and short stimulus durations, binocular combination is more linear and contrast summation is phase-dependent. To account for phase-dependent contrast summation, we incorporated a fusion remapping mechanism into our model, using disparity energy to shift the monocular phases towards the cyclopean phase in order to align the two eyes' images through motor/sensory fusion. The Ding-Sperling model with motor/sensory fusion mechanism gives a reasonable account of the phase dependence of binocular contrast combination and can account for either the perceived phase or the perceived contrast of a cyclopean sine wave separately; however it requires different model parameters for the two. However, when fit to both phase and contrast data simultaneously, the Ding-Sperling model fails. Incorporating interocular gain enhancement into the model results in a significant improvement in fitting both phase and contrast data simultaneously, successfully accounting for both linear summation at low contrast energy and strong nonlinearity at high contrast energy. PMID:23397038

Empirical mode decomposition processing to improve multifocal-visual-evoked-potential signal analysis in multiple sclerosis

PubMed Central

2018-01-01

Objective To study the performance of multifocal-visual-evoked-potential (mfVEP) signals filtered using empirical mode decomposition (EMD) in discriminating, based on amplitude, between control and multiple sclerosis (MS) patient groups, and to reduce variability in interocular latency in control subjects. Methods MfVEP signals were obtained from controls, clinically definitive MS and MS-risk progression patients (radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS)). The conventional method of processing mfVEPs consists of using a 1–35 Hz bandpass frequency filter (XDFT). The EMD algorithm was used to decompose the XDFT signals into several intrinsic mode functions (IMFs). This signal processing was assessed by computing the amplitudes and latencies of the XDFT and IMF signals (XEMD). The amplitudes from the full visual field and from ring 5 (9.8–15° eccentricity) were studied. The discrimination index was calculated between controls and patients. Interocular latency values were computed from the XDFT and XEMD signals in a control database to study variability. Results Using the amplitude of the mfVEP signals filtered with EMD (XEMD) obtains higher discrimination index values than the conventional method when control, MS-risk progression (RIS and CIS) and MS subjects are studied. The lowest variability in interocular latency computations from the control patient database was obtained by comparing the XEMD signals with the XDFT signals. Even better results (amplitude discrimination and latency variability) were obtained in ring 5 (9.8–15° eccentricity of the visual field). Conclusions Filtering mfVEP signals using the EMD algorithm will result in better identification of subjects at risk of developing MS and better accuracy in latency studies. This could be applied to assess visual cortex activity in MS diagnosis and evolution studies. PMID:29677200

Interocular velocity difference contributes to stereomotion speed perception

NASA Technical Reports Server (NTRS)

Brooks, Kevin R.

2002-01-01

Two experiments are presented assessing the contributions of the rate of change of disparity (CD) and interocular velocity difference (IOVD) cues to stereomotion speed perception. Using a two-interval forced-choice paradigm, the perceived speed of directly approaching and receding stereomotion and of monocular lateral motion in random dot stereogram (RDS) targets was measured. Prior adaptation using dysjunctively moving random dot stimuli induced a velocity aftereffect (VAE). The degree of interocular correlation in the adapting images was manipulated to assess the effectiveness of each cue. While correlated adaptation involved a conventional RDS stimulus, containing both IOVD and CD cues, uncorrelated adaptation featured an independent dot array in each monocular half-image, and hence lacked a coherent disparity signal. Adaptation produced a larger VAE for stereomotion than for monocular lateral motion, implying effects at neural sites beyond that of binocular combination. For motion passing through the horopter, correlated and uncorrelated adaptation stimuli produced equivalent stereomotion VAEs. The possibility that these results were due to the adaptation of a CD mechanism through random matches in the uncorrelated stimulus was discounted in a control experiment. Here both simultaneous and sequential adaptation of left and right eyes produced similar stereomotion VAEs. Motion at uncrossed disparities was also affected by both correlated and uncorrelated adaptation stimuli, but showed a significantly greater VAE in response to the former. These results show that (1) there are two separate, specialised mechanisms for encoding stereomotion: one through IOVD, the other through CD; (2) the IOVD cue dominates the perception of stereomotion speed for stimuli passing through the horopter; and (3) at a disparity pedestal both the IOVD and the CD cues have a significant influence.

Optical and Biometric Characteristics of Anisomyopia in Human Adults

PubMed Central

Tian, Yibin; Tarrant, Janice; Wildsoet, Christine F.

2011-01-01

Purpose To investigate the role of higher order optical aberrations and thus retinal image degradation in the development of myopia, through the characterization of anisomyopia in human adults in terms of their optical and biometric characteristics. Methods The following data were collected from both eyes of fifteen young adult anisometropic myopes and sixteen isometropic myopes: subjective and objective refractive errors, corneal power and shape, monochromatic optical aberrations, anterior chamber depth, lens thickness, vitreous chamber depth, and best corrected visual acuity. Monochromatic aberrations were analyzed in terms of their higher order components, and further analyzed in terms of 31 optical quality metrics. Interocular differences for the two groups (anisomyopes vs. isomyopes) were compared and the relationship between measured ocular parameters and refractive errors also analyzed across all eyes. Results As expected, anisomyopes and isomyopes differed significantly in terms of interocular differences in vitreous chamber depth, axial length and refractive error. However, interocular differences in other optical properties showed no significant intergroup differences. Overall, higher myopia was associated with deeper anterior and vitreous chambers, higher astigmatism, more prolate corneas, and more positive spherical aberration. Other measured optical and biometric parameters were not significantly correlated with spherical refractive error, although some optical quality metrics and corneal astigmatism were significantly correlated with refractive astigmatism. Conclusions An optical cause for anisomyopia related to increased higher order aberrations is not supported by our data. Corneal shape changes and increased astigmatism in more myopic eyes may be a by-product of the increased anterior chamber growth in these eyes; likewise, the increased positive spherical aberration in more myopic eyes may be a product of myopic eye growth. PMID:21797915

Human short-latency ocular vergence responses produced by interocular velocity differences

PubMed Central

Sheliga, B. M.; Quaia, C.; FitzGibbon, E. J.; Cumming, B. G.

2016-01-01

We studied human short-latency vergence eye movements to a novel stimulus that produces interocular velocity differences without a changing disparity signal. Sinusoidal luminance gratings moved in opposite directions (left vs. right; up vs. down) in the two eyes. The grating seen by each eye underwent ¼-wavelength shifts with each image update. This arrangement eliminated changing disparity cues, since the phase difference between the eyes alternated between 0° and 180°. We nevertheless observed robust short-latency vergence responses (VRs), whose sign was consistent with the interocular velocity differences (IOVDs), indicating that the IOVD cue in isolation can evoke short-latency VRs. The IOVD cue was effective only when the images seen by the two eyes overlapped in space. We observed equally robust VRs for opposite horizontal motions (left in one eye, right in the other) and opposite vertical motions (up in one eye, down in the other). Whereas the former are naturally generated by objects moving in depth, the latter are not part of our normal experience. To our knowledge, this is the first demonstration of a behavioral consequence of vertical IOVD. This may reflect the fact that some neurons in area MT are sensitive to these motion signals (Czuba, Huk, Cormack, & Kohn, 2014). VRs were the strongest for spatial frequencies in the range of 0.35–1 c/°, much higher than the optimal spatial frequencies for evoking ocular-following responses observed during frontoparallel motion. This suggests that the two motion signals are detected by different neuronal populations. We also produced IOVD using moving uncorrelated one-dimensional white-noise stimuli. In this case the most effective stimuli have low speed, as predicted if the drive originates in neurons tuned to high spatial frequencies (Sheliga, Quaia, FitzGibbon, & Cumming, 2016). PMID:27548089

Statis omnidirectional stereoscopic display system

NASA Astrophysics Data System (ADS)

Barton, George G.; Feldman, Sidney; Beckstead, Jeffrey A.

1999-11-01

A unique three camera stereoscopic omnidirectional viewing system based on the periscopic panoramic camera described in the 11/98 SPIE proceedings (AM13). The 3 panoramic cameras are equilaterally combined so each leg of the triangle approximates the human inter-ocular spacing allowing each panoramic camera to view 240 degree(s) of the panoramic scene, the most counter clockwise 120 degree(s) being the left eye field and the other 120 degree(s) segment being the right eye field. Field definition may be by green/red filtration or time discrimination of the video signal. In the first instance a 2 color spectacle is used in viewing the display or in the 2nd instance LCD goggles are used to differentiate the R/L fields. Radially scanned vidicons or re-mapped CCDs may be used. The display consists of three vertically stacked 120 degree(s) segments of the panoramic field of view with 2 fields/frame. Field A being the left eye display and Field B the right eye display.

Impaired Velocity Processing Reveals an Agnosia for Motion in Depth.

PubMed

Barendregt, Martijn; Dumoulin, Serge O; Rokers, Bas

2016-11-01

Many individuals with normal visual acuity are unable to discriminate the direction of 3-D motion in a portion of their visual field, a deficit previously referred to as a stereomotion scotoma. The origin of this visual deficit has remained unclear. We hypothesized that the impairment is due to a failure in the processing of one of the two binocular cues to motion in depth: changes in binocular disparity over time or interocular velocity differences. We isolated the contributions of these two cues and found that sensitivity to interocular velocity differences, but not changes in binocular disparity, varied systematically with observers' ability to judge motion direction. We therefore conclude that the inability to interpret motion in depth is due to a failure in the neural mechanisms that combine velocity signals from the two eyes. Given these results, we argue that the deficit should be considered a prevalent but previously unrecognized agnosia specific to the perception of visual motion. © The Author(s) 2016.

Releasing Ski-Smad4 mediated suppression is essential to license Th17 differentiation

PubMed Central

Zhang, Song; Takaku, Motoki; Zou, Liyun; Gu, Ai-di; Chou, Wei-chun; Zhang, Ge; Wu, Bing; Kong, Qing; Thomas, Seddon Y.; Serody, Jonathan S.; Chen, Xian; Xu, Xiaojiang; Wade, Paul A.; Cook, Donald N.; Ting, Jenny P.; Wan, Yisong Y.

2017-01-01

Th17 cells are critically involved in host defense, inflammation, and autoimmunity1–5. TGF-β is instrumental in Th17 differentiation by cooperating with IL-66,7. Yet, the mechanism of how TGF-β enables Th17 differentiation remains elusive. Here we reveal that TGF-β licenses Th17 differentiation by releasing Ski-Smad4-complex suppressed RORγt expression. We found serendipitously that, unlike wild-type T cells, Smad4-deficient T cells differentiated into Th17 cells in the absence of TGF-β signaling in a RORγt-dependent manner. Ectopic Smad4 expression suppressed the RORγt expression and Th17 differentiation of Smad4-deficient T cells. Unexpectedly however, TGF-β neutralized Smad4 mediated suppression without affecting Smad4 binding to Rorc locus. Proteomic analysis revealed that Smad4 interacted with Ski, a transcriptional repressor degraded upon TGF-β stimulation. Ski controlled the histone acetylation/de-acetylation of Rorc locus and Th17 differentiation via Smad4 because ectopic Ski expression inhibited H3K9Ac of Rorc locus, Rorc expression and Th17 differentiation in a Smad4-dependent manner. Therefore, TGF-β-induced disruption of Ski releases Ski-Smad4 complex imposed suppression of RORγt to license Th17 differentiation. This study reveals a critical mechanism by which TGF-β controls Th17 differentiation and uncovers Ski-Smad4 axis as a potential therapeutic target for treating Th17 related diseases. PMID:29072299

Tilt aftereffect following adaptation to translational Glass patterns

PubMed Central

Pavan, Andrea; Hocketstaller, Johanna; Contillo, Adriano; Greenlee, Mark W.

2016-01-01

Glass patterns (GPs) consist of randomly distributed dot pairs (dipoles) whose orientations are determined by specific geometric transforms. We assessed whether adaptation to stationary oriented translational GPs suppresses the activity of orientation selective detectors producing a tilt aftereffect (TAE). The results showed that adaptation to GPs produces a TAE similar to that reported in previous studies, though reduced in amplitude. This suggests the involvement of orientation selective mechanisms. We also measured the interocular transfer (IOT) of the GP-induced TAE and found an almost complete IOT, indicating the involvement of orientation selective and binocularly driven units. In additional experiments, we assessed the role of attention in TAE from GPs. The results showed that distraction during adaptation similarly modulates the TAE after adapting to both GPs and gratings. Moreover, in the case of GPs, distraction is likely to interfere with the adaptation process rather than with the spatial summation of local dipoles. We conclude that TAE from GPs possibly relies on visual processing levels in which the global orientation of GPs has been encoded by neurons that are mostly binocularly driven, orientation selective and whose adaptation-related neural activity is strongly modulated by attention. PMID:27005949

Binocular combination of stimulus orientation.

PubMed

Yehezkel, O; Ding, J; Sterkin, A; Polat, U; Levi, D M

2016-11-01

When two sine waves that differ slightly in orientation are presented to the two eyes separately, a single cyclopean sine wave is perceived. However, it is unclear how the brain calculates its orientation. Here, we used a signal detection rating method to estimate the perceived orientation when the two eyes were presented with Gabor patches that differed in both orientation and contrast. We found a nearly linear combination of orientation when both targets had the same contrast. However, the binocular percept shifted away from the linear prediction towards the orientation with the higher contrast, depending on both the base contrast and the contrast ratio. We found that stimuli that differ slightly in orientation are combined into a single percept, similarly for monocular and binocular presentation, with a bias that depends on the interocular contrast ratio. Our results are well fitted by gain-control models, and are consistent with a previous study that favoured the DSKL model that successfully predicts binocular phase and contrast combination and binocular contrast discrimination. In this model, the departures from linearity may be explained on the basis of mutual suppression and mutual enhancement, both of which are stronger under dichoptic than monocular conditions.

Dazzling Glare: Protection Criteria Versus Visual Performance

DTIC Science & Technology

1989-06-07

6 3 Coherent vs Noncoherent Intraocular Glare ................................................................ 7 4 Coherent vs... Noncoherent Interocular Glare ................................................ 8.............. 5 Filtered Xenon Are Lamp vs Helium Neon Laser...glare effects in order to design more effective protective eyewear and to ensure that those who might be exposed in an operational setting know what

Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation.

PubMed

Zhang, Song; Takaku, Motoki; Zou, Liyun; Gu, Ai-di; Chou, Wei-Chun; Zhang, Ge; Wu, Bing; Kong, Qing; Thomas, Seddon Y; Serody, Jonathan S; Chen, Xian; Xu, Xiaojiang; Wade, Paul A; Cook, Donald N; Ting, Jenny P Y; Wan, Yisong Y

2017-11-02

T helper 17 (T H 17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in T H 17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables T H 17 cell differentiation remains elusive. Here we reveal that TGFβ enables T H 17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into T H 17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and T H 17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and T H 17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and T H 17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable T H 17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls T H 17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating T H 17-related diseases.

The Demise of the Magic Lantern Show

ERIC Educational Resources Information Center

Schneider, Edward W.

2006-01-01

Extracting and applying lessons from history is rarely easy and sometimes risky but there are moments when historical records are so compelling that they rise above mere proof to the level of interocular impact. In this article, the author shares his similar experience while visiting his colleague, Professor Bruce Clark, at the University of…

Binocular Combination of Second-Order Stimuli

PubMed Central

Zhou, Jiawei; Liu, Rong; Zhou, Yifeng; Hess, Robert F.

2014-01-01

Phase information is a fundamental aspect of visual stimuli. However, the nature of the binocular combination of stimuli defined by modulations in contrast, so-called second-order stimuli, is presently not clear. To address this issue, we measured binocular combination for first- (luminance modulated) and second-order (contrast modulated) stimuli using a binocular phase combination paradigm in seven normal adults. We found that the binocular perceived phase of second-order gratings depends on the interocular signal ratio as has been previously shown for their first order counterparts; the interocular signal ratios when the two eyes were balanced was close to 1 in both first- and second-order phase combinations. However, second-order combination is more linear than previously found for first-order combination. Furthermore, binocular combination of second-order stimuli was similar regardless of whether the carriers in the two eyes were correlated, anti-correlated, or uncorrelated. This suggests that, in normal adults, the binocular phase combination of second-order stimuli occurs after the monocular extracting of the second-order modulations. The sensory balance associated with this second-order combination can be obtained from binocular phase combination measurements. PMID:24404180

A complete investigation of monocular and binocular functions in clinically treated amblyopia.

PubMed

Zhao, Wuxiao; Jia, Wu-Li; Chen, Ge; Luo, Yan; Lin, Borong; He, Qing; Lu, Zhong-Lin; Li, Min; Huang, Chang-Bing

2017-09-06

The gold standard of a successful amblyopia treatment is full recovery of visual acuity (VA) in the amblyopic eye, but there has been no systematic study on both monocular and binocular visual functions. In this research, we aimed to quantify visual qualities with a variety of perceptual tasks in subjects with treated amblyopia. We found near stereoacuity and pAE dominance in binocular rivalry in "treated" amblyopia were largely comparable to those of normal subjects. CSF of the pAE remained deficient in high spatial frequencies. The binocular contrast summation ratio is significantly lower than normal standard. The interocular balance point is 34%, indicating that contrast in pAE is much less effective as the same contrast in pFE in binocular phase combination. Although VA, stereoacuity and binocular rivalry at low spatial frequency in treated amblyopes were normal or nearly normal, the pAE remained "lazy" in high frequency domain, binocular contrast summation, and interocular phase combination. Our results suggest that structured monocular and binocular training are necessary to fully recover deficient functions in amblyopia.

The Limits of Human Stereopsis in Space and Time

PubMed Central

Kane, David; Guan, Phillip

2014-01-01

To encode binocular disparity, the visual system determines the image patches in one eye that yield the highest correlation with patches in the other eye. The computation of interocular correlation occurs after spatiotemporal filtering of monocular signals, which leads to restrictions on disparity variations that can support depth perception. We quantified those restrictions by measuring humans' ability to see disparity variation at a wide range of spatial and temporal frequencies. Lower-disparity thresholds cut off at very low spatiotemporal frequencies, which is consistent with the behavior of V1 neurons. Those thresholds are space–time separable, suggesting that the underlying neural mechanisms are separable. We also found that upper-disparity limits were characterized by a spatiotemporal, disparity-gradient limit; to be visible, disparity variation cannot exceed a fixed amount for a given interval in space–time. Our results illustrate that the disparity variations that humans can see are very restricted compared with the corresponding luminance variations. The results also provide insight into the neural mechanisms underlying depth from disparity, such as why stimuli with long interocular delays can still yield clear depth percepts. PMID:24453329

Accuracy of noncycloplegic retinoscopy, retinomax autorefractor, and SureSight vision screener for detecting significant refractive errors.

PubMed

Kulp, Marjean Taylor; Ying, Gui-Shuang; Huang, Jiayan; Maguire, Maureen; Quinn, Graham; Ciner, Elise B; Cyert, Lynn A; Orel-Bixler, Deborah A; Moore, Bruce D

2014-03-06

To evaluate, by receiver operating characteristic (ROC) analysis, the ability of noncycloplegic retinoscopy (NCR), Retinomax Autorefractor (Retinomax), and SureSight Vision Screener (SureSight) to detect significant refractive errors (RE) among preschoolers. Refraction results of eye care professionals using NCR, Retinomax, and SureSight (n = 2588) and of nurse and lay screeners using Retinomax and SureSight (n = 1452) were compared with masked cycloplegic retinoscopy results. Significant RE was defined as hyperopia greater than +3.25 diopters (D), myopia greater than 2.00 D, astigmatism greater than 1.50 D, and anisometropia greater than 1.00 D interocular difference in hyperopia, greater than 3.00 D interocular difference in myopia, or greater than 1.50 D interocular difference in astigmatism. The ability of each screening test to identify presence, type, and/or severity of significant RE was summarized by the area under the ROC curve (AUC) and calculated from weighted logistic regression models. For detection of each type of significant RE, AUC of each test was high; AUC was better for detecting the most severe levels of RE than for all REs considered important to detect (AUC 0.97-1.00 vs. 0.92-0.93). The area under the curve of each screening test was high for myopia (AUC 0.97-0.99). Noncycloplegic retinoscopy and Retinomax performed better than SureSight for hyperopia (AUC 0.92-0.99 and 0.90-0.98 vs. 0.85-0.94, P ≤ 0.02), Retinomax performed better than NCR for astigmatism greater than 1.50 D (AUC 0.95 vs. 0.90, P = 0.01), and SureSight performed better than Retinomax for anisometropia (AUC 0.85-1.00 vs. 0.76-0.96, P ≤ 0.07). Performance was similar for nurse and lay screeners in detecting any significant RE (AUC 0.92-1.00 vs. 0.92-0.99). Each test had a very high discriminatory power for detecting children with any significant RE.

Redundant mechanisms are involved in suppression of default cell fates during embryonic mesenchyme and notochord induction in ascidians.

PubMed

Kodama, Hitoshi; Miyata, Yoshimasa; Kuwajima, Mami; Izuchi, Ryoichi; Kobayashi, Ayumi; Gyoja, Fuki; Onuma, Takeshi A; Kumano, Gaku; Nishida, Hiroki

2016-08-01

During embryonic induction, the responding cells invoke an induced developmental program, whereas in the absence of an inducing signal, they assume a default uninduced cell fate. Suppression of the default fate during the inductive event is crucial for choice of the binary cell fate. In contrast to the mechanisms that promote an induced cell fate, those that suppress the default fate have been overlooked. Upon induction, intracellular signal transduction results in activation of genes encoding key transcription factors for induced tissue differentiation. It is elusive whether an induced key transcription factor has dual functions involving suppression of the default fates and promotion of the induced fate, or whether suppression of the default fate is independently regulated by other factors that are also downstream of the signaling cascade. We show that during ascidian embryonic induction, default fates were suppressed by multifold redundant mechanisms. The key transcription factor, Twist-related.a, which is required for mesenchyme differentiation, and another independent transcription factor, Lhx3, which is dispensable for mesenchyme differentiation, sequentially and redundantly suppress the default muscle fate in induced mesenchyme cells. Similarly in notochord induction, Brachyury, which is required for notochord differentiation, and other factors, Lhx3 and Mnx, are likely to suppress the default nerve cord fate redundantly. Lhx3 commonly suppresses the default fates in two kinds of induction. Mis-activation of the autonomously executed default program in induced cells is detrimental to choice of the binary cell fate. Multifold redundant mechanisms would be required for suppression of the default fate to be secure. Copyright © 2016 Elsevier Inc. All rights reserved.

Human immunodeficiency virus type 1 enhancer-binding protein 3 is essential for the expression of asparagine-linked glycosylation 2 in the regulation of osteoblast and chondrocyte differentiation.

PubMed

Imamura, Katsuyuki; Maeda, Shingo; Kawamura, Ichiro; Matsuyama, Kanehiro; Shinohara, Naohiro; Yahiro, Yuhei; Nagano, Satoshi; Setoguchi, Takao; Yokouchi, Masahiro; Ishidou, Yasuhiro; Komiya, Setsuro

2014-04-04

Human immunodeficiency virus type 1 enhancer-binding protein 3 (Hivep3) suppresses osteoblast differentiation by inducing proteasomal degradation of the osteogenesis master regulator Runx2. In this study, we tested the possibility of cooperation of Hivep1, Hivep2, and Hivep3 in osteoblast and/or chondrocyte differentiation. Microarray analyses with ST-2 bone stroma cells demonstrated that expression of any known osteochondrogenesis-related genes was not commonly affected by the three Hivep siRNAs. Only Hivep3 siRNA promoted osteoblast differentiation in ST-2 cells, whereas all three siRNAs cooperatively suppressed differentiation in ATDC5 chondrocytes. We further used microarray analysis to identify genes commonly down-regulated in both MC3T3-E1 osteoblasts and ST-2 cells upon knockdown of Hivep3 and identified asparagine-linked glycosylation 2 (Alg2), which encodes a mannosyltransferase residing on the endoplasmic reticulum. The Hivep3 siRNA-mediated promotion of osteoblast differentiation was negated by forced Alg2 expression. Alg2 suppressed osteoblast differentiation and bone formation in cultured calvarial bone. Alg2 was immunoprecipitated with Runx2, whereas the combined transfection of Runx2 and Alg2 interfered with Runx2 nuclear localization, which resulted in suppression of Runx2 activity. Chondrocyte differentiation was promoted by Hivep3 overexpression, in concert with increased expression of Creb3l2, whose gene product is the endoplasmic reticulum stress transducer crucial for chondrogenesis. Alg2 silencing suppressed Creb3l2 expression and chondrogenesis of ATDC5 cells, whereas infection of Alg2-expressing virus promoted chondrocyte maturation in cultured cartilage rudiments. Thus, Alg2, as a downstream mediator of Hivep3, suppresses osteogenesis, whereas it promotes chondrogenesis. To our knowledge, this study is the first to link a mannosyltransferase gene to osteochondrogenesis.

The Effect of Interocular Contrast and Ocular Dominance on the Perception of Motion-in-Depth in 3-D Displays

DTIC Science & Technology

1981-08-01

Sokolov, 1911), by a plate containing a series of slits (Kanolt, 1918), or by lenticular sheets (Ives, 1930). A recently developed autostereoscopic...dioptic power and orientation were inserted in the stimulus deflector to correct the observer’s astigmatism . Spherical error, if 13 OBSERVER’S I

Differential BPFs with Multiple Transmission Zeros Based on Terminated Coupled Lines

NASA Astrophysics Data System (ADS)

Niu, Yiming; Yang, Guo; Wu, Wen

2018-04-01

Differential bandpass filters (BPFs) named Filter A and Filter B based on Terminated Coupled Lines (TCLs) are proposed in this letter. The TCLs contributes to not only three poles in differential-mode (DM) for wideband filtering response but also multiple zeros in both DM and common-mode (CM) offering wide DM out-of-band rejection and good CM suppression. Fabricated filters centred at 3.5 GHz with wide DM passband and wideband CM suppression have been designed and measured. The filters improved the noise suppression capability of the communication and radiometer systems. The simulated and measured results are in good agreement.

[Advances in postoperative thyroid-stimulating hormone suppression therapy in females with thyroid cancer].

PubMed

Song, F; Yi, H L

2018-05-07

Differentiated thyroid cancer is the most common malignant carcinoma in female population.Postoperative long-term thyroid-stimulating hormone(TSH) suppression therapy can reduce the risk of recurrence for differentiated thyroid cancer and control the progress of the disease, but it also induces simultaneously subclinical hypothyroidism and imposes negative effect on female. In addition to cardiovascular disease, TSH suppression therapy can lead to the alteration of sex hormone metabolism, menstrual disorder, poor influence on pregnancy and osteoporosis. This article reviews the recent studies on postoperative TSH suppression therapy in women with thyroid cancer.

Bropirimine inhibits osteoclast differentiation through production of interferon-β

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

Suzuki, Hiroaki; Mochizuki, Ayako; Yoshimura, Kentaro

Bropirimine is a synthetic agonist for toll-like receptor 7 (TLR7). In this study, we investigated the effects of bropirimine on differentiation and bone-resorbing activity of osteoclasts in vitro. Bropirimine inhibited osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) induced by receptor activator of nuclear factor κB ligand (RANKL) in a concentration-dependent manner. Furthermore, it suppressed the mRNA expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), a master transcription factor for osteoclast differentiation, without affecting BMM viability. Bropirimine also inhibited osteoclast differentiation induced in co-cultures of mouse bone marrow cells (BMCs) and mouse osteoblastic UAMS-32 cells in the presencemore » of activated vitamin D{sub 3}. Bropirimine partially suppressed the expression of RANKL mRNA in UAMS-32 cells induced by activated vitamin D{sub 3}. Finally, the anti-interferon-β (IFN-β) antibody restored RANKL-dependent differentiation of BMMs into osteoclasts suppressed by bropirimine. These results suggest that bropirimine inhibits differentiation of osteoclast precursor cells into osteoclasts via TLR7-mediated production of IFN-β.« less

Human cerebral potentials evoked by moving dynamic random dot stereograms.

PubMed

Herpers, M J; Caberg, H B; Mol, J M

1981-07-01

In 11 normal healthy human subjects an evoked potential was elicited by moving dynamic random dot stereograms. The random dots were generated by a minicomputer. An average of each of 8 EEG channels of the subjects tested was made. The maximum of the cerebral evoked potentials thus found was localized in the central and parietal region. No response earlier than 130--150 msec after the stimulus could be proved. The influence of fixation, the number of dots provided, an interocular interstimulus interval in the presentation of the dots, and lense accommodation movements on the evoked stereoptic potentials was investigated and discussed. An interocular interstimulus interval (left eye leading) in the presentation of the dots caused an increase in latency of the response much longer than the imposed interstimulus interval itself. It was shown that no accommodation was needed to perceive the depth impression, and to evoke the cerebral response with random dot stereograms. There are indications of an asymmetry between the two hemispheres in the handling of depth perception after 250 msec. The potential distribution of the evoked potentials strongly suggests that they are not generated in the occipital region.

Cortical mechanisms for afterimage formation: evidence from interocular grouping

PubMed Central

Dong, Bo; Holm, Linus; Bao, Min

2017-01-01

Whether the retinal process alone or retinal and cortical processes jointly determine afterimage (AI) formation has long been debated. Based on the retinal rebound responses, recent work proposes that afterimage signals are exclusively generated in the retina, although later modified by cortical mechanisms. We tested this notion with the method of “indirect proof”. Each eye was presented with a 2-by-2 checkerboard of horizontal and vertical grating patches. Each corresponding patch of the two checkerboards was perpendicular to each other, which produces binocular rivalry, and can generate percepts ranging from complete interocular grouping to either monocular pattern. The monocular percepts became more frequent with higher contrast. Due to adaptation, the visual system is less sensitive during the AIs than during the inductions with AI-similar contrast. If the retina is the only origin of AIs, comparable contrast appearance would require stronger retinal signals in the AIs than in the inductions, thus leading to more frequent monocular percepts in the AIs than in the inductions. Surprisingly, subjects saw the fully coherent stripes significantly more often in AIs. Our results thus contradict the retinal generation notion, and suggest that in addition to the retina, cortex is directly involved in the generation of AI signals. PMID:28112230

Myostatin acts as an autocrine/paracrine negative regulator in myoblast differentiation from human induced pluripotent stem cells

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

Gao, Fei; Kishida, Tsunao; Ejima, Akika

Highlights: ► iPS-derived cells express myostatin and its receptor upon myoblast differentiation. ► Myostatin inhibits myoblast differentiation by inhibiting MyoD and Myo5a induction. ► Silencing of myostatin promotes differentiation of human iPS cells into myoblasts. -- Abstract: Myostatin, also known as growth differentiation factor (GDF-8), regulates proliferation of muscle satellite cells, and suppresses differentiation of myoblasts into myotubes via down-regulation of key myogenic differentiation factors including MyoD. Recent advances in stem cell biology have enabled generation of myoblasts from pluripotent stem cells, but it remains to be clarified whether myostatin is also involved in regulation of artificial differentiation of myoblastsmore » from pluripotent stem cells. Here we show that the human induced pluripotent stem (iPS) cell-derived cells that were induced to differentiate into myoblasts expressed myostatin and its receptor during the differentiation. An addition of recombinant human myostatin (rhMyostatin) suppressed induction of MyoD and Myo5a, resulting in significant suppression of myoblast differentiation. The rhMyostatin treatment also inhibited proliferation of the cells at a later phase of differentiation. RNAi-mediated silencing of myostatin promoted differentiation of human iPS-derived embryoid body (EB) cells into myoblasts. These results strongly suggest that myostatin plays an important role in regulation of myoblast differentiation from iPS cells of human origin. The present findings also have significant implications for potential regenerative medicine for muscular diseases.« less

Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17

PubMed Central

Guinea-Viniegra, Juan; Zenz, Rainer; Scheuch, Harald; Jiménez, María; Bakiri, Latifa; Petzelbauer, Peter; Wagner, Erwin F.

2012-01-01

Squamous cell carcinomas (SCCs) are heterogeneous and aggressive skin tumors for which innovative, targeted therapies are needed. Here, we identify a p53/TACE pathway that is negatively regulated by FOS and show that the FOS/p53/TACE axis suppresses SCC by inducing differentiation. We found that epidermal Fos deletion in mouse tumor models or pharmacological FOS/AP-1 inhibition in human SCC cell lines induced p53 expression. Epidermal cell differentiation and skin tumor suppression were caused by a p53-dependent transcriptional activation of the metalloprotease TACE/ADAM17 (TNF-α–converting enzyme), a previously unknown p53 target gene that was required for NOTCH1 activation. Although half of cutaneous human SCCs display p53-inactivating mutations, restoring p53/TACE activity in mouse and human skin SCCs induced tumor cell differentiation independently of the p53 status. We propose FOS/AP-1 inhibition or p53/TACE reactivating strategies as differentiation-inducing therapies for SCCs. PMID:22772468

C-terminus of HSC70-Interacting Protein (CHIP) Inhibits Adipocyte Differentiation via Ubiquitin- and Proteasome-Mediated Degradation of PPARγ

PubMed Central

Kim, Jung-Hoon; Shin, Soyeon; Seo, Jinho; Lee, Eun-Woo; Jeong, Manhyung; Lee, Min-sik; Han, Hyun-Ji; Song, Jaewhan

2017-01-01

PPARγ (Peroxisome proliferator-activated receptor γ) is a nuclear receptor involved in lipid homeostasis and related metabolic diseases. Acting as a transcription factor, PPARγ is a master regulator for adipocyte differentiation. Here, we reveal that CHIP (C-terminus of HSC70-interacting protein) suppresses adipocyte differentiation by functioning as an E3 ligase of PPARγ. CHIP directly binds to and induces ubiquitylation of the PPARγ protein, leading to proteasome-dependent degradation. Stable overexpression or knockdown of CHIP inhibited or promoted adipogenesis, respectively, in 3T3-L1 cells. On the other hand, a CHIP mutant defective in E3 ligase could neither regulate PPARγ protein levels nor suppress adipogenesis, indicating the importance of CHIP-mediated ubiquitylation of PPARγ in adipocyte differentiation. Lastly, a CHIP null embryo fibroblast exhibited augmented adipocyte differentiation with increases in PPARγ and its target protein levels. In conclusion, CHIP acts as an E3 ligase of PPARγ, suppressing PPARγ-mediated adipogenesis. PMID:28059128

Binocular treatment of amblyopia using videogames (BRAVO): study protocol for a randomised controlled trial.

PubMed

Guo, Cindy X; Babu, Raiju J; Black, Joanna M; Bobier, William R; Lam, Carly S Y; Dai, Shuan; Gao, Tina Y; Hess, Robert F; Jenkins, Michelle; Jiang, Yannan; Kowal, Lionel; Parag, Varsha; South, Jayshree; Staffieri, Sandra Elfride; Walker, Natalie; Wadham, Angela; Thompson, Benjamin

2016-10-18

Amblyopia is a common neurodevelopmental disorder of vision that is characterised by visual impairment in one eye and compromised binocular visual function. Existing evidence-based treatments for children include patching the nonamblyopic eye to encourage use of the amblyopic eye. Currently there are no widely accepted treatments available for adults with amblyopia. The aim of this trial is to assess the efficacy of a new binocular, videogame-based treatment for amblyopia in older children and adults. We hypothesise that binocular treatment will significantly improve amblyopic eye visual acuity relative to placebo treatment. The BRAVO study is a double-blind, randomised, placebo-controlled multicentre trial to assess the effectiveness of a novel videogame-based binocular treatment for amblyopia. One hundred and eight participants aged 7 years or older with anisometropic and/or strabismic amblyopia (defined as ≥0.2 LogMAR interocular visual acuity difference, ≥0.3 LogMAR amblyopic eye visual acuity and no ocular disease) will be recruited via ophthalmologists, optometrists, clinical record searches and public advertisements at five sites in New Zealand, Canada, Hong Kong and Australia. Eligible participants will be randomised by computer in a 1:1 ratio, with stratification by age group: 7-12, 13-17 and 18 years and older. Participants will be randomised to receive 6 weeks of active or placebo home-based binocular treatment. Treatment will be in the form of a modified interactive falling-blocks game, implemented on a 5th generation iPod touch device viewed through red/green anaglyphic glasses. Participants and those assessing outcomes will be blinded to group assignment. The primary outcome is the change in best-corrected distance visual acuity in the amblyopic eye from baseline to 6 weeks post randomisation. Secondary outcomes include distance and near visual acuity, stereopsis, interocular suppression, angle of strabismus (where applicable) measured at baseline, 3, 6, 12 and 24 weeks post randomisation. Treatment compliance and acceptability will also be assessed along with quality of life for adult participants. The BRAVO study is the first randomised controlled trial of a home-based videogame treatment for older children and adults with amblyopia. The results will indicate whether a binocular approach to amblyopia treatment conducted at home is effective for patients aged 7 years or older. This trial was registered in Australia and New Zealand Clinical Trials Registry ( ACTRN12613001004752 ) on 10 September 2013.

[The importance of bisoprolol in prevention of heart left ventricular hypertrophy in patients with long term L-thyroxin suppressive therapy, after the operation of differentiated thyroid carcinoma].

PubMed

Matuszewska, Gabriela; Marek, Bogdan; Kajdaniuk, Dariusz; Przywara-Chowaniec, Brygida; Jarzab, Jerzy; Jarzab, Barbara

2007-01-01

Patients with differentiated thyroid carcinoma have to undergo radical surgical treatment, which includes total thyreoidectomy, radioiodine therapy and a life-time suppressive therapy with L-thyroxine. The aim of this study was a prospective evaluation of left ventricular hypertrophy during L suppressive-thyroxine treatment in patients treated for differentiated thyroid carcinoma. The examined group comprised 50 patients with differentiated thyroid carcinoma, treated by total thyroidectomy and 131I therapy. Echocardiographic measurements were needed for estimation of left ventricular mass and its index, according to recommendations of American Echocardiography Society. During two-years long suppressive therapy we observed a significant rise in left ventricular mass. In woman group left ventricular mass was increased from 168+/-39 g to 204+/-45 g (p<0.001) and in men from 205+/-60 to 320+/-21 g. Likewise, left ventricular mass index was increased in women group from 96+/-18 g/m(2) to 116+/-25 g/m(2) (p<0.001) and in men group from 107+/-37 g/m(2) to 158+/-28 g/m(2). Simultaneous treatment with bisoprolol caused a regression of left myocardial hypertrophy. Already after 6 months of simultaneous treatment with L-thyroxin and bisoprolol, for left ventricular mass was reduced to normal: in woman 165+/-35 g, and in men to 178+/-38 g. Analogous results were obtained left ventricular mass index. After 6 months it was reduced to 94+/-12 g/m(2) in woman and in men to 132+/-32 g/m(2). 1. In differentiated thyroid cancer patients, treated postoperatively with L-thyroxine suppressive therapy, left ventricular hypertrophy is observed already during the first year of suppressive therapy and progresses during the next year of treatment. 2 Addition of a beta-adrenergic antagonist to suppressive doses of L-thyroxine causes a regression of left ventricular hypertrophy, thus, beta-adrenergic antagonists should be administered in this group of patients.

Accuracy of Noncycloplegic Retinoscopy, Retinomax Autorefractor, and SureSight Vision Screener for Detecting Significant Refractive Errors

PubMed Central

Kulp, Marjean Taylor; Ying, Gui-shuang; Huang, Jiayan; Maguire, Maureen; Quinn, Graham; Ciner, Elise B.; Cyert, Lynn A.; Orel-Bixler, Deborah A.; Moore, Bruce D.

2014-01-01

Purpose. To evaluate, by receiver operating characteristic (ROC) analysis, the ability of noncycloplegic retinoscopy (NCR), Retinomax Autorefractor (Retinomax), and SureSight Vision Screener (SureSight) to detect significant refractive errors (RE) among preschoolers. Methods. Refraction results of eye care professionals using NCR, Retinomax, and SureSight (n = 2588) and of nurse and lay screeners using Retinomax and SureSight (n = 1452) were compared with masked cycloplegic retinoscopy results. Significant RE was defined as hyperopia greater than +3.25 diopters (D), myopia greater than 2.00 D, astigmatism greater than 1.50 D, and anisometropia greater than 1.00 D interocular difference in hyperopia, greater than 3.00 D interocular difference in myopia, or greater than 1.50 D interocular difference in astigmatism. The ability of each screening test to identify presence, type, and/or severity of significant RE was summarized by the area under the ROC curve (AUC) and calculated from weighted logistic regression models. Results. For detection of each type of significant RE, AUC of each test was high; AUC was better for detecting the most severe levels of RE than for all REs considered important to detect (AUC 0.97–1.00 vs. 0.92–0.93). The area under the curve of each screening test was high for myopia (AUC 0.97–0.99). Noncycloplegic retinoscopy and Retinomax performed better than SureSight for hyperopia (AUC 0.92–0.99 and 0.90–0.98 vs. 0.85–0.94, P ≤ 0.02), Retinomax performed better than NCR for astigmatism greater than 1.50 D (AUC 0.95 vs. 0.90, P = 0.01), and SureSight performed better than Retinomax for anisometropia (AUC 0.85–1.00 vs. 0.76–0.96, P ≤ 0.07). Performance was similar for nurse and lay screeners in detecting any significant RE (AUC 0.92–1.00 vs. 0.92–0.99). Conclusions. Each test had a very high discriminatory power for detecting children with any significant RE. PMID:24481262

Evaluating the Role of Contingency in Differentially Reinforced Tic Suppression

ERIC Educational Resources Information Center

Himle, Michael B.; Woods, Douglas W.; Bunaciu, Liviu

2008-01-01

The current study evaluated the effects of tokens delivered on differential reinforcement of zero-rate behavior (DRO) schedules or noncontingently on tic suppression in 4 children with tics. Tic frequency was lower in 3 of 4 children when tokens were delivered contingent on the absence of tics than when tokens were delivered noncontingently.…

High Glucose Inhibits Neural Stem Cell Differentiation Through Oxidative Stress and Endoplasmic Reticulum Stress.

PubMed

Chen, Xi; Shen, Wei-Bin; Yang, Penghua; Dong, Daoyin; Sun, Winny; Yang, Peixin

2018-06-01

Maternal diabetes induces neural tube defects by suppressing neurogenesis in the developing neuroepithelium. Our recent study further revealed that high glucose inhibited embryonic stem cell differentiation into neural lineage cells. However, the mechanism whereby high glucose suppresses neural differentiation is unclear. To investigate whether high glucose-induced oxidative stress and endoplasmic reticulum (ER) stress lead to the inhibition of neural differentiation, the effect of high glucose on neural stem cell (the C17.2 cell line) differentiation was examined. Neural stem cells were cultured in normal glucose (5 mM) or high glucose (25 mM) differentiation medium for 3, 5, and 7 days. High glucose suppressed neural stem cell differentiation by significantly decreasing the expression of the neuron marker Tuj1 and the glial cell marker GFAP and the numbers of Tuj1 + and GFAP + cells. The antioxidant enzyme superoxide dismutase mimetic Tempol reversed high glucose-decreased Tuj1 and GFAP expression and restored the numbers of neurons and glial cells differentiated from neural stem cells. Hydrogen peroxide treatment imitated the inhibitory effect of high glucose on neural stem cell differentiation. Both high glucose and hydrogen peroxide triggered ER stress, whereas Tempol blocked high glucose-induced ER stress. The ER stress inhibitor, 4-phenylbutyrate, abolished the inhibition of high glucose or hydrogen peroxide on neural stem cell differentiation. Thus, oxidative stress and its resultant ER stress mediate the inhibitory effect of high glucose on neural stem cell differentiation.

Nemo-like kinase (NLK) expression in osteoblastic cells and suppression of osteoblastic differentiation

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

Nifuji, Akira, E-mail: nifuji-a@tsurumi-u.ac.jp; Department of Pharmacology, Tsurumi University School of Dental Medicine, Yokohama; Ideno, Hisashi

2010-04-15

Mitogen-activated protein kinases (MAPKs) regulate proliferation and differentiation in osteoblasts. The vertebral homologue of nemo, nemo-like kinase (NLK), is an atypical MAPK that targets several signaling components, including the T-cell factor/lymphoid enhancer factor (TCF/Lef1) transcription factor. Recent studies have shown that NLK forms a complex with the histone H3-K9 methyltransferase SETDB1 and suppresses peroxisome proliferator-activated receptor (PPAR)-gamma:: action in the mesenchymal cell line ST2. Here we investigated whether NLK regulates osteoblastic differentiation. We showed that NLK mRNA is expressed in vivo in osteoblasts at embryonic day 18.5 (E18.5) mouse calvariae. By using retrovirus vectors, we performed forced expression of NLKmore » in primary calvarial osteoblasts (pOB cells) and the mesenchymal cell line ST2. Wild-type NLK (NLK-WT) suppressed alkaline phosphatase activity and expression of bone marker genes such as alkaline phosphatase, type I procollagen, runx2, osterix, steopontin and osteocalcin in these cells. NLK-WT also decreased type I collagen protein expression in pOB and ST2 cells. Furthermore, mineralized nodule formation was reduced in pOB cells overexpressing NLK-WT. In contrast, kinase-negative form of NLK (NLK-KN) did not suppress or partially suppress ALP activity and bone marker gene expression in pOB and ST2 cells. NLK-KN did not suppress nodule formation in pOB cells. In addition to forced expression, suppression of endogenous NLK expression by siRNA increased bone marker gene expression in pOB and ST2 cells. Finally, transcriptional activity analysis of gene promoters revealed that NLK-WT suppressed Wnt1 activation of TOP flash promoter and Runx2 activation of the osteocalcin promoter. Taken together, these results suggest that NLK negatively regulates osteoblastic differentiation.« less

Arsenite suppression of BMP signaling in human keratinocytes

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

Phillips, Marjorie A.; Qin, Qin; Hu, Qin

2013-06-15

Arsenic, a human skin carcinogen, suppresses differentiation of cultured keratinocytes. Exploring the mechanism of this suppression revealed that BMP-6 greatly increased levels of mRNA for keratins 1 and 10, two of the earliest differentiation markers expressed, a process prevented by co-treatment with arsenite. BMP also stimulated, and arsenite suppressed, mRNA for FOXN1, an important transcription factor driving early keratinocyte differentiation. Keratin mRNAs increased slowly after BMP-6 addition, suggesting they are indirect transcriptional targets. Inhibition of Notch1 activation blocked BMP induction of keratins 1 and 10, while FOXN1 induction was largely unaffected. Supporting a requirement for Notch1 signaling in keratin induction,more » BMP increased levels of activated Notch1, which was blocked by arsenite. BMP also greatly decreased active ERK, while co-treatment with arsenite maintained active ERK. Inhibition of ERK signaling mimicked BMP by inducing keratin and FOXN1 mRNAs and by increasing active Notch1, effects blocked by arsenite. Of 6 dual-specificity phosphatases (DUSPs) targeting ERK, two were induced by BMP unless prevented by simultaneous exposure to arsenite and EGF. Knockdown of DUSP2 or DUSP14 using shRNAs greatly reduced FOXN1 and keratins 1 and 10 mRNA levels and their induction by BMP. Knockdown also decreased activated Notch1, keratin 1 and keratin 10 protein levels, both in the presence and absence of BMP. Thus, one of the earliest effects of BMP is induction of DUSPs, which increases FOXN1 transcription factor and activates Notch1, both required for keratin gene expression. Arsenite prevents this cascade by maintaining ERK signaling, at least in part by suppressing DUSP expression. - Highlights: • BMP induces FOXN1 transcription. • BMP induces DUSP2 and DUSP14, suppressing ERK activation. • Arsenite suppresses levels of phosphorylated Smad1/5 and FOXN1 and DUSP mRNA. • These actions rationalize arsenite suppression of keratinocyte differentiation.« less

DLP™-based dichoptic vision test system

NASA Astrophysics Data System (ADS)

Woods, Russell L.; Apfelbaum, Henry L.; Peli, Eli

2010-01-01

It can be useful to present a different image to each of the two eyes while they cooperatively view the world. Such dichoptic presentation can occur in investigations of stereoscopic and binocular vision (e.g., strabismus, amblyopia) and vision rehabilitation in clinical and research settings. Various techniques have been used to construct dichoptic displays. The most common and most flexible modern technique uses liquid-crystal (LC) shutters. When used in combination with cathode ray tube (CRT) displays, there is often leakage of light from the image intended for one eye into the view of the other eye. Such interocular crosstalk is 14% even in our state of the art CRT-based dichoptic system. While such crosstalk may have minimal impact on stereo movie or video game experiences, it can defeat clinical and research investigations. We use micromirror digital light processing (DLP™) technology to create a novel dichoptic visual display system with substantially lower interocular crosstalk (0.3% remaining crosstalk comes from the LC shutters). The DLP system normally uses a color wheel to display color images. Our approach is to disable the color wheel, synchronize the display directly to the computer's sync signal, allocate each of the three (former) color presentations to one or both eyes, and open and close the LC shutters in synchrony with those color events.

Averrhoa carambola L. peel extract suppresses adipocyte differentiation in 3T3-L1 cells.

PubMed

Rashid, Asyifah Mohamed; Lu, Kaihui; Yip, Yew Mun; Zhang, Dawei

2016-02-01

Obesity is associated with an increased risk of many chronic diseases. Recently, a growing body of evidence has shown that phytochemicals may inhibit adipogenesis and obesity. In this study, we report for the first time, the ability of Averrhoa carambola L. peel extract commonly known as star fruit (SFP) to effectively suppress adipocyte differentiation in 3T3-L1 preadipocytes and therefore, address it as a potential candidate to treat obesity and its related diseases. (-)-Epicatechin was identified as a bioactive compound likely responsible for this suppression. As the genetic expression studies revealed that the adipogenic activity of SFP extract was due to the simultaneous downregulation of the C/EBPα and PPARγ as well as the upregulation of PPARα receptor genes, a detailed computational docking study was also elucidated to reveal the likely binding mode of (-)-epicatechin to the receptor of interest, accounting for the likely mechanism that results in the overall suppression of adipocyte differentiation.

Extending the Stabilized Supralinear Network model for binocular image processing.

PubMed

Selby, Ben; Tripp, Bryan

2017-06-01

The visual cortex is both extensive and intricate. Computational models are needed to clarify the relationships between its local mechanisms and high-level functions. The Stabilized Supralinear Network (SSN) model was recently shown to account for many receptive field phenomena in V1, and also to predict subtle receptive field properties that were subsequently confirmed in vivo. In this study, we performed a preliminary exploration of whether the SSN is suitable for incorporation into large, functional models of the visual cortex, considering both its extensibility and computational tractability. First, whereas the SSN receives abstract orientation signals as input, we extended it to receive images (through a linear-nonlinear stage), and found that the extended version behaved similarly. Secondly, whereas the SSN had previously been studied in a monocular context, we found that it could also reproduce data on interocular transfer of surround suppression. Finally, we reformulated the SSN as a convolutional neural network, and found that it scaled well on parallel hardware. These results provide additional support for the plausibility of the SSN as a model of lateral interactions in V1, and suggest that the SSN is well suited as a component of complex vision models. Future work will use the SSN to explore relationships between local network interactions and sophisticated vision processes in large networks. Copyright © 2017 Elsevier Ltd. All rights reserved.

Deletion of Ten-m3 Induces the Formation of Eye Dominance Domains in Mouse Visual Cortex

PubMed Central

Merlin, Sam; Horng, Sam; Marotte, Lauren R.; Sur, Mriganka; Sawatari, Atomu

2013-01-01

The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex. PMID:22499796

5-Hydroxyferulic acid methyl ester isolated from wasabi leaves inhibits 3T3-L1 adipocyte differentiation.

PubMed

Misawa, Naoki; Hosoya, Takahiro; Yoshida, Shuhei; Sugimoto, Osamu; Yamada-Kato, Tomoe; Kumazawa, Shigenori

2018-02-26

To investigate the compounds present in wasabi leaves (Wasabia japonica Matsumura) that inhibit the adipocyte differentiation, activity-guided fractionation was performed on these leaves. 5-Hydroxyferulic acid methyl ester (1: 5-HFA ester), one of the phenylpropanoids, was isolated from wasabi leaves as a compound that inhibits the adipocyte differentiation. Compound 1 suppressed the intracellular lipid accumulation of 3T3-L1 cells without significant cytotoxicity. Gene expression analysis revealed that 1 suppressed the mRNA expression of 2 master regulators of adipocyte differentiation, PPARγ and C/EBPα. Furthermore, 1 downregulated the expression of adipogenesis-related genes, GLUT4, LPL, SREBP-1c, ACC, and FAS. Protein expression analysis revealed that 1 suppressed PPARγ protein expression. Moreover, to investigate the relationship between the structure and activity of inhibiting the adipocyte differentiation, we synthesized 12 kinds of phenylpropanoid analog. Comparison of the activity among 1 and its analogs suggested that the compound containing the substructure that possess a common functional group at the ortho position such as a catechol group exhibits the activity of inhibiting the adipocyte differentiation. Taken together, our findings suggest that 1 from wasabi leaves inhibits adipocyte differentiation via the downregulation of PPARγ. Copyright © 2018 John Wiley & Sons, Ltd.

Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells

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

Kim, Hyun-Ju, E-mail: biohjk@knu.ac.kr; Yoon, Hye-Jin; Yoon, Kyung-Ae

Lipocalin-2 (LCN2) is a member of the lipocalin superfamily and plays a critical role in the regulation of various physiological processes, such as inflammation and obesity. In this study, we report that LCN2 negatively modulates the proliferation and differentiation of osteoclast precursors, resulting in impaired osteoclast formation. The overexpression of LCN2 in bone marrow-derived macrophages or the addition of recombinant LCN2 protein inhibits the formation of multinuclear osteoclasts. LCN2 suppresses macrophage colony-stimulating factor (M-CSF)-induced proliferation of osteoclast precursor cells without affecting their apoptotic cell death. Interestingly, LCN2 decreases the expression of the M-CSF receptor, c-Fms, and subsequently blocks its downstreammore » signaling cascades. In addition, LCN2 inhibits RANKL-induced osteoclast differentiation and attenuates the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are important modulators in osteoclastogenesis. Mechanistically, LCN2 inhibits NF-κB signaling pathways, as demonstrated by the suppression of IκBα phosphorylation, nuclear translocation of p65, and NF-κB transcriptional activity. Thus, LCN2 is an anti-osteoclastogenic molecule that exerts its effects by retarding the proliferation and differentiation of osteoclast lineage cells. - Highlights: • LCN2 expression is regulated during osteoclast development. • LCN2 suppresses M-CSF-mediated osteoclast precursor proliferation. • LCN2 inhibits RANKL-induced osteoclast differentiation.« less

4E-BP1 regulates the differentiation of white adipose tissue.

PubMed

Tsukiyama-Kohara, Kyoko; Katsume, Asao; Kimura, Kazuhiro; Saito, Masayuki; Kohara, Michinori

2013-07-01

4E Binding protein 1 (4E-BP1) suppresses translation initiation. The absence of 4E-BP1 drastically reduces the amount of adipose tissue in mice. To address the role of 4E-BP1 in adipocyte differentiation, we characterized 4E-BP1(-/-) mice in this study. The lack of 4E-BP1 decreased the amount of white adipose tissue and increased the amount of brown adipose tissue. In 4E-BP1(-/-) MEF cells, PPARγ coactivator 1 alpha (PGC-1α) expression increased and exogenous 4E-BP1 expression suppressed PGC-1α expression. The level of 4E-BP1 expression was higher in white adipocytes than in brown adipocytes and showed significantly greater up-regulation in white adipocytes than in brown adipocytes during preadipocyte differentiation into mature adipocytes. The amount of PGC-1α was consistently higher in HB cells (a brown preadipocyte cell line) than in HW cells (a white preadipocyte cell line) during differentiation. Moreover, the ectopic over-expression of 4E-BP1 suppressed PGC-1α expression in white adipocytes, but not in brown adipocytes. Thus, the results of our study indicate that 4E-BP1 may suppress brown adipocyte differentiation and PGC-1α expression in white adipose tissues. © 2013 The Authors Genes to Cells © 2013 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin

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

De Abrew, K. Nadira; Phadnis, Ashwini S.; Genetics Program, Michigan State University, East Lansing, MI 48824

2011-04-15

Exposure to the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters B-cell differentiation and suppresses antibody production. Previous genomic studies in mouse B cells identified Bach2 as a direct target of the AHR. Bach2 is known to repress expression of Prdm1, a key transcription factor involved in B-cell differentiation, by binding to Maf elements (MAREs) in the regulatory regions of the gene. Chromatin immunoprecipitation followed by quantitative PCR in TCDD-treated lipopolysaccharide (LPS)-activated B cells showed increased binding of the AHR within the first intron in the Bach2 gene. The binding was further confirmed by electrophoretic mobility shift assay (EMSA). TCDDmore » also induced expression of Bach2 in activated as well as resting B cells from 2 to 24 h post-treatment in a time- and concentration-dependent manner. Expression of Prdm1 was decreased by TCDD at 24 h and was consistent with repression by Bach2. Increased DNA binding activity to the intron 5 MARE with increasing TCDD concentrations was observed by EMSA. Supershifts identified the presence of Bach2 in the DNA binding complex associated with the intron 5 MARE of Prdm1. Functional validation of the role of Bach2 in the suppression of B-cell differentiation by TCDD was performed using RNA interference (RNAi). Knockdown of Bach2 showed approximately 40% reversal in the TCDD-induced suppression of IgM secretion when compared to controls. The results suggest that the transcriptional regulation of Bach2 by the AHR is one of the mechanisms involved in the suppression of B-cell differentiation by TCDD.« less

Regulation of Bach2 by the Aryl-hydrocarbon Receptor as a Mechanism for Suppression of B-cell Differentiation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

PubMed Central

De Abrew, K. Nadira; Phadnis, Ashwini S.; Crawford, Robert B.; Kaminski, Norbert E.; Thomas, Russell S.

2011-01-01

Exposure to the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alters B cell differentiation and suppresses antibody production. Previous genomic studies in mouse B cells identified Bach2 as a direct target of the AHR. Bach2 is known to repress expression of Prdm1, a key transcription factor involved in B cell differentiation, by binding to Maf elements (MAREs) in the regulatory regions of the gene. Chromatin immunopreciptiation followed by quantitative PCR in TCDD-treated lipopolysaccharide (LPS)-activated B cells showed increased binding of the AHR within the first intron in the Bach2 gene. The binding was further confirmed by electrophoretic mobility shift assay (EMSA). TCDD also induced expression of Bach2 in activated as well as resting B cells from 2 to 24 h post-treatment in a time and concentration-dependent manner. Expression of Prdm1 was decreased by TCDD at 24 h and was consistent with repression by Bach2. Increased DNA binding activity to the intron 5 MARE with increasing TCDD concentration was observed by EMSA. Supershifts identified the presence of Bach2 in the DNA binding complex associated with the intron5 MARE of Prdm1. Functional validation of the role of Bach2 in the suppression of B-cell differentiation by TCDD was performed using RNAi. Knockdown of Bach2 showed approximately 40% reversal in the TCDD-induced suppression of IgM secretion when compared to controls. The results suggest that the transcriptional regulation of Bach2 by the AHR is one of the mechanisms involved in the suppression of B-cell differentiation by TCDD. PMID:21296099

Butein, a Tetrahydroxychalcone, Suppresses Cancer-induced Osteoclastogenesis Through Inhibition of RANKL Signaling

PubMed Central

Sung, Bokyung; Cho, Sung-Gook; Liu, Mingyao; Aggarwal, Bharat B.

2011-01-01

Osteoclastogenesis is associated with aging and various age-related inflammatory chronic diseases, including cancer. Receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL), a member of the tumor necrosis factor superfamily, has been implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We therefore investigated whether butein, a tetrahydroxychalcone, could inhibit RANKL signaling and suppress osteoclastogenesis induced by RANKL or tumor cells. We found that human multiple myeloma cells (MM.1S and U266), breast tumor cells (MDA-MB-231), and prostate tumor cells (PC-3) induced differentiation of macrophages to osteoclasts, as indicated by TRAP-positive cells, and that butein suppressed this process. The chalcone also suppressed the expression of RANKL by the tumor cells. We further found that butein suppressed RANKL-induced NF-κB activation and that this suppression correlated with the inhibition of IκBα kinase and suppression of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Finally, butein also suppressed the RANKL-induced differentiation of macrophages to osteoclasts in a dose-dependent and time-dependent manner. Collectively, our results indicate that butein suppresses the osteoclastogenesis induced by tumor cells and by RANKL, by suppression of the NF-κB activation pathway. PMID:21170936

A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.

PubMed

Chen, Q; Muramoto, K; Masaaki, N; Ding, Y; Yang, H; Mackey, M; Li, W; Inoue, Y; Ackermann, K; Shirota, H; Matsumoto, I; Spyvee, M; Schiller, S; Sumida, T; Gusovsky, F; Lamphier, M

2010-05-01

Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

Induction of suppression through human T cell interactions.

PubMed

Lydyard, P M; Hayward, A R

1980-02-01

Concanavalin A (Con A) activated T cells, devoid of cells bearing Fc receptors for IgG (T - TG) help human B lymphocytes to differentiate into plasma cells (PC) in response to pokeweed mitogen (PWM). PC differentiation is reduced when adult T cells are added to such cultures. The radiosensitivity of suppression and the radioresistance of help enabled us to show that adult T cells include a suppressor-precursor which is activated by irradiated Con A-precultured T cells. Newborn T cells which include active suppressors, are both poor stimulators of suppressor-precursors and poor helpers of B cells. Our results suggest that at least two cells may mediate Con A-induced suppression, one which suppresses directly and is radiosensitive and another which is radioresistant and stimulates suppressor-precursors in a target population of T cells.

Roles for miR-375 in Neuroendocrine Differentiation and Tumor Suppression via Notch Pathway Suppression in Merkel Cell Carcinoma.

PubMed

Abraham, Karan J; Zhang, Xiao; Vidal, Ricardo; Paré, Geneviève C; Feilotter, Harriet E; Tron, Victor A

2016-04-01

Dysfunction of key miRNA pathways regulating basic cellular processes is a common driver of many cancers. However, the biological roles and/or clinical applications of such pathways in Merkel cell carcinoma (MCC), a rare but lethal cutaneous neuroendocrine (NE) malignancy, have yet to be determined. Previous work has established that miR-375 is highly expressed in MCC tumors, but its biological role in MCC remains unknown. Herein, we show that elevated miR-375 expression is a specific feature of well-differentiated MCC cell lines that express NE markers. In contrast, miR-375 is strikingly down-regulated in highly aggressive, undifferentiated MCC cell lines. Enforced miR-375 expression in these cells induced NE differentiation, and opposed cancer cell viability, migration, invasion, and survival, pointing to tumor-suppressive roles for miR-375. Mechanistically, miR-375-driven phenotypes were caused by the direct post-transcriptional repression of multiple Notch pathway proteins (Notch2 and RBPJ) linked to cancer and regulation of cell fate. Thus, we detail a novel molecular axis linking tumor-suppressive miR-375 and Notch with NE differentiation and cancer cell behavior in MCC. Our findings identify miR-375 as a putative regulator of NE differentiation, provide insight into the cell of origin of MCC, and suggest that miR-375 silencing may promote aggressive cancer cell behavior through Notch disinhibition. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Repetition Suppression and Multi-Voxel Pattern Similarity Differentially Track Implicit and Explicit Visual Memory

PubMed Central

Chun, Marvin M.; Kuhl, Brice A.

2013-01-01

Repeated exposure to a visual stimulus is associated with corresponding reductions in neural activity, particularly within visual cortical areas. It has been argued that this phenomenon of repetition suppression is related to increases in processing fluency or implicit memory. However, repetition of a visual stimulus can also be considered in terms of the similarity of the pattern of neural activity elicited at each exposure—a measure that has recently been linked to explicit memory. Despite the popularity of each of these measures, direct comparisons between the two have been limited, and the extent to which they differentially (or similarly) relate to behavioral measures of memory has not been clearly established. In the present study, we compared repetition suppression and pattern similarity as predictors of both implicit and explicit memory. Using functional magnetic resonance imaging, we scanned 20 participants while they viewed and categorized repeated presentations of scenes. Repetition priming (facilitated categorization across repetitions) was used as a measure of implicit memory, and subsequent scene recognition was used as a measure of explicit memory. We found that repetition priming was predicted by repetition suppression in prefrontal, parietal, and occipitotemporal regions; however, repetition priming was not predicted by pattern similarity. In contrast, subsequent explicit memory was predicted by pattern similarity (across repetitions) in some of the same occipitotemporal regions that exhibited a relationship between priming and repetition suppression; however, explicit memory was not related to repetition suppression. This striking double dissociation indicates that repetition suppression and pattern similarity differentially track implicit and explicit learning. PMID:24027275

Myostatin Suppression of Akirin1 Mediates Glucocorticoid-Induced Satellite Cell Dysfunction

PubMed Central

Dong, Yanjun; Pan, Jenny S.; Zhang, Liping

2013-01-01

Glucocorticoids production is increased in many pathological conditions that are associated with muscle loss, but their role in causing muscle wasting is not fully understood. We have demonstrated a new mechanism of glucocorticoid-induced muscle atrophy: Dexamethasone (Dex) suppresses satellite cell function contributing to the development of muscle atrophy. Specifically, we found that Dex decreases satellite cell proliferation and differentiation in vitro and in vivo. The mechanism involved Dex-induced upregulation of myostatin and suppression of Akirin1, a promyogenic gene. When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth. In addition, silencing myostatin in myoblasts or satellite cells prevented Dex from suppressing Akirin1 expression and cellular proliferation and differentiation. Finally, overexpression of Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation, theses improvements were no longer suppressed by Dex. We conclude that glucocorticoids stimulate myostatin which inhibits Akirin1 expression and the reparative functions of satellite cells. These responses attribute to muscle atrophy. Thus, inhibition of myostatin or increasing Akirin1 expression could lead to therapeutic strategies for improving satellite cell activation and enhancing muscle growth in diseases associated with increased glucocorticoid production. PMID:23516508

Myostatin suppression of Akirin1 mediates glucocorticoid-induced satellite cell dysfunction.

PubMed

Dong, Yanjun; Pan, Jenny S; Zhang, Liping

2013-01-01

Glucocorticoids production is increased in many pathological conditions that are associated with muscle loss, but their role in causing muscle wasting is not fully understood. We have demonstrated a new mechanism of glucocorticoid-induced muscle atrophy: Dexamethasone (Dex) suppresses satellite cell function contributing to the development of muscle atrophy. Specifically, we found that Dex decreases satellite cell proliferation and differentiation in vitro and in vivo. The mechanism involved Dex-induced upregulation of myostatin and suppression of Akirin1, a promyogenic gene. When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth. In addition, silencing myostatin in myoblasts or satellite cells prevented Dex from suppressing Akirin1 expression and cellular proliferation and differentiation. Finally, overexpression of Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation, theses improvements were no longer suppressed by Dex. We conclude that glucocorticoids stimulate myostatin which inhibits Akirin1 expression and the reparative functions of satellite cells. These responses attribute to muscle atrophy. Thus, inhibition of myostatin or increasing Akirin1 expression could lead to therapeutic strategies for improving satellite cell activation and enhancing muscle growth in diseases associated with increased glucocorticoid production.

Application of Bayes' to the prediction of referral decisions made by specialist optometrists in relation to chronic open angle glaucoma.

PubMed

Gurney, J C; Ansari, E; Harle, D; O'Kane, N; Sagar, R V; Dunne, M C M

2018-02-09

To determine the accuracy of a Bayesian learning scheme (Bayes') applied to the prediction of clinical decisions made by specialist optometrists in relation to the referral refinement of chronic open angle glaucoma. This cross-sectional observational study involved collection of data from the worst affected or right eyes of a consecutive sample of cases (n = 1,006) referred into the West Kent Clinical Commissioning Group Community Ophthalmology Team (COT) by high street optometrists. Multilevel classification of each case was based on race, sex, age, family history of chronic open angle glaucoma, reason for referral, Goldmann Applanation Tonometry (intraocular pressure and interocular asymmetry), optic nerve head assessment (vertical size, cup disc ratio and interocular asymmetry), central corneal thickness and visual field analysis (Hodapp-Parrish-Anderson classification). Randomised stratified tenfold cross-validation was applied to determine the accuracy of Bayes' by comparing its output to the clinical decisions of three COT specialist optometrists; namely, the decision to discharge, follow-up or refer each case. Outcomes of cross-validation, expressed as means and standard deviations, showed that the accuracy of Bayes' was high (95%, 2.0%) but that it falsely discharged (3.4%, 1.6%) or referred (3.1%, 1.5%) some cases. The results indicate that Bayes' has the potential to augment the decisions of specialist optometrists.

The effect of cyclic phosphatidic acid on the proliferation and differentiation of mouse cerebellar granule precursor cells during cerebellar development.

PubMed

Konakazawa, Misa; Gotoh, Mari; Murakami-Murofushi, Kimiko; Hamano, Ayana; Miyamoto, Yasunori

2015-07-21

The proliferation and differentiation of cerebellar granule cell precursors (GCPs) are highly regulated spatiotemporally during development. We focused on cyclic phosphatidic acid (cPA) as a lipid mediator with a cyclic phosphate group as a regulatory factor of GCPs. While its structure is similar to that of lysophosphatidic acid (LPA), its function is very unique. cPA is known to be present in the cerebellum at high levels, but its function has not been fully elucidated. In this study, we examined the role of cPA on the proliferation and differentiation of GCPs. A cell cycle analysis of GCPs revealed that cPA reduced the number of phospho-histone H3 (Phh3)-positive cells and bromodeoxy uridine (BrdU)-incorporated cells and increased an index of the cell cycle exit. We next analyzed the effect of cPA on GCP differentiation using Tuj1 as a neuronal marker of final differentiation. The results show that cPA increased the number of Tuj1-positive cells. Further analysis of the proliferation of GCPs showed that cPA suppressed Sonic hedgehog (Shh)-dependent proliferation, but did not suppress insulin-like growth factor-1 (IGF-1)-dependent proliferation. P2Y5 (LPA6), an LPA receptor, is highly expressed in GCPs. The knockdown of P2Y5 suppressed the inhibitory effect of cPA on the proliferation of GCPs, suggesting that P2Y5 is a candidate receptor for cPA. Thus, cPA suppresses the Shh-dependent proliferation of GCPs and promotes the differentiation of GCPs through P2Y5. These results demonstrate that cPA plays a critical role in the development of GCPs. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

High cell density suppresses BMP4-induced differentiation of human pluripotent stem cells to produce macroscopic spatial patterning in a unidirectional perfusion culture chamber.

PubMed

Tashiro, Shota; Le, Minh Nguyen Tuyet; Kusama, Yuta; Nakatani, Eri; Suga, Mika; Furue, Miho K; Satoh, Taku; Sugiura, Shinji; Kanamori, Toshiyuki; Ohnuma, Kiyoshi

2018-04-19

Spatial pattern formation is a critical step in embryogenesis. Bone morphogenetic protein 4 (BMP4) and its inhibitors are major factors for the formation of spatial patterns during embryogenesis. However, spatial patterning of the human embryo is unclear because of ethical issues and isotropic culture environments resulting from conventional culture dishes. Here, we utilized human pluripotent stem cells (hiPSCs) and a simple anisotropic (unidirectional perfusion) culture chamber, which creates unidirectional conditions, to measure the cell community effect. The influence of cell density on BMP4-induced differentiation was explored during static culture using a conventional culture dish. Immunostaining of the early differentiation marker SSEA-1 and the mesendoderm marker BRACHYURY revealed that high cell density suppressed differentiation, with small clusters of differentiated and undifferentiated cells formed. Addition of five-fold higher concentration of BMP4 showed similar results, suggesting that suppression was not caused by depletion of BMP4 but rather by high cell density. Quantitative RT-PCR array analysis showed that BMP4 induced multi-lineage differentiation, which was also suppressed under high-density conditions. We fabricated an elongated perfusion culture chamber, in which proteins were transported unidirectionally, and hiPSCs were cultured with BMP4. At low density, the expression was the same throughout the chamber. However, at high density, SSEA-1 and BRACHYURY were expressed only in upstream cells, suggesting that some autocrine/paracrine factors inhibited the action of BMP4 in downstream cells to form the spatial pattern. Human iPSCs cultured in a perfusion culture chamber might be useful for studying in vitro macroscopic pattern formation in human embryogenesis. Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation

PubMed Central

Takahashi, Yutaka; Carpino, Nick; Cross, James C.; Torres, Miguel; Parganas, Evan; Ihle, James N.

2003-01-01

Suppressor of cytokine signaling 3 (SOCS3) binds cytokine receptors and thereby suppresses cytokine signaling. Deletion of SOCS3 causes an embryonic lethality that is rescued by a tetraploid rescue approach, demonstrating an essential role in placental development and a non-essential role in embryo development. Rescued SOCS3-deficient mice show a perinatal lethality with cardiac hypertrophy. SOCS3-deficient placentas have reduced spongiotrophoblasts and increased trophoblast secondary giant cells. Enforced expression of SOCS3 in a trophoblast stem cell line (Rcho-1) suppresses giant cell differentiation. Conversely, SOCS3-deficient trophoblast stem cells differentiate more readily to giant cells in culture, demonstrating that SOCS3 negatively regulates trophoblast giant cell differentiation. Leukemia inhibitory factor (LIF) promotes giant cell differentiation in vitro, and LIF receptor (LIFR) deficiency results in loss of giant cell differentiation in vivo. Finally, LIFR deficiency rescues the SOCS3-deficient placental defect and embryonic lethality. The results establish SOCS3 as an essential regulator of LIFR signaling in trophoblast differentiation. PMID:12554639

Integrator complex plays an essential role in adipose differentiation

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

Otani, Yuichiro; Nakatsu, Yusuke; Sakoda, Hideyuki

2013-05-03

Highlights: •IntS6 and IntS11 are subunits of the Integrator complex. •Expression levels of IntS6 and IntS11 were very low in 3T3-L1 fibroblast. •IntS6 and IntS11 were upregulated during adipose differentiation. •Suppression of IntS6 or IntS11 expression inhibited adipose differentiation. -- Abstract: The dynamic process of adipose differentiation involves stepwise expressions of transcription factors and proteins specific to the mature fat cell phenotype. In this study, it was revealed that expression levels of IntS6 and IntS11, subunits of the Integrator complex, were increased in 3T3-L1 cells in the period when the cells reached confluence and differentiated into adipocytes, while being reducedmore » to basal levels after the completion of differentiation. Suppression of IntS6 or IntS11 expression using siRNAs in 3T3-L1 preadipocytes markedly inhibited differentiation into mature adipocytes, based on morphological findings as well as mRNA analysis of adipocyte-specific genes such as Glut4, perilipin and Fabp4. Although Pparγ2 protein expression was suppressed in IntS6 or IntS11-siRNA treated cells, adenoviral forced expression of Pparγ2 failed to restore the capacity for differentiation into mature adipocytes. Taken together, these findings demonstrate that increased expression of Integrator complex subunits is an indispensable event in adipose differentiation. Although further study is necessary to elucidate the underlying mechanism, the processing of U1, U2 small nuclear RNAs may be involved in cell differentiation steps.« less

Subpopulations of M-MDSCs from mice infected by an immunodeficiency-causing retrovirus and their differential suppression of T- vs B-cell responses.

PubMed

O'Connor, Megan A; Fu, Whitney W; Green, Kathy A; Green, William R

2015-11-01

Monocytic (CD11b(+)Ly6G(±/Lo)Ly6C(+)) myeloid derived suppressor cells (M-MDSCs) expand following murine retroviral LP-BM5 infection and suppress ex vivo polyclonal T-cell and B-cell responses. M-MDSCs 3 weeks post LP-BM5 infection have decreased suppression of T-cell, but not B-cell, responses and alterations in the degree of iNOS/NO dependence of suppression. M-MDSCs from LP-BM5 infected mice were sorted into four quadrant populations (Ly6C/CD11b density): all quadrants suppressed B-cell responses, but only M-MDSCs expressing the highest levels of Ly6C and CD11b (Q2) significantly suppressed T-cell responses. Further subdivision of this Q2 population revealed the Ly6C(+/Hi) M-MDSC subpopulation as the most suppressive, inhibiting T- and B-cell responses in a full, or partially, iNOS/NO-dependent manner, respectively. In contrast, the lower/moderate levels of suppression by the Ly6C(+/Lo) and Ly6C(+/Mid) M-MDSC Q2 subpopulations, whether versus T- and/or B-cells, displayed little/no iNOS dependency for suppression. These results highlight differential phenotypic and functional immunosuppressive M-MDSC subsets in a retroviral immunodeficiency model. Published by Elsevier Inc.

Prostacyclin Suppresses Twist Expression in the Presence of Indomethacin in Bone Marrow-Derived Mesenchymal Stromal Cells

PubMed Central

Kemper, Oliver; Herten, Monika; Fischer, Johannes; Haversath, Marcel; Beck, Sascha; Classen, Tim; Warwas, Sebastian; Tassemeier, Tjark; Landgraeber, Stefan; Lensing-Höhn, Sabine; Krauspe, Rüdiger; Jäger, Marcus

2014-01-01

Background Iloprost, a stable prostacyclin I2 analogue, seems to have an osteoblast-protective potential, whereas indomethacin suppresses new bone formation. The aim of this study was to investigate human bone marrow stromal cell (BMSC) proliferation and differentiation towards the osteoblastic lineage by administration of indomethacin and/or iloprost. Material/Methods Human bone marrow cells were obtained from 3 different donors (A=26 yrs/m; B=25 yrs/f, C=35 yrs/m) via vacuum aspiration of the iliac crest followed by density gradient centrifugation and flow cytometry with defined antigens (CD105+/73+/45−/14−). The cells were seeded and incubated as follows: without additives (Group 0; donor A/B/C), with 10−7 M iloprost only (Group 0+ilo; A/B), with indomethacin only in concentrations of 10−6 M (Group 1, A), 10−5 M (Group 2, B), 10−4 M (Group 3, A/B), and together with 10−7 M iloprost (Groups 4–6, A/B/C). On Day 10 and 28, UV/Vis spectrometric and immunocytochemical assays (4 samples per group and donor) were performed to investigate cell proliferation (cell count measurement) and differentiation towards the osteoblastic lineage (CD34−, CD45−, CD105+, type 1 collagen (Col1), osteocalcin (OC), alkaline phosphatase (ALP), Runx2, Twist, specific ALP-activity). Results Indomethacin alone suppressed BMSC differentiation towards the osteoblastic lineage by downregulation of Runx2, Col1, and ALP. In combination with indomethacin, iloprost increased cell proliferation and differentiation and it completely suppressed Twist expression at Day 10 and 28. Iloprost alone did not promote cell proliferation, but moderately enhanced Runx2 and Twist expression. However, the proliferative effects and the specific ALP-activity varied donor-dependently. Conclusions Iloprost partially antagonized the suppressing effects of indomethacin on BMSC differentiation towards the osteoblast lineage. It enhanced the expression of Runx2 and, only in the presence of indomethacin, it completely suppressed Twist. Thus, in the treatment of avascular osteonecrosis or painful bone marrow edema, the undesirable effects of indomethacin might be counterbalanced by iloprost. PMID:25382306

miR-203 and miR-320 Regulate Bone Morphogenetic Protein-2-Induced Osteoblast Differentiation by Targeting Distal-Less Homeobox 5 (Dlx5).

PubMed

Laxman, Navya; Mallmin, Hans; Nilsson, Olle; Kindmark, Andreas

2016-12-23

MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17-24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5 , which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.

miR-203 and miR-320 Regulate Bone Morphogenetic Protein-2-Induced Osteoblast Differentiation by Targeting Distal-Less Homeobox 5 (Dlx5)

PubMed Central

Laxman, Navya; Mallmin, Hans; Nilsson, Olle; Kindmark, Andreas

2016-01-01

MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism. PMID:28025541

DNMT1 maintains progenitor function in self-renewing somatic tissue.

PubMed

Sen, George L; Reuter, Jason A; Webster, Daniel E; Zhu, Lilly; Khavari, Paul A

2010-01-28

Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance, the role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unclear. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis showed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, UHRF1 (refs 9, 10), a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A and B, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.

Suppression of KV7/KCNQ potassium channel enhances neuronal differentiation of PC12 cells.

PubMed

Zhou, Najing; Huang, Sha; Li, Li; Huang, Dongyang; Yan, Yunli; Du, Xiaona; Zhang, Hailin

2016-10-01

Membrane potential shift driven by electrical activity is critical in determining the cell fate of proliferation or differentiation. As such, the ion channels that underlie the membrane electrical activity play an important role in cell proliferation/differentiation. KV7/KCNQ potassium channels are critical in determining the resting membrane potentials in many neuronal cells. However, the role of these channels in cell differentiation is not well studied. In the present study, we used PC12 cells as well as primary cultured rat cortical neurons to study the role and mechanism of KV7/KCNQ in neuronal differentiation. NGF induced PC12 cell differentiation into neuron-like cells with growth of neurites showing typical growth cone-like extensions. The Kv7/KCNQ blocker XE991 promoted NGF-induced neurite outgrowth, whereas Kv7/KCNQ opener retigabine (RTG) inhibited outgrowth. M-type Kv7 channels are likely involved in regulating neurite growth because overexpression of KCNQ2/Q3 inhibited neurite growth whereas suppression of KCNQ2/Q3 with shRNA promoted neurite growth. Membrane depolarization possibly underpins enhanced neurite growth induced by the suppression of Kv7/KCNQ. Additionally, high extracellular K(+) likely induced membrane depolarization and also promoted neurite growth. Finally, T-type Ca(2+) channels may be involved in membrane-depolarization-induced neurite growth. This study provides a new perspective for understanding neuronal differentiation as well as KV7/KCNQ channel function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Mangiferin corrects the imbalance of Th17/Treg cells in mice with TNBS-induced colitis.

PubMed

Lim, Su-Min; Jeong, Jin-Ju; Choi, Hyun Sik; Chang, Hwan Bong; Kim, Dong-Hyun

2016-05-01

In the previous study, 80% ethanol extract of the rhizome mixture of Anemarrhena asphodeloides and Coptidis chinensis (AC) and its main constituent mangiferin improved TNBS-induced colitis in mice by inhibiting macrophage activation related to the innate immunity. In the preliminary study, we found that AC could inhibit Th17 cell differentiation in mice with TNBS-induced colitis. Therefore, we investigated whether AC and it main constituent mangiferin are capable of inhibiting inflammation by regulating T cell differentiation related to the adaptive immunity in vitro and in vivo. AC and mangiferin potently suppressed colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis. They also suppressed TNBS-induced Th17 cell differentiation and IL-17 expression, but increased TNBS-suppressed Treg cell differentiation and IL-10 expression. Moreover, AC and mangiferin strongly inhibited the expression of TNF-α and IL-17, as well as the activation of NF-κB. Furthermore, mangiferin potently inhibited the differentiation of splenocytes into Th7 cells and increased the differentiation into Treg cells in vitro. Mangiferin also inhibited RORγt and IL-17 expression and STAT3 activation in splenocytes and induced Foxp3 and IL-10 expression and STAT5 activation. Based on these findings, mangiferin may ameliorate colitis by the restoration of disturbed Th17/Treg cells and inhibition of macrophage activation. Copyright © 2016 Elsevier B.V. All rights reserved.

Arctigenin suppresses receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast differentiation in bone marrow-derived macrophages.

PubMed

Kim, A-Ram; Kim, Hyuk Soon; Lee, Jeong Min; Choi, Jung Ho; Kim, Se Na; Kim, Do Kyun; Kim, Ji Hyung; Mun, Se Hwan; Kim, Jie Wan; Jeon, Hyun Soo; Kim, Young Mi; Choi, Wahn Soo

2012-05-05

Osteoclasts, multinucleated bone-resorbing cells, are closely associated with bone diseases such as rheumatoid arthritis and osteoporosis. Osteoclasts are derived from hematopoietic precursor cells, and their differentiation is mediated by two cytokines, including macrophage colony stimulating factor and receptor activator of nuclear factor κB ligand (RANKL). Previous studies have shown that arctigenin exhibits an anti-inflammatory effect. However, the effect of arctigenin on osteoclast differentiation is yet to be elucidated. In this study, we found that arctigenin inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages in a dose-dependent manner and suppressed RANKL-mediated bone resorption. Additionally, the expression of typical marker proteins, such as NFATc1, c-Fos, TRAF6, c-Src, and cathepsin K, were significantly inhibited. Arctigenin inhibited the phosphorylation of Erk1/2, but not p38 and JNK, in a dose-dependent manner. Arctigenin also dramatically suppressed immunoreceptor tyrosine-based activation motif-mediated costimulatory signaling molecules, including Syk and PLCγ2, and Gab2. Notably, arctigenin inhibited the activation of Syk through RANKL stimulation. Furthermore, arctigenin prevented osteoclast differentiation in the calvarial bone of mice following stimulation with lipopolysaccharide. Our results show that arctigenin inhibits osteoclast differentiation in vitro and in vivo. Therefore, arctigenin may be useful for treating rheumatoid arthritis and osteoporosis. Copyright © 2012 Elsevier B.V. All rights reserved.

Noisy Spiking in Visual Area V2 of Amblyopic Monkeys.

PubMed

Wang, Ye; Zhang, Bin; Tao, Xiaofeng; Wensveen, Janice M; Smith, Earl L; Chino, Yuzo M

2017-01-25

Interocular decorrelation of input signals in developing visual cortex can cause impaired binocular vision and amblyopia. Although increased intrinsic noise is thought to be responsible for a range of perceptual deficits in amblyopic humans, the neural basis for the elevated perceptual noise in amblyopic primates is not known. Here, we tested the idea that perceptual noise is linked to the neuronal spiking noise (variability) resulting from developmental alterations in cortical circuitry. To assess spiking noise, we analyzed the contrast-dependent dynamics of spike counts and spiking irregularity by calculating the square of the coefficient of variation in interspike intervals (CV 2 ) and the trial-to-trial fluctuations in spiking, or mean matched Fano factor (m-FF) in visual area V2 of monkeys reared with chronic monocular defocus. In amblyopic neurons, the contrast versus response functions and the spike count dynamics exhibited significant deviations from comparable data for normal monkeys. The CV 2 was pronounced in amblyopic neurons for high-contrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV 2 , and m-FF of spontaneous activity were also elevated in amblyopic neurons. These contrast-dependent spiking irregularities were correlated with the level of binocular suppression in these V2 neurons and with the severity of perceptual loss for individual monkeys. Our results suggest that the developmental alterations in normalization mechanisms resulting from early binocular suppression can explain much of these contrast-dependent spiking abnormalities in V2 neurons and the perceptual performance of our amblyopic monkeys. Amblyopia is a common developmental vision disorder in humans. Despite the extensive animal studies on how amblyopia emerges, we know surprisingly little about the neural basis of amblyopia in humans and nonhuman primates. Although the vision of amblyopic humans is often described as being noisy by perceptual and modeling studies, the exact nature or origin of this elevated perceptual noise is not known. We show that elevated and noisy spontaneous activity and contrast-dependent noisy spiking (spiking irregularity and trial-to-trial fluctuations in spiking) in neurons of visual area V2 could limit the visual performance of amblyopic primates. Moreover, we discovered that the noisy spiking is linked to a high level of binocular suppression in visual cortex during development. Copyright © 2017 the authors 0270-6474/17/370922-14$15.00/0.

Adult-type myogenesis of the frog Xenopus laevis specifically suppressed by notochord cells but promoted by spinal cord cells in vitro.

PubMed

Yamane, Hitomi; Ihara, Setsunosuke; Kuroda, Masaaki; Nishikawa, Akio

2011-08-01

Larval-to-adult myogenic conversion occurs in the dorsal muscle but not in the tail muscle during Xenopus laevis metamorphosis. To know the mechanism for tail-specific suppression of adult myogenesis, response character was compared between adult myogenic cells (Ad-cells) and larval tail myogenic cells (La-cells) to a Sonic hedgehog (Shh) inhibitor, notochord (Nc) cells, and spinal cord (SC) cells in vitro. Cyclopamine, an Shh inhibitor, suppressed the differentiation of cultured Ad (but not La) cells, suggesting the significance of Shh signaling in promoting adult myogenesis. To test the possibility that Shh-producing axial elements (notochord and spinal cord) regulate adult myogenesis, Ad-cells or La-cells were co-cultured with Nc or SC cells. The results showed that differentiation of Ad-cells were strongly inhibited by Nc cells but promoted by SC cells. If Ad-cells were "separately" co-cultured with Nc cells without direct cell-cell interactions, adult differentiation was not inhibited but rather promoted, suggesting that Nc cells have two roles, one is a short-range suppression and another is a long-range promotion for adult myogenesis. Immunohistochemical analysis showed both notochord and spinal cord express the N-terminal Shh fragment throughout metamorphosis. The "spinal cord-promotion" and long-range effect by Nc cells on adult myogenesis is thus involved in Shh signaling, while the signaling concerning the short-range "Nc suppression" will be determined by future studies. Interestingly, these effects, "Nc suppression" and "SC promotion" were not observed for La-cells. Situation where the spinal cord/notochord cross-sectional ratio is quite larger in tadpole trunk than in the tail seems to contribute to trunk-specific promotion and tail-specific suppression of adult myogenesis during Xenopus metamorphosis.

Oligopeptides of Chorionic Gonadotropin β-Subunit in Induction of T Cell Differentiation into Treg and Th17.

PubMed

Zamorina, S A; Shirshev, S V

2015-11-01

The role of oligopeptides of chorionic gonadotropin β-subunit (LQGV, AQGV, and VLPALP) in induction of differentiation into T-regulatory lymphocytes (Treg) and IL-17-producing lymphocytes (Th17) was studied in an in vitro system. Chorionic gonadotropin and oligopeptides promoted CD4(+) cell differentiation into functionally active Treg (FOXP3(+)GITR(+) and FOXP3(+)CTLA-4(+)), while chorionic gonadotropin and AQGV additionally stimulated IL-10 production by these cells. In parallel, chorionic gonadotropin and oligopeptides prevented CD4(+) cell differentiation into Th17 lymphocytes (ROR-gt(+)IL-17A(+)) and suppressed IL-17A secretion. Hence, oligopeptides of chorionic gonadotropin β-subunit promoted differentiation of CD4(+) cells into Treg and, in parallel, suppress Th17 induction, thus virtually completely reproducing the effects of the hormone, which opens new vista for their use in clinical practice.

Differential Roles of Thought Suppression and Dispositional Mindfulness in Posttraumatic Stress Symptoms and Craving

PubMed Central

Garland, Eric; Roberts-Lewis, Amelia

2012-01-01

Exposure to traumatic events often results in severe distress which may elicit self-medication behaviors. Yet, some individuals exposed to trauma do not develop post-traumatic stress symptoms and comorbid addictive impulses. In the wake of traumatic events, psychological processes like thought suppression and mindfulness may modulate post-traumatic stress and craving for substances. We examined the differential roles of mindfulness and suppression in comorbid post-traumatic stress and craving in a sample of 125 persons with extensive trauma histories and psychiatric symptoms in residential treatment for substance dependence. Results indicated that thought suppression, rather than extent of trauma history, significantly predicted post-traumatic stress symptom severity while dispositional mindfulness significantly predicted both post-traumatic stress symptoms and craving. In multiple regression models, mindfulness and thought suppression combined explained nearly half of the variance in post-traumatic stress symptoms and one-quarter of the variance in substance craving. Moreover, multivariate path analysis indicated that prior traumatic experience was associated with greater thought suppression, which in turn was correlated with increased post-traumatic stress symptoms and drug craving, whereas dispositional mindfulness was associated with decreased suppression, post-traumatic stress, and craving. The maladaptive strategy of thought suppression appears to be linked with adverse psychological consequences of traumatic life events. In contrast, dispositional mindfulness appears to be a protective factor that buffers individuals from experiencing more severe post-traumatic stress symptoms and craving. PMID:22385734

Reciprocal role of vitamin D receptor on β-catenin regulated keratinocyte proliferation and differentiation.

PubMed

Hu, Lizhi; Bikle, Daniel D; Oda, Yuko

2014-10-01

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), suppresses the proliferation while promoting the differentiation of keratinocytes through the vitamin D receptor (VDR). β-Catenin, on the other hand, promotes proliferation and blocks epidermal differentiation, although it stimulates hair follicle differentiation. In intestinal epithelia VDR binds β-catenin and blocks its proliferative effects. In this study we investigated the role of 1,25(OH)2D3/VDR on β-catenin regulated gene transcription during keratinocyte proliferation and differentiation. 1,25(OH)2D3 suppressed promoter reporter activity driven by synthetic and natural TCF/β-catenin response elements. Over-expression of VDR further suppressed these TCF/β-catenin promoter activities. 1,25(OH)2D3 also suppressed the mRNA expression of the β-catenin regulated gene Gli1 through VDR. These data were consistent with our previous observations that VDR silencing resulted in keratinocyte hyperproliferation with increased expression of Gli1 in vitro, whereas VDR null skin showed hyperproliferation in vivo. In contrast, 1,25(OH)2D3 induced expression of another β-catenin regulated gene, PADI1, important for both epidermal and hair follicle differentiation. Deletion of VDR resulted in defects in hair differentiation in vivo, with decreased expression of β-catenin regulated hair differentiation genes such as PADI1, hair keratin KRT31 and calcium binding protein S100a3. These genes possess vitamin D response elements (VDRE) adjacent to TCF/β-catenin response elements and are regulated by both VDR and β-catenin signaling. Therefore, we propose that VDR and β-catenin interact reciprocally to promote VDR stimulation of genes involved with differentiation that contain both VDR and β-catenin response elements while inhibiting β-catenin stimulation of genes involved with proliferation. Thus the major finding of this study is that while 1,25(OH)2D3/VDR inhibits the actions of β-catenin to promote keratinocyte proliferation, 1,25(OH)2D3/VDR promotes the ability of β-catenin to stimulate hair follicle differentiation. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Suppression of murine preadipocyte differentiation and reduction of visceral fat accumulation by a Petasites japonicus ethanol extract in mice fed a high-fat diet.

PubMed

Watanabe, Takayuki; Hata, Keishi; Hiwatashi, Kazuyuki; Hori, Kazuyuki; Suzuki, Nao; Itoh, Hideaki

2010-01-01

We investigated in this study the anti-obesity effect of an extract of Petasites japonicus (a culinary vegetable from Eastern Asia) on a murine adipocyte cell line (3T3-L1) and on diet-induced obesity-prone mice. An ethanol extract of P. japonicus. (PJET) suppressed 3T3-L1 preadipocyte differentiation; however, a hot water extract of P. japonicus (PJHW) exhibited no effect on cell differentiation. PJET significantly attenuated three adipogenetic transcription factors, peroxisome proliferator-activated receptor gamma2, CCAAT/enhancer-binding protein and sterol regulatory element-binding protein 1C, at the mRNA level and suppressed the gene expression of fatty acid synthetase. An experiment with diet-induced obesity-prone C57BL/6J mice showed that PJET lowered the body weight gain and visceral fat tissue accumulation, and ameliorated the plasma cholesterol concentration. These findings suggest that P. japonicus might be an effective food against obesity.

Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

PubMed

Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; do Rosario Andre, Maria; Brazier-Mitouart, Helene; Waite, Janelle C; Chan, April S; Kalter, Julie; Ramos, Ilyssa; Wu, Qi; Williams, Caitlin; Wolchok, Jedd D; Chapman, Paul B; Peinado, Hector; Anandasabapathy, Niroshana; Ocean, Allyson J; Kaplan, Rosandra N; Greenfield, Jeffrey P; Bromberg, Jacqueline; Skokos, Dimitris; Lyden, David

2015-04-29

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.

Modulation of Dendritic Cell Activation and Subsequent Th1 Cell Polarization by Lidocaine

PubMed Central

Chung, Yeonseok

2015-01-01

Dendritic cells play an essential role in bridging innate and adaptive immunity by recognizing cellular stress including pathogen- and damage-associated molecular patterns and by shaping the types of antigen-specific T cell immunity. Although lidocaine is widely used in clinical settings that trigger cellular stress, it remains unclear whether such treatment impacts the activation of innate immune cells and subsequent differentiation of T cells. Here we showed that lidocaine inhibited the production of IL–6, TNFα and IL–12 from dendritic cells in response to toll-like receptor ligands including lipopolysaccharide, poly(I:C) and R837 in a dose-dependent manner. Notably, the differentiation of Th1 cells was significantly suppressed by the addition of lidocaine while the same treatment had little effect on the differentiation of Th17, Th2 and regulatory T cells in vitro. Moreover, lidocaine suppressed the ovalbumin-specific Th1 cell responses in vivo induced by the adoptive transfer of ovalbumin-pulsed dendritic cells. These results demonstrate that lidocaine inhibits the activation of dendritic cells in response to toll-like receptor signals and subsequently suppresses the differentiation of Th1 cell responses. PMID:26445366

(beta)-catenin mediates the specification of endoderm cells in ascidian embryos.

PubMed

Imai, K; Takada, N; Satoh, N; Satou, Y

2000-07-01

In the present study, we addressed the role of (beta)-catenin in the specification of embryonic cells of the ascidians Ciona intestinalis and C. savignyi and obtained the following results: (1) During cleavages, (beta)-catenin accumulated in the nuclei of vegetal blastomeres, suggesting that it plays a role in the specification of endoderm. (2) Mis- and/or overexpression of (beta)-catenin induced the development of an endoderm-specific alkaline phosphatase (AP) in presumptive notochord cells and epidermis cells without affecting differentiation of primary lineage muscle cells. (3) Downregulation of (beta)-catenin induced by the overexpression of cadherin resulted in the suppression of endoderm cell differentiation. This suppression was compensated for by the differentiation of extra epidermis cells. (4) Specification of notochord cells did not take place in the absence of endoderm differentiation. Both the overexpression of (beta)-catenin in presumptive notochord cells and the downregulation of (beta)-catenin in presumptive endoderm cells led to the suppression of Brachyury gene expression, resulting in the failure of notochord specification. These results suggest that the accumulation of (beta)-catenin in the nuclei of endoderm progenitor cells is the first step in the process of ascidian endoderm specification.

TLR10 suppresses the activation and differentiation of monocytes with effects on DC-mediated adaptive immune responses

PubMed Central

Hess, Nicholas J.; Felicelli, Christopher; Grage, Jennifer; Tapping, Richard I.

2017-01-01

TLRs are important pattern-recognition receptors involved in the activation of innate immune responses against foreign pathogens. TLR10 is the only TLR family member without a known ligand, signaling pathway, or clear cellular function. Previous work has shown that TLR10 suppresses proinflammatory cytokine production in response to TLR agonists in a mixed human mononuclear cell population. We report that TLR10 is preferentially expressed on monocytes and suppresses proinflammatory cytokine production resulting from either TLR or CD40 stimulation. TLR10 engagement affects both the MAPK and Akt signaling pathways, leading to changes in the transcriptome of isolated human monocytes. Differentiation of monocytes into dendritic cells in the presence of an αTLR10 mAb reduced the expression of maturation markers and the induction of proinflammatory cytokines, again in response to either TLR or CD40 stimulation. Finally, in coculture experiments, TLR10 differentiated dendritic cells exhibited a decreased capacity to activate T cells as measured by IL-2 and IFN-γ production. These data demonstrate that TLR10 is a novel regulator of innate immune responses and of the differentiation of primary human monocytes into effective dendritic cells. PMID:28235773

DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue

PubMed Central

Sen, George L.; Reuter, Jason A.; Webster, Daniel E.; Zhu, Lilly; Khavari, Paul A.

2010-01-01

Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation1,2. DNA methylation3,4,5 provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1)6,7 maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance,8 a clear role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unknown. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis revealed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, we show that UHRF1,9,10 a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A11,12 and B13, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue. PMID:20081831

Anti-proliferative and differentiation-inducing activities of the green tea catechin epigallocatechin-3-gallate (EGCG) on the human eosinophilic leukemia EoL-1 cell line.

PubMed

Lung, H L; Ip, W K; Wong, C K; Mak, N K; Chen, Z Y; Leung, K N

2002-12-06

A novel approach for the treatment of leukemia is the differentiation therapy in which immature leukemia cells are induced to attain a mature phenotype when exposed to differentiation inducers, either alone or in combinations with other chemotherapeutic or chemopreventive drugs. Over the past decade, numerous studies indicated that green tea catechins (GTC) could suppress the growth and induce apoptosis on a number of human cancer cell lines. However, the differentiation-inducing activity of GTC on human tumors remains poorly understood. In the present study, the effect of the major GTC epigallocatechin-3-gallate (EGCG) on the proliferation and differentiation of a human eosinophilc leukemic cell line, EoL-1, was examined. Our results showed that EGCG suppressed the proliferation of the EoL-1 cells in a dose-dependent manner, with an estimated IC(50) value of 31.5 microM. On the other hand, EGCG at a concentration of 40 microM could trigger the EoL-1 cells to undergo morphological differentiation into mature eosinophil-like cells. Using RT-PCR and flow cytometry, it was found that EGCG upregulated the gene and protein expression of two eosinophil-specific granule proteins, the major basic protein (MBP) and eosinophil peroxidase (EPO), in EoL-1 cells. Taken together, our findings suggest that EGCG can exhibit anti-leukemic activity on a human eosinophilic cell line EoL-1 by suppressing the proliferation and by inducing the differentiation of the leukemia cells.

Mindfulness-based cognitive therapy may reduce thought suppression in previously suicidal participants: findings from a preliminary study.

PubMed

Hepburn, Silvia R; Crane, Catherine; Barnhofer, Thorsten; Duggan, Danielle S; Fennell, Melanie J V; Williams, J Mark G

2009-06-01

Thought suppression is a strategy aimed at mental control that may paradoxically increase the frequency of unwanted thoughts. This preliminary study examined effects of mindfulness-based cognitive therapy (MBCT) on thought suppression and depression in individuals with past depression and suicidality. In a randomized controlled trial design, 68 participants were allocated to an MBCT group or a treatment-as-usual waitlist control. Measures of thought suppression and depression were taken pre- and post-treatment. MBCT did not reduce thought suppression as measured by the White Bear Suppression Inventory, but significantly reduced self-reported attempts to suppress in the previous week. Preliminary evidence suggests that MBCT for suicidality may reduce thought suppression, but differential effects on thought suppression measures warrant further studies.

MEK5 suppresses osteoblastic differentiation

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

Kaneshiro, Shoichi; Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871; Otsuki, Dai

Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and is activated by its upstream kinase, MAPK kinase 5 (MEK5), which is a member of the MEK family. Although the role of MEK5 has been investigated in several fields, little is known about its role in osteoblastic differentiation. In this study, we have demonstrated the role of MEK5 in osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. We found that treatment with BIX02189, an inhibitor of MEK5, increased alkaline phosphatase (ALP) activity and the gene expression of ALP, osteocalcinmore » (OCN) and osterix, as well as it enhanced the calcification of the extracellular matrix. Moreover, osteoblastic cell proliferation decreased at a concentration of greater than 0.5 μM. In addition, knockdown of MEK5 using siRNA induced an increase in ALP activity and in the gene expression of ALP, OCN, and osterix. In contrast, overexpression of wild-type MEK5 decreased ALP activity and attenuated osteoblastic differentiation markers including ALP, OCN and osterix, but promoted cell proliferation. In summary, our results indicated that MEK5 suppressed the osteoblastic differentiation, but promoted osteoblastic cell proliferation. These results implied that MEK5 may play a pivotal role in cell signaling to modulate the differentiation and proliferation of osteoblasts. Thus, inhibition of MEK5 signaling in osteoblasts may be of potential use in the treatment of osteoporosis. - Highlights: • MEK5 inhibitor BIX02189 suppresses proliferation of osteoblasts. • MEK5 knockdown and MEK5 inhibitor promote differentiation of osteoblasts. • MEK5 overexpression inhibits differentiation of osteoblasts.« less

Reference ranges for foetal nasal bone length, prenasal thickness, and interocular distance at 18 to 24 weeks' gestation in low-risk pregnancies.

PubMed

Altunkeser, Ayşegül; Körez, M Kazım

2017-12-12

The aim of the present study was to establish the normal ranges for foetal nasal bone length (NBL), prenasal skin thickness (PNT), interocular distance (IOD), and ratio of prenasal thickness to- nasal bone length (PNT/ NBL) at 18-24 weeks using two-dimensional (2D) ultrasound. This study was a retrospective study of prenatal ultrasonographic records from 407 foetuses between 18 and 24 weeks gestational age (GA). The NBL, PNT, IOD, PNT/ NBL ratio, biparietal diameter (BPD), and femur length (FL) were investigated. The relationships among NBL, PNT, IOD, PNT/ NBL, and GA were evaluated. Additionally, descriptive statistics for NBL, PNT, and IOD values for each gestational week were obtained. There was a significant association between GA and NBL, PNT, and IOD between 18 and 24 weeks. NBL increased from a mean of 5.5 mm to 8.3 mm, PNT increased from a mean of 3.5 mm to 5.1 mm, and IOD increased from a mean of 11.1 mm to 14.5 mm. PNT/NBL ratio did not change with gestational age. This study showed normal ranges for NBL, PNT, IOD, and PNT/ NBL ratios for foetuses between 18 and 24 weeks in low-risk pregnancies. There was a positive linear relationship between GA and NBL, PNT, and IOD. The PNT/NBL ratio might be a more useful measurement than NBL or PNT alone.

A comparison of interocular differences in patients with pigment dispersion syndrome.

PubMed

Yip, Leonard W; Sothornwit, Nisa; Berkowitz, Jonathan; Mikelberg, Frederick S

2009-01-01

Pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) are characterized by loss of iris pigment because of reverse pupillary block. The loss of iris pigment is manifested as transillumination defects. Differences in ocular anatomy have been found between subjects with PDS and controls. Our study aims to see if differences in interocular anatomic features are also related to differences in the quantity of transillumination defects between eyes. This is an observational case series of 30 eyes of 15 subjects with PDS/PG in at least 1 eye. Patients underwent refraction, exophthalmometry, corneal and anterior chamber analysis by Pentacam, biometry, A-scan, ultrasound biomicroscopy, and anterior segment digital photography. The Pentacam mean central radii of the posterior corneal surface (cornea back Rm), vertical central radius of curvature of the posterior corneal surface (cornea back Rv), and keratometric power deviation (influence of the posterior surface of the cornea on refractive power) were statistically different between eyes with greater pigment loss and eyes with lesser pigment loss. Eyes with greater pigment loss had a larger back radius of corneal curvature and a correspondingly numerically smaller keratometric power deviation. Other measurements of ocular anatomy were not statistically significant. A flatter curvature of the posterior corneal surface of the eye is associated with increased pigment loss in PDS and PG. The authors postulate that this could result in a difference in the biomechanical properties of the cornea, increased deformation with blinking, and a pumping action resulting in the reverse pupil block of PDS.

Experience-induced interocular plasticity of vision in infancy.

PubMed

Tschetter, Wayne W; Douglas, Robert M; Prusky, Glen T

2011-01-01

Animal model studies of amblyopia have generally concluded that enduring effects of monocular deprivation (MD) on visual behavior (i.e., loss of visual acuity) are limited to the deprived eye, and are restricted to juvenile life. We have previously reported, however, that lasting effects of MD on visual function can be elicited in adulthood by stimulating visuomotor experience through the non-deprived eye. To test whether stimulating experience would also induce interocular plasticity of vision in infancy, we assessed in rats from eye-opening on postnatal day (P) 15, the effect of pairing MD with the daily experience of measuring thresholds for optokinetic tracking (OKT). MD with visuomotor experience from P15 to P25 led to a ~60% enhancement of the spatial frequency threshold for OKT through the non-deprived eye during the deprivation, which was followed by loss-of-function (~60% below normal) through both eyes when the deprived eye was opened. Reduced thresholds were maintained into adulthood with binocular OKT experience from P25 to P30. The ability to generate the plasticity and maintain lost function was dependent on visual cortex. Strictly limiting the period of deprivation to infancy by opening the deprived eye at P19 resulted in a comparable loss-of-function. Animals with reduced OKT responses also had significantly reduced visual acuity, measured independently in a discrimination task. Thus, experience-dependent cortical plasticity that can lead to amblyopia is present earlier in life than previously recognized.

Accommodative Performance of Children With Unilateral Amblyopia

PubMed Central

Manh, Vivian; Chen, Angela M.; Tarczy-Hornoch, Kristina; Cotter, Susan A.; Candy, T. Rowan

2015-01-01

Purpose. The purpose of this study was to compare the accommodative performance of the amblyopic eye of children with unilateral amblyopia to that of their nonamblyopic eye, and also to that of children without amblyopia, during both monocular and binocular viewing. Methods. Modified Nott retinoscopy was used to measure accommodative performance of 38 subjects with unilateral amblyopia and 25 subjects with typical vision from 3 to 13 years of age during monocular and binocular viewing at target distances of 50, 33, and 25 cm. The relationship between accommodative demand and interocular difference (IOD) in accommodative error was assessed in each group. Results. The mean IOD in monocular accommodative error for amblyopic subjects across all three viewing distances was 0.49 diopters (D) (95% confidence interval [CI], ±1.12 D) in the 180° meridian and 0.54 D (95% CI, ±1.27 D) in the 90° meridian, with the amblyopic eye exhibiting greater accommodative errors on average. Interocular difference in monocular accommodative error increased significantly with increasing accommodative demand; 5%, 47%, and 58% of amblyopic subjects had monocular errors in the amblyopic eye that fell outside the upper 95% confidence limit for the better eye of control subjects at viewing distances of 50, 33, and 25 cm, respectively. Conclusions. When viewing monocularly, children with unilateral amblyopia had greater mean accommodative errors in their amblyopic eyes than in their nonamblyopic eyes, and when compared with control subjects. This could lead to unintended retinal image defocus during patching therapy for amblyopia. PMID:25626970

Functional assessment of the visual pathway with multifocal visual evoked potentials, and their relationship with disability in patients with multiple sclerosis.

PubMed

Blanco, Román; Pérez-Rico, Consuelo; Puertas-Muñoz, Inmaculada; Ayuso-Peralta, Lucía; Boquete, Luciano; Arévalo-Serrano, Juan

2014-02-01

To objectively evaluate the visual function, and the relationship between disability and optic nerve dysfunction, in patients with multiple sclerosis (MS) and optic neuritis (ON), using multifocal visual evoked potentials (mfVEP). This observational, cross-sectional study assessed 28 consecutive patients with clinically definite MS, according to the McDonald criteria, and 19 age-matched healthy subjects. Disability was recorded using the Expanded Disability Status Scale (EDSS) score. The patients' mfVEP were compared to their clinical, psychophysical (Humphrey perimetry) and structural (optic coherence tomography (OCT)) diagnostic test data. We observed a significant agreement between mfVEP amplitude and Humphrey perimetry/OCT in MS-ON eyes, and between mfVEP amplitude and OCT in MS but non-ON eyes. We found significant differences in EDSS score between patients with abnormal and normal mfVEP amplitudes. Abnormal mfVEP amplitude defects (from interocular and monocular probability analysis) were found in 67.9% and 73.7% of the MS-ON and MS-non-ON group eyes, respectively. Delayed mfVEP latencies (interocular and monocular probability analysis) were seen in 70.3% and 73.7% of the MS-ON and MS-non-ON groups, respectively. We found a significant relationship between mfVEP amplitude and disease severity, as measured by EDSS score, that suggested there is a role for mfVEP amplitude as a functional biomarker of axonal loss in MS.

microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest

PubMed Central

Zhao, Zhenze; Ma, Xiuye; Sung, Derek; Li, Monica; Kosti, Adam; Lin, Gregory; Chen, Yidong; Pertsemlidis, Alexander; Hsiao, Tzu-Hung; Du, Liqin

2015-01-01

microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms—inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets- MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR-449a-mediated tumor suppressive pathway in neuroblastoma prognosis. PMID:25760387

Myeloblastic leukemia cells conditionally blocked by myc-estrogen receptor chimeric transgenes for terminal differentiation coupled to growth arrest and apoptosis.

PubMed

Selvakumaran, M; Liebermann, D; Hoffman-Liebermann, B

1993-05-01

Conditional mutants of the myeloblastic leukemic M1 cell line, expressing the chimeric mycer transgene, have been established. It is shown that M1 mycer cells, like M1, undergo terminal differentiation coupled to growth arrest and programmed cell death (apoptosis) after treatment with the physiologic differentiation inducer interleukin-6. However, when beta-estradiol is included in the culture medium, M1 mycer cells respond to differentiation inducers like M1 myc cell lines, where the differentiation program is blocked at an intermediate stage. By manipulating the function of the mycer transgene product, it is shown that there is a 10-hour window during myeloid differentiation, from 30 to 40 hours after the addition of the differentiation inducer, when the terminal differentiation program switches from being dependent on c-myc suppression to becoming c-myc suppression independent, where activation of c-myc has no apparent effect on mature macrophages. M1 mycer cell lines provide a powerful tool to increase our understanding of the role of c-myc in normal myelopoiesis and in leukemogenesis, also providing a strategy to clone c-myc target genes.

Development of Relative Disparity Sensitivity in Human Visual Cortex.

PubMed

Norcia, Anthony M; Gerhard, Holly E; Meredith, Wesley J

2017-06-07

Stereopsis is the primary cue underlying our ability to make fine depth judgments. In adults, depth discriminations are supported largely by relative rather than absolute binocular disparity, and depth is perceived primarily for horizontal rather than vertical disparities. Although human infants begin to exhibit disparity-specific responses between 3 and 5 months of age, it is not known how relative disparity mechanisms develop. Here we show that the specialization for relative disparity is highly immature in 4- to 6-month-old infants but is adult-like in 4- to 7-year-old children. Disparity-tuning functions for horizontal and vertical disparities were measured using the visual evoked potential. Infant relative disparity thresholds, unlike those of adults, were equal for vertical and horizontal disparities. Their horizontal disparity thresholds were a factor of ∼10 higher than adults, but their vertical disparity thresholds differed by a factor of only ∼4. Horizontal relative disparity thresholds for 4- to 7-year-old children were comparable with those of adults at ∼0.5 arcmin. To test whether infant immaturity was due to spatial limitations or insensitivity to interocular correlation, highly suprathreshold horizontal and vertical disparities were presented in alternate regions of the display, and the interocular correlation of the interdigitated regions was varied from 0% to 100%. This manipulation regulated the availability of coarse-scale relative disparity cues. Adult and infant responses both increased with increasing interocular correlation by similar magnitudes, but adult responses increased much more for horizontal disparities, further evidence for qualitatively immature stereopsis based on relative disparity at 4-6 months of age. SIGNIFICANCE STATEMENT Stereopsis, our ability to sense depth from horizontal image disparity, is among the finest spatial discriminations made by the primate visual system. Fine stereoscopic depth discriminations depend critically on comparisons of disparity relationships in the image that are supported by relative disparity cues rather than the estimation of single, absolute disparities. Very young human and macaque infants are sensitive to absolute disparity, but no previous study has specifically studied the development of relative disparity sensitivity, a hallmark feature of adult stereopsis. Here, using high-density EEG recordings, we show that 4- to 6-month-old infants display both quantitative and qualitative response immaturities for relative disparity information. Relative disparity responses are adult-like no later than 4-7 years of age. Copyright © 2017 the authors 0270-6474/17/375608-12$15.00/0.

Effects of tributyltin on early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes).

PubMed

Horie, Yoshifumi; Yamagishi, Takahiro; Shintaku, Yoko; Iguchi, Taisen; Tatarazako, Norihisa

2018-07-01

Tributyltin, an organotin compound, was used worldwide as an antifouling agent in aquatic environments and there has been much concern about the toxicological and ecotoxicological properties of organotin compounds. Even though it has been prohibited worldwide, tributyltin is still detected at low concentrations in aquatic environments. Here we investigated the effects of tributyltin on the early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes). In adults, exposure to tributyltin at 3.82 μg/L suppressed fecundity and fertility and increased mortality. At 10.48 μg/L all medaka died by the sixth day of exposure. Exposure to tributyltin during early life-stages induced no significant differences in mortality or embryonic development, but growth was suppressed in groups exposed to 0.13 and 0.68 μg/L. Furthermore, there was no abnormal gonadal development in Japanese medaka exposed to tributyltin. These results provide evidence of the negative effects of tributyltin on reproduction in a teleost fish. Tributyltin did not affect gonadal sex differentiation in Japanese medaka, but fecundity and fertility were suppressed, although it is not clear whether this suppression resulted from the endocrine-disrupting action of tributyltin or its toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes

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

Chen, Yanyan; The First Affiliated Hospital, China Medical University, Shenyang 110001; Xue, Peng

2013-12-15

Transcriptional signaling through the antioxidant response element (ARE), orchestrated by the Nuclear factor E2-related factor 2 (Nrf2), is a major cellular defense mechanism against oxidative or electrophilic stress. Here, we reported that isoniazid (INH), a widely used antitubercular drug, displays a substantial inhibitory property against ARE activities in diverse mouse and human cells. In 3T3-L1 preadipocytes, INH concentration-dependently suppressed the ARE-luciferase reporter activity and mRNA expression of various ARE-dependent antioxidant genes under basal and oxidative stressed conditions. In keeping with our previous findings that Nrf2-ARE plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein β (C/EBPβ) andmore » peroxisome proliferator-activated receptor γ (PPARγ), suppression of ARE signaling by INH hampered adipogenic differentiation of 3T3-L1 cells and human adipose-derived stem cells (ADSCs). Following adipogenesis induced by hormonal cocktails, INH-treated 3T3-L1 cells and ADSCs displayed significantly reduced levels of lipid accumulation and attenuated expression of C/EBPα and PPARγ. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by INH occurred in the early stage of terminal adipogenic differentiation, where reduced expression of C/EBPβ and C/EBPδ was observed. To our knowledge, the present study is the first to demonstrate that INH suppresses ARE signaling and interrupts with the transcriptional network of adipogenesis, leading to impaired adipogenic differentiation. The inhibition of ARE signaling may be a potential underlying mechanism by which INH attenuates cellular antioxidant response contributing to various complications. - Highlights: • Isoniazid suppresses ARE-mediated transcriptional activity. • Isoniazid inhibits adipogenesis in preadipocytes. • Isoniazid suppresses adipogenic gene expression during adipogenesis.« less

If waking and dreaming consciousness became de-differentiated, would schizophrenia result?

PubMed

Llewellyn, Sue

2011-12-01

If both waking and dreaming consciousness are functional, their de-differentiation would be doubly detrimental. Differentiation between waking and dreaming is achieved through neuromodulation. During dreaming, without external sensory data and with mesolimbic dopaminergic input, hyper-cholinergic input almost totally suppresses the aminergic system. During waking, with sensory gates open, aminergic modulation inhibits cholinergic and mesocortical dopaminergic suppresses mesolimbic. These neuromodulatory systems are reciprocally interactive and self-organizing. As a consequence of neuromodulatory reciprocity, phenomenologically, the self and the world that appear during dreaming differ from those that emerge during waking. As a result of self-organizing, the self and the world in both states are integrated. Some loss of self-organization would precipitate a degree of de-differentiation between waking and dreaming, resulting in a hybrid state which would be expressed heterogeneously, both neurobiologically and phenomenologically. As a consequence of progressive de-differentiation, certain identifiable psychiatric disorders may emerge. Ultimately, schizophrenia, a disorganized-fragmented self, may result. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of diosgenin on metabolic dysfunction: Role of ERβ in the regulation of PPARγ

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

Wang, Xin, E-mail: xinwang@fmmu.edu.cn; Liu, Jun; Long, Zi

The present study was designed to investigate the effect of diosgenin (DSG) on metabolic dysfunction and to elucidate the possible molecular mechanisms. High fat (HF) diet-fed mice and 3T3-L1 preadipocytes was used to evaluate the effect of DSG. We showed that DSG attenuated metabolic dysfunction in HF diet-fed mice, as evidenced by reduction of blood glucose level and improvement of glucose and insulin intolerance. DSG ameliorated oxidative stress, reduced body weight, fat pads, and systematic lipid profiles and attenuated lipid accumulation. DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size through regulating key factors. DSG inhibited PPARγ and its targetmore » gene expression both in differentiated 3T3-L1 adipocytes and fat tissues in HF diet-fed mice. Overexpression of PPARγ suppressed DSG-inhibited adipocyte differentiation. DSG significantly increased nuclear expression of ERβ. Inhibition of ERβ significantly suppressed DSG-exerted suppression of adipocyte differentiation and PPARγ expression. In response to DSG stimulation, ERβ bound with RXRα and dissociated RXRα from PPARγ, leading to the reduction of transcriptional activity of PPARγ. These data provide new insight into the mechanisms underlying the inhibitory effect of DSG on adipocyte differentiation and demonstrate that ERβ-exerted regulation of PPARγ expression and activity is critical for DSG-inhibited adipocyte differentiation. - Highlights: • Diosgenin (DSG) attenuated metabolic dysfunction in high fat (HF) diet-fed mice. • DSG reduced oxidative stress and lipid accumulation in HF diet-fed mice. • DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size. • DSG induced the binding of ERβ with RXRα. • DSG-induced activation of ERβ dissociated RXRα from PPARγ and reduced PPARγ activity.« less

Differential muscle regulatory factor gene expression between larval and adult myogenesis in the frog Xenopus laevis: adult myogenic cell-specific myf5 upregulation and its relation to the notochord suppression of adult muscle differentiation.

PubMed

Yamane, Hitomi; Nishikawa, Akio

2013-08-01

During Xenopus laevis metamorphosis, larval-to-adult muscle conversion depends on the differential responses of adult and larval myogenic cells to thyroid hormone. Essential differences in cell growth, differentiation, and hormone-dependent life-or-death fate have been reported between cultured larval (tail) and adult (hindlimb) myogenic cells. A previous study revealed that tail notochord cells suppress terminal differentiation in adult (but not larval) myogenic cells. However, little is known about the differences in expression patterns of myogenic regulatory factors (MRF) and the satellite cell marker Pax7 between adult and larval myogenic cells. In the present study, we compared mRNA expression of these factors between the two types. At first, reverse transcription polymerase chain reaction analysis of hindlimb buds showed sequential upregulation of myf5, myogenin, myod, and mrf4 during stages 50-54, when limb buds elongate and muscles begin to form. By contrast, in the tail, there was no such increase during the same period. Secondary, these results were duplicated in vitro: adult myogenic cells upregulated myf5, myod, and pax7 in the early culture period, followed by myogenin upregulation and myotube differentiation, while larval myogenic cells did not upregulate these genes and precociously started myotube differentiation. Thirdly, myf5 upregulation and early-phase proliferation in adult myogenic cells were potently inhibited by the presence of notochord cells, suggesting that notochord cells suppress adult myogenesis through inhibiting the transition from Myf5(-) stem cells to Myf5(+) committed myoblasts. All of the data presented here suggest that myf5 upregulation can be a good criterion for the activation of adult myogenesis during X. laevis metamorphosis.

A role for Hippo/YAP-signaling in FGF-induced lens epithelial cell proliferation and fibre differentiation.

PubMed

Dawes, L J; Shelley, E J; McAvoy, J W; Lovicu, F J

2018-04-01

Recent studies indicate an important role for the transcriptional co-activator Yes-associated protein (YAP), and its regulatory pathway Hippo, in controlling cell growth and fate during lens development; however, the exogenous factors that promote this pathway are yet to be identified. Given that fibroblast growth factor (FGF)-signaling is an established regulator of lens cell behavior, the current study investigates the relationship between this pathway and Hippo/YAP-signaling during lens cell proliferation and fibre differentiation. Rat lens epithelial explants were cultured with FGF2 to induce epithelial cell proliferation or fibre differentiation. Immunolabeling methods were used to detect the expression of Hippo-signaling components, Total and Phosphorylated YAP, as well as fibre cell markers, Prox-1 and β-crystallin. FGF-induced lens cell proliferation was associated with a strong nuclear localisation of Total-YAP and low-level immuno-staining for phosphorylated-YAP. FGF-induced lens fibre differentiation was associated with a significant increase in cytoplasmic phosphorylated YAP (inactive state) and enhanced expression of core Hippo-signaling components. Inhibition of YAP with Verteporfin suppressed FGF-induced lens cell proliferation and ablated cell elongation during lens fibre differentiation. Inhibition of either FGFR- or MEK/ERK-signaling suppressed FGF-promoted YAP nuclear translocation. Here we propose that FGF promotes Hippo/YAP-signaling during lens cell proliferation and differentiation, with FGF-induced nuclear-YAP expression playing an essential role in promoting the proliferation of lens epithelial cells. An FGF-induced switch from proliferation to differentiation, hence regulation of lens growth, may play a key role in mediating Hippo suppression of YAP transcriptional activity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Methods for Dichoptic Stimulus Presentation in Functional Magnetic Resonance Imaging - A Review

PubMed Central

Choubey, Bhaskar; Jurcoane, Alina; Muckli, Lars; Sireteanu, Ruxandra

2009-01-01

Dichoptic stimuli (different stimuli displayed to each eye) are increasingly being used in functional brain imaging experiments using visual stimulation. These studies include investigation into binocular rivalry, interocular information transfer, three-dimensional depth perception as well as impairments of the visual system like amblyopia and stereodeficiency. In this paper, we review various approaches of displaying dichoptic stimulus used in functional magnetic resonance imaging experiments. These include traditional approaches of using filters (red-green, red-blue, polarizing) with optical assemblies as well as newer approaches of using bi-screen goggles. PMID:19526076

Association of external auditory canal atresia, vertical talus, and hypertelorism: confirmation of Rasmussen syndrome.

PubMed

Julia, Sophie; Pedespan, Jean Michel; Boudard, Philippe; Barbier, Richard; Gavilan-Cellie, Isabelle; Chateil, Jean François; Lacombe, Didier

2002-06-15

In 1979, Rasmussen et al. reported six members of a family with congenital, bilateral, symmetrical, and isolated subtotal atresia of the external auditory canal, bilateral foot abnormalities, and increased interocular distance. The family history suggested autosomal dominant inheritance of the syndrome. We report a 3-year-old girl whose symptoms are compatible with this diagnosis. Therefore, we suggest confirmation of the description by Rasmussen et al. as a distinct entity and suggest the term Rasmussen syndrome for this condition. Copyright 2002 Wiley-Liss, Inc.

Osthole Attenuates Inflammatory Responses and Regulates the Expression of Inflammatory Mediators in HepG2 Cells Grown in Differentiated Medium from 3T3-L1 Preadipocytes.

PubMed

Wu, Shu-Ju

2015-09-01

This study explored the anti-inflammatory mechanisms by which osthole acted on HepG2 cells cultured in a differentiated medium from cultured 3T3-L1 preadipocyte cells. HepG2 cells, a human liver cell line, were treated with various concentrations of osthole in differentiated media from cultured 3T3-L1 cells to evaluate proinflammatory cytokines, inflammatory mediators, and signaling pathways. We used enzyme-linked immunosorbent assay kits to determine the levels of proinflammatory cytokines, real-time polymerase chain reaction to assay the mRNA expression, and western blot to determine the expression of cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) proteins. We also investigated inflammatory mechanism pathway members, including mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa-B (NF-κB). Osthole was able to suppress the levels of proinflammatory cytokines interleukin (IL)-1β and IL-6, as well as chemokines monocyte chemoattractant protein-1 and IL-8. In addition, COX-2 was suppressed and HO-1 expression was increased in a concentration-dependent manner. Osthole was also able to decrease IκB-α phosphorylation and suppress the phosphorylation of MAPKs. These results suggest that osthole has anti-inflammatory effects as demonstrated by the decreased proinflammatory cytokine and mediator production through suppression of the NF-κB and MAPK signaling pathways in HepG2 cells when they are incubated on the differentiated medium from 3T3-L1 cells.

Diverse Neurotoxicants Target the Differentiation of Embryonic Neural Stem Cells into Neuronal and Glial Phenotypes

PubMed Central

Slotkin, Theodore A.; Skavicus, Samantha; Card, Jennifer; Levin, Edward D.; Seidler, Frederic J.

2016-01-01

The large number of compounds that need to be tested for developmental neurotoxicity drives the need to establish in vitro models to evaluate specific neurotoxic endpoints. We used neural stem cells derived from rat neuroepithelium on embryonic day 14 to evaluate the impact of diverse toxicants on their ability to differentiate into glia and neurons: a glucocorticoid (dexamethasone), organophosphate insecticides (chlorpyrifos, diazinon, parathion), insecticides targeting the GABAA receptor (dieldrin, fipronil), heavy metals (Ni2+, Ag+), nicotine and tobacco smoke extract. We found three broad groupings of effects. One diverse set of compounds, dexamethasone, the organophosphate pesticides, Ni2+ and nicotine, suppressed expression of the glial phenotype while having little or no effect on the neuronal phenotype. The second pattern was restricted to the pesticides acting on GABAA receptors. These compounds promoted the glial phenotype and suppressed the neuronal phenotype. Notably, the actions of compounds eliciting either of these differentiation patterns were clearly unrelated to deficits in cell numbers: dexamethasone, dieldrin and fipronil all reduced cell numbers, whereas organophosphates and Ni2+ had no effect. The third pattern, shared by Ag+ and tobacco smoke extract, clearly delineated cytotoxicity, characterized major cell loss with suppression of differentiation into both glial and neuronal phenotypes; but here again, there was some selectivity in that glia were suppressed more than neurons. Our results, from this survey with diverse compounds, point to convergence of neurotoxicant effects on a specific “decision node” that controls the emergence of neurons and glia from neural stem cells. PMID:27816694

Tumor necrosis factor-α suppresses adipogenic and osteogenic differentiation of human periodontal ligament stem cell by inhibiting miR-21/Spry1 functional axis.

PubMed

Yang, Nan; Li, Yang; Wang, Guang; Ding, Yin; Jin, Yan; Xu, Yiquan

Periodontitis is a chronic infectious disease that leads to progressive destruction of periodontal tissue. Human periodontal ligament stem cells (PDLSCs) are the most favorable candidate for the reconstruction of tissues destroyed by periodontal diseases. PDLSCs derived from inflammatory microenvironment show attenuated differentiation potential, however the mechanism is still unclear. MicroRNAs (miRNAs) are a newly discovered class of posttranscriptional regulators, and they play key roles in regulating cell differentiation. Recent studies have demonstrated that inflammatory cytokines could regulate miRNAs and contribute to some inflammatory diseases. Tumor necrosis factor (TNF-α) is a potent negative regulator of cell differentiation. Elevated levels of TNF-α were confirmed to be associated with the severity of periodontal disease. Here, we found TNF-α inhibited the adipogenic and osteogenic differentiation of PDLSCs. Based on this, we hypothesized that TNF-α could participate in PDLSC differentiation by regulating miRNA signal pathway. Moreover, we demonstrated that the expression of miR-21 was suppressed by TNF-α in impaired adipogenic and osteogenic differentiation of PDLSCs. Upregulating miR-21 can partly rescue TNF-α-impaired adipogenesis and osteogenesis by repressing its target gene Spry1, suggested that miR-21/Spry1 functional axis plays critical role in PDLSC differentiation under inflammatory microenvironment. During adipogenesis and osteogenesis, TNF-α significantly increased Spry1 levels and overexpression of miR-21 dramatically decreased Spry1 levels in the presence of TNF-α, indicated important roles of miR-21 in modulating link between TNF-α and Spry1. Our findings introduce a molecular mechanism in which TNF-α suppresses adipogenic and osteogenic differentiation of PDLSCs by inhibiting miR-21/Spry1 functional axis. This study may indicate a molecular basis for novel therapeutic strategies against periodontitis and other inflammatory diseases. Copyright © 2017. Published by Elsevier B.V.

A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.

PubMed

Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

2014-10-01

Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

PD-1 regulates extrathymic regulatory T-cell differentiation

PubMed Central

Chen, Xiufen; Fosco, Dominick; Kline, Douglas E.; Meng, Liping; Nishi, Saki; Savage, Peter A.; Kline, Justin

2014-01-01

Regulatory T (Treg) cells and the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway are both critical for maintaining peripheral tolerance to self antigens. A significant subset of Treg cells constitutively expresses PD-1, which prompted an investigation into the role of PD-1/PD-L1 interactions in Treg-cell development, function and induction in vivo. The phenotype and abundance of Treg cells was not significantly altered in PD-1-deficient mice. The thymic development of polyclonal and monospecific Treg cells was not negatively impacted by PD-1 deficiency. The suppressive function of PD-1−/− Treg cells was similar to their PD-1+/+ counterparts both in vitro and in vivo. However, in three different in vivo experimental settings, PD-1−/− conventional CD4+ T cells demonstrated a strikingly diminished tendency toward differentiation into peripherally induced Treg (pTreg) cells. Our results demonstrate that PD-1 is dispensable for thymic (tTreg) Treg-cell development and suppressive function, but is critical for the extrathymic differentiation of pTreg cells in vivo. These data suggest that antibody blockade of the PD-1/PD-L1 pathway may augment T-cell responses by acting directly on conventional T cells, and also by suppressing the differentiation of pTreg cells. PMID:24975127

Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.

PubMed

Pujol, P; Daures, J P; Nsakala, N; Baldet, L; Bringer, J; Jaffiol, C

1996-12-01

We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

Effects of let-7b and TLX on the proliferation and differentiation of retinal progenitor cells in vitro

PubMed Central

Ni, Ni; Zhang, Dandan; Xie, Qing; Chen, Junzhao; Wang, Zi; Deng, Yuan; Wen, Xuyang; Zhu, Mengyu; Ji, Jing; Fan, Xianqun; Luo, Min; Gu, Ping

2014-01-01

MicroRNAs manifest significant functions in brain neural stem cell (NSC) self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. Let-7b is expressed in the mammalian brain and regulates NSC proliferation and differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal. Whether let-7b and TLX act as important regulators in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. Here, our data show that let-7b and TLX play important roles in controlling RPC fate determination in vitro. Let-7b suppresses TLX expression to negatively regulate RPC proliferation and accelerate the neuronal and glial differentiation of RPCs. The overexpression of let-7b downregulates TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, whereas antisense knockdown of let-7b produces robust TLX expression,enhanced RPC proliferation and decreased differentiation. Moreover, the inhibition of endogenous TLX by small interfering RNA suppresses RPC proliferation and promotes RPC differentiation. Furthermore, overexpression of TLX rescues let-7b-induced proliferation deficiency and weakens the RPC differentiation enhancement caused by let-7b alone. These results suggest that let-7b, by forming a negative feedback loop with TLX, provides a novel model to regulate the proliferation and differentiation of retinal progenitors in vitro. PMID:25327364

Effects of let-7b and TLX on the proliferation and differentiation of retinal progenitor cells in vitro.

PubMed

Ni, Ni; Zhang, Dandan; Xie, Qing; Chen, Junzhao; Wang, Zi; Deng, Yuan; Wen, Xuyang; Zhu, Mengyu; Ji, Jing; Fan, Xianqun; Luo, Min; Gu, Ping

2014-10-20

MicroRNAs manifest significant functions in brain neural stem cell (NSC) self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. Let-7b is expressed in the mammalian brain and regulates NSC proliferation and differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal. Whether let-7b and TLX act as important regulators in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. Here, our data show that let-7b and TLX play important roles in controlling RPC fate determination in vitro. Let-7b suppresses TLX expression to negatively regulate RPC proliferation and accelerate the neuronal and glial differentiation of RPCs. The overexpression of let-7b downregulates TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, whereas antisense knockdown of let-7b produces robust TLX expression,enhanced RPC proliferation and decreased differentiation. Moreover, the inhibition of endogenous TLX by small interfering RNA suppresses RPC proliferation and promotes RPC differentiation. Furthermore, overexpression of TLX rescues let-7b-induced proliferation deficiency and weakens the RPC differentiation enhancement caused by let-7b alone. These results suggest that let-7b, by forming a negative feedback loop with TLX, provides a novel model to regulate the proliferation and differentiation of retinal progenitors in vitro.

SacB-SacR gene cassette as the negative selection marker to suppress Agrobacterium overgrowth in Agrobacterium-mediated plant transformation

USDA-ARS?s Scientific Manuscript database

Agrobacterium overgrowth is a common problem in Agrobacterium-mediated plant transformation. To suppress the Agrobacterium overgrowth, various antibiotics have been used during plant tissue culture steps. The antibiotics are expensive and may adversely affect plant cell differentiation and reduce ...

Effect of essential amino acids on enteroids: Methionine deprivation suppresses proliferation and affects differentiation in enteroid stem cells

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

Saito, Yuki; Iwatsuki, Ken; Hanyu, Hikaru

We investigated the effects of essential amino acids on intestinal stem cell proliferation and differentiation using murine small intestinal organoids (enteroids) from the jejunum. By selectively removing individual essential amino acids from culture medium, we found that 24 h of methionine (Met) deprivation markedly suppressed cell proliferation in enteroids. This effect was rescued when enteroids cultured in Met deprivation media for 12 h were transferred to complete medium, suggesting that Met plays an important role in enteroid cell proliferation. In addition, mRNA levels of the stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) decreased in enteroids grown in Met deprivationmore » conditions. Consistent with this observation, Met deprivation also attenuated Lgr5-EGFP fluorescence intensity in enteroids. In contrast, Met deprivation enhanced mRNA levels of the enteroendocrine cell marker chromogranin A (ChgA) and markers of K cells, enterochromaffin cells, goblet cells, and Paneth cells. Immunofluorescence experiments demonstrated that Met deprivation led to an increase in the number of ChgA-positive cells. These results suggest that Met deprivation suppresses stem cell proliferation, thereby promoting differentiation. In conclusion, Met is an important nutrient in the maintenance of intestinal stem cells and Met deprivation potentially affects cell differentiation. - Highlights: • Met influences the proliferation of enteroids. • Met plays a crucial role in the maintenance of stem cells. • Met deprivation potentially promotes differentiation into secretory cells.« less

Tunable Microfibers Suppress Fibrotic Encapsulation via Inhibition of TGFβ Signaling

PubMed Central

Allen, Jessica; Ryu, Jubin; Maggi, Alessandro; Flores, Bianca; Greer, Julia R.

2016-01-01

Fibrotic encapsulation limits the efficacy and lifetime of implantable biomedical devices. Microtopography has shown promise in the regulation of myofibroblast differentiation, a key driver of fibrotic encapsulation. However, existing studies have not systematically isolated the requisite geometric parameters for suppression of myofibroblast differentiation via microtopography, and there has not been in vivo validation of this technology to date. To address these issues, a novel lamination method was developed to afford more control over topography dimensions. Specifically, in this study we focus on fiber length and its effect on myofibroblast differentiation. Fibroblasts cultured on films with microfibers exceeding 16 μm in length lost the characteristic morphology associated with myofibroblast differentiation, while shorter microfibers of 6 μm length failed to produce this phenotype. This increase in length corresponded to a 50% decrease in fiber stiffness, which acts as a mechanical cue to influence myofibroblast differentiation. Longer microfiber films suppressed expression of myofibroblast-specific genes (αSMA, Col1α2, and Col3α1) and TGFβ signaling components (TGFβ1, TβR2, and Smad3). About 16 μm long microfiber films subcutaneously implanted in a mouse wound-healing model generated a substantially thinner fibrotic capsule and less deposition of collagen in the wound bed. Together, these results identify a critical feature length threshold for microscale topography-mediated repression of fibrotic encapsulation. This study also demonstrates a simple and powerful strategy to improve surface biocompatibility and reduce fibrotic encapsulation around implanted materials. PMID:26507808

Sub-toxic concentrations of nano-ZnO and nano-TiO2 suppress neurite outgrowth in differentiated PC12 cells.

PubMed

Irie, Tomohiko; Kawakami, Tsuyoshi; Sato, Kaoru; Usami, Makoto

2017-01-01

Nanomaterials have been extensively used in our daily life, and may also induce health effects and toxicity. Nanomaterials can translocate from the outside to internal organs, including the brain. For example, both nano-ZnO and nano-TiO 2 translocate into the brain via the olfactory pathway in rodents, possibly leading to toxic effects on the brain. Although the effects of nano-ZnO and nano-TiO 2 on neuronal viability or neuronal excitability have been studied, no work has focused on how these nanomaterials affect neuronal differentiation and development. In this study, we investigated the effects of nano-ZnO and nano-TiO 2 on neurite outgrowth of PC12 cells, a useful model system for neuronal differentiation. Surprisingly, the number, length, and branching of differentiated PC12 neurites were significantly suppressed by the 7-day exposure to nano-ZnO (in the range of 1.0 × 10 -4 to 1.0 × 10 -1 µg/mL), at which the cell viability was not affected. The number and length were also significantly inhibited by the 7-day exposure to nano-TiO 2 (1.0 × 10 -3 to 1.0 µg/mL), which did not have cytotoxic effects. These results demonstrate that the neurite outgrowth in differentiated PC12 cells was suppressed by sub-cytotoxic concentrations of nano-ZnO or nano-TiO 2 .

Differential roles of resistance to proactive interference and suppression of prepotent responses in overgeneral memory.

PubMed

Comas, Michelle; Valentino, Kristin; Johnson, Anne F; Gibson, Bradley S; Taylor, Courtney

2018-06-12

Overgeneral memory (OGM), difficulty in retrieving specific autobiographical memories, is a robust phenomenon related to the onset and course of depressive and posttraumatic stress disorders. Inhibitory mechanisms are theorized to underlie OGM; however, empirical support for this link is equivocal. The current study examines the differential roles of two aspects of inhibitory control in association with OGM: suppression of prepotent responses and resistance to proactive interference (PI). Only resistance to PI was expected to be negatively related to OGM, whereby individuals with greater ability to resist PI would have reduced OGM. Participants (n = 49) completed a self-report measure of depressive symptoms and engaged in two tasks aimed at assessing resistance to PI and suppression of prepotent responses. Participants also completed a task assessing overgeneral autobiographical memory. As hypothesized, resistance to PI, but not suppression of prepotent responses negatively predicted OGM above and beyond the influence of depressive symptoms. Because a double dissociation was not examined, we cannot address the potential independence of the submechanisms of inhibitory control that we assessed. Results exemplify the differential associations of two components of inhibition and OGM, suggesting that resistance to PI, in particular, may contribute to the development and/or maintenance of OGM and associated depressive disorders. Directions for future research are discussed. Copyright © 2018. Published by Elsevier Ltd.

Effects of brief daily periods of unrestricted vision during early monocular form deprivation on development of visual area 2.

PubMed

Zhang, Bin; Tao, Xiaofeng; Wensveen, Janice M; Harwerth, Ronald S; Smith, Earl L; Chino, Yuzo M

2011-09-14

Providing brief daily periods of unrestricted vision during early monocular form deprivation reduces the depth of amblyopia. To gain insights into the neural basis of the beneficial effects of this treatment, the binocular and monocular response properties of neurons were quantitatively analyzed in visual area 2 (V2) of form-deprived macaque monkeys. Beginning at 3 weeks of age, infant monkeys were deprived of clear vision in one eye for 12 hours every day until 21 weeks of age. They received daily periods of unrestricted vision for 0, 1, 2, or 4 hours during the form-deprivation period. After behavioral testing to measure the depth of the resulting amblyopia, microelectrode-recording experiments were conducted in V2. The ocular dominance imbalance away from the affected eye was reduced in the experimental monkeys and was generally proportional to the reduction in the depth of amblyopia in individual monkeys. There were no interocular differences in the spatial properties of V2 neurons in any subject group. However, the binocular disparity sensitivity of V2 neurons was significantly higher and binocular suppression was lower in monkeys that had unrestricted vision. The decrease in ocular dominance imbalance in V2 was the neuronal change most closely associated with the observed reduction in the depth of amblyopia. The results suggest that the degree to which extrastriate neurons can maintain functional connections with the deprived eye (i.e., reducing undersampling for the affected eye) is the most significant factor associated with the beneficial effects of brief periods of unrestricted vision.

Effects of Brief Daily Periods of Unrestricted Vision during Early Monocular Form Deprivation on Development of Visual Area 2

PubMed Central

Zhang, Bin; Tao, Xiaofeng; Wensveen, Janice M.; Harwerth, Ronald S.; Smith, Earl L.

2011-01-01

Purpose. Providing brief daily periods of unrestricted vision during early monocular form deprivation reduces the depth of amblyopia. To gain insights into the neural basis of the beneficial effects of this treatment, the binocular and monocular response properties of neurons were quantitatively analyzed in visual area 2 (V2) of form-deprived macaque monkeys. Methods. Beginning at 3 weeks of age, infant monkeys were deprived of clear vision in one eye for 12 hours every day until 21 weeks of age. They received daily periods of unrestricted vision for 0, 1, 2, or 4 hours during the form-deprivation period. After behavioral testing to measure the depth of the resulting amblyopia, microelectrode-recording experiments were conducted in V2. Results. The ocular dominance imbalance away from the affected eye was reduced in the experimental monkeys and was generally proportional to the reduction in the depth of amblyopia in individual monkeys. There were no interocular differences in the spatial properties of V2 neurons in any subject group. However, the binocular disparity sensitivity of V2 neurons was significantly higher and binocular suppression was lower in monkeys that had unrestricted vision. Conclusions. The decrease in ocular dominance imbalance in V2 was the neuronal change most closely associated with the observed reduction in the depth of amblyopia. The results suggest that the degree to which extrastriate neurons can maintain functional connections with the deprived eye (i.e., reducing undersampling for the affected eye) is the most significant factor associated with the beneficial effects of brief periods of unrestricted vision. PMID:21849427

Choice is good, but relevance is excellent: autonomy-enhancing and suppressing teacher behaviours predicting students' engagement in schoolwork.

PubMed

Assor, Avi; Kaplan, Haya; Roth, Guy

2002-06-01

This article examines two questions concerning teacher-behaviours that are characterised in Self-Determination Theory (Ryan & Deci, 2000) as autonomy-supportive or suppressive: (1) Can children differentiate among various types of autonomy-enhancing and suppressing teacher behaviours? (2) Which of those types of behaviour are particularly important in predicting feelings toward and engagement in schoolwork? It was hypothesised that teacher behaviours that help students to understand the relevance of schoolwork for their personal interests and goals are particularly important predictors of engagement in schoolwork. Israeli students in grades 3-5 (N = 498) and in grades 6-8 (N = 364) completed questionnaires assessing the variables of interest. Smallest Space Analyses indicated that both children and early adolescents can differentiate among three types of autonomy enhancing teacher behaviours - fostering relevance, allowing criticism, and providing choice - and three types of autonomy suppressing teacher behaviours - suppressing criticism, intruding, and forcing unmeaningful acts. Regression analyses supported the hypothesis concerning the importance of teacher behaviours that clarify the personal relevance of schoolwork. Among the autonomy-suppressing behaviours, 'Criticism-suppression' was the best predictor of feelings and engagement. The findings underscore the active and empathic nature of teachers' role in supporting students' autonomy, and suggest that autonomy-support is important not only for early adolescents but also for children. Discussion of potential determinants of the relative importance of various autonomy-affecting teacher actions suggests that provision of choice should not always be viewed as a major indicator of autonomy support.

Eye Dominance Predicts fMRI Signals in Human Retinotopic Cortex

PubMed Central

Mendola, Janine D.; Conner, Ian P.

2009-01-01

There have been many attempts to define eye dominance in normal subjects, but limited consensus exists, and relevant physiological data is scarce. In this study, we consider two different behavioral methods for assignment of eye dominance, and how well they predict fMRI signals evoked by monocular stimulation. Sighting eye dominance was assessed with two standard tests, the Porta Test, and a ‘hole in hand’ variation of the Miles Test. Acuity dominance was tested with a standard eye chart and with a computerized test of grating acuity. We found limited agreement between the sighting and acuity methods for assigning dominance in our individual subjects. We then compared the fMRI response generated by dominant eye stimulation to that generated by non-dominant eye, according to both methods, in 7 normal subjects. The stimulus consisted of a high contrast hemifield stimulus alternating with no stimulus in a blocked paradigm. In separate scans, we used standard techniques to label the borders of visual areas V1, V2, V3, VP, V4, V3A, and MT. These regions of interest (ROIs) were used to analyze each visual area separately. We found that percent change in fMRI BOLD signal was stronger for the dominant eye as defined by the acuity method, and this effect was significant for areas located in the ventral occipital territory (V1v, V2v, VP, V4). In contrast, assigning dominance based on sighting produced no significant interocular BOLD differences. We conclude that interocular BOLD differences in normal subjects exist, and may be predicted by acuity measures. PMID:17194544

Stereomotion speed perception: contributions from both changing disparity and interocular velocity difference over a range of relative disparities

NASA Technical Reports Server (NTRS)

Brooks, Kevin R.; Stone, Leland S.

2004-01-01

The role of two binocular cues to motion in depth-changing disparity (CD) and interocular velocity difference (IOVD)- was investigated by measuring stereomotion speed discrimination and static disparity discrimination performance (stereoacuity). Speed discrimination thresholds were assessed both for random dot stereograms (RDS), and for their temporally uncorrelated equivalents, dynamic random dot stereograms (DRDS), at relative disparity pedestals of -19, 0, and +19 arcmin. While RDS stimuli contain both CD and IOVD cues, DRDS stimuli carry only CD information. On average, thresholds were a factor of 1.7 higher for DRDS than for RDS stimuli with no clear effect of relative disparity pedestal. Results were similar for approaching and receding targets. Variations in stimulus duration had no significant effect on thresholds, and there was no observed correlation between stimulus displacement and perceived speed, confirming that subjects responded to stimulus speed in each condition. Stereoacuity was equally good for our RDS and DRDS stimuli, showing that the difference in stereomotion speed discrimination performance for these stimuli was not due to any difference in the precision of the disparity cue. In addition, when we altered stereomotion stimulus trajectory by independently manipulating the speeds and directions of its monocular half-images, perceived stereomotion speed remained accurate. This finding is inconsistent with response strategies based on properties of either monocular half-image motion, or any ad hoc combination of the monocular speeds. We conclude that although subjects are able to discriminate stereomotion speed reliably on the basis of CD information alone, IOVD provides a precise additional cue to stereomotion speed perception.

Effect of occlusion amblyopia after prescribed full-time occlusion on long-term visual acuity outcomes.

PubMed

Longmuir, Susannah; Pfeifer, Wanda; Scott, William; Olson, Richard

2013-01-01

To investigate the incidence and characteristics of occlusion amblyopia with prescribed full-time patching and determine its effect on long-term visual acuity outcomes. The records of patients younger than 10 years diagnosed as having amblyopia between 1970 and 2000 were retrospectively reviewed. Patients were prescribed full-time occlusion and observed until completion of therapy. Of 597 patients treated for amblyopia by full-time patching, 115 were diagnosed as having occlusion amblyopia (19.3%). Seventy-five percent (86 of 115) developed occlusion amblyopia during the first episode of full-time patching. Occlusion amblyopia occurred more frequently in children prescribed full-time patching at an earlier age (P = .0002), with an odds ratio of 8.56 (95% confidence interval: 2.73, 26.84) in children younger than 36 months and 2.66 (95% confidence interval: 0.96, 7.37) in children between 36 and 59 months old. Seven of the patients with occlusion amblyopia did not reverse fixation and continued to fixate with the initially amblyopic eye after treatment. Final visual acuity in these eyes with occlusion amblyopia was 20/30 or better. After cessation of treatment, the final interocular difference in visual acuity was less in patients with a history of occlusion amblyopia (P = .003). Occlusion amblyopia occurred at all ages, but the incidence decreased with increasing age. Patients who developed occlusion amblyopia with prescribed full-time occlusion had less interocular visual acuity difference than patients who did not, suggesting that development of occlusion amblyopia can indicate the potential for the development of better vision in the originally amblyopic eye. Copyright 2013, SLACK Incorporated.

End-stage renal disease, dialysis, kidney transplantation and their impact on CD4+ -T-cell differentiation.

PubMed

Schaier, Matthias; Leick, Angele; Uhlmann, Lorenz; Kälble, Florian; Morath, Christian; Eckstein, Volker; Ho, Anthony; Mueller-Tidow, Carsten; Meuer, Stefan; Mahnke, Karsten; Sommerer, Claudia; Zeier, Martin; Steinborn, Andrea

2018-05-02

Premature aging of both CD4 + -regulatory- (Tregs) and CD4 + -responder-T-cells (Tresps) in end-stage renal disease (ESRD) patients is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible co-stimulatory (ICOS + -) and ICOS - -recent thymic emigrant (RTE)-Tregs/Tresps, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS + - and ICOS - -RTE-Tregs/Tresps into ICOS + - or ICOS - -CD31 - -Memory-Tregs/Tresps and examined whether diverging pathways affected the suppressive activity of ICOS + - and ICOS - -Tregs in co-culture with autologous Tresps. Compared to healthy controls, we found an increased differentiation of ICOS + -RTE-Tregs/Tresps and ICOS - -RTE-Tregs via CD31 + -memory-Tregs/Tresps into CD31 - -memory-Tregs/Tresps in ESRD and dialysis patients. In contrast, ICOS - -RTE-Tresps showed an increased differentiation via ICOS - -mature naïve (MN)-Tresps into CD31 - -memory-Tresps. Thereby, the ratio of ICOS + -Tregs/ICOS + -Tresps was not changed, while that of ICOS - -Tregs/ICOS - -Tresps was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS + - and ICOS - -RTE-Tresps proceeded, while that of ICOS + -RTE-Tregs ceased and that of ICOS - -RTE-Tregs switched to an increased differentiation via ICOS - -MN-Tregs. Consequently, the ratios of ICOS + -Tregs/ICOS + -Tresps and of ICOS - -Tregs/ICOS - -Tresps decreased significantly, reducing the suppressive activity of Tregs markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS + - and ICOS - -Tregs preserves the functional activity of Tregs in ESRD patients, but this cannot be maintained during long-term renal replacement therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

miR-383 negatively regulates osteoblastic differentiation of bone marrow mesenchymal stem cells in rats by targeting Satb2.

PubMed

Tang, Jianfei; Zhang, Zeng; Jin, Xiangyun; Shi, Huipeng

2018-06-14

Emerging evidence indicates that microRNAs (miRNAs, miRs) play diverse roles in the regulation of biological processes, including osteoblastic differentiation. In this study, we found that miR-383 is a critical regulator of osteoblastic differentiation. We showed that miR-383 was downregulated during osteoblastic differentiation of rat bone marrow mesenchymal stem cells (BMSCs). Overexpression of miR-383 suppressed osteoblastic differentiation of BMSCs by downregulating alkaline phosphatase (ALP), matrix mineralization, and mRNA and protein levels of RUNX2 and OCN, whereas a knockdown of miR-383 promoted osteoblastic differentiation in vitro. The results of in vivo analysis indicated that inhibition of miR-383 expression enhanced the efficacy of new bone formation in a rat calvarial defect model. Mechanistic experiments revealed that special AT-rich-sequence-binding protein 2 (Satb2) was a direct and functional target of miR-383. Knockdown of Satb2 had inhibitory effects resembling those of miR-383 on the osteoblast differentiation of rat BMSCs. In addition, the positive effect of miR-383 suppression on osteoblastic differentiation was apparently abrogated by Satb2 silencing. Collectively, these results indicate that miR-383 plays an inhibitory role in osteogenic differentiation of rat BMSCs and may act by targeting Satb2. Copyright © 2017. Published by Elsevier Inc.

Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway.

PubMed

Abdallah, Basem M; Alzahrani, Abdullah M; Kassem, Moustapha

2018-05-01

Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Src Homology 2–containing 5-Inositol Phosphatase (SHIP) Suppresses an Early Stage of Lymphoid Cell Development through Elevated Interleukin-6 Production by Myeloid Cells in Bone Marrow

PubMed Central

Nakamura, Koji; Kouro, Taku; Kincade, Paul W.; Malykhin, Alexander; Maeda, Kazuhiko; Coggeshall, K. Mark

2004-01-01

The Src homology (SH)2–containing inositol 5-phosphatase (SHIP) negatively regulates a variety of immune responses through inhibitory immune receptors. In SHIP−/− animals, we found that the number of early lymphoid progenitors in the bone marrow was significantly reduced and accompanied by expansion of myeloid cells. We exploited an in vitro system using hematopoietic progenitors that reproduced the in vivo phenotype of SHIP−/− mice. Lineage-negative marrow (Lin−) cells isolated from wild-type mice failed to differentiate into B cells when cocultured with those of SHIP−/− mice. Furthermore, culture supernatants of SHIP−/− Lin− cells suppressed the B lineage expansion of wild-type lineage-negative cells, suggesting the presence of a suppressive cytokine. SHIP−/− Lin− cells contained more IL-6 transcripts than wild-type Lin− cells, and neutralizing anti–IL-6 antibody rescued the B lineage expansion suppressed by the supernatants of SHIP−/− Lin− cells. Finally, we found that addition of recombinant IL-6 to cultures of wild-type Lin− bone marrow cells reproduced the phenotype of SHIP−/− bone marrow cultures: suppression of B cell development and expansion of myeloid cells. The results identify IL-6 as an important regulatory cytokine that can suppress B lineage differentiation and drive excessive myeloid development in bone marrow. PMID:14718513

Assessing the efficiency of Wolbachia driven Aedes mosquito suppression by delay differential equations.

PubMed

Huang, Mugen; Luo, Jiaowan; Hu, Linchao; Zheng, Bo; Yu, Jianshe

2017-12-14

To suppress wild population of Aedes mosquitoes, the primary transmission vector of life-threatening diseases such as dengue, malaria, and Zika, an innovative strategy is to release male mosquitoes carrying the bacterium Wolbachia into natural areas to drive female sterility by cytoplasmic incompatibility. We develop a model of delay differential equations, incorporating the strong density restriction in the larval stage, to assess the delicate impact of life table parameters on suppression efficiency. Through mathematical analysis, we find the sufficient and necessary condition for global stability of the complete suppression state. This condition, combined with the experimental data for Aedes albopictus population in Guangzhou, helps us predict a large range of releasing intensities for suppression success. In particular, we find that if the number of released infected males is no less than four times the number of mosquitoes in wild areas, then the mosquito density in the peak season can be reduced by 95%. We introduce an index to quantify the dependence of suppression efficiency on parameters. The invariance of some quantitative properties of the index values under various perturbations of the same parameter justifies the applicability of this index, and the robustness of our modeling approach. The index yields a ranking of the sensitivity of all parameters, among which the adult mortality has the highest sensitivity and is considerably more sensitive than the natural larvae mortality. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro

PubMed Central

Choudhary, Shilpa; Blackwell, Katherine; Voznesensky, Olga; Roy, Abhijit Deb; Pilbeam, Carol

2014-01-01

Intermittent PTH is the major anabolic therapy for osteoporosis while continuous PTH causes bone loss. PTH acts on the osteoblast (OB) lineage to regulate bone resorption and formation. PTH also induces cyclooxygenase-2 (COX-2), producing prostaglandin E2 (PGE2) that can act on both OBs and osteoclasts (OCs). Because intermittent PTH is more anabolic in Cox-2 knockout (KO) than wild type (WT) mice, we hypothesized COX-2 might contribute to the effects of continuous PTH by suppressing PTH-stimulated differentiation of mesenchymal stem cells into OBs. We compared effects of continuous PTH on bone marrow stromal cells (BMSCs) and primary OBs (POBs) from Cox-2 KO mice, mice with deletion of PGE2 receptors (Ptger4 and Ptger2 KO mice), and WT controls. PTH increased OB differentiation in BMSCs only in the absence of COX-2 expression or activity. In the absence of COX-2, PTH stimulated differentiation if added during the first week of culture. In Cox-2 KO BMSCs, PTH-stimulated differentiation was prevented by adding PGE2 to cultures. Co-culture of POBs with M-CSF-expanded bone marrow macrophages (BMMs) showed that the inhibition of PTH-stimulated OB differentiation required not only COX-2 or PGE2 but also BMMs. Sufficient PGE2 to mediate the inhibitory effect was made by either WT POBs or WT BMMs. The inhibitory effect mediated by COX-2/PGE2 was transferred by conditioned media from RANKL-treated BMMs and could be blocked by osteoprotegerin, which interferes with RANKL binding to its receptor on OC lineage cells. Deletion of Ptger4, but not Ptger2, in BMMs prevented the inhibition of PTH-stimulated OB differentiation. As expected, PGE2 also stimulated OB differentiation, but when given in combination with PTH, the stimulatory effects of both were abrogated. These data suggest that PGE2, acting via EP4R on BMMs committed to the OC lineage, stimulated secretion of a factor or factors that acted to suppress PTH-stimulated OB differentiation. This suppression of OB differentiation could contribute to the bone loss seen with continuous PTH in vivo. PMID:23639875

Targeted deletion of Atg5 reveals differential roles of autophagy in keratin K5-expressing epithelia

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

Sukseree, Supawadee; Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok; Rossiter, Heidemarie

2013-01-11

Highlights: Black-Right-Pointing-Pointer We generated mice lacking Atg5 and autophagy in keratin K5-positive epithelia. Black-Right-Pointing-Pointer Suppression of autophagy in thymic epithelium was not associated with signs of autoimmunity. Black-Right-Pointing-Pointer Autophagy was required for normal terminal differentiation of preputial gland cells. Black-Right-Pointing-Pointer Autophagy-deficient cells of the preputial glands degraded nuclear DNA prematurely. -- Abstract: Autophagy contributes to the homeostasis of many tissues, yet its role in epithelia is incompletely understood. A recent report proposed that Atg5-dependent autophagy in thymic epithelial cells is essential for their function in the negative selection of self-reactive T-cells and, thus, for the suppression of tissue inflammation. Heremore » we crossed mice carrying floxed alleles of the Atg5 gene with mice expressing the Cre recombinase under the control of the keratin K5 promoter to suppress autophagy in all K5-positive epithelia. The efficiency of autophagy abrogation was confirmed by immunoanalyses of LC3, which was converted to the autophagy-associated LC3-II form in normal but not Atg5-deficient cells, and of p62, which accumulated in Atg5-deficient cells. Mice carrying the epithelium-specific deletion of Atg5 showed normal weight gain, absence of tissue inflammation, and a normal morphology of the thymic epithelium. By contrast, autophagy-deficient epithelial cells of the preputial gland showed aberrant eosinophilic staining in histology and premature degradation of nuclear DNA during terminal differentiation. Taken together, the results of this study suggest that autophagy is dispensable for the suppression of autoimmunity by thymic epithelial cells but essential for normal differentiation of the preputial gland in mice.« less

Tributyltin induces distinct effects on cortical and trabecular bone in female C57Bl/6J mice.

PubMed

Watt, James; Baker, Amelia H; Meeks, Brett; Pajevic, Paola D; Morgan, Elise F; Gerstenfeld, Louis C; Schlezinger, Jennifer J

2018-09-01

The retinoid X receptors (RXR), peroxisome proliferator activated receptor gamma (PPARγ), and liver X receptors (LXR) all have been shown to regulate bone homeostasis. Tributyltin (TBT) is an environmental contaminant that is a dual RXRα/β and PPARγ agonist. TBT induces RXR, PPARγ, and LXR-mediated gene transcription and suppresses osteoblast differentiation in vitro. Bone marrow multipotent mesenchymal stromal cells derived from female C57BL/6J mice were more sensitive to suppression of osteogenesis by TBT than those derived from male mice. In vivo, oral gavage of 12 week old female, C57Bl/6J mice with 10 mg/kg TBT for 10 weeks resulted in femurs with a smaller cross-sectional area and thinner cortex. Surprisingly, TBT induced significant increases in trabecular thickness, number, and bone volume fraction. TBT treatment did not change the Rankl:Opg RNA ratio in whole bone, and histological analyses showed that osteoclasts in the trabecular space were minimally reduced. In contrast, expression of cardiotrophin-1, an osteoblastogenic cytokine secreted by osteoclasts, increased. In primary bone marrow macrophage cultures, TBT marginally inhibited the number of osteoclasts that differentiated, in spite of significantly suppressing expression of osteoclast markers Nfatc1, Acp5, and Ctsk and resorptive activity. TBT induced expression of RXR- and LXR-dependent genes in whole bone and in vitro osteoclast cultures. However, only an RXR antagonist, but not an LXR antagonist, significantly inhibited TBTs ability to suppress osteoclast differentiation. These results suggest that TBT has distinct effects on cortical versus trabecular bone, likely resulting from independent effects on osteoblast and osteoclast differentiation that are mediated through RXR. © 2018 Wiley Periodicals, Inc.

The Mixture of Anemarrhena asphodeloides and Coptis chinensis Attenuates High-Fat Diet-Induced Colitis in Mice.

PubMed

Lim, Su-Min; Choi, Hyun-Sik; Kim, Dong-Hyun

2017-01-01

Anemarrhena asphodeloides (AA, family Liliaceae) inhibits macrophage activation by inhibiting IRAK1 phosphorylation and helper T (Th)17 differentiation. Coptis chinensis (CC, family Ranunculaceae), which inhibits macrophage activation by inhibiting the binding of lipopolysaccharide (LPS) on toll-like receptor 4 and inducing regulatory T (Treg) cell differentiation. The mixture of AA and CC (AC-mix) synergistically attenuates 2,4,6-trinitrobenzenesulfonic acid or dextran sulfate sodium-induced colitis in mice by inhibiting NF-[Formula: see text]B activation and regulating Th17/Treg balance. In the present study, we examined the effect of AC-mix on high-fat diet (HFD)-induced colitis in mice, which induced NF-[Formula: see text]B activation and disturbed Th17/Treg balance. Long-term feeding of HFD in mice caused colitis, including increased macroscopic score and myeloperoxidase activity. Oral administration of AC-mix (20[Formula: see text]mg/kg) suppressed HFD-induced myeloperoxidase activity by 68% ([Formula: see text]). Furthermore, treatment with the AC-mix (20[Formula: see text]mg/kg) inhibited HFD-induced activation of NF-[Formula: see text]B and expression of cyclooxygenase-2, inducible NO synthase, interleukin (IL)-17, and tumor necrosis factor-alpha but increased HFD- suppressed expression of IL-10. AC-mix suppressed HFD-induced differentiation into Th17 cells by 46% ([Formula: see text]) and increased HFD-induced differentiation into regulatory T cells 2.2-fold ([Formula: see text]). AC-mix also suppressed the HFD-induced Proteobacteria/Bacteroidetes ratio on the gut microbiota by 48% ([Formula: see text]). These findings suggest that AC-mix can ameliorate HFD-induced colitis by regulating innate and adaptive immunities and correcting the disturbance of gut microbiota.

Differential Characteristics Based Iterative Multiuser Detection for Wireless Sensor Networks

PubMed Central

Chen, Xiaoguang; Jiang, Xu; Wu, Zhilu; Zhuang, Shufeng

2017-01-01

High throughput, low latency and reliable communication has always been a hot topic for wireless sensor networks (WSNs) in various applications. Multiuser detection is widely used to suppress the bad effect of multiple access interference in WSNs. In this paper, a novel multiuser detection method based on differential characteristics is proposed to suppress multiple access interference. The proposed iterative receive method consists of three stages. Firstly, a differential characteristics function is presented based on the optimal multiuser detection decision function; then on the basis of differential characteristics, a preliminary threshold detection is utilized to find the potential wrongly received bits; after that an error bit corrector is employed to correct the wrong bits. In order to further lower the bit error ratio (BER), the differential characteristics calculation, threshold detection and error bit correction process described above are iteratively executed. Simulation results show that after only a few iterations the proposed multiuser detection method can achieve satisfactory BER performance. Besides, BER and near far resistance performance are much better than traditional suboptimal multiuser detection methods. Furthermore, the proposed iterative multiuser detection method also has a large system capacity. PMID:28212328

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats.

PubMed

Luck, Christian; DeMarco, Vincent G; Mahmood, Abuzar; Gavini, Madhavi P; Pulakat, Lakshmi

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750  μ g/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters ( E / E ', E '/ A ', E / Vp ) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFN γ , and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes.

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

PubMed Central

Luck, Christian; DeMarco, Vincent G.; Mahmood, Abuzar; Gavini, Madhavi P.

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E′, E′/A′, E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes. PMID:28408970

β-Catenin Mediates Anti-adipogenic and Anticancer Effects of Arctigenin in Preadipocytes and Breast Cancer Cells.

PubMed

Lee, Jihye; Imm, Jee-Young; Lee, Seong-Ho

2017-03-29

Arctigenin is a lignan abundant in Asteraceae plants and has anti-inflammatory, antiobesity, and anticancer activities. Obesity is one of the leading causes of several types of cancers including breast cancer. The current study was performed to investigate if arctigenin suppresses differentiation of preadipocytes and proliferation of breast cancer cells and to explore potential molecular mechanisms. Treatment of arctigenin reduced lipid accumulation in differentiated 3T3-L1 adipocytes in a dose- and time-dependent manner without toxicity. Arctigenin suppressed the expression of peroxisome proliferator-activated receptor-gamma (PPARγ), CCAAT/enhancer-binding protein-alpha (C/EBPα), perilipin, and fatty acid binding protein 4 (FABP4) in a dose-dependent manner in differentiated 3T3-L1 cells. Both total and unphosphorylated (active) β-catenin were increased in whole cell lysates and the nuclear fraction of differentiated 3T3-L1 cells treated with 25 μM arctigenin. On the other hand, arctigenin decreased proliferation of two human breast cancer cells (MCF-7 and MDA-MB-231). Arctigenin induced apoptosis and decreased expression of total and unphosphorylated (active) β-catenin and cyclin D1 in MCF-7, but not in MDA-MB-231. These data indicate that arctigenin suppressed adipogenesis in preadipocytes and activated apoptosis in estrogen receptor (ER) positive breast cancer cells through modulating expression of β-catenin.

[Poorly differentiated thyroid carcinomas: new therapeutic considerations].

PubMed

Graf, Hans

2005-10-01

For most differentiated thyroid carcinomas, as papillary and follicular carcinomas, following total thyroidectomy and 131I therapy for thyroid remnant ablation, treatment with thyroid hormones to suppress TSH levels will reduce the growth of any remaining thyroid cancer cells, and thyroid cell-specific radiation therapy will either cure or control the disease. Thyroid carcinomas are considered poorly differentiated when they start to lose such functions as iodine uptake and thyrotropin-dependence for growth and production of thyroid proteins like NIS, thyroglobulin and desiodases. One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progressed despite surgery, (131)I and T4 suppression of TSH. With the better knowledge of the abnormal molecular signaling in thyroid cancer cells, actually known targeted cancer therapies, directed against molecules involved in neoplastic transformation, are being used. As the critical molecular requirements for tumor initiation, maintenance and progression are identified, combination therapies with targeted agents acting on each of them will improve the treatment of poorly differentiated thyroid carcinoma.

Suppression subtractive hybridization as a tool to identify anthocyanin metabolism-related genes in apple skin.

PubMed

Ban, Yusuke; Moriguchi, Takaya

2010-01-01

The pigmentation of anthocyanins is one of the important determinants for consumer preference and marketability in horticultural crops such as fruits and flowers. To elucidate the mechanisms underlying the physiological process leading to the pigmentation of anthocyanins, identification of the genes differentially expressed in response to anthocyanin accumulation is a useful strategy. Currently, microarrays have been widely used to isolate differentially expressed genes. However, the use of microarrays is limited by its high cost of special apparatus and materials. Therefore, availability of microarrays is limited and does not come into common use at present. Suppression subtractive hybridization (SSH) is an alternative tool that has been widely used to identify differentially expressed genes due to its easy handling and relatively low cost. This chapter describes the procedures for SSH, including RNA extraction from polysaccharides and polyphenol-rich samples, poly(A)+ RNA purification, evaluation of subtraction efficiency, and differential screening using reverse northern in apple skin.

Differentially Fed Metal Frame Antenna With Common Mode Suppression for Biomedical Smartband Applications

NASA Astrophysics Data System (ADS)

Xu, Li-Jie; Duan, Zhu

2018-04-01

This paper proposes a differentially fed metal frame antenna for biomedical smartband applications. It occupies a planar area of 40 × 20 mm, operating at 2.45-GHz industrial, scientific, and medical band. The proposed antenna is composed of an external metal frame and an internal metal box acting as ground for electronics. Through a differential feeding to two copper strips located between the metal frame and the metal box, a rectangular ring slot is excited with common mode suppression capability. The antenna prototype is designed in free space, and then adapted to on-body scenario for both repeater and transmitter cases. Additionally, the proposed differential feeding is modified to the traditional single port, demonstrating the half-size miniaturization technique. Finally, the simulated results are verified by measurement. The proposed antenna's simple structure and satisfactory performance makes it a perfect candidate for future medical smartband applications, monitoring the physiological parameters of humans for health-care purposes.

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

PubMed Central

Xie, Yufen; Zhou, Sichang; Jiang, Zhongliang; Dai, Jing; Puscheck, Elizabeth E; Lee, Icksoo; Parker, Graham; Hüttemann, Maik; Rappolee, Daniel A

2014-01-01

Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. Implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor (FGF)4 enabled highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24 hr despite FGF4. However, hypoxic stress supported differentiation poorly after 4–7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential, maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited differentiation at the differentiation optimum at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5–2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation. PMID:25239494

An analytical technique for predicting the characteristics of a flexible wing equipped with an active flutter-suppression system and comparison with wind-tunnel data

NASA Technical Reports Server (NTRS)

Abel, I.

1979-01-01

An analytical technique for predicting the performance of an active flutter-suppression system is presented. This technique is based on the use of an interpolating function to approximate the unsteady aerodynamics. The resulting equations are formulated in terms of linear, ordinary differential equations with constant coefficients. This technique is then applied to an aeroelastic model wing equipped with an active flutter-suppression system. Comparisons between wind-tunnel data and analysis are presented for the wing both with and without active flutter suppression. Results indicate that the wing flutter characteristics without flutter suppression can be predicted very well but that a more adequate model of wind-tunnel turbulence is required when the active flutter-suppression system is used.

Utility of fat-suppressed sequences in differentiation of aggressive vs typical asymptomatic haemangioma of the spine.

PubMed

Nabavizadeh, Seyed Ali; Mamourian, Alexander; Schmitt, James E; Cloran, Francis; Vossough, Arastoo; Pukenas, Bryan; Loevner, Laurie A; Mohan, Suyash

2016-01-01

While haemangiomas are common benign vascular lesions involving the spine, some behave in an aggressive fashion. We investigated the utility of fat-suppressed sequences to differentiate between benign and aggressive vertebral haemangiomas. Patients with the diagnosis of aggressive vertebral haemangioma and available short tau inversion-recovery or T2 fat saturation sequence were included in the study. 11 patients with typical asymptomatic vertebral body haemangiomas were selected as the control group. Region of interest signal intensity (SI) analysis of the entire haemangioma as well as the portion of each haemangioma with highest signal on fat-saturation sequences was performed and normalized to a reference normal vertebral body. A total of 8 patients with aggressive vertebral haemangioma and 11 patients with asymptomatic typical vertebral haemangioma were included. There was a significant difference between total normalized mean SI ratio (3.14 vs 1.48, p = 0.0002), total normalized maximum SI ratio (5.72 vs 2.55, p = 0.0003), brightest normalized mean SI ratio (4.28 vs 1.72, p < 0.0001) and brightest normalized maximum SI ratio (5.25 vs 2.45, p = 0.0003). Multiple measures were able to discriminate between groups with high sensitivity (>88%) and specificity (>82%). In addition to the conventional imaging features such as vertebral expansion and presence of extravertebral component, quantitative evaluation of fat-suppression sequences is also another imaging feature that can differentiate aggressive haemangioma and typical asymptomatic haemangioma. The use of quantitative fat-suppressed MRI in vertebral haemangiomas is demonstrated. Quantitative fat-suppressed MRI can have a role in confirming the diagnosis of aggressive haemangiomas. In addition, this application can be further investigated in future studies to predict aggressiveness of vertebral haemangiomas in early stages.

Chemical peeling by SA-PEG remodels photo-damaged skin: suppressing p53 expression and normalizing keratinocyte differentiation.

PubMed

Dainichi, Teruki; Amano, Satoshi; Matsunaga, Yukiko; Iriyama, Shunsuke; Hirao, Tetsuji; Hariya, Takeshi; Hibino, Toshihiko; Katagiri, Chika; Takahashi, Motoji; Ueda, Setsuko; Furue, Masutaka

2006-02-01

Chemical peeling with salicylic acid in polyethylene glycol vehicle (SA-PEG), which specifically acts on the stratum corneum, suppresses the development of skin tumors in UVB-irradiated hairless mice. To elucidate the mechanism through which chemical peeling with SA-PEG suppresses skin tumor development, the effects of chemical peeling on photodamaged keratinocytes and cornified envelopes (CEs) were evaluated in vivo. Among UVB-irradiated hairless mice, the structural atypia and expression of p53 protein in keratinocytes induced by UVB irradiation were intensely suppressed in the SA-PEG-treated mice 28 days after the start of weekly SA-PEG treatments when compared to that in the control UVB-irradiated mice. Incomplete expression of filaggrin and loricrin in keratinocytes from the control mice was also improved in keratinocytes from the SA-PEG-treated mice. In photo-exposed human facial skin, immature CEs were replaced with mature CEs 4 weeks after treatment with SA-PEG. Restoration of photodamaged stratum corneum by treatment with SA-PEG, which may affect remodeling of the structural environment of the keratinocytes, involved the normalization of keratinocyte differentiation and suppression of skin tumor development. These results suggest that the stratum corneum plays a protective role against carcinogenesis, and provide a novel strategy for the prevention of photo-induced skin tumors.

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma.

PubMed

Wang, Yun; Huang, Nanxin; Li, Hongli; Liu, Shubao; Chen, Xianjun; Yu, Shichang; Wu, Nan; Bian, Xiu-Wu; Shen, Hai-Ying; Li, Chengren; Xiao, Lan

2017-06-06

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.

Extrinsic and intrinsic mechanisms by which mesenchymal stem cells suppress the immune system

PubMed Central

Coulson-Thomas, Vivien J.; Coulson-Thomas, Yvette M.; Gesteira, Tarsis F.; Kao, Winston W.-Y.

2016-01-01

Mesenchymal stem cells (MSCs) are a group of fibroblast-like multipotent mesenchymal stromal cells that have the ability to differentiate into osteoblasts, adipocytes, and chondrocytes. Recent studies have demonstrated that MSCs possess a unique ability to exert suppressive and regulatory effects on both adaptive and innate immunity in an autologous and allogeneic manner. A vital step in stem cell transplantation is overcoming the potential graft-versus-host disease, which is a limiting factor to transplantation success. Given that MSCs attain powerful differentiation capabilities and also present immunosuppressive properties, which enable them to survive host immune rejection, MSCs are of great interest. Due to their ability to differentiate into different cell types and to suppress and modulate the immune system, MSCs are being developed for treating a plethora of diseases, including immune disorders. Moreover, in recent years, MSCs have been genetically engineered to treat and sometimes even cure some diseases, and the use of MSCs for cell therapy presents new perspectives for overcoming tissue rejection. In this review, we discuss the potential extrinsic and intrinsic mechanisms that underlie MSCs’ unique ability to modulate inflammation, and both innate and adaptive immunity. PMID:26804815

Berberine Suppresses Adipocyte Differentiation via Decreasing CREB Transcriptional Activity

PubMed Central

Deng, Ruyuan; Wang, Ning; Zhang, Yuqing; Wang, Yao; Liu, Yun; Li, Fengying; Wang, Xiao; Zhou, Libin

2015-01-01

Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, has been demonstrated to lower blood glucose, blood lipid, and body weight in patients with type 2 diabetes mellitus. The anti-obesity effect of berberine has been attributed to its anti-adipogenic activity. However, the underlying molecular mechanism remains largely unknown. In the present study, we found that berberine significantly suppressed the expressions of CCAAT/enhancer-binding protein (C/EBP)α, peroxisome proliferators-activated receptor γ2 (PPARγ2), and other adipogenic genes in the process of adipogenesis. Berberine decreased cAMP-response element-binding protein (CREB) phosphorylation and C/EBPβ expression at the early stage of 3T3-L1 preadipocyte differentiation. In addition, CREB phosphorylation and C/EBPβ expression induced by 3-isobutyl-1-methylxanthine (IBMX) and forskolin were also attenuated by berberine. The binding activities of cAMP responsive element (CRE) stimulated by IBMX and forskolin were inhibited by berberine. The binding of phosphorylated CREB to the promoter of C/EBPβ was abrogated by berberine after the induction of preadipocyte differentiation. These results suggest that berberine blocks adipogenesis mainly via suppressing CREB activity, which leads to a decrease in C/EBPβ-triggered transcriptional cascades. PMID:25928058

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma

PubMed Central

Li, Hongli; Liu, Shubao; Chen, Xianjun; Yu, Shichang; Wu, Nan; Bian, Xiu-Wu; Li, Chengren

2017-01-01

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma. PMID:28415586

Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways.

PubMed

Pandey, Manoj K; Kale, Vijay P; Song, Chunhua; Sung, Shen-shu; Sharma, Arun K; Talamo, Giampaolo; Dovat, Sinisa; Amin, Shantu G

2014-10-01

Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-κB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1α-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. Published by Elsevier Inc.

FOXO1-suppressed miR-424 regulates the proliferation and osteogenic differentiation of MSCs by targeting FGF2 under oxidative stress

NASA Astrophysics Data System (ADS)

Li, Liangping; Qi, Qihua; Luo, Jiaquan; Huang, Sheng; Ling, Zemin; Gao, Manman; Zhou, Zhiyu; Stiehler, Maik; Zou, Xuenong

2017-02-01

Recently, microRNAs (miRNAs) have been identified as key regulators of the proliferation and differentiation of mesenchymal stem cells (MSCs). Our previous in vivo study and other in vitro studies using miRNA microarrays suggest that miR-424 is involved in the regulation of bone formation. However, the role and mechanism of miR-424 in bone formation still remain unknown. Here, we identified that the downregulation of miR-424 mediates bone formation under oxidative stress, and we explored its underlying mechanism. Our results showed that miR-424 was significantly downregulated in an anterior lumbar interbody fusion model of pigs and in a cell model of oxidative stress induced by H2O2. The overexpression of miR-424 inhibited proliferation and osteogenic differentiation shown by a decrease in alkaline phosphatase (ALP) activity, mineralization and osteogenic markers, including RUNX2 and ALP, whereas the knockdown of miR-424 led to the opposite results. Moreover, miR-424 exerts its effects by targeting FGF2. Furthermore, we found that FOXO1 suppressed miR-424 expression and bound to its promoter region. FOXO1 enhanced proliferation and osteogenic differentiation in part through the miR-424/FGF2 pathway. These results indicated that FOXO1-suppressed miR-424 regulates both the proliferation and osteogenic differentiation of MSCs via targeting FGF2, suggesting that miR-424 might be a potential novel therapeutic strategy for promoting bone formation.

Comparative Metatranscriptomics of Wheat Rhizosphere Microbiomes in Disease Suppressive and Non-suppressive Soils for Rhizoctonia solani AG8

PubMed Central

Hayden, Helen L.; Savin, Keith W.; Wadeson, Jenny; Gupta, Vadakattu V. S. R.; Mele, Pauline M.

2018-01-01

The soilborne fungus Rhizoctonia solani anastomosis group (AG) 8 is a major pathogen of grain crops resulting in substantial production losses. In the absence of resistant cultivars of wheat or barley, a sustainable and enduring method for disease control may lie in the enhancement of biological disease suppression. Evidence of effective biological control of R. solani AG8 through disease suppression has been well documented at our study site in Avon, South Australia. A comparative metatranscriptomic approach was applied to assess the taxonomic and functional characteristics of the rhizosphere microbiome of wheat plants grown in adjacent fields which are suppressive and non-suppressive to the plant pathogen R. solani AG8. Analysis of 12 rhizosphere metatranscriptomes (six per field) was undertaken using two bioinformatic approaches involving unassembled and assembled reads. Differential expression analysis showed the dominant taxa in the rhizosphere based on mRNA annotation were Arthrobacter spp. and Pseudomonas spp. for non-suppressive samples and Stenotrophomonas spp. and Buttiauxella spp. for the suppressive samples. The assembled metatranscriptome analysis identified more differentially expressed genes than the unassembled analysis in the comparison of suppressive and non-suppressive samples. Suppressive samples showed greater expression of a polyketide cyclase, a terpenoid biosynthesis backbone gene (dxs) and many cold shock proteins (csp). Non-suppressive samples were characterised by greater expression of antibiotic genes such as non-heme chloroperoxidase (cpo) which is involved in pyrrolnitrin synthesis, and phenazine biosynthesis family protein F (phzF) and its transcriptional activator protein (phzR). A large number of genes involved in detoxifying reactive oxygen species (ROS) and superoxide radicals (sod, cat, ahp, bcp, gpx1, trx) were also expressed in the non-suppressive rhizosphere samples most likely in response to the infection of wheat roots by R. solani AG8. Together these results provide new insight into microbial gene expression in the rhizosphere of wheat in soils suppressive and non-suppressive to R. solani AG8. The approach taken and the genes involved in these functions provide direction for future studies to determine more precisely the molecular interplay of plant-microbe-pathogen interactions with the ultimate goal of the development of management options that promote beneficial rhizosphere microflora to reduce R. solani AG8 infection of crops. PMID:29780371

Increased extracellular and intracellular Ca{sup 2+} lead to adipocyte accumulation in bone marrow stromal cells by different mechanisms

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

Hashimoto, Ryota, E-mail: hryota@juntendo.ac.jp; Katoh, Youichi, E-mail: katoyo@juntendo-urayasu.jp; Department of Cardiology, Juntendo University Faculty of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421

2015-02-20

Mesenchymal stem cells found in bone marrow stromal cells (BMSCs) are the common progenitors for both adipocyte and osteoblast. An increase in marrow adipogenesis is associated with age-related osteopenia and anemia. Both extracellular and intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub o} and [Ca{sup 2+}]{sub i}) are versatile signaling molecules that are involved in the regulation of cell functions, including proliferation and differentiation. We have recently reported that upon treatment of BMSCs with insulin and dexamethasone, both high [Ca{sup 2+}]{sub o} and high [Ca{sup 2+}]{sub i} enhanced adipocyte accumulation, which suggested that increases in [Ca{sup 2+}]{sub o} caused by bone resorption maymore » accelerate adipocyte accumulation in aging and diabetic patients. In this study, we used primary mouse BMSCs to investigate the mechanisms by which high [Ca{sup 2+}]{sub o} and high [Ca{sup 2+}]{sub i} may enhance adipocyte accumulation. In the process of adipocyte accumulation, two important keys are adipocyte differentiation and the proliferation of BMSCs, which have the potential to differentiate into adipocytes. Use of MTT assay and real-time RT-PCR revealed that high [Ca{sup 2+}]{sub i} (ionomycin)-dependent adipocyte accumulation is caused by enhanced proliferation of BMSCs but not enhanced differentiation into adipocytes. Using fura-2 fluorescence-based approaches, we showed that high [Ca{sup 2+}]{sub o} (addition of CaCl{sub 2}) leads to increases in [Ca{sup 2+}]{sub i}. Flow cytometric methods revealed that high [Ca{sup 2+}]{sub o} suppressed the phosphorylation of ERK independently of intracellular Ca{sup 2+}. The inhibition of ERK by U0126 and PD0325901 enhanced the differentiation of BMSCs into adipocytes. These data suggest that increased extracellular Ca{sup 2+} provides the differentiation of BMSCs into adipocytes by the suppression of ERK activity independently of increased intracellular Ca{sup 2+}, which results in BMSC proliferation. - Highlights: • Both high [Ca{sup 2+}]{sub o} and high [Ca{sup 2+}]{sub i} enhanced adipocyte accumulation in BMSCs. • High [Ca{sup 2+}]{sub i} enhanced the proliferation of BMSCs but not adipocyte differentiation. • High [Ca{sup 2+}]{sub o} suppressed the phosphorylation of ERK in BMSCs. • Inhibition of ERK enhanced the differentiation of BMSCs into adipocytes. • High [Ca{sup 2+}]{sub o}-mediated suppression of ERK may be a new therapy target for anemia.« less

Differential suppression of upper airway motor activity during carbachol-induced, REM sleep-like atonia.

PubMed

Fenik, V; Davies, R O; Pack, A I; Kubin, L

1998-10-01

Microinjections of carbachol into the pontine tegmentum of decerebrate cats have been used to study the mechanisms underlying the suppression of postural and respiratory motoneuronal activity during the resulting rapid eye movement (REM) sleep-like atonia. During REM sleep, distinct respiratory muscles are differentially affected; e.g., the activity of the diaphragm shows little suppression, whereas the activity of some upper airway muscles is quite strong. To determine the pattern of the carbachol-induced changes in the activity of different groups of upper airway motoneurons, we simultaneously recorded the efferent activity of the recurrent laryngeal nerve (RL), pharyngeal branch of the vagus nerve (Phar), and genioglossal branch of the hypoglossal (XII) and phrenic (Phr) nerves in 12 decerebrate, paralyzed, vagotomized, and artificially ventilated cats. Pontine carbachol caused a stereotyped suppression of the spontaneous activity that was significantly larger in Phar expiratory (to 8.3% of control) and XII inspiratory motoneurons (to 15%) than in Phr inspiratory (to 87%), RL inspiratory (to 79%), or RL expiratory motoneurons (to 72%). The suppression in upper airway motor output was significantly greater than the depression caused by a level of hypocapnia that reduced Phr activity as much as carbachol. We conclude that pontine carbachol evokes a stereotyped pattern of suppression of upper airway motor activity. Because carbachol evokes a state having many neurophysiological characteristics similar to those of REM sleep, it is likely that pontine cholinoceptive neurons have similar effects on the activity of upper airway motoneurons during both states.

Experimental Model to Study the Role of Retinoblastoma Gene Product (pRb) for Determination of Adipocyte Differentiation.

PubMed

Popov, B V; Shilo, P S; Zhidkova, O V; Zaichik, A M; Petrov, N S

2015-06-01

Using stable constitutive expression of retinoblastoma gene product (pRb) in polypotent mesenchymal 10T1/2 cells we obtained stable cell lines hyperexpressing functionally active or inactive mutant pRb. The cells producing active exogenous pRb demonstrated high sensitivity to adipocyte differentiation inductors, whereas production of inactive form of the exogenous protein suppressed adipocyte differentiation. The obtained lines can serve as the experimental model for studying the role of pRb in determination of adipocyte differentiation.

Assessing Binocular Interaction in Amblyopia and Its Clinical Feasibility

PubMed Central

Kwon, MiYoung; Lu, Zhong-Lin; Miller, Alexandra; Kazlas, Melanie; Hunter, David G.; Bex, Peter J.

2014-01-01

Purpose To measure binocular interaction in amblyopes using a rapid and patient-friendly computer-based method, and to test the feasibility of the assessment in the clinic. Methods Binocular interaction was assessed in subjects with strabismic amblyopia (n = 7), anisometropic amblyopia (n = 6), strabismus without amblyopia (n = 15) and normal vision (n = 40). Binocular interaction was measured with a dichoptic phase matching task in which subjects matched the position of a binocular probe to the cyclopean perceived phase of a dichoptic pair of gratings whose contrast ratios were systematically varied. The resulting effective contrast ratio of the weak eye was taken as an indicator of interocular imbalance. Testing was performed in an ophthalmology clinic under 8 mins. We examined the relationships between our binocular interaction measure and standard clinical measures indicating abnormal binocularity such as interocular acuity difference and stereoacuity. The test-retest reliability of the testing method was also evaluated. Results Compared to normally-sighted controls, amblyopes exhibited significantly reduced effective contrast (∼20%) of the weak eye, suggesting a higher contrast requirement for the amblyopic eye compared to the fellow eye. We found that the effective contrast ratio of the weak eye covaried with standard clincal measures of binocular vision. Our results showed that there was a high correlation between the 1st and 2nd measurements (r = 0.94, p<0.001) but without any significant bias between the two. Conclusions Our findings demonstrate that abnormal binocular interaction can be reliably captured by measuring the effective contrast ratio of the weak eye and quantitative assessment of binocular interaction is a quick and simple test that can be performed in the clinic. We believe that reliable and timely assessment of deficits in a binocular interaction may improve detection and treatment of amblyopia. PMID:24959842

Contributing factors to VEP grating acuity deficit and inter-ocular acuity difference in children with cerebral visual impairment.

PubMed

Cavascan, Nívea Nunes; Salomão, Solange Rios; Sacai, Paula Yuri; Pereira, Josenilson Martins; Rocha, Daniel Martins; Berezovsky, Adriana

2014-04-01

To investigate contributing factors to visual evoked potential (VEP) grating acuity deficit (GAD) and inter-ocular acuity difference (IAD) measured by sweep-VEPs in children with cerebral visual impairment (CVI). VEP GAD was calculated for the better acuity eye by subtracting acuity thresholds from mean normal VEP grating acuity according to norms from our own laboratory. Deficits were categorized as mild (0.17 ≤ deficit < 0.40 log units), moderate (0.40 ≤ deficit < 0.70 log units) or severe (deficit ≥0.70 log units). Maximum acceptable IAD was 0.10 log units. A group of 115 children (66 males-57 %) with ages ranging from 1.2 to 166.5 months (median = 17.7) was examined. VEP GAD ranged from 0.17 to 1.28 log units (mean = 0.68 ± 0.27; median = 0.71), and it was mild in 23 (20 %) children, moderate in 32 (28 %) and severe in 60 (52 %). Severe deficit was significantly associated with older age and anti-seizure drug therapy. IAD ranged from 0 to 0.49 log units (mean = 0.06 ± 0.08; median = 0.04) and was acceptable in 96 (83 %) children. Children with strabismus and nystagmus had IAD significantly larger compared to children with orthoposition. In a large cohort of children with CVI, variable severity of VEP GAD was found, with more than half of the children with severe deficits. Older children and those under anti-seizure therapy were at higher risk for larger deficits. Strabismus and nystagmus provided larger IADs. These results should be taken into account on the clinical management of children with this leading cause of bilateral visual impairment.

Baseline OCT Measurements in the Idiopathic Intracranial Hypertension Treatment Trial, Part I: Quality Control, Comparisons, and Variability

PubMed Central

2014-01-01

Purpose. Optical coherence tomography (OCT) has been used to investigate papilledema in single-site, mostly retrospective studies. We investigated whether spectral-domain OCT (SD-OCT), which provides thickness and volume measurements of the optic nerve head and retina, could reliably demonstrate structural changes due to papilledema in a prospective multisite clinical trial setting. Methods. At entry, 126 subjects in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) with mild visual field loss had optic disc and macular scans, using the Cirrus SD-OCT. Images were analyzed by using the proprietary commercial and custom 3D-segmentation algorithms to calculate retinal nerve fiber layer (RNFL), total retinal thickness (TRT), optic nerve head volume (ONHV), and retinal ganglion cell layer (GCL) thickness. We evaluated variability, with interocular comparison and correlation between results for both methods. Results. The average RNFL thickness > 95% of normal controls in 90% of eyes and the RNFL, TRT, ONH height, and ONHV showed strong (r > 0.8) correlations for interocular comparisons. Variability for repeated testing of OCT parameters was low for both methods and intraclass correlations > 0.9 except for the proprietary GCL thickness. The proprietary algorithm–derived RNFL, TRT, and GCL thickness measurements had failure rates of 10%, 16%, and 20% for all eyes respectively, which were uncommon with 3D-segmentation–derived measurements. Only 7% of eyes had GCL thinning that was less than fifth percentile of normal age-matched control eyes by both methods. Conclusions. Spectral-domain OCT provides reliable continuous variables and quantified assessment of structural alterations due to papilledema. (ClinicalTrials.gov number, NCT01003639.) PMID:25370510

Effects of Topical Latanoprost on Intraocular Pressure and Myopia Progression in Young Guinea Pigs

PubMed Central

El-Nimri, Nevin W.; Wildsoet, Christine F.

2018-01-01

Purpose To determine whether latanoprost, a prostaglandin analog proven to be very effective in reducing intraocular pressure (IOP) in humans, can also slow myopia progression in the guinea pig form deprivation (FD) model. Methods Two-week-old pigmented guinea pigs underwent monocular FD and daily topical latanoprost (0.005%, n = 10) or artificial tears (control, n = 10) starting 1 week after the initiation of FD, with all treatments continuing for a further 9 weeks. Tonometry, retinoscopy, and high-frequency A-scan ultrasonography were used to monitor IOP, refractive error, and ocular axial dimensions, respectively. Results Latanoprost significantly reduced IOP and slowed myopia progression. Mean interocular IOP differences (±SEM) recorded at baseline and week 10 were −0.30 ± 0.51 and 1.80 ± 1.16 mm Hg (P = 0.525) for the control group and 0.07 ± 0.35 and −5.17 ± 0.96 mm Hg (P < 0.001) for the latanoprost group. Equivalent interocular differences for optical axial length at baseline and week 10 were 0.00 ± 0.015 and 0.29 ± 0.04 mm (P < 0.001; control) and 0.02 ± 0.02 and 0.06 ± 0.02 mm (P = 0.202; latanoprost), and for refractive error were +0.025 ± 0.36 and −8.2 ± 0.71 diopter (D) (P < 0.001; control), and −0.15 ± 0.35 and −2.25 ± 0.54 D (P = 0.03; latanoprost). Conclusions In the FD guinea pig model, latanoprost significantly reduces the development of myopia. Although further investigations into underlying mechanisms are needed, the results open the exciting possibility of a new line of myopia control therapy. PMID:29847673

Relationship between binocular vision, visual acuity, and fine motor skills.

PubMed

O'Connor, Anna R; Birch, Eileen E; Anderson, Susan; Draper, Hayley

2010-12-01

The aims of this study were to analyze the relationship between the performance on fine motor skills tasks and peripheral and bifoveal sensory fusion, phasic and tonic motor fusion, the level of visual acuity (VA) in the poorer seeing eye, and the interocular VA difference. Subjects aged 12 to 28 years with a range of levels of binocular vision and VA performed three tasks: Purdue pegboard (number of pegs placed in 30 s), bead threading task (with two sizes of bead to increase the difficulty, time taken to thread a fixed number of beads), and a water pouring task (accuracy and time to pour a fixed quantity into five glass cylinders). Ophthalmic measures included peripheral (Worth 4 dot) and bifoveal (4 prism diopter) sensory fusion, phasic (prism bar) and tonic (Risley rotary prism) motor fusion ranges, and monocular VA. One hundred twenty-one subjects with a mean age of 18.8 years were tested; 18.2% had a manifest strabismus. Performance on fine motor skills tasks was significantly better in subjects with sensory and motor fusion compared with those without for most tasks, with significant differences between those with and without all measures of fusion on the pegboard and bead task. Both the acuity in the poorer seeing eye (highest r value of all motor tasks = 0.43) and the interocular acuity difference were statistically significantly related to performance on the motor skill tasks. Both sensory and motor fusion and good VA in both eyes are of benefit in the performance of fine motor skills tasks, with the presence of some binocular vision being beneficial compared with no fusion on certain sensorimotor tasks. This evidence supports the need to maximize fusion and VA outcomes.

Multifocal visual evoked potentials reveal normal optic nerve projections in human carriers of oculocutaneous albinism type 1a.

PubMed

Hoffmann, Michael B; Wolynski, Barbara; Meltendorf, Synke; Behrens-Baumann, Wolfgang; Käsmann-Kellner, Barbara

2008-06-01

In albinism, part of the temporal retina projects abnormally to the contralateral hemisphere. A residual misprojection is also evident in feline carriers that are heterozygous for tyrosinase-related albinism. This study was conducted to test whether such residual abnormalities can also be identified in human carriers of oculocutaneous tyrosinase-related albinism (OCA1a). In eight carriers heterozygous for OCA1a and in eight age- and sex-matched control subjects, monocular pattern-reversal and -onset multifocal visual evoked potentials (mfVEPs) were recorded at 60 locations comprising a visual field of 44 degrees diameter (VERIS 5.01; EDI, San Mateo, CA). For each eye and each stimulus location, interhemispheric difference potentials were calculated and correlated with each other, to assess the lateralization of the responses: positive and negative correlations indicate lateralizations on the same or opposite hemispheres, respectively. Misrouted optic nerves are expected to yield negative interocular correlations. The analysis also allowed for the assessment of the sensitivity and specificity of the detection of projection abnormalities. No significant differences were obtained for the distributions of the interocular correlation coefficients of controls and carriers. Consequently, no local representation abnormalities were observed in the group of OCA1a carriers. For pattern-reversal and -onset stimulation, an assessment of the control data yielded similar specificity (97.9% and 94.6%) and sensitivity (74.4% and 74.8%) estimates for the detection of projection abnormalities. The absence of evidence for projection abnormalities in human OCA1a carriers contrasts with the previously reported evidence for abnormalities in cat-carriers of tyrosinase-related albinism. This discrepancy suggests that animal models of albinism may not provide a match to human albinism.

Bilateral symmetry in vision and influence of ocular surgical procedures on binocular vision: A topical review.

PubMed

Arba Mosquera, Samuel; Verma, Shwetabh

2016-01-01

We analyze the role of bilateral symmetry in enhancing binocular visual ability in human eyes, and further explore how efficiently bilateral symmetry is preserved in different ocular surgical procedures. The inclusion criterion for this review was strict relevance to the clinical questions under research. Enantiomorphism has been reported in lower order aberrations, higher order aberrations and cone directionality. When contrast differs in the two eyes, binocular acuity is better than monocular acuity of the eye that receives higher contrast. Anisometropia has an uncommon occurrence in large populations. Anisometropia seen in infancy and childhood is transitory and of little consequence for the visual acuity. Binocular summation of contrast signals declines with age, independent of inter-ocular differences. The symmetric associations between the right and left eye could be explained by the symmetry in pupil offset and visual axis which is always nasal in both eyes. Binocular summation mitigates poor visual performance under low luminance conditions and strong inter-ocular disparity detrimentally affects binocular summation. Considerable symmetry of response exists in fellow eyes of patients undergoing myopic PRK and LASIK, however the method to determine whether or not symmetry is maintained consist of comparing individual terms in a variety of ad hoc ways both before and after the refractive surgery, ignoring the fact that retinal image quality for any individual is based on the sum of all terms. The analysis of bilateral symmetry should be related to the patients' binocular vision status. The role of aberrations in monocular and binocular vision needs further investigation. Copyright © 2016 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.

Macrophage differentiation induced by PMA is mediated by activation of RhoA/ROCK signaling.

PubMed

Yang, Lifeng; Dai, Fan; Tang, Lian; Le, Yulan; Yao, Wenjuan

2017-01-01

In order to investigate the effects of RhoA/ROCK signaling in macrophage differentiation, we used 100 ng/mL PMA to induce macrophage differentiation from U937 cells in vitro. The observation of cell morphology and the expression of CD68 and SR-A were performed to confirm the differentiation induced by PMA. Western blot analysis showed that the expression of ROCK1 and ROCK2 and the phosphorylation of MYPT1 were significantly increased after PMA treatment. Pulldown assay showed that the activation of RhoA was obviously enhanced when U937 cells were treated with PMA. In order to further demonstrate whether RhoA/ROCK signaling could mediate the macrophage differentiation induced by PMA, we successfully suppressed the expression of RhoA, ROCK1 and ROCK2 by performing siRNA technology in U937 cells, respectively. The macrophage differentiation and the expression of CD68 and SR-A were significantly inhibited by the suppression of RhoA, ROCK1 or ROCK2 in PMA-induced U937 cells, indicating that the macrophage differentiation induced by PMA is associated with RhoA/ROCK signaling pathway. In addition, we pretreated U937 cells with Y27632 (ROCK inhibitor, 20 μM) for 30 min and then observed the macrophage differentiation induced by PMA. The result illustrated that Y27632 pretreatment obviously inhibited PMA-induced differentiation and the expression of CD68 and SR-A. In conclusion, the activation of RhoA/ROCK signaling is responsible for the macrophage differentiation induced by PMA.

Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation.

PubMed

Kaneshiro, Shoichi; Ebina, Kosuke; Shi, Kenrin; Yoshida, Kiyoshi; Otsuki, Dai; Yoshikawa, Hideki; Higuchi, Chikahisa

2015-09-01

The Tec family of nonreceptor tyrosine kinases has been shown to play a key role in inflammation and bone destruction. Bruton tyrosine kinase (Btk) has been the most widely studied because of its critical role in B cells. Furthermore, recent evidence has demonstrated that blocking Btk signaling is effective in ameliorating lymphoma progression and experimental arthritis. The role of Btk in osteoblastic differentiation has not been well elucidated. In this study, we demonstrated the role of Btk in osteoblastic differentiation and investigated the effects of a Btk inhibitor on osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells, primary calvarial osteoblasts, and bone marrow stromal ST2 cells. Btk expression was detected in all three cell lines. Btk inhibition stimulated mRNA expression of osteoblastic markers (alkaline phosphatase, osteocalcin, and osterix) and promoted mineralization of the extracellular matrix. In addition, Btk knockdown caused increased mRNA expression of osteoblastic markers. Furthermore, Btk inhibition suppressed the phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NFκB), and protein kinase Cα (PKCα). Our results indicate that Btk may regulate osteoblastic differentiation through the MAPK, NFκB, and PKCα signaling pathways.

Cutting Edge: Differential Regulation of PTEN by TCR, Akt, and FoxO1 Controls CD4+ T Cell Fate Decisions.

PubMed

Hawse, William F; Sheehan, Robert P; Miskov-Zivanov, Natasa; Menk, Ashley V; Kane, Lawrence P; Faeder, James R; Morel, Penelope A

2015-05-15

Signaling via the Akt/mammalian target of rapamycin pathway influences CD4(+) T cell differentiation; low levels favor regulatory T cell induction and high levels favor Th induction. Although the lipid phosphatase phosphatase and tensin homolog (PTEN) suppresses Akt activity, the control of PTEN activity is poorly studied in T cells. In this study, we identify multiple mechanisms that regulate PTEN expression. During Th induction, PTEN function is suppressed via lower mRNA levels, lower protein levels, and an increase in C-terminal phosphorylation. Conversely, during regulatory T cell induction, PTEN function is maintained through the stabilization of PTEN mRNA transcription and sustained protein levels. We demonstrate that differential Akt/mammalian target of rapamycin signaling regulates PTEN transcription via the FoxO1 transcription factor. A mathematical model that includes multiple modes of PTEN regulation recapitulates our experimental findings and demonstrates how several feedback loops determine differentiation outcomes. Collectively, this work provides novel mechanistic insights into how differential regulation of PTEN controls alternate CD4(+) T cell fate outcomes. Copyright © 2015 by The American Association of Immunologists, Inc.

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

PubMed Central

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

2017-01-01

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

Tumor necrosis factor-alpha inhibits differentiation of myogenic cells in human urethral rhabdosphincter.

PubMed

Shinohara, Mayuka; Sumino, Yasuhiro; Sato, Fuminori; Kiyono, Tohru; Hashimoto, Naohiro; Mimata, Hiromitsu

2017-06-01

To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence. © 2017 The Japanese Urological Association.

AB72. Mysteries of TGF-β paradox in benign and malignant cells

PubMed Central

Lee, Chung; Grayhack, John T.

2014-01-01

TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells, a phenomenon known as TGF-β paradox. To date, the mechanism of this paradox still remains as a scientific mystery. In this review, we present our experience, alone with the literature, in an attempt to offer answers to this mystery. First, we observed that, upon TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to a suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events offer the explanation to the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and will help us to develop novel anti-cancer strategies.

Mysteries of TGF-β Paradox in Benign and Malignant Cells.

PubMed

Zhang, Qiang; Yu, Nengwang; Lee, Chung

2014-01-01

TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.

Mangiferin positively regulates osteoblast differentiation and suppresses osteoclast differentiation

PubMed Central

Sekiguchi, Yuusuke; Mano, Hiroshi; Nakatani, Sachie; Shimizu, Jun; Kataoka, Aya; Ogura, Kana; Kimira, Yoshifumi; Ebata, Midori; Wada, Masahiro

2017-01-01

Mangiferin is a polyphenolic compound present in Salacia reticulata. It has been reported to reduce bone destruction and inhibit osteoclastic differentiation. This study aimed to determine whether mangiferin directly affects osteoblast and osteoclast proliferation and differentiation, and gene expression in MC3T3-E1 osteoblastic cells and osteoclast-like cells derived from primary mouse bone marrow macrophage cells. Mangiferin induced significantly greater WST-1 activity, indicating increased cell proliferation. Mangiferin induced significantly increased alkaline phosphatase staining, indicating greater cell differentiation. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that mangiferin significantly increased the mRNA level of runt-related transcription factor 2 (RunX2), but did not affect RunX1 mRNA expression. Mangiferin significantly reduced the formation of tartrate-resistant acid phosphatase-positive multinuclear cells. RT-PCR demonstrated that mangiferin significantly increased the mRNA level of estrogen receptor β (ERβ), but did not affect the expression of other osteoclast-associated genes. Mangiferin may inhibit osteoclastic bone resorption by suppressing differentiation of osteoclasts and promoting expression of ERβ mRNA in mouse bone marrow macrophage cells. It also has potential to promote osteoblastic bone formation by promoting cell proliferation and inducing cell differentiation in preosteoblast MC3T3-E1 cells via RunX2. Mangiferin may therefore be useful in improving bone disease outcomes. PMID:28627701

Mangiferin positively regulates osteoblast differentiation and suppresses osteoclast differentiation.

PubMed

Sekiguchi, Yuusuke; Mano, Hiroshi; Nakatani, Sachie; Shimizu, Jun; Kataoka, Aya; Ogura, Kana; Kimira, Yoshifumi; Ebata, Midori; Wada, Masahiro

2017-08-01

Mangiferin is a polyphenolic compound present in Salacia reticulata. It has been reported to reduce bone destruction and inhibit osteoclastic differentiation. This study aimed to determine whether mangiferin directly affects osteoblast and osteoclast proliferation and differentiation, and gene expression in MC3T3‑E1 osteoblastic cells and osteoclast‑like cells derived from primary mouse bone marrow macrophage cells. Mangiferin induced significantly greater WST‑1 activity, indicating increased cell proliferation. Mangiferin induced significantly increased alkaline phosphatase staining, indicating greater cell differentiation. Reverse transcription‑polymerase chain reaction (RT‑PCR) demonstrated that mangiferin significantly increased the mRNA level of runt‑related transcription factor 2 (RunX2), but did not affect RunX1 mRNA expression. Mangiferin significantly reduced the formation of tartrate‑resistant acid phosphatase‑positive multinuclear cells. RT‑PCR demonstrated that mangiferin significantly increased the mRNA level of estrogen receptor β (ERβ), but did not affect the expression of other osteoclast‑associated genes. Mangiferin may inhibit osteoclastic bone resorption by suppressing differentiation of osteoclasts and promoting expression of ERβ mRNA in mouse bone marrow macrophage cells. It also has potential to promote osteoblastic bone formation by promoting cell proliferation and inducing cell differentiation in preosteoblast MC3T3‑E1 cells via RunX2. Mangiferin may therefore be useful in improving bone disease outcomes.

Mysteries of TGF-β Paradox in Benign and Malignant Cells

PubMed Central

Zhang, Qiang; Yu, Nengwang; Lee, Chung

2014-01-01

TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies. PMID:24860782

Anti-adipogenic effects of KD025 (SLx-2119), a ROCK2-specific inhibitor, in 3T3-L1 cells.

PubMed

Diep, Duy Trong Vien; Hong, Kyungki; Khun, Triyeng; Zheng, Mei; Ul-Haq, Asad; Jun, Hee-Sook; Kim, Young-Bum; Chun, Kwang-Hoon

2018-02-06

Adipose tissue is a specialized organ that synthesizes and stores fat. During adipogenesis, Rho and Rho-associated kinase (ROCK) 2 are inactivated, which enhances the expression of pro-adipogenic genes and induces the loss of actin stress fibers. Furthermore, pan ROCK inhibitors enhance adipogenesis in 3T3-L1 cells. Here, we show that KD025 (formerly known as SLx-2119), a ROCK2-specific inhibitor, suppresses adipogenesis in 3T3-L1 cells partially through a ROCK2-independent mechanism. KD025 downregulated the expression of key adipogenic transcription factors PPARγ and C/EBPα during adipogenesis in addition to lipogenic factors FABP4 and Glut4. Interestingly, adipogenesis was blocked by KD025 during days 1~3 of differentiation; after differentiation terminated, lipid accumulation was unaffected. Clonal expansion occurred normally in KD025-treated cells. These results suggest that KD025 could function during the intermediate stage after clonal expansion. Data from depletion of ROCKs showed that KD025 suppressed cell differentiation partially independent of ROCK's activity. Furthermore, no further loss of actin stress fibers emerged in KD025-treated cells during and after differentiation compared to control cells. These results indicate that in contrast to the pro-adipogenic effect of pan-inhibitors, KD025 suppresses adipogenesis in 3T3-L1 cells by regulating key pro-adipogenic factors. This outcome further implies that KD025 could be a potential anti-adipogenic/obesity agent.

The NuRD complex component p66 suppresses photoreceptor neuron regeneration in planarians.

PubMed

Vásquez-Doorman, Constanza; Petersen, Christian P

2016-06-01

Regeneration involves precise control of cell fate to produce an appropriate complement of tissues formed within a blastema. Several chromatin-modifying complexes have been identified as required for regeneration in planarians, but it is unclear whether this class of molecules uniformly promotes the production of differentiated cells. We identify a function for p66, encoding a DNA-binding protein component of the NuRD (nucleosome remodeling and deacetylase) complex, as well as the chromodomain helicase chd4, in suppressing production of photoreceptor neurons (PRNs) in planarians. This suppressive effect appeared restricted to PRNs because p66 inhibition did not influence numbers of eye pigment cup cells (PCCs) and decreased numbers of brain neurons and epidermal progenitors. PRNs from p66(RNAi) animals differentiated with some abnormalities but nonetheless produced arrestin+ projections to the brain. p66 inhibition produced excess ovo+otxA+ PRN progenitors without affecting numbers of ovo+otxA- PCC progenitors, and ovo and otxA were each required for the p66(RNAi) excess PRN phenotype. Together these results suggest that p66 acts through the NuRD complex to suppress PRN production by limiting expression of lineage-specific transcription factors.

DRAGON, a GPI-anchored membrane protein, inhibits BMP signaling in C2C12 myoblasts.

PubMed

Kanomata, Kazuhiro; Kokabu, Shoichiro; Nojima, Junya; Fukuda, Toru; Katagiri, Takenobu

2009-06-01

Bone morphogenetic proteins (BMPs) induce osteoblastic differentiation of myoblasts via binding to cell surface receptors. Repulsive guidance molecules (RGMs) have been identified as BMP co-receptors. We report here that DRAGON/RGMb, a member of the RGM family, suppressed BMP signaling in C2C12 myoblasts via a novel mechanism. All RGMs were expressed in C2C12 cells that were differentiated into myocytes and osteoblastic cells, but RGMc was not detected in immature cells. In C2C12 cells, only DRAGON suppressed ALP and Id1 promoter activities induced by BMP-4 or by constitutively activated BMP type I receptors. This inhibition by DRAGON was dependent on the secretory form of the von Willbrand factor type D domain. DRAGON even suppressed BMP signaling induced by constitutively activated Smad1. Over-expression of neogenin did not alter the inhibitory capacity of DRAGON. Taken together, these findings indicate that DRAGON may be an inhibitor of BMP signaling in C2C12 myoblasts. We also suggest that a novel molecule(s) expressed on the cell membrane may mediate the signal transduction of DRAGON in order to suppress BMP signaling in C2C12 myoblasts.

Yeast-derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-derived Suppressor Cells by Inducing PMN-MDSC Apoptosis and M-MDSC Differentiation to APC in Cancer

PubMed Central

Albeituni, Sabrin H.; Ding, Chuanlin; Liu, Min; Hu, Xiaoling; Luo, Fengling; Kloecker, Goetz; Bousamra, Micahel; Zhang, Huang-ge; Yan, Jun

2016-01-01

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. Herein, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP), a ligand to engage and activate dectin-1, oral treatment in vivo significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of PMN-MDSC but not M-MDSC, and decreased PMN-MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80+CD11c+ cells in vitro that served as potent antigen-presenting cells (APC) to induce Ag-specific CD4+ and CD8+ T cell responses in a dectin-1 dependent manner. In addition, ERK1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c+ cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated subcutaneously with LLC cells. This effect was dependent of the dectin-1 receptor. Strikingly, patients with non-small cell lung cancer (NSCLC) that had received WGP treatment for 10–14 days prior to any other treatment had a decreased frequency of CD14−HLA-DR−CD11b+CD33+ MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer. PMID:26810222

Interleukin-6 and soluble interleukin-6 receptor suppress osteoclastic differentiation by inducing PGE(2) production in chondrocytes.

PubMed

Honda, Kazuhiro

2011-03-01

This study examined how interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6r) influence osteoclastic differentiation through the function of chondrocytes. Chondrocytes were cultured with or without IL-6 and/or sIL-6r in the presence or absence of NS398, a specific inhibitor of cyclooxygenase (COX)-2, for up to 28 days. Chondrocytes were also cultured with or without IL-6 and sIL-6r for 28 days, and the conditioned medium from cells cultured without IL-6 and sIL-6r was used to induce differentiation of RAW264.7 cells into osteoclast precursors. Osteoclastic differentiation was assessed by tartrate-resistant acid phosphatase (TRAP) staining. Expression of osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), COX-2, and prostaglandin E(2) (PGE(2)) increased in cells exposed to IL-6 and sIL-6r, whereas expression of macrophage colony-stimulating factor (M-CSF) and bone resorption-related enzymes decreased. NS398 blocked the stimulatory/suppressive effects of IL-6 and sIL-6r on the expression of OPG, RANKL, and M-CSF. Fewer TRAP-positive multinucleated cells were detected after treatment with conditioned medium from IL-6- and sIL-6r-treated chondrocytes than after treatment with conditioned medium from untreated chondrocytes. These results suggest that IL-6 and sIL-6r interfere with osteoclast function through the involvement of chondrocytes. Specifically, they appear to suppress the differentiation of osteoclast precursors into osteoclasts by inducing chondrocytic PGE(2) production, which, in turn, increases OPG secretion and decreases M-CSF secretion by chondrocytes.

Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication.

PubMed

Qin, Yiwen; Peng, Yuanzhen; Zhao, Wei; Pan, Jianping; Ksiezak-Reding, Hanna; Cardozo, Christopher; Wu, Yingjie; Divieti Pajevic, Paola; Bonewald, Lynda F; Bauman, William A; Qin, Weiping

2017-06-30

Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Limited Diagnostic Utility of Plasma Adrenocorticotropic Hormone for Differentiation between Adrenal Cushing Syndrome and Cushing Disease.

PubMed

Hong, A Ram; Kim, Jung Hee; Hong, Eun Shil; Kim, I Kyeong; Park, Kyeong Seon; Ahn, Chang Ho; Kim, Sang Wan; Shin, Chan Soo; Kim, Seong Yeon

2015-09-01

Measurement of the plasma adrenocorticotropic hormone (ACTH) level has been recommended as the first diagnostic test for differentiating between ACTH-independent Cushing syndrome (CS) and ACTH-dependent CS. When plasma ACTH values are inconclusive, a differential diagnosis of CS can be made based upon measurement of the serum dehydroepiandrosterone sulfate (DHEA-S) level and results of the high-dose dexamethasone suppression test (HDST). The aim of this study was to assess the utility of plasma ACTH to differentiate adrenal CS from Cushing' disease (CD) and compare it with that of the HDST results and serum DHEA-S level. We performed a retrospective, multicenter study from January 2000 to May 2012 involving 92 patients with endogenous CS. The levels of plasma ACTH, serum cortisol, 24-hour urine free cortisol (UFC) after the HDST, and serum DHEA-S were measured. Fifty-seven patients had adrenal CS and 35 patients had CD. The area under the curve of plasma ACTH, serum DHEA-S, percentage suppression of serum cortisol, and UFC after HDST were 0.954, 0.841, 0.950, and 0.997, respectively (all P<0.001). The cut-off values for plasma ACTH, percentage suppression of serum cortisol, and UFC after HDST were 5.3 pmol/L, 33.3%, and 61.6%, respectively. The sensitivity and specificity of plasma ACTH measurement were 84.2% and 94.3%, those of serum cortisol were 95.8% and 90.6%, and those of UFC after the HDST were 97.9% and 96.7%, respectively. Significant overlap in plasma ACTH levels was seen between patients with adrenal CS and those with CD. The HDST may be useful in differentiating between these forms of the disease, especially when the plasma ACTH level alone is not conclusive.

Pulsed electromagnetic field inhibits RANKL-dependent osteoclastic differentiation in RAW264.7 cells through the Ca{sup 2+}-calcineurin-NFATc1 signaling pathway

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

Zhang, Jie; Xu, Haixia; Han, Zhongyu

Pulsed electromagnetic field (PEMF) has been reported to improve bone healing in osteoporosis patients. However, the precise mechanism has remained largely unknown. This study aimed to investigate the effects of PEMF on nuclear factor κB ligand (RANKL)-dependent osteoclastic differentiation and the Ca{sup 2+}-calcineurin-NFATc1 signaling pathway in RAW264.7 cells in vitro. Treating RAW264.7 cells with RANKL for 4 days induced osteoclastic differentiation in vitro, and the formation of multinucleated osteoclasts, bone resorption-pit formation, tartrate-resistant acid phosphatase (TRAP) activity and the protein levels of cathepsin K, TRAP, Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and matrix metalloproteinase 9 (MMP-9) were significantly decreased. The mRNA levelsmore » of specific genes related to osteoclastogenesis (TRAP, NFATc1, CTSK and MMP-9) were also reduced. Moreover, the oscillations of intracellular Ca{sup 2+} in RANKL-dependent RAW264.7 cells were suppressed by PEMF, as well as by inhibitors of membrane and store-operated Ca{sup 2+} channels. Meanwhile, calcineurin activity was increased, although its protein level was not changed. PEMF increased phospho-NFATc1 in the cytosol while suppressing the nuclear translocation of NFATc1, thus inhibiting osteoclastic differentiation by suppressing the Ca{sup 2+}-calcineurin-NFATc1 signaling pathway. Although many questions remain unresolved, to our knowledge, this is the first report demonstrating that PEMF is beneficial against RANKL-dependent osteoclastic differentiation in RAW264.7 cells in vitro via inhibiting the Ca{sup 2+}-calcineurin-NFATc1 signaling pathway.« less

Pulsed electromagnetic field inhibits RANKL-dependent osteoclastic differentiation in RAW264.7 cells through the Ca2+-calcineurin-NFATc1 signaling pathway.

PubMed

Zhang, Jie; Xu, Haixia; Han, Zhongyu; Chen, Ping; Yu, Qiang; Lei, Yutian; Li, Zongze; Zhao, Ming; Tian, Jing

2017-01-08

Pulsed electromagnetic field (PEMF) has been reported to improve bone healing in osteoporosis patients. However, the precise mechanism has remained largely unknown. This study aimed to investigate the effects of PEMF on nuclear factor κB ligand (RANKL)-dependent osteoclastic differentiation and the Ca 2+ -calcineurin-NFATc1 signaling pathway in RAW264.7 cells in vitro. Treating RAW264.7 cells with RANKL for 4 days induced osteoclastic differentiation in vitro, and the formation of multinucleated osteoclasts, bone resorption-pit formation, tartrate-resistant acid phosphatase (TRAP) activity and the protein levels of cathepsin K, TRAP, Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and matrix metalloproteinase 9 (MMP-9) were significantly decreased. The mRNA levels of specific genes related to osteoclastogenesis (TRAP, NFATc1, CTSK and MMP-9) were also reduced. Moreover, the oscillations of intracellular Ca 2+ in RANKL-dependent RAW264.7 cells were suppressed by PEMF, as well as by inhibitors of membrane and store-operated Ca 2+ channels. Meanwhile, calcineurin activity was increased, although its protein level was not changed. PEMF increased phospho-NFATc1 in the cytosol while suppressing the nuclear translocation of NFATc1, thus inhibiting osteoclastic differentiation by suppressing the Ca 2+ -calcineurin-NFATc1 signaling pathway. Although many questions remain unresolved, to our knowledge, this is the first report demonstrating that PEMF is beneficial against RANKL-dependent osteoclastic differentiation in RAW264.7 cells in vitro via inhibiting the Ca 2+ -calcineurin-NFATc1 signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Magnetic field amplification by the r-mode instability

NASA Astrophysics Data System (ADS)

Chugunov, A. I.; Friedman, J. L.; Lindblom, L.; Rezzolla, L.

2017-12-01

We discuss the magnetic field enhancement by unstable r-modes (driven by the gravitational radiation reaction force) in rotating stars. In the absence of a magnetic field, gravitational radiation exponentially increases the r-mode amplitude α, and accelerates differential rotation (secular motion of fluid elements). For a magnetized star, differential rotation enhances the magnetic field energy. Rezzolla et al (2000-2001) argued that if the magnetic energy grows faster than the gravitational radiation reaction force pumps energy into the r-modes, then the r-mode instability is suppressed. Chugunov (2015) demonstrated that without gravitational radiation, differential rotation can be treated as a degree of freedom decoupled from the r-modes and controlled by the back reaction of the magnetic field. In particular, the magnetic field windup does not damp r-modes. Here we discuss the effect of the back reaction of the magnetic field on differential rotation of unstable r-modes, and show that it limits the generated magnetic field and the magnetic energy growth rate preventing suppression of the r-mode instability by magnetic windup at low saturation amplitudes, α ≪ 1, predicted by current models.

miR-96 promotes osteogenic differentiation by suppressing HBEGF-EGFR signaling in osteoblastic cells.

PubMed

Yang, Mingfu; Pan, Yong; Zhou, Yue

2014-12-20

MicroRNAs (miRNAs) are a class of small non-coding RNAs with important roles in various biological and pathological processes, including osteoblast differentiation. Here, we identified miR-96 as a positive regulator of osteogenic differentiation in a mouse osteoblastic cell line (MC3T3-E1) and in mouse bone marrow-derived mesenchymal stem cells. Moreover, we found that miR-96 down-regulates post-transcriptional expression of heparin-binding EGF-like growth factor (HB-EGF) by specifically binding to the 3'untranslated region of HB-EGF mRNA. Furthermore, in MC3T3-E1 cells, miR-96-induced HB-EGF down-regulation suppressed the phosphorylation of epidermal growth factor receptor (EGFR) and of extracellular signal-regulated kinase 1 (ERK1) and AKT, which both lie downstream of EGFR activation. Taken together, miR-96 promotes osteogenic differentiation by inhibiting HB-EGF and by blocking the HB-EGF-EGFR signaling pathway in osteoblastic cells. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

86% internal differential efficiency from 8 to 9 µm-emitting, step-taper active-region quantum cascade lasers.

PubMed

Kirch, Jeremy D; Chang, Chun-Chieh; Boyle, Colin; Mawst, Luke J; Lindberg, Don; Earles, Tom; Botez, Dan

2016-10-17

8.4 μm-emitting quantum cascade lasers (QCLs) have been designed to have, right from threshold, both carrier-leakage suppression and miniband-like carrier extraction. The slope-efficiency characteristic temperature T₁, the signature of carrier-leakage suppression, is found to be 665 K. Resonant-tunneling carrier extraction from both the lower laser level (ll) and the level below it, coupled with highly effective ll-depopulation provide a very short ll lifetime (~0.12 ps). As a result the laser-transition differential efficiency reaches 89%, and the internal differential efficiency η_id, derived from a variable mirror-loss study, is found to be 86%, in good agreement with theory. A study of 8.8 μm-emitting QCLs also provides an η_id value of 86%. A corrected equation for the external differential efficiency is derived which leads to a fundamental limit of ~90% for the η_id values of mid-infrared QCLs. In turn, the fundamental wallplug-efficiency limits become ~34% higher than previously predicted.

Binocular contrast discrimination needs monocular multiplicative noise

PubMed Central

Ding, Jian; Levi, Dennis M.

2016-01-01

The effects of signal and noise on contrast discrimination are difficult to separate because of a singularity in the signal-detection-theory model of two-alternative forced-choice contrast discrimination (Katkov, Tsodyks, & Sagi, 2006). In this article, we show that it is possible to eliminate the singularity by combining that model with a binocular combination model to fit monocular, dichoptic, and binocular contrast discrimination. We performed three experiments using identical stimuli to measure the perceived phase, perceived contrast, and contrast discrimination of a cyclopean sine wave. In the absence of a fixation point, we found a binocular advantage in contrast discrimination both at low contrasts (<4%), consistent with previous studies, and at high contrasts (≥34%), which has not been previously reported. However, control experiments showed no binocular advantage at high contrasts in the presence of a fixation point or for observers without accommodation. We evaluated two putative contrast-discrimination mechanisms: a nonlinear contrast transducer and multiplicative noise (MN). A binocular combination model (the DSKL model; Ding, Klein, & Levi, 2013b) was first fitted to both the perceived-phase and the perceived-contrast data sets, then combined with either the nonlinear contrast transducer or the MN mechanism to fit the contrast-discrimination data. We found that the best model combined the DSKL model with early MN. Model simulations showed that, after going through interocular suppression, the uncorrelated noise in the two eyes became anticorrelated, resulting in less binocular noise and therefore a binocular advantage in the discrimination task. Combining a nonlinear contrast transducer or MN with a binocular combination model (DSKL) provides a powerful method for evaluating the two putative contrast-discrimination mechanisms. PMID:26982370

Binocular contrast discrimination needs monocular multiplicative noise.

PubMed

Ding, Jian; Levi, Dennis M

2016-01-01

The effects of signal and noise on contrast discrimination are difficult to separate because of a singularity in the signal-detection-theory model of two-alternative forced-choice contrast discrimination (Katkov, Tsodyks, & Sagi, 2006). In this article, we show that it is possible to eliminate the singularity by combining that model with a binocular combination model to fit monocular, dichoptic, and binocular contrast discrimination. We performed three experiments using identical stimuli to measure the perceived phase, perceived contrast, and contrast discrimination of a cyclopean sine wave. In the absence of a fixation point, we found a binocular advantage in contrast discrimination both at low contrasts (<4%), consistent with previous studies, and at high contrasts (≥34%), which has not been previously reported. However, control experiments showed no binocular advantage at high contrasts in the presence of a fixation point or for observers without accommodation. We evaluated two putative contrast-discrimination mechanisms: a nonlinear contrast transducer and multiplicative noise (MN). A binocular combination model (the DSKL model; Ding, Klein, & Levi, 2013b) was first fitted to both the perceived-phase and the perceived-contrast data sets, then combined with either the nonlinear contrast transducer or the MN mechanism to fit the contrast-discrimination data. We found that the best model combined the DSKL model with early MN. Model simulations showed that, after going through interocular suppression, the uncorrelated noise in the two eyes became anticorrelated, resulting in less binocular noise and therefore a binocular advantage in the discrimination task. Combining a nonlinear contrast transducer or MN with a binocular combination model (DSKL) provides a powerful method for evaluating the two putative contrast-discrimination mechanisms.

Effects of Activin and TGFβ on p21 in Colon Cancer

PubMed Central

Cabral, Jennifer; Gomez, Jessica; Jung, Barbara

2012-01-01

Activin and TGFβ share SMAD signaling and colon cancers can inactivate either pathway alone or simultaneously. The differential effects of activin and TGFβ signaling in colon cancer have not been previously dissected. A key downstream target of TGFβ signaling is the cdk2 inhibitor p21 (p21cip1/waf1). Here, we evaluate activin-specific effects on p21 regulation and resulting functions. We find that TGFβ is a more potent inducer of growth suppression, while activin is a more potent inducer of apoptosis. Further, growth suppression and apoptosis by both ligands are dependent on SMAD4. However, activin downregulates p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination and proteasomal degradation to enhance migration, while TGFβ upregulates p21 in a SMAD4-dependent fashion to affect growth arrest. Activin-induced growth suppression and cell death are dependent on p21, while activin-induced migration is counteracted by p21. Further, primary colon cancers show differential p21 expression consistent with their ACVR2/TGFBR2 receptor status. In summary, we report p21 as a differentially affected activin/TGFβ target and mediator of ligand-specific functions in colon cancer, which may be exploited for future risk stratification and therapeutic intervention. PMID:22761777

Pasteurella multocida Toxin Manipulates T Cell Differentiation

PubMed Central

Hildebrand, Dagmar; Heeg, Klaus; Kubatzky, Katharina F.

2015-01-01

Pasteurella multocida causes various diseases in a broad range of wild and domestic animals. Toxigenic strains of the serotypes A and D produce an AB protein toxin named Pasteurella multocida toxin (PMT). PMT constitutively activates the heterotrimeric G protein subunits Gαq, Gα13, and Gαi through deamidation of a glutamine residue, which results in cytoskeletal rearrangements as well as increased proliferation and survival of the host cell. In human monocytes, PMT alters the lipopolysaccharide (LPS)-induced activation toward a phenotype that suppresses T cell activation. Here we describe that the toxin also modulates CD4-positive T helper (Th) cells directly. PMT amplifies the expansion of Th cells through enhanced cell cycle progression and suppression of apoptosis and manipulates the differentiation of Th subclasses through activation of Signal Transducers and Activators of Transcription (STAT) family members and induction of subtype-specific master transcription factors. A large population of toxin-treated T cells is double-positive for Foxp3 and RORγt, the transcription factors expressed by Treg and Th17 cells, respectively. This suggests that these cells could have the potential to turn into Th17 cells or suppressive Treg cells. However, in terms of function, the PMT-differentiated cells behave as inflammatory Th17 cells that produce IL-17 and trigger T cell proliferation. PMID:26635744

Extremely High Expression of Antisense RNA for Wilms' Tumor 1 in Active Osteoclasts: Suppression of Wilms' Tumor 1 Protein Expression during Osteoclastogenesis.

PubMed

Li, Yin-Ji; Kukita, Akiko; Kyumoto-Nakamura, Yukari; Kukita, Toshio

2016-09-01

Wilms' tumor 1 (WT1), a zinc-finger transcription regulator of the early growth response family, identified as the product of a tumor suppressor gene of Wilms' tumors, bears potential ability to induce macrophage differentiation in blood cell differentiation. Herein, we examined the involvement of WT1 in the regulation of osteoclastogenesis. We detected a high level of WT1 protein expression in osteoclast precursors; however, WT1 expression was markedly suppressed during osteoclastogenesis. We examined expression of WT1 transcripts in bone tissue by RNA in situ hybridization. We found a high level of antisense transcripts in osteoclasts actively resorbing bone in mandible of newborn rats. Expression of antisense WT1 RNA in mandible was also confirmed by Northern blot analysis and strand-specific RT-PCR. Overexpression of antisense WT1 RNA in RAW-D cells, an osteoclast precursor cell line, resulted in a marked enhancement of osteoclastogenesis, suggesting that antisense WT1 RNA functions to suppress expression of WT1 protein in osteoclastogenesis. High level expression of antisense WT1 RNA may contribute to commitment to osteoclastogenesis, and may allow osteoclasts to maintain or stabilize their differentiation state. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice.

PubMed

Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

2015-01-01

Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo.

Isoflurane and ketamine:xylazine differentially affect intraocular pressure-associated scotopic threshold responses in Sprague-Dawley rats.

PubMed

Choh, Vivian; Gurdita, Akshay; Tan, Bingyao; Feng, Yunwei; Bizheva, Kostadinka; McCulloch, Daphne L; Joos, Karen M

2017-10-01

Amplitudes of electroretinograms (ERG) are enhanced during acute, moderate elevation of intraocular pressure (IOP) in rats anaesthetised with isoflurane. As anaesthetics alone are known to affect ERG amplitudes, the present study compares the effects of inhalant isoflurane and injected ketamine:xylazine on the scotopic threshold response (STR) in rats with moderate IOP elevation. Isoflurane-anaesthetised (n = 9) and ketamine:xylazine-anaesthetised (n = 6) rats underwent acute unilateral IOP elevation using a vascular loop anterior to the equator of the right eye. STRs to a luminance series (subthreshold to -3.04 log scotopic cd s/m 2 ) were recorded from each eye of Sprague-Dawley rats before, during, and after IOP elevation. Positive STR (pSTR) amplitudes for all conditions were significantly smaller (p = 0.0001) for isoflurane- than for ketamine:xylazine-anaesthetised rats. In addition, ketamine:xylazine was associated with a progressive increase in pSTR amplitudes over time (p = 0.0028). IOP elevation was associated with an increase in pSTR amplitude (both anaesthetics p < 0.0001). The absolute interocular differences in IOP-associated enhancement of pSTR amplitudes for ketamine:xylazine and isoflurane were similar (66.3 ± 35.5 vs. 54.2 ± 24.1 µV, respectively). However, the fold increase in amplitude during IOP elevation was significantly higher in the isoflurane- than in the ketamine:xylazine-anaesthetised rats (16.8 ± 29.7x vs. 2.1 ± 2.7x, respectively, p = 0.0004). The anaesthetics differentially affect the STRs in the rat model with markedly reduced amplitudes with isoflurane compared to ketamine:xylazine. However, the IOP-associated enhancement is of similar absolute magnitude for the two anaesthetics, suggesting that IOP stress and anaesthetic effects operate on separate retinal mechanisms.

Diagnostic value of conventional visual evoked potentials applied to patients with multiple sclerosis.

PubMed

Balnytė, Renata; Ulozienė, Ingrida; Rastenytė, Daiva; Vaitkus, Antanas; Malcienė, Lina; Laučkaitė, Kristina

2011-01-01

The aim of this study was to determine the sensitivity and specificity of this classical technique employed at the Hospital of Lithuanian University of Health Sciences for the patients with multiple sclerosis and to assess its possible correlations with affected neurological systems. Pattern shift visual evoked potentials were recorded in 63 patients with multiple sclerosis, 17 (27%) of whom had a history of optic neuritis, and in 63 control patients with other neurological diseases. The latencies and amplitudes of P100 were measured. In total, 126 patients were referred to the inpatient department of neurology for differential diagnosis of demyelinating disorders between January and December of 2007. Abnormalities of visual evoked potentials were observed by 73% more frequently in patients with multiple sclerosis than in control patients (α=0.05, β<0.01). The combined monocular/interocular test showed a specificity of 90.5% and a sensitivity of 82.5%. The probability of an affection of the pyramidal system was 5 times greater (95% CI, 2.2-11.0; P<0.01) and the probability of the optic pathways involvement was 4.8 times greater (95% CI, 1.9-11.9; P<0.01) in patients with multiple sclerosis than in controls. Conventional visual evoked potentials must be reappraised in light of their diagnostic value in multiple sclerosis given their high diagnostic efficiency, relatively easy, short, and cheap implementation, and easy availability in everyday clinical practice.

Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner

PubMed Central

Lohanatha, Ferenz L.; Hahne, Martin; Strehl, Cindy; Fangradt, Monique; Tran, Cam Loan; Schönbeck, Kerstin; Hoff, Paula; Ode, Andrea; Perka, Carsten; Duda, Georg N.; Buttgereit, Frank

2012-01-01

Background Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages. Methodology/Principal Findings Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O2) or hypoxic (less than 2% O2) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil-Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1α by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1α and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA-mediated knockdown of HIF-1α enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis. Conclusions/Significance Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches. PMID:23029528

Peroxisome proliferator-activated receptor-β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53- and SOX2-mediated cell differentiation.

PubMed

Yao, Pei-Li; Chen, Liping; Dobrzański, Tomasz P; Zhu, Bokai; Kang, Boo-Hyon; Müller, Rolf; Gonzalez, Frank J; Peters, Jeffrey M

2017-05-01

Neuroblastoma is a common childhood cancer typically treated by inducing differentiation with retinoic acid (RA). Peroxisome proliferator-activated receptor-β/δ, (PPARβ/δ) is known to promote terminal differentiation of many cell types. In the present study, PPARβ/δ was over-expressed in three human neuroblastoma cell lines, NGP, SK-N-BE(2), and IMR-32, that exhibit high, medium, and low sensitivity, respectively, to retinoic acid-induced differentiation to determine if PPARβ/δ and retinoic acid receptors (RARs) could be jointly targeted to increase the efficacy of treatment. All-trans-RA (atRA) decreased expression of SRY (sex determining region Y)-box 2 (SOX2), a stem cell regulator and marker of de-differentiation, in NGP and SK-N-BE(2) cells with inactive or mutant tumor suppressor p53, respectively. However, atRA did not suppress SOX2 expression in IMR-32 cells carrying wild-type p53. Over-expression and/or ligand activation of PPARβ/δ reduced the average volume and weight of ectopic tumor xenografts from NGP, SK-N-BE(2), or IMR-32 cells compared to controls. Compared with that found with atRA, PPARβ/δ suppressed SOX2 expression in NGP and SK-N-BE(2) cells and ectopic xenografts, and was also effective in suppressing SOX2 expression in IMR-32 cells that exhibit higher p53 expression compared to the former cell lines. Combined, these observations demonstrate that activating or over-expressing PPARβ/δ induces cell differentiation through p53- and SOX2-dependent signaling pathways in neuroblastoma cells and tumors. This suggests that combinatorial activation of both RARα and PPARβ/δ may be suitable as an alternative therapeutic approach for RA-resistant neuroblastoma patients. Published [2016]. This article is a U.S. Government work and is in the public domain in the USA.

TMS suppression of right pars triangularis, but not pars opercularis, improves naming in aphasia

PubMed Central

Naeser, Margaret A.; Martin, Paula I.; Theoret, Hugo; Kobayashi, Masahito; Fregni, Felipe; Nicholas, Marjorie; Tormos, Jose M.; Steven, Megan S.; Baker, Errol H.; Pascual-Leone, Alvaro

2011-01-01

This study sought to discover if an optimum 1 cm2 area in the non-damaged right hemisphere (RH) was present, which could temporarily improve naming in chronic, nonfluent aphasia patients when suppressed with repetitive transcranial magnetic stimulation (rTMS). Ten minutes of slow, 1 Hz rTMS was applied to suppress different RH ROIs in eight aphasia cases. Picture naming and response time (RT) were examined before, and immediately after rTMS. In aphasia patients, suppression of right pars triangularis (PTr) led to significant increase in pictures named, and significant decrease in RT. Suppression of right pars opercularis (POp), however, led to significant increase in RT, but no change in number of pictures named. Eight normals named all pictures correctly; similar to aphasia patients, RT significantly decreased following rTMS to suppress right PTr, versus right POp. Differential effects following suppression of right PTr versus right POp suggest different functional roles for these regions. PMID:21864891

AhR and Arnt differentially regulate NF-κB signaling and chemokine responses in human bronchial epithelial cells

PubMed Central

2014-01-01

Background The aryl hydrocarbon receptor (AhR) has gradually emerged as a regulator of inflammation in the lung and other tissues. AhR may interact with the p65-subunit of the nuclear factor (NF)-κB transcription factors, but reported outcomes of AhR/NF-κB-interactions are conflicting. Some studies suggest that AhR possess pro-inflammatory activities while others suggest that AhR may be anti-inflammatory. The present study explored the impact of AhR and its binding partner AhR nuclear translocator (Arnt) on p65-activation and two differentially regulated chemokines, CXCL8 (IL-8) and CCL5 (RANTES), in human bronchial epithelial cells (BEAS-2B). Results Cells were exposed to CXCL8- and CCL5-inducing chemicals, 1-nitropyrene (1-NP) and 1-aminopyrene (1-AP) respectively, or the synthetic double-stranded RNA analogue, polyinosinic-polycytidylic acid (Poly I:C) which induced both chemokines. Only CXCL8, and not CCL5, appeared to be p65-dependent. Yet, constitutively active unligated AhR suppressed both CXCL8 and CCL5, as shown by siRNA knock-down and the AhR antagonist α-naphthoflavone. Moreover, AhR suppressed activation of p65 by TNF-α and Poly I:C as assessed by luciferase-assay and p65-phosphorylation at serine 536, without affecting basal p65-activity. In contrast, Arnt suppressed only CXCL8, but did not prevent the p65-activation directly. However, Arnt suppressed expression of the NF-κB-subunit RelB which is under transcriptional regulation by p65. Furthermore, AhR-ligands alone at high concentrations induced a moderate CXCL8-response, without affecting CCL5, but suppressed both CXCL8 and CCL5-responses by Poly I:C. Conclusion AhR and Arnt may differentially and independently regulate chemokine-responses induced by both inhaled pollutants and pulmonary infections. Constitutively active, unligated AhR suppressed the activation of p65, while Arnt may possibly interfere with the action of activated p65. Moreover, ligand-activated AhR suppressed CXCL8 and CCL5 responses by other agents, but AhR ligands alone induced CXCL8 responses when given at sufficiently high concentrations, thus underscoring the duality of AhR in regulation of inflammation. We propose that AhR-signaling may be a weak activator of p65-signaling that suppresses p65-activity induced by strong activators of NF-κB, but that its anti-inflammatory properties also are due to interference with additional pathways. PMID:25201625

Nicotine Affects Bone Resorption and Suppresses the Expression of Cathepsin K, MMP-9 and Vacuolar-Type H+-ATPase d2 and Actin Organization in Osteoclasts

PubMed Central

Tanaka, Hideki; Tanabe, Natsuko; Kawato, Takayuki; Nakai, Kumiko; Kariya, Taro; Matsumoto, Sakurako; Zhao, Ning; Motohashi, Masafumi; Maeno, Masao

2013-01-01

Tobacco smoking is an important risk factor for the development of several cancers, osteoporosis, and inflammatory diseases such as periodontitis. Nicotine is one of the major components of tobacco. In previous study, we showed that nicotine inhibits mineralized nodule formation by osteoblasts, and the culture medium from osteoblasts containing nicotine and lipopolysaccharide increases osteoclast differentiation. However, the direct effect of nicotine on the differentiation and function of osteoclasts is poorly understood. Thus, we examined the direct effects of nicotine on the expression of nicotine receptors and bone resorption-related enzymes, mineral resorption, actin organization, and bone resorption using RAW264.7 cells and bone marrow cells as osteoclast precursors. Cells were cultured with 10−5, 10−4, or 10−3 M nicotine and/or 50 µM α-bungarotoxin (btx), an 7 nicotine receptor antagonist, in differentiation medium containing the soluble RANKL for up 7 days. 1–5, 7, 9, and 10 nicotine receptors were expressed on RAW264.7 cells. The expression of 7 nicotine receptor was increased by the addition of nicotine. Nicotine suppressed the number of tartrate-resistant acid phosphatase positive multinuclear osteoclasts with large nuclei(≥10 nuclei), and decreased the planar area of each cell. Nicotine decreased expression of cathepsin K, MMP-9, and V-ATPase d2. Btx inhibited nicotine effects. Nicotine increased CA II expression although decreased the expression of V-ATPase d2 and the distribution of F-actin. Nicotine suppressed the planar area of resorption pit by osteoclasts, but did not affect mineral resorption. These results suggest that nicotine increased the number of osteoclasts with small nuclei, but suppressed the number of osteoclasts with large nuclei. Moreover, nicotine reduced the planar area of resorption pit by suppressing the number of osteoclasts with large nuclei, V-ATPase d2, cathepsin K and MMP-9 expression and actin organization. PMID:23555029

Utility of fat-suppressed sequences in differentiation of aggressive vs typical asymptomatic haemangioma of the spine

PubMed Central

Nabavizadeh, Seyed Ali; Mamourian, Alexander; Schmitt, James E; Cloran, Francis; Vossough, Arastoo; Pukenas, Bryan; Loevner, Laurie A

2016-01-01

Objective: While haemangiomas are common benign vascular lesions involving the spine, some behave in an aggressive fashion. We investigated the utility of fat-suppressed sequences to differentiate between benign and aggressive vertebral haemangiomas. Methods: Patients with the diagnosis of aggressive vertebral haemangioma and available short tau inversion-recovery or T2 fat saturation sequence were included in the study. 11 patients with typical asymptomatic vertebral body haemangiomas were selected as the control group. Region of interest signal intensity (SI) analysis of the entire haemangioma as well as the portion of each haemangioma with highest signal on fat-saturation sequences was performed and normalized to a reference normal vertebral body. Results: A total of 8 patients with aggressive vertebral haemangioma and 11 patients with asymptomatic typical vertebral haemangioma were included. There was a significant difference between total normalized mean SI ratio (3.14 vs 1.48, p = 0.0002), total normalized maximum SI ratio (5.72 vs 2.55, p = 0.0003), brightest normalized mean SI ratio (4.28 vs 1.72, p < 0.0001) and brightest normalized maximum SI ratio (5.25 vs 2.45, p = 0.0003). Multiple measures were able to discriminate between groups with high sensitivity (>88%) and specificity (>82%). Conclusion: In addition to the conventional imaging features such as vertebral expansion and presence of extravertebral component, quantitative evaluation of fat-suppression sequences is also another imaging feature that can differentiate aggressive haemangioma and typical asymptomatic haemangioma. Advances in knowledge: The use of quantitative fat-suppressed MRI in vertebral haemangiomas is demonstrated. Quantitative fat-suppressed MRI can have a role in confirming the diagnosis of aggressive haemangiomas. In addition, this application can be further investigated in future studies to predict aggressiveness of vertebral haemangiomas in early stages. PMID:26511277

Multiple negative differential resistance devices with ultra-high peak-to-valley current ratio for practical multi-valued logic and memory applications

NASA Astrophysics Data System (ADS)

Shin, Sunhae; Rok Kim, Kyung

2015-06-01

In this paper, we propose a novel multiple negative differential resistance (NDR) device with ultra-high peak-to-valley current ratio (PVCR) over 106 by combining tunnel diode with a conventional MOSFET, which suppresses the valley current with transistor off-leakage level. Band-to-band tunneling (BTBT) in tunnel junction provides the first peak, and the second peak and valley are generated from the suppression of diffusion current in tunnel diode by the off-state MOSFET. The multiple NDR curves can be controlled by doping concentration of tunnel junction and the threshold voltage of MOSFET. By using complementary multiple NDR devices, five-state memory is demonstrated only with six transistors.

Note: innovative demodulation scheme for coherent detectors in cosmic microwave background experiments.

PubMed

Ishidoshiro, K; Chinone, Y; Hasegawa, M; Hazumi, M; Nagai, M; Tajima, O

2012-05-01

We propose an innovative demodulation scheme for coherent detectors used in cosmic microwave background polarization experiments. Removal of non-white noise, e.g., narrow-band noise, in detectors is one of the key requirements for the experiments. A combination of modulation and demodulation is used to extract polarization signals as well as to suppress such noise. Traditional demodulation, which is based on the two-point numerical differentiation, works as a first-order high pass filter for the noise. The proposed demodulation is based on the three-point numerical differentiation. It works as a second-order high pass filter. By using a real detector, we confirmed significant improvements of suppression power for the narrow-band noise. We also found improvement of the noise floor.

Creating Tic Suppression: Comparing the Effects of Verbal Instruction to Differential Reinforcement

ERIC Educational Resources Information Center

Woods, Douglas W.; Himle, Michael B.

2004-01-01

The purpose of this study was to compare two methods designed to produce tic reduction in 4 children with Tourette's syndrome. Specifically, a verbal instruction not to engage in tics was compared to a verbal instruction plus differential reinforcement of zero-rate behavior (DRO). Results showed that the DRO-enhanced procedure yielded greater…

bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression.

PubMed

Li, Xiaosu; Chen, Rui; Zhu, Sijun

2017-11-15

Balancing self-renewal and differentiation of stem cells requires differential expression of self-renewing factors in two daughter cells generated from the asymmetric division of the stem cells. In Drosophila type II neural stem cell (or neuroblast, NB) lineages, the expression of the basic helix-loop-helix-Orange (bHLH-O) family proteins, including Deadpan (Dpn) and E(spl) proteins, is required for maintaining the self-renewal and identity of type II NBs, whereas the absence of these self-renewing factors is essential for the differentiation of intermediate neural progenitors (INPs) generated from type II NBs. Here, we demonstrate that Dpn maintains type II NBs by suppressing the expression of Earmuff (Erm). We provide evidence that Dpn and E(spl) proteins suppress Erm by directly binding to C-sites and N-boxes in the cis-regulatory region of erm. Conversely, the absence of bHLH-O proteins in INPs allows activation of erm and Erm-mediated maturation of INPs. Our results further suggest that Pointed P1 (PntP1) mediates the dedifferentiation of INPs resulting from the loss of Erm or overexpression of Dpn or E(spl) proteins. Taken together, these findings reveal mechanisms underlying the regulation of the maintenance of type II NBs and differentiation of INPs through the differential expression of bHLH-O family proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2*

PubMed Central

Dudakovic, Amel; Camilleri, Emily T.; Xu, Fuhua; Riester, Scott M.; McGee-Lawrence, Meghan E.; Bradley, Elizabeth W.; Paradise, Christopher R.; Lewallen, Eric A.; Thaler, Roman; Deyle, David R.; Larson, A. Noelle; Lewallen, David G.; Dietz, Allan B.; Stein, Gary S.; Montecino, Martin A.; Westendorf, Jennifer J.; van Wijnen, Andre J.

2015-01-01

Epigenetic control of gene expression is critical for normal fetal development. However, chromatin-related mechanisms that activate bone-specific programs during osteogenesis have remained underexplored. Therefore, we investigated the expression profiles of a large cohort of epigenetic regulators (>300) during osteogenic differentiation of human mesenchymal cells derived from the stromal vascular fraction of adipose tissue (AMSCs). Molecular analyses establish that the polycomb group protein EZH2 (enhancer of zeste homolog 2) is down-regulated during osteoblastic differentiation of AMSCs. Chemical inhibitor and siRNA knockdown studies show that EZH2, a histone methyltransferase that catalyzes trimethylation of histone 3 lysine 27 (H3K27me3), suppresses osteogenic differentiation. Blocking EZH2 activity promotes osteoblast differentiation and suppresses adipogenic differentiation of AMSCs. High throughput RNA sequence (mRNASeq) analysis reveals that EZH2 inhibition stimulates cell cycle inhibitory proteins and enhances the production of extracellular matrix proteins. Conditional genetic loss of Ezh2 in uncommitted mesenchymal cells (Prrx1-Cre) results in multiple defects in skeletal patterning and bone formation, including shortened forelimbs, craniosynostosis, and clinodactyly. Histological analysis and mRNASeq profiling suggest that these effects are attributable to growth plate abnormalities and premature cranial suture closure because of precocious maturation of osteoblasts. We conclude that the epigenetic activity of EZH2 is required for skeletal patterning and development, but EZH2 expression declines during terminal osteoblast differentiation and matrix production. PMID:26424790

Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells

PubMed Central

2013-01-01

Background The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. Methods To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0–2 μM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti-adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. Results Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARγ and C/EBPα, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARγ, C/EBPα, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. Conclusions These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway during the early stages of adipogenesis. PMID:23919458

Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells.

PubMed

Gwon, So Young; Ahn, Ji Yun; Jung, Chang Hwa; Moon, Bo Kyung; Ha, Tae Youl

2013-08-06

The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0-2 μM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti-adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARγ and C/EBPα, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARγ, C/EBPα, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway during the early stages of adipogenesis.

Developmental regulation by cytokines of bone marrow-derived dendritic cells and epidermal Langerhans cells.

PubMed

Yamaguchi, Y

1998-01-01

Dendritic cells (DC) are specialized antigen-presenting cells involved in T cell-mediated immune responses. Differentiation and functional maturation of the DC are now known to be regulated by various cytokines, including TGF-beta1. The experiments of this study examined the effect of other cytokines, such as IL-4, IL-10 and IL-6, on the differentiation and maturation of bone marrow (BM)-derived DC (BM-DC) and epidermal Langerhans cells (LC). When IL-6 or IL-10 was added to cultures of BM cells in the presence of GM-CSF, both cytokines, as in the case of TGF-beta1, suppressed the maturation of DC in terms of the expression of adhesion and costimulatory molecules and T cell-stimulating activity. In contrast, IL-4 was not suppressive but rather supportive for the differentiation of DC. However, these suppressive cytokines hardly counteracted the maturation-inducing activity of TNF-alpha when added to cultures of immature DC. In addition, they appeared to block the overmaturation of DC, which is characterized by a loss of MHC class II molecules. Regarding LC maturation in epidermal cell cultures, IL-6 and IL-10 were inhibitory for the expression of CD86 and CD80 in a dose-dependent fashion. Unlike BM-DC, LC maturation was slightly enhanced by TGF-beta1. The protein antigen-presentation by LC to Th1 clone was not affected by IL-6, but slightly reduced by IL-10. These results suggest that each cytokine contributes to regulate the differentiation and maturation of DC at a different developmental stage.

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.

PubMed

Okano, Takaichi; Saegusa, Jun; Nishimura, Keisuke; Takahashi, Soshi; Sendo, Sho; Ueda, Yo; Morinobu, Akio

2017-02-10

Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

Conditions Inducing Excessive O-GlcNAcylation Inhibit BMP2-Induced Osteogenic Differentiation of C2C12 Cells.

PubMed

Gu, Hanna; Song, Mina; Boonanantanasarn, Kanitsak; Baek, Kyunghwa; Woo, Kyung Mi; Ryoo, Hyun-Mo; Baek, Jeong-Hwa

2018-01-09

Hyperglycemic conditions in diabetic patients can affect various cellular functions, including the modulation of osteogenic differentiation. However, the molecular mechanisms by which hyperglycemia affects osteogenic differentiation are yet to be clarified. This study aimed to investigate whether the aberrant increase in protein O -linked-β- N -acetylglucosamine glycosylation ( O -GlcNAcylation) contributes to the suppression of osteogenic differentiation due to hyperglycemia. To induce osteogenic differentiation, C2C12 cells were cultured in the presence of recombinant human bone morphogenetic protein 2 (BMP2). Excessive protein O -GlcNAcylation was induced by treating C2C12 cells with high glucose, glucosamine, or N -acetylglucosamine concentrations or by O -GlcNAc transferase (OGT) overexpression. The effect of O -GlcNAcylation on osteoblast differentiation was then confirmed by examining the expression levels of osteogenic marker gene mRNAs, activity of alkaline phosphatase, and transcriptional activity of Runx2, a critical transcription factor for osteoblast differentiation and bone formation. Cell treatment with high glucose, glucosamine or N -acetylglucosamine increased O -GlcNAcylation of Runx2 and the total levels of O -GlcNAcylated proteins, which led to a decrease in the transcriptional activity of Runx2, expression levels of osteogenic marker genes (Runx2, osterix, alkaline phosphatase, and type I collagen), and activity of alkaline phosphatase. These inhibitory effects were rescued by lowering protein O -GlcNAcylation levels by adding STO45849, an OGT inhibitor, or by overexpressing β- N -acetylglucosaminidase. Our findings suggest that excessive protein O -GlcNAcylation contributes to high glucose-suppressed osteogenic differentiation.

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

PubMed Central

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

2016-01-01

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

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

Xiao, Fei; Zhai, Zanjing; Jiang, Chuan

Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle-induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniinmore » inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-κB and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure. - Highlights: • Geraniin suppresses osteoclasts formation and function in vitro. • Geraniin impairs RANKL-induced nuclear factor-κB and ERK signaling pathway. • Geraniin suppresses osteolysis in vivo. • Geraniin may be used for treating osteoclast related diseases.« less

Probing the Effector and Suppressive Functions of Human T Cell Subsets Using Antigen-Specific Engineered T Cell Receptors

PubMed Central

Imberg, Keren; Mercer, Frances; Zhong, Shi; Krogsgaard, Michelle; Unutmaz, Derya

2013-01-01

Activation of T cells through the engagement of the T cell receptors (TCRs) with specific peptide-MHC complexes on antigen presenting cells (APCs) is the major determinant for their proliferation, differentiation and display of effector functions. To assess the role of quantity and quality of peptide-MHC presentation in eliciting T cell activation and suppression functions, we genetically engineered human T cells with two TCRs that recognize HLA-A*0201-restricted peptides derived from either HIV or melanoma antigens. The engineered-TCRs are highly functional in both CD8+ and CD4+ T cells as assessed by the upregulation of activation markers, induction of cytokine secretion and cytotoxicity. We further demonstrated that engineered-TCRs can also be expressed on naïve human T cells, which are stimulated through APCs presenting specific peptides to induce T cell proliferation and acquire effector functions. Furthermore, regulatory T cells (Tregs) ectopically expressing the engineered-TCRs are activated in an antigen-specific fashion and suppress T cell proliferation. In this system, the inhibitory activity of peptide-stimulated Tregs require the presence of dendritic cells (DCs) in the culture, either as presenters or as bystander cells, pointing to a critical role for DCs in suppression by Tregs. In conclusion, the engineered-TCR system reported here advances our ability to understand the differentiation pathways of naïve T cells into antigen-specific effector cells and the role of antigen-specific signaling in Treg-mediated immune suppression. PMID:23437112

Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice.

PubMed

Wang, Yung-Chun; Chuang, Ya-Hui; Shao, Qiang; Chen, Jian-Fu; Chen, Shi-You

2018-04-13

The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-β/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether long noncoding RNAs also regulate SMC differentiation remains largely unknown. Here, using the murine cell line C3H10T1/2, we found that brain cytoplasmic RNA 1 (BC1) is an important regulator of SMC differentiation. BC1 overexpression suppressed, whereas BC1 knockdown promoted, TGF-β-induced SMC differentiation, as indicated by altered cell morphology and expression of multiple SMC markers, including smooth muscle α-actin (αSMA), calponin, and smooth muscle 22α (SM22α). BC1 appeared to block SMAD3 activity and inhibit SMC marker gene transcription. Mechanistically, BC1 bound to SMAD3 via RNA SMAD-binding elements (rSBEs) and thus impeded TGF-β-induced SMAD3 translocation to the nucleus. This prevented SMAD3 from binding to SBEs in SMC marker gene promoters, an essential event in SMC marker transcription. In vivo , BC1 overexpression in mouse embryos impaired vascular SMC differentiation, leading to structural defects in the artery wall, such as random breaks in the elastic lamina, abnormal collagen deposition on SM fibers, and disorganized extracellular matrix proteins in the media of the neonatal aorta. Our results suggest that BC1 is a suppressor of SMC differentiation during vascular development. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

α2 Integrin, extracellular matrix metalloproteinase inducer, and matrix metalloproteinase-3 act sequentially to induce differentiation of mouse embryonic stem cells into odontoblast-like cells

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

Ozeki, Nobuaki; Kawai, Rie; Hase, Naoko

We previously reported that interleukin 1β acts via matrix metalloproteinase (MMP)-3 to regulate cell proliferation and suppress apoptosis in α2 integrin-positive odontoblast-like cells differentiated from mouse embryonic stem (ES) cells. Here we characterize the signal cascade underpinning odontoblastic differentiation in mouse ES cells. The expression of α2 integrin, extracellular matrix metalloproteinase inducer (Emmprin), and MMP-3 mRNA and protein were all potently increased during odontoblastic differentiation. Small interfering RNA (siRNA) disruption of the expression of these effectors potently suppressed the expression of the odontoblastic biomarkers dentin sialophosphoprotein, dentin matrix protein-1 and alkaline phosphatase, and blocked odontoblast calcification. Our siRNA, western blotmore » and blocking antibody analyses revealed a unique sequential cascade involving α2 integrin, Emmprin and MMP-3 that drives ES cell differentiation into odontoblasts. This cascade requires the interaction between α2 integrin and Emmprin and is potentiated by exogenous MMP-3. Finally, although odontoblast-like cells potently express α2, α6, αV, β1, and β3, integrins, we confirmed that β1 integrin acts as the trigger for ES cell differentiation, apparently in complex with α2 integrin. These results demonstrate a unique and unanticipated role for an α2 integrin-, Emmprin-, and MMP-3-mediated signaling cascade in driving mouse ES cell differentiation into odontoblast-like cells. - Highlights: • Odontoblast differentiation requires activation of α2 integrin, Emmprin and MMP-3. • α2 integrin, Emmprin and MMP-3 form a sequential signaling cascade. • β1 integrin acts a specific trigger for odontoblast differentiation. • The role of these effectors is highly novel and unanticipated.« less

The inhibition of macrophage foam cell formation by tetrahydroxystilbene glucoside is driven by suppressing vimentin cytoskeleton.

PubMed

Yao, Wenjuan; Huang, Lei; Sun, Qinju; Yang, Lifeng; Tang, Lian; Meng, Guoliang; Xu, Xiaole; Zhang, Wei

2016-10-01

Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Differential permeability of the blood-testis barrier during reinitiation of spermatogenesis in adult male rats.

PubMed

Haverfield, Jenna T; Meachem, Sarah J; Nicholls, Peter K; Rainczuk, Katarzyna E; Simpson, Evan R; Stanton, Peter G

2014-03-01

The blood-testis barrier (BTB) sequesters meiotic spermatocytes and differentiating spermatids away from the vascular environment. We aimed to assess whether meiosis and postmeiotic differentiation could occur when the BTB is permeable. Using a model of meiotic suppression and reinitiation, BTB function was assessed using permeability tracers of small, medium, and large (0.6-, 70-, and 150-kDa) sizes to emulate blood- and lymphatic-borne factors that could cross the BTB. Adult rats (n = 9/group) received the GnRH antagonist acyline (10 wk) to suppress gonadotropins, followed by testosterone (24cm Silastic implant), for 2, 4, 7, 10, 15, and 35 days. In acyline-suppressed testes, all tracers permeated the seminiferous epithelium. As spermatocytes up to diplotene stage XIII reappeared, both the 0.6- and 70-kDa tracers, but not 150 kDa, permeated around these cells. Intriguingly, the 0.6- and 70-kDa tracers were excluded from pachytene spermatocytes at stages VII and VIII but not in subsequent stages. The BTB became progressively impermeable to the 0.6- and 70-kDa tracers as stages IV-VII round spermatids reappeared in the epithelium. This coincided with the appearance of the tight junction protein, claudin-12, in Sertoli cells and at the BTB. We conclude that meiosis can occur when the BTB is permeable to factors up to 70 kDa during the reinitiation of spermatogenesis. Moreover, BTB closure corresponds with the presence of particular pachytene spermatocytes and round spermatids. This research has implications for understanding the effects of BTB dynamics in normal spermatogenesis and also potentially in states where spermatogenesis is suppressed, such as male hormonal contraception or infertility.

Anti-atherogenic activity of wild grape (Vitis thunbergii) extract antagonizing smooth muscle cell proliferation and migration promoted by neighboring macrophages.

PubMed

Kang, Sang-Wook; Kim, Min Soo; Kim, Hyun-Sung; Lee, Yong-Jin; Kang, Young-Hee

2012-06-01

The proliferation and migration of vascular smooth muscle cells (SMCs) play critical roles in intimal thickening and neointimal hyperplasia in early-phase atherosclerosis. This study tested whether wild grape extract (WGE) suppressed the proliferation and migration of human aortic SMCs induced by neighboring macrophages. Cellular expression of fibrogenic connective tissue growth factor (CTGF) and secretion of collagen IV and matrix metalloproteinase (MMP)-2 were determined in SMCs exposed to THP-1-differentiated macrophage-conditioned media. Proliferation was enhanced in SMCs exposed to macrophage-conditioned media collected during the early stage of differentiation, which was attenuated by treatment with ≥ 10 µg/ml WGE. Increased secretion of CTGF and collagen IV macrophage-conditioned media was suppressed in WGE-supplemented SMCs. TGF-β1-promoted production of CTGF and collagen IV was suppressed by blocking TGF-β receptors of R1 and R2 in SMCs. WGE repressed macrophage-conditioned media-upregulated MMP-2 secretion, indicating that WGE had an ability to encumber plaque rupture within atherosclerotic lesions. In addition, ≥ 1 µg/ml WGE ameliorated the migration of SMCs promoted by neighboring macrophages. These results demonstrate that WGE retarded neointimal hyperplasia and thickening within atherosclerotic plaques largely comprising of macrophages and SMCs. Therefore, WGE may be developed as an anti-proliferative and anti-migratory agent targeting SMCs in the proximity of newly differentiated and resident macrophages.

Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

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

Yu, Mingxiang, E-mail: yu.mingxiang@zs-hospital.sh.cn; Chen, Xianying; Lv, Chaoyang

Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with bothmore » bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases.« less

Adenosine A(2B) receptor antagonist PSB603 suppresses tumor growth and metastasis by inhibiting induction of regulatory T cells.

PubMed

Kaji, Wakako; Tanaka, Satomi; Tsukimoto, Mitsutoshi; Kojima, Shuji

2014-04-01

Regulatory T cells (Treg) play a role in suppression of immune response, including anti-tumor immunity. We have recently reported that treatment of naïve CD4 T cells with adenosine A(2B) receptor antagonist PSB603 under Treg-skewing conditions inhibits expression of Foxp3, a marker of differentiation to Treg, without blocking IL-2 production or CD25 expression, which are activation markers, in CD4 T cells. We hypothesized that PSB603 suppresses cancer growth and metastasis by inhibiting induction of Treg, thereby facilitating anti-tumor immunity. In this study, we first examined the effect of PSB603 on tumor growth in B16 melanoma-bearing C57BL/6 mice. Administration of PSB603 significantly suppressed the increase of tumor volume as well as the increase of Treg population in these mice. The populations of CD4 and CD8 T cells were higher and splenic lymphocyte-mediated cytotoxicity towards B16 melanoma was significantly increased in PSB603-treated mice. We confirmed that PSB603 did not reduce the viability of B16 melanoma cells in vitro. Moreover, we also examined the effect of PSB603 on tumor metastasis in pulmonary metastasis model mice intravenously injected with B16 melanoma cells. The metastasis was also suppressed in PSB603-treated mice, in which the population of Treg was significantly lower. Overall, our results suggest that A(2B) receptor antagonist PSB603 enhances anti-tumor immunity by inhibiting differentiation to Treg, resulting in a delay of tumor growth and a suppression of metastasis.

Differential Effects of Small Molecule WNT Agonists on the Multilineage Differentiation Capacity of Human Mesenchymal Stem Cells.

PubMed

Narcisi, Roberto; Arikan, Ozan H; Lehmann, Johannes; Ten Berge, Derk; van Osch, Gerjo J V M

2016-11-01

Human bone marrow-derived mesenchymal stem cells (MSCs) are promising candidates for cell-based therapies, but loss of expansion and differentiation potential in vitro limits their applicability. Recently we showed that WNT3A protein promoted MSC proliferation and enhanced their chondrogenic potential, while simultaneously suppressing the propensity of the cartilage to undergo hypertrophic maturation. Since WNT3A protein is costly and rapidly loses its activity in culture, we investigated the possibility of replacing it with cheaper commercially available WNT agonists, specifically lithium chloride (LiCl), CHIR99021 (CHIR), SKL2001, and AMBMP. Of these, we found that only CHIR and LiCl stimulated MSC proliferation. Moreover, CHIR enhanced the chondrogenic capacity of MSCs, whereas LiCl predominantly increased the osteo- and adipogenic capacity. The different WNT agonists also differentially impacted the surface marker profile of the MSCs, possibly explaining the observed differences. Moreover, CHIR suppressed the hypertrophic propensity of the MSC-derived cartilage after in vivo implantation to an extent approaching that of WNT3A protein. These results indicate that CHIR may be a promising alternative for WNT3A protein for certain applications of human bone marrow-derived MSCs.

Fisetin induces Sirt1 expression while inhibiting early adipogenesis in 3T3-L1 cells.

PubMed

Kim, Sang Chon; Kim, Yoo Hoon; Son, Sung Wook; Moon, Eun-Yi; Pyo, Suhkneung; Um, Sung Hee

2015-11-27

Fisetin (3,7,3',4'-tetrahydroxyflavone) is a naturally found flavonol in many fruits and vegetables and is known to have anti-aging, anti-cancer and anti-viral effects. However, the effects of fisetin on early adipocyte differentiation and the epigenetic regulator controlling adipogenic transcription factors remain unclear. Here, we show that fisetin inhibits lipid accumulation and suppresses the expression of PPARγ in 3T3-L1 cells. Fisetin suppressed early stages of preadipocyte differentiation, and induced expression of Sirt1. Depletion of Sirt1 abolished the inhibitory effects of fisetin on intracellular lipid accumulation and on PPARγ expression. Mechanistically, fisetin facilitated Sirt1-mediated deacetylation of PPARγ and FoxO1, and enhanced the association of Sirt1 with the PPARγ promoter, leading to suppression of PPARγ transcriptional activity, thereby repressing adipogenesis. Lowering Sirt1 levels reversed the effects of fisetin on deacetylation of PPARγ and increased PPARγ transactivation. Collectively, our results suggest the effects of fisetin in increasing Sirt1 expression and in epigenetic control of early adipogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Differential Sensitivity of Target Genes to Translational Repression by miR-17~92

PubMed Central

Jin, Hyun Yong; Oda, Hiroyo; Chen, Pengda; Kang, Seung Goo; Valentine, Elizabeth; Liao, Lujian; Zhang, Yaoyang; Gonzalez-Martin, Alicia; Shepherd, Jovan; Head, Steven R.; Kim, Pyeung-Hyeun; Fu, Guo; Liu, Wen-Hsien; Han, Jiahuai

2017-01-01

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. PMID:28241004

Responses of plant seedlings to hypergravity: cellular and molecular aspects

NASA Astrophysics Data System (ADS)

Hoson, T.; Yoshioka, R.; Soga, K.; Wakabayashi, K.; Takeba, G.

Hypergravity produced by centrifugation has been used to analyze the responses of plant seedlings to gravity stimulus. Elongation growth of stem organs is suppressed by hypergravity, which can be recognized as a way for plants to resist gravitational force. The mechanisms inducing growth suppression under hypergravity conditions were analyzed at cellular and molecular levels. When growth was suppressed by hypergravity, a decrease in the cell wall extensibility was brought about in various plants. Hypergravity also induced a cell wall thickening and an increase in the molecular mass of the certain hemicellulosic polysaccharides. Both a decrease in the activities hydrolyzing such polysaccharides and an increase in the apoplast pH were involved in such changes in the cell wall constituents. Thus, the cell wall metabolism is greatly modified under hypergravity conditions, which causes a decrease in the cell wall extensibility, thereby inhibiting elongation growth in stem organs. On the other hand, to identify genes involved in hypergravity-induced growth suppression, changes in gene expression by hypergravity treatment were analyzed in Arabidopsis hypocotyls by differential display method. Sixty-two genes were expressed differentially: expression levels of 39 genes increased, whereas those of 23 genes decreased under hypergravity conditions. The expression of these genes was further analyzed using RT-PCR. One of genes upregulated by hypergravity encoded hydroxymethylglutaryl-CoA reductase (HMGR), which catalyzes a reaction producing mevalonic acid, a key precursor of hormones such as gibberellic acid and abscisic acid. The expression of HMGR gene increased within several hours after hypergravity treatment. Also, compactin, an inhibitor of HMGR activity, prevented hypergravity-induced growth suppression, suggesting that HMGR is involved in suppression of Arabidopsis hypocotyl growth by hypergravity. In addition, hypergravity increased the expression levels of CCR1 and ERD15, which were shown to take part in the signaling pathway of environmental stimuli such as temperature and water. These cellular and molecular changes appear to be involved in a series of events leading to growth suppression of stem organs under hypergravity conditions.

Different effects on bone strength and cell differentiation in pre pubertal caloric restriction versus hypothalamic suppression✩,✩✩

PubMed Central

Joshi, R.N.; Safadi, F.F.; Barbe, M.F.; Carpio-Cano, Fe Del; Popoff, S.N.; Yingling, V.R.

2013-01-01

Hypothalamic amenorrhea and energy restriction during puberty affect peak bone mass accrual. One hypothesis suggests energy restriction alters hypothalamic function resulting in suppressed estradiol levels leading to bone loss. However, both positive and negative results have been reported regarding energy restriction and bone strength. Therefore, the purpose of this study was to investigate energy restriction and hypothalamic suppression during pubertal onset on bone mechanical strength and the osteogenic capacity of bone marrow-derived cells in two models: female rats treated with gonadotropin releasing hormone antagonists (GnRH-a) or 30% energy restriction. At 23 days of age, female Sprague Dawley rats were assigned to three groups: control group (C, n=10), GnRH-a group (n=10), and Energy Restriction (ER, n=12) group. GnRH-a animals received daily injections for 27 days. The animals in the ER group received 70% of the control animals’ intake. After sacrifice (50 days of age), body weight, uterine and muscle weights were measured. Bone marrow-derived stromal cells were cultured and assayed for proliferation and differentiation into osteoblasts. Outcome measures included bone strength, bone histomorphometry and architecture, serum IGF-1 and osteocalcin. GnRH-a suppressed uterine weight, decreased osteoblast proliferation, bone strength, trabecular bone volume and architecture compared to control. Elevated serum IGF-1 and osteocalcin levels and body weight were found. The ER model had an increase in osteoblast proliferation compared to the GnRH-a group, similar bone strength relative to body weight and increased trabecular bone volume in the lumbar spine compared to control. The ER animals were smaller but had developed bone strength sufficient for their size. In contrast, suppressed estradiol via hypothalamic suppression resulted in bone strength deficits and trabecular bone volume loss. In summary, our results support the hypothesis that during periods of nutritional stress the increased vertebral bone volume may be an adaptive mechanism to store mineral which differs from suppressed estradiol resulting from hypothalamic suppression. PMID:21807131

Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells

PubMed Central

Watt, James; Schlezinger, Jennifer J.

2015-01-01

Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of toxicants is likely, albeit at low doses, the fact that multiple toxicants are capable of suppressing bone formation supports the hypothesis that environmental PPARγ ligands represent an emerging threat to human bone health. PMID:25777084

Persimmon tannin represses 3T3-L1 preadipocyte differentiation via up-regulating expression of miR-27 and down-regulating expression of peroxisome proliferator-activated receptor-γ in the early phase of adipogenesis.

PubMed

Zou, Bo; Ge, Zhenzhen; Zhu, Wei; Xu, Ze; Li, Chunmei

2015-12-01

Currently, obesity has become a worldwide health problem. Adipocyte differentiation is closely associated with the onset of obesity. Our previous studies suggested that persimmon tannin might be a potent anti-adipogenic dietary bioactive compound. However, the mechanism of persimmon tannin on adipocyte differentiation is still unknown. The purpose of this study was to investigate the effect of persimmon tannin on adipogenic differentiation in 3T3-L1 preadipocytes and the underlying mechanisms. Adipogenic differentiation was induced by cocktail in the presence or absence of persimmon tannin. Intracellular lipid accumulation was determined by Oil red O staining and enzymatic colorimetric methods. Gene expression and protein levels were measured by real time RT-PCR and Western blot. Persimmon tannin inhibited intracellular lipid accumulation markedly, and the inhibitory effect was largely limited to the early stage of adipocyte differentiation. Persimmon tannin suppressed the expression of C/EBPα and peroxisome proliferator-activated receptor-γ (PPARγ), significantly. Furthermore, genes related to lipogenesis, such as sterol regulatory element-binding protein 1, were down-regulated by persimmon tannin. In addition, adipocyte fatty acid binding protein (aP2), which is a target gene of PPARγ, was suppressed by persimmon tannin notably. Correspondingly, the expression of miR-27a and miR-27b were up-regulated by persimmon tannin from Day 2 to Day 8 significantly. Persimmon tannin inhibited adipocyte differentiation through regulation of PPARγ, C/EBPα and miR-27 in early stage of adipogenesis.

A HIF-1alpha-related gene involved in cell protection from hypoxia by suppression of mitochondrial function.

PubMed

Kakinuma, Yoshihiko; Katare, Rajesh G; Arikawa, Mikihiko; Muramoto, Kazuyo; Yamasaki, Fumiyasu; Sato, Takayuki

2008-01-23

Recently, we reported that acetylcholine-induced hypoxia-inducible factor-1alpha protects cardiomyocytes from hypoxia; however, the downstream factors reducing hypoxic stress are unknown. We identified apoptosis inhibitor (AI) gene as being differentially expressed between von Hippel Lindau (VHL) protein-positive cells with high levels of GRP78 expression and VHL-negative cells with lower GRP levels, using cDNA subtraction. AI decreased GRP78 level, suppressed mitochondrial function, reduced oxygen consumption and, ultimately, suppressed hypoxia-induced apoptosis. By contrast, knockdown of the AI gene increased mitochondrial function. Hypoxic cardiomyocytes and ischemic myocardium showed increased AI mRNA expression. These findings suggest that AI is involved in suppressing mitochondrial function, thereby leading to cellular stress eradication and consequently to protection during hypoxia.

Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function.

PubMed

Nam, Sorim; Kang, Kyeongah; Cha, Jae Seon; Kim, Jung Woo; Lee, Hee Gu; Kim, Yonghwan; Yang, Young; Lee, Myeong-Sok; Lim, Jong-Seok

2016-12-01

Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6G high Ly6C low Gr1 high CD11b + ) and MO-MDSCs (Ly6G - Ly6C high Gr-1 int CD11b + ) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. However, the roles of IRF4 in myeloid cell differentiation are unclear. In this study, we found that IRF4 expression was remarkably suppressed during the development of MDSCs in the tumor microenvironment. Both the mRNA and protein levels of IRF4 in MDSCs were gradually reduced, depending on the development of tumors in the 4T1 model. siRNA-mediated knockdown of IRF4 in bone marrow cells promoted the differentiation of PMN-MDSCs. Similarly, IRF4 inhibition in bone marrow cells using simvastatin, which has been known to inhibit IRF4 expression, increased PMN-MDSC numbers. In contrast, IRF4 overexpression in bone marrow cells inhibited the total numbers of MDSCs, especially PMN-MDSCs. Notably, treatment with IL-4, an upstream regulator of IRF4, induced IRF4 expression in the bone marrow cells, and consequently, IL-4-induced IRF4 expression resulted in a decrease in PMN-MDSC numbers. Finally, we confirmed that IRF4 expression in MDSCs can modulate their activity to inhibit T cell proliferation through IL-10 production and ROS generation, and myeloid-specific deletion of IRF4 leads to the increase of MDSC differentiation. Our present findings indicate that IRF4 reduction induced by tumor formation can increase the number of MDSCs, and increases in the IRF4 expression in MDSCs may infringe on the immune-suppressive function of MDSCs. © Society for Leukocyte Biology.

Evaluation of a combination of sodium hypochlorite and polyhexamethylene biguanide as an egg wash for red-eared slider turtles (Trachemys scripta elegans) to suppress or eliminate Salmonella organisms on egg surfaces and in hatchlings.

PubMed

Mitchell, Mark A; Adamson, Trinka W; Singleton, Charles B; Roundtree, Marlana K; Bauer, Rudy W; Acierno, Mark J

2007-02-01

To evaluate a combination of 2 nonantibiotic microbicide compounds, sodium hypochlorite (NaOCl) and polyhexamethylene biguanide (PHMB), as a treatment to suppress or eliminate Salmonella spp from red-eared slider (RES) turtle (Trachemys scripta elegans) eggs and hatchlings. 2,738 eggs from 8 turtle farms in Louisiana. Eggs were randomly sorted into 3 or, when sufficient eggs were available, 4 treatment groups as follows: control, pressure-differential egg treatment with NaOCl and gentamicin, NaOCl and PHMB bath treatment, and pressure-differential egg treatment with NaOCl and PHMB. Bacterial cultures were performed from specimens of eggs and hatchlings and evaluated for Salmonella spp. RES turtle eggs treated with NaOCl and PHMB as a bath (odds ratio [OR], 0.2 [95% confidence interval (CI), 0.1 to 0.3]) or as a pressure-differential dip (OR, 0.01 [95% CI, 0.001 to 0.07]) or with gentamicin as a pressure-differential dip (OR, 0.1 [95% CI, 0.06 to 0.2]) were significantly less likely to have Salmonella-positive culture results than control-group eggs. Concern over reptile-associated salmonellosis in children in the United States is so great that federal regulations prohibit the sale of turtles that are < 10.2 cm in length. Currently, turtle farms treat eggs with gentamicin solution. Although this has reduced Salmonella shedding, it has also resulted in antimicrobial resistance. Results of our study indicate that a combination of NaOCl and PHMB may be used to suppress or eliminate Salmonella spp on RES turtle eggs and in hatchlings.

The proliferation and differentiation of primary pig preadipocytes is suppressed when cultures are incubated at 37°Celsius compared to euthermic conditions in pigs

PubMed Central

Bohan, Amy E; Purvis, Katelyn N; Bartosh, Julia L; Brandebourg, Terry D

2014-01-01

Given similarities in metabolic parameters and cardiovascular physiology, the pig is well positioned as a biomedical model for metabolic disease and obesity in humans. Better understanding molecular mechanisms governing porcine adipocyte hyperplasia may provide insight into the regulation of adipose tissue development that is useful both when considering the pig as a commodity and when extrapolating porcine data to human disease. Primary cultures of pig stromal-vascular cells have served as a useful tool for investigating factors that regulate preadipocyte proliferation and differentiation. However, such cultures have generally been maintained at 37°C in vitro despite euthermia being 39°C in pigs. To address potential concerns about the physiological relevance of culturing primary pig preadipocytes under what would be hypothermic conditions in vivo, the objective of this study was to investigate the effect of culture temperature on the proliferation and differentiation of pig preadipocytes in primary culture. Culturing primary preadipocytes at 37 rather than 39°C decreases their proliferation rates based upon cleavage of the tetrazolium salt, MTT (P < 0.001), reduction of resazurin (P < 0.001), and daily cell counts (P < 0.001). Likewise, culturing primary porcine preadipocytes at 37°C suppressed their adipogenic potential based upon monitoring adipogenesis morphologically, biochemically, and via the expression of mRNA encoding adipogenic marker genes. Collectively, these data indicate the proliferation and differentiation of primary pig preadipocytes is suppressed when cultures are incubated at 37°C compared to normal body temperature of pigs. This may confound investigation of factors that impact adipocyte hyperplasia in the pig. PMID:26317057

Decursin inhibits vasculogenesis in early tumor progression by suppression of endothelial progenitor cell differentiation and function.

PubMed

Jung, Seok Yun; Choi, Jin Hwa; Kwon, Sang-Mo; Masuda, Haruchika; Asahara, Takayuki; Lee, You-Mie

2012-05-01

Endothelial progenitor cells (EPCs) contribute to the tumor vasculature during tumor progression. Decursin isolated from the herb Angelica gigas is known to possess potent anti-inflammatory activities. Recently, we reported that decursin is a novel candidate for an angiogenesis inhibitor [Jung et al., 2009]. In this study, we investigated whether decursin regulates EPC differentiation and function to inhibit tumor vasculogenesis. We isolated AC133+ cells from human cord blood and decursin significantly decreased the number of EPC colony forming units of human cord blood-derived AC133+ cells that produce functional EPC progenies. Decursin dose-dependently decreased the cell number of EPC committing cells as demonstrated by EPC expansion studies. Decursin inhibited EPC differentiation from progenitor cells into spindle-shaped EPC colonies. Additionally, decursin inhibited proliferation and migration of early EPCs isolated from mouse bone marrow. Furthermore, decursin suppressed expression of angiopoietin-2, angiopoietin receptor Tie-2, Flk-1 (vascular endothelial growth factor receptor-2), and endothelial nitric oxide synthase in mouse BM derived EPCs in a dose-dependent manner. Decursin suppressed tube formation ability of EPCs in collaboration with HUVEC. Decursin (4 mg/kg) inhibited tumor-induced mobilization of circulating EPCs (CD34 + /VEGFR-2+ cells) from bone marrow and early incorporation of Dil-Ac-LDL-labeled or green fluorescent protein (GFP)+ EPCs into neovessels of xenograft Lewis lung carcinoma tumors in wild-type- or bone-marrow-transplanted mice. Accordingly, decursin attenuated EPC-derived endothelial cells in neovessels of Lewis lung carcinoma tumor masses grown in mice. Together, decursin likely affects EPC differentiation and function, thereby inhibiting tumor vasculogenesis in early tumorigenesis. Copyright © 2012 Wiley Periodicals, Inc.

Compensatory Cellular Reactions to Nonsteroidal Anti-Inflammatory Drugs on Osteogenic Differentiation in Canine Bone Marrow-Derived Mesenchymal Stem Cells

PubMed Central

OH, Namgil; KIM, Sangho; HOSOYA, Kenji; OKUMURA, Masahiro

2014-01-01

ABSTRACT The suppressive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the bone healing process have remained controversial, since no clinical data have clearly shown the relationship between NSAIDs and bone healing. The aim of this study was to assess the compensatory response of canine bone marrow-derived mesenchymal stem cells (BMSCs) to several classes of NSAIDs, including carprofen, meloxicam, indomethacin and robenacoxib, on osteogenic differentiation. Each of the NSAIDs (10 µM) was administered during 20 days of the osteogenic process with human recombinant IL-1β (1 ng/ml) as an inflammatory stimulator. Gene expression of osteoblast differentiation markers (alkaline phosphatase and osteocalcin), receptors of PGE2 (EP2 and EP4) and enzymes for prostaglandin (PG) E2 synthesis (COX-1, COX-2, cPGES and mPGES-1) was measured by using quantitative reverse transcription-polymerase chain reaction. Protein production levels of alkaline phosphatase, osteocalcin and PGE2 were quantified using an alkaline phosphatase activity assay, osteocalcin immunoassay and PGE2 immunoassay, respectively. Histologic analysis was performed using alkaline phosphatase staining, von Kossa staining and alizarin red staining. Alkaline phosphatase and calcium deposition were suppressed by all NSAIDs. However, osteocalcin production showed no significant suppression by NSAIDs. Gene expression levels of PGE2-related receptors and enzymes were upregulated during continuous treatment with NSAIDs, while certain channels for PGE2 synthesis were utilized differently depending on the kind of NSAIDs. These data suggest that canine BMSCs have a compensatory mechanism to restore PGE2 synthesis, which would be an intrinsic regulator to maintain differentiation of osteoblasts under NSAID treatment. PMID:24419976

Osteoblast-like MC3T3-E1 Cells Prefer Glycolysis for ATP Production but Adipocyte-like 3T3-L1 Cells Prefer Oxidative Phosphorylation.

PubMed

Guntur, Anyonya R; Gerencser, Akos A; Le, Phuong T; DeMambro, Victoria E; Bornstein, Sheila A; Mookerjee, Shona A; Maridas, David E; Clemmons, David E; Brand, Martin D; Rosen, Clifford J

2018-06-01

Mesenchymal stromal cells (MSCs) are early progenitors that can differentiate into osteoblasts, chondrocytes, and adipocytes. We hypothesized that osteoblasts and adipocytes utilize distinct bioenergetic pathways during MSC differentiation. To test this hypothesis, we compared the bioenergetic profiles of preosteoblast MC3T3-E1 cells and calvarial osteoblasts with preadipocyte 3T3L1 cells, before and after differentiation. Differentiated MC3T3-E1 osteoblasts met adenosine triphosphate (ATP) demand mainly by glycolysis with minimal reserve glycolytic capacity, whereas nondifferentiated cells generated ATP through oxidative phosphorylation. A marked Crabtree effect (acute suppression of respiration by addition of glucose, observed in both MC3T3-E1 and calvarial osteoblasts) and smaller mitochondrial membrane potential in the differentiated osteoblasts, particularly those incubated at high glucose concentrations, indicated a suppression of oxidative phosphorylation compared with nondifferentiated osteoblasts. In contrast, both nondifferentiated and differentiated 3T3-L1 adipocytes met ATP demand primarily by oxidative phosphorylation despite a large unused reserve glycolytic capacity. In sum, we show that nondifferentiated precursor cells prefer to use oxidative phosphorylation to generate ATP; when they differentiate to osteoblasts, they gain a strong preference for glycolytic ATP generation, but when they differentiate to adipocytes, they retain the strong preference for oxidative phosphorylation. Unique metabolic programming in mesenchymal progenitor cells may influence cell fate and ultimately determine the degree of bone formation and/or the development of marrow adiposity. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research.

6-Gingerol Suppresses Adipocyte-Derived Mediators of Inflammation In Vitro and in High-Fat Diet-Induced Obese Zebra Fish.

PubMed

Choi, Jia; Kim, Kui-Jin; Kim, Byung-Hak; Koh, Eun-Jeong; Seo, Min-Jung; Lee, Boo-Yong

2017-02-01

The present study was performed to investigate the molecular mechanism of 6-gingerol on adipocyte-mediated systemic inflammation in vitro and in high-fat diet-induced obese zebra fish. 6-Gingerol decreased adipogenesis due to the suppression of adipocyte differentiation markers, including peroxisome proliferator-activated receptor gamma, CCAATT enhancer binding protein α , and adipocyte protein 2, and triglyceride synthesis enzymes, including sterol regulatory element-binding protein-1, fatty acid synthase, lysophosphatidic acid acyltransferase, and acyl-coA : diacylglycerol acyltransferase 1, in 3T3-L1. A coculture insert system using 3T3-L1 with RAW 264.7 (coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages) revealed that 6-gingerol increased anti-inflammatory cytokine interleukin-10. The expression of TNF α , monocyte chemotactic protein-1, interleukin-1 β , and interleukin-6 were decreased in the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages treated with 6-gingerol. Moreover, the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages treated with 6-gingerol inhibited the protein expression of TNF α and monocyte chemotactic protein-1 in RAW 264.7. 6-Gingerol decreased c-JUN N-terminal kinase and I kappa B kinase beta and its downstream target AP-1 expression in the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages. Furthermore, 6-gingerol decreased the expression of inducible nitric oxide synthase stimulated by the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages in RAW 264.7 and attenuated nitric oxide production in diet-induced obese zebra fish. Our results suggest that 6-gingerol suppresses inflammation through the regulation of the c-JUN N-terminal kinase-I kappa B kinase beta and its downstream targets. Georg Thieme Verlag KG Stuttgart · New York.

Transient upregulation of CBFA1 in response to bone morphogenetic protein-2 and transforming growth factor beta1 in C2C12 myogenic cells coincides with suppression of the myogenic phenotype but is not sufficient for osteoblast differentiation.

PubMed

Lee, M H; Javed, A; Kim, H J; Shin, H I; Gutierrez, S; Choi, J Y; Rosen, V; Stein, J L; van Wijnen, A J; Stein, G S; Lian, J B; Ryoo, H M

1999-04-01

The bone morphogenetic protein (BMP)-2 is a potent osteoinductive signal, inducing bone formation in vivo and osteoblast differentiation from non-osseous cells in vitro. The runt domain-related protein Cbfa1/PEBP2alphaA/AML-3 is a critical component of bone formation in vivo and transcriptional regulator of osteoblast differentiation. To investigate the relationship between the extracellular BMP-2 signal, Cbfa1, and osteogenesis, we examined expression of Cbfa1 and osteoblastic genes during the BMP-2 induced osteogenic transdifferentiation of the myoblastic cell line C2C12. BMP-2 treatment completely blocked myotube formation and transiently induced expression of Cbfa1 and the bone-related homeodomain protein Msx-2 concomitant with loss of the myoblast phenotype. While induction of collagen type I and alkaline phosphatase (AP) expression coincided with Cbfa1 expression, Cbfa1 mRNA was strikingly downregulated at the onset of expression of osteopontin (OPN) and osteocalcin (OCN) genes, reflecting the mature osteoblast phenotype. TGF-beta1 treatment effectively suppressed myogenesis and induced Cbfa1 expression but was insufficient to support osteoblast differentiation reflected by the absence of ALP, OPN, and OCN. We addressed whether induction of Cbfa1 in response to BMP-2 results in the transcriptional activation of the OC promoter which contains three enhancer Cbfa1 elements. Transfection studies show BMP-2 suppresses OC promoter activity in C2C12, but not in osteoblastic ROS 17/2.8 cells. Maximal suppression of OC promoter activity in response to BMP-2 requires sequences in the proximal promoter (up to nt -365) and may occur independent of the three Cbfa sites. Taken together, our results demonstrate a dissociation of Cbfa1 expression from development of the osteoblast phenotype. Our findings suggest that Cbfal may function transiently to divert a committed myoblast to a potentially osteogenic cell. However, other factors induced by BMP-2 appear to be necessary for complete expression of the osteoblast phenotype.

RORγt antagonist suppresses M3 muscarinic acetylcholine receptor-induced Sjögren's syndrome-like sialadenitis.

PubMed

Tahara, M; Tsuboi, H; Segawa, S; Asashima, H; Iizuka-Koga, M; Hirota, T; Takahashi, H; Kondo, Y; Matsui, M; Matsumoto, I; Sumida, T

2017-02-01

We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3 + T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R -/- ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1 -/- ) mice (M3R -/- →Rag-1 -/- ) with MIS. Immunized M3R -/- mice (pretransfer treatment) and M3R -/- →Rag-1 -/- mice (post-transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide-stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme-linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4 + T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)-γ and interleukin (IL)-17 production significantly compared with phosphate-buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4 + T cells rather than CD11c + cells. Post-transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN-γ and IL-17 production (P < 0·05). In vitro, A213 suppressed IFN-γ and IL-17 production from M3R-stimulated splenocytes and CD4 + T cells of immunized M3R -/- mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL-17 production from Th17 differentiated CD4 + T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS-like sialadenitis through suppression of IL-17 and IFN-γ production by M3R-specific T cells. © 2016 British Society for Immunology.

PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.

PubMed

Inagaki, Yuichiro; Hayakawa, Fumihiko; Hirano, Daiki; Kojima, Yuki; Morishita, Takanobu; Yasuda, Takahiko; Naoe, Tomoki; Kiyoi, Hitoshi

2016-06-24

Plasma cell differentiation is initiated by antigen stimulation of the B cell receptor (BCR) and is regulated by BLIMP1. Prior to the stimulation of BCR, BLIMP1 is suppressed by PAX5, which is a key transcriptional repressor that maintains B cell identity. The upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed after the BCR stimulation. These events are considered to trigger plasma cell differentiation; however, the mechanisms responsible currently remain unclear. We herein demonstrated that the BCR signaling component, SYK, caused PAX5 tyrosine phosphorylation in vitro and in cells. Transcriptional repression on the BLIMP1 promoter by PAX5 was attenuated by this phosphorylation. The BCR stimulation induced the phosphorylation of SYK, tyrosine phosphorylation of PAX5, and up-regulation of BLIMP1 mRNA expression in B cells. The tyrosine phosphorylation of PAX5 co-operatively functioned with PAX5 serine phosphorylation by ERK1/2, which was our previous findings, to cancel the PAX5-dependent repression of BLIMP1. This co-operation may be a trigger for plasma cell differentiation. These results imply that PAX5 phosphorylation by a BCR signal is the initial event in plasma cell differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

One- and two-dimensional antenna arrays for microwave wireless power transfer (MWPT) systems and dual-antenna transceivers

NASA Astrophysics Data System (ADS)

Lin, Yo-Sheng; Hu, Chun-Hao; Chang, Chi-Ho; Tsao, Ping-Chang

2018-06-01

In this work, we demonstrate novel one-dimensional (1D) and two-dimensional (2D) antenna arrays for both microwave wireless power transfer (MWPT) systems and dual-antenna transceivers. The antenna array can be used as the MWPT receiving antenna of an integrated MWPT and Bluetooth (BLE) communication module (MWPT-BLE module) for smart CNC (computer numerical control) spindle incorporated with the cloud computing system SkyMars. The 2D antenna array has n rows of 1 × m 1D array, and each array is composed of multiple (m) differential feeding antenna elements. Each differential feeding antenna element is a differential feeding structure with a microstrip antenna stripe. The stripe length is shorter than one wavelength to minimise the antenna area and to prevent being excited to a high-order mode. That is, the differential feeding antenna element can suppress the even mode. The mutual coupling between the antenna elements can be suppressed, and the isolation between the receiver and the transmitter can be enhanced. An inclination angle of the main beam aligns with the broadside, and the main beam is further concentrated and shrunk at the elevation direction. Moreover, if more differential feeding antenna elements are used, antenna gain and isolation can be further enhanced. The excellent performance of the proposed antenna arrays indicates that they are suitable for both MWPT systems and dual-antenna transceivers.

Sensitivity of Neural Stem Cell Survival, Differentiation and Neurite Outgrowth within 3D Hydrogels to Environmental Heavy Metals

PubMed Central

Tasneem, Sameera; Farrell, Kurt; Lee, Moo-Yeal; Kothapalli, Chandrasekhar R.

2015-01-01

We investigated the sensitivity of embryonic murine neural stem cells exposed to 10 pM – 10 μM concentrations of three heavy metals (Cd, Hg, Pb), continuously for 14 days within 3D collagen hydrogels. Critical endpoints for neurogenesis such as survival, differentiation and neurite outgrowth were assessed. Results suggest significant compromise in cell viability within the first four days at concentrations ≥ 10 nM, while lower concentrations induced a more delayed effect. Mercury and lead suppressed neural differentiation at as low as 10 pM concentration within 7 days, while all three metals inhibited neural and glial differentiation by day 14. Neurite outgrowth remained unaffected at lower cadmium or mercury concentrations (≤ 100 pM), but was completely repressed beyond day 1 at higher concentrations. Higher metal concentrations (≥ 100 pM) suppressed NSC differentiation to motor or dopaminergic neurons. Cytokines and chemokines released by NSCs, and the sub-cellular mechanisms by which metals induce damage to NSCs have been quantified and correlated to phenotypic data. The observed degree of toxicity in NSC cultures is in the order: lead > mercury > cadmium. Results point to the use of biomimetic 3D culture models to screen the toxic effects of heavy metals during developmental stages, and investigate their underlying mechanistic pathways. PMID:26621541

Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase.

PubMed Central

Whalen, A M; Galasinski, S C; Shapiro, P S; Nahreini, T S; Ahn, N G

1997-01-01

The K562 erythroleukemia cell line was used to study the molecular mechanisms regulating lineage commitment of hematopoietic stem cells. Phorbol esters, which initiate megakaryocyte differentiation in this cell line, caused a rapid increase in extracellular-signal-regulated kinase (ERK), which remained elevated for 2 h and returned to near-basal levels by 24 h. In the absence of extracellular stimuli, ERK could be activated by expression of constitutively active mutants of mitogen-activated protein (MAP) kinase kinase (MKK), resulting in cell adhesion and spreading, increased cell size, inhibition of cell growth, and induction of the platelet-specific integrin alphaIIb beta3, all hallmarks of megakaryocytic differentiation. In contrast, expression of wild-type MKK had little effect. In addition, constitutively active MKK suppressed the expression of an erythroid marker, alpha-globin, indicating the ability to suppress cellular responses necessary for alternative cell lineages. The MKK inhibitor PD98059 blocked MKK/ERK activation and cellular responses to phorbol ester, demonstrating that activation of MKK is necessary and sufficient to induce a differentiation program along the megakaryocyte lineage. Thus, the MAP kinase cascade, which promotes cell growth and proliferation in many cell types, instead inhibits cell proliferation and initiates lineage-specific differentiation in K562 cells, establishing a model system to investigate the mechanisms by which this signal transduction pathway specifies cell fate and developmental processes. PMID:9121442

Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase.

PubMed

Whalen, A M; Galasinski, S C; Shapiro, P S; Nahreini, T S; Ahn, N G

1997-04-01

The K562 erythroleukemia cell line was used to study the molecular mechanisms regulating lineage commitment of hematopoietic stem cells. Phorbol esters, which initiate megakaryocyte differentiation in this cell line, caused a rapid increase in extracellular-signal-regulated kinase (ERK), which remained elevated for 2 h and returned to near-basal levels by 24 h. In the absence of extracellular stimuli, ERK could be activated by expression of constitutively active mutants of mitogen-activated protein (MAP) kinase kinase (MKK), resulting in cell adhesion and spreading, increased cell size, inhibition of cell growth, and induction of the platelet-specific integrin alphaIIb beta3, all hallmarks of megakaryocytic differentiation. In contrast, expression of wild-type MKK had little effect. In addition, constitutively active MKK suppressed the expression of an erythroid marker, alpha-globin, indicating the ability to suppress cellular responses necessary for alternative cell lineages. The MKK inhibitor PD98059 blocked MKK/ERK activation and cellular responses to phorbol ester, demonstrating that activation of MKK is necessary and sufficient to induce a differentiation program along the megakaryocyte lineage. Thus, the MAP kinase cascade, which promotes cell growth and proliferation in many cell types, instead inhibits cell proliferation and initiates lineage-specific differentiation in K562 cells, establishing a model system to investigate the mechanisms by which this signal transduction pathway specifies cell fate and developmental processes.

Effects of Human Mesenchymal Stem Cells Coculture on Calcium-Induced Differentiation of Normal Human Keratinocytes.

PubMed

Sah, Shyam Kishor; Kim, Hae Young; Lee, Ji Hae; Lee, Seong-Wook; Kim, Hyung-Sik; Kim, Yeon-Soo; Kang, Kyung-Sun; Kim, Tae-Yoon

2017-06-01

The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we cocultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes to evaluate their paracrine effect in the presence of high extracellular calcium (Ca 2+ ) concentration. High Ca 2+ environment to keratinocytes can disrupt normal skin barrier function due to abnormal/premature differentiation of keratinocytes. Surprisingly, we found that MSCs suppress both proliferation and differentiation of keratinocytes under a high Ca 2+ environment in transforming growth factors β1 (TGFβ1)-dependent manner. Furthermore, we determined that MSCs can regulate the mitogen-activated protein kinases, phosphatidylinositol 3-kinase/protein kinase B, and protein kinase C pathways in Ca 2+ -induced differentiated keratinocytes. Knockdown of TGFβ1 from MSCs results in decreased suppression of differentiation with significantly increased proliferation of keratinocytes compared with control MSCs. MSCs-derived TGFβ1 further induced growth inhibition of keratinocyte in high extracellular Ca 2+ environment as analyzed by a decrease in DNA synthesis, accumulation of phosphorylated retinoblastoma protein, cdc2, and increased mRNA level of p21, and independent of TGFβ1/SMAD pathway. Taken together, we found that MSCs-derived TGFβ1 is a critical regulator of keratinocyte function, and involves multiple proximal signaling cascades. Stem Cells 2017;35:1592-1602. © 2017 AlphaMed Press.

Effects of extracellular calcium on viability and osteogenic differentiation of bone marrow stromal cells in vitro.

PubMed

Cheng, Shaowen; Wang, Wei; Lin, Zhongqin; Zhou, Ping; Zhang, Xiaolei; Zhang, Wei; Chen, Qingyu; Kou, Dongquan; Ying, Xiaozhou; Shen, Yue; Cheng, Xiaojie; Yu, Ziming; Peng, Lei; Lu, Chuanzhu

2013-09-01

Bone marrow stromal cells (BMSCs) have been extensively used for tissue engineering. However, the effect of Ca(2+) on the viability and osteogenic differentiation of BMSCs has yet to be evaluated. To determine the dose-dependent effect of Ca(2+) on viability and osteogenesis of BMSCs in vitro, BMSCs were cultured in calcium-free DMEM medium supplemented with various concentrations of Ca(2+) (0, 1, 2, 3, 4, and 5 mM) from calcium citrate. Cell viability was analyzed by MTT assay and osteogenic differentiation was evaluated by alkaline phosphatase (ALP) assay, Von Kossa staining, and real-time PCR. Ca(2+) stimulated BMSCs viability in a dose-dependent manner. At slightly higher concentrations (4 and 5 mM) in the culture, Ca(2+) significantly inhibited the activity of ALP on days 7 and 14 (P < 0.01 or P < 0.05), significantly suppressed collagen synthesis (P < 0.01 or P < 0.05), and significantly elevated calcium deposition (P < 0.01) and mRNA levels of osteocalcin (P < 0.01 or P < 0.05) and osteopontin (P < 0.01 or P < 0.05). Therefore, elevated concentrations of extracellular calcium may promote cell viability and late-stage osteogenic differentiation, but may suppress early-stage osteogenic differentiation in BMSCs.

Tangeretin Inhibits IL-12 Expression and NF-κB Activation in Dendritic Cells and Attenuates Colitis in Mice.

PubMed

Eun, Su-Hyeon; Woo, Je-Te; Kim, Dong-Hyun

2017-04-01

In the preliminary study, tangeretin (5,6,7,8,4'-pentamethoxy flavone), a major constituent of the pericarp of Citrus sp., inhibited TNF- α , IL-12, and IL-23 expression and nuclear factor kappa-B activation in lipopolysaccharide-stimulated dendritic cells; however, it did not affect IL-10 expression. Furthermore, tangeretin (5, 10, and 20 µM) suppressed the activation and translocation of nuclear factor kappa-B (p65) into the nuclei in vitro by inhibiting the binding of lipopolysaccharide on dendritic cells. Oral administration of tangeretin (10 and 20 mg/kg) suppressed the inflammatory responses, such as nuclear factor kappa-B and mitogen-activated protein kinase activation and myeloperoxidase activity, in the colon of mice with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Tangeretin increased 2,4,6-trinitrobenzene sulfonic acid-suppressed expression of tight junction proteins occludin, claudin-1, and ZO-1. Tangeretin also inhibited 2,4,6-trinitrobenzene sulfonic acid-induced differentiation of Th1 and Th17 cells as well as the expression of T-bet, ROR γ t, interferon- γ , IL-12, IL-17, and TNF- α . However, tangeretin increased 2,4,6-trinitrobenzene sulfonic acid-suppressed differentiation of regulatory T cells as well as the expression of Foxp3 and IL-10. These results suggest that oral administration of tangeretin may attenuate colitis by suppressing IL-12 and TNF- α expression and nuclear factor kappa-B activation through the inhibition of lipopolysaccharide binding on immune cells such as dendritic cells. Georg Thieme Verlag KG Stuttgart · New York.

Hypergravity-induced changes in gene expression in Arabidopsis hypocotyls

NASA Astrophysics Data System (ADS)

Yoshioka, R.; Soga, K.; Wakabayashi, K.; Takeba, G.; Hoson, T.

2003-05-01

Under hypergravity conditions, the cell wall of stem organs becomes mechanically rigid and elongation growth is suppressed, which can be recognized as the mechanism for plants to resist gravitational force. The changes in gene expression by hypergravity treatment were analyzed in Arabidopsis hypocotyls by the differential display method, for identifying genes involved in hypergravity-induced growth suppression. Sixty-two cDNA clones were expressed differentially between the control and 300 g conditions: the expression levels of 39 clones increased, whereas those of 23 clones decreased under hypergravity conditions. Sequence analysis and database searching revealed that 12 clones, 9 up-regulated and 3 down-regulated, have homology to known proteins. The expression of these genes was further analyzed using RT-PCR. Finally, six genes were confirmed to be up-regulated by hypergravity. One of such genes encoded 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR), which catalyzes a reaction producing mevalonic acid, a key precursor ofterpenoids such as membrane sterols and several types of hormones. The expression of HMGR gene increased within several hours after hypergravity treatment. Also, compactin, an inhibitor of HMGR, prevented hypergravity-induced growth suppression, suggesting that HMGR is involved in suppression of Arabidopsis hypocotyl growth by hypergravity. In addition, hypergravity increased the expression levels of genes encoding CCR1 and ERD15, which were shown to take part in the signaling pathway of environmental stimuli such as temperature and water, and those of the α-tubulin gene. These genes may be involved in a series of cellular events leading to growth suppression of stem organs under hypergravity conditions.

Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development.

PubMed

Wang, C Q; Udupa, K B; Lipschitz, D A

1995-01-01

Interferon-gamma (INF-gamma) has been shown to suppress erythropoiesis and perhaps to contribute to the anemia of chronic disease. In this study we demonstrated that the concentration of INF gamma required to suppress murine burst forming unit-erythroid (BFU-E) growth was significantly less than that required to suppress colony forming unit-erythroid (CFU-E) growth. INF gamma acted at the most primitive step in erythroid progenitor cell differentiation and proliferation, as inhibition was maximal when added at the time of BFU-E culture initiation. Inhibition was progressively less if INF gamma addition was delayed after culture initiation. The effects of INF gamma on BFU-E did not require the presence of interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF alpha), or granulocyte macrophage colony stimulating factor (GM-CSF), as its effects were not neutralized by monoclonal antibodies against IL-1 alpha, TNF alpha, or GM-CSF. This applied whether INF gamma was added to culture with individual antibodies or with a combination of all three antibodies. INF gamma was not required for IL-1 alpha- or TNF alpha-induced suppression of BFU-E, as their effects were not neutralized by a monoclonal anti-INF gamma antibody. In contrast, GM-CSF-induced suppression of BFU-E was negated by the simultaneous addition of anti-INF gamma. We have previously shown that the addition of TNF alpha does not suppress BFU-E growth in cultures from marrow depleted of macrophages. Suppression did occur, however, if a small concentration of INF gamma that does not inhibit and increasing concentration of TNF alpha were added to culture, suggesting a synergistic effect between INF-gamma and TNF alpha. These observations suggest that INF gamma is a potent direct inhibitor of erythroid colony growth in vitro. It exerts its negative regulatory effect primarily on the earliest stages of erythroid progenitor cell differentiation and proliferation, as much higher doses are required to suppress late erythroid cell development. INF gamma is also involved in GM-CSF-induced inhibition of BFU-E colony growth.

Immune Modulation by Coxiella burnetii: Characterization of a Phase 1 Immunosuppressive Complex Differentially Expressed among Strains

DTIC Science & Technology

1988-01-01

components may bear compositional similarities to a Mycobacterium leprae glycolipid, which is capable of inducing suppression of mitogenic responses of...of the phenolic glycolipid of M. leprae (20). Suppressor cell- inducing epitopes have also been demonstrated in the lysozyme 256 WAAG AND WILLIAMS...V., Brennan. P. J., Rada, E., Convit, J., and Bloom, B. R. Lymphocyte suppression in leprosy induced by a unique M. leprae glycolipid. Nature 308:194

Umbilical Cord-derived Mesenchymal Stem Cells Instruct Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF

PubMed Central

Deng, Yinan; Zhang, Yingcai; Ye, Linsen; Zhang, Tong; Cheng, Jintao; Chen, Guihua; Zhang, Qi; Yang, Yang

2016-01-01

Human UC-MSCs are regarded as an attractive alternative to BM-MSCs for clinical applications due to their easy preparation, higher proliferation and lower immunogenicity. However, the mechanisms underlying immune suppression by UC-MSCs are still unclear. We studied the mechanism of inhibition by UC-MSCs during the differentiation of monocytes into DCs and focused on the specific source and the role of the involved cytokines. We found that UC-MSCs suppressed monocyte differentiation into DCs and instructed monocytes towards other cell types, with clear decreases in the expression of co-stimulatory molecules, in the secretion of inflammatory factors and in allostimulatory capacity. IL6, HGF and IL10 might be involved in this process because they were detected at higher levels in a coculture system. UC-MSCs produce IL-6 and HGF, and neutralization of IL-6 and HGF reversed the suppressive effect of UC-MSCs. IL10 was not produced by UC-MSCs but was exclusively produced by monocytes after exposure to UC-MSCs, IL-6 or HGF. In summary, we found that the UC-MSC-mediated inhibitory effect was dependent on IL6 and HGF secreted by UC-MSCs and that this effect induced monocyte-derived cells to produce IL10, which might indirectly strengthen the suppressive effect of UC-MSCs. PMID:27917866

Quantitative EEG patterns of differential in-flight workload

NASA Technical Reports Server (NTRS)

Sterman, M. B.; Mann, C. A.; Kaiser, D. A.

1993-01-01

Four test pilots were instrumented for in-flight EEG recordings using a custom portable recording system. Each flew six, two minute tracking tasks in the Calspan NT-33 experimental trainer at Edwards AFB. With the canopy blacked out, pilots used a HUD display to chase a simulated aircraft through a random flight course. Three configurations of flight controls altered the flight characteristics to achieve low, moderate, and high workload, as determined by normative Cooper-Harper ratings. The test protocol was administered by a command pilot in the back seat. Corresponding EEG and tracking data were compared off-line. Tracking performance was measured as deviation from the target aircraft and combined with control difficulty to achieve an estimate of 'cognitive workload'. Trended patterns of parietal EEG activity at 8-12 Hz were sorted according to this classification. In all cases, high workload produced a significantly greater suppression of 8-12 Hz activity than low workload. Further, a clear differentiation of EEG trend patterns was obtained in 80 percent of the cases. High workload produced a sustained suppression of 8-12 Hz activity, while moderate workload resulted in an initial suppression followed by a gradual increment. Low workload was associated with a modulated pattern lacking any periods of marked or sustained suppression. These findings suggest that quantitative analysis of appropriate EEG measures may provide an objective and reliable in-flight index of cognitive effort that could facilitate workload assessment.

Umbilical Cord-derived Mesenchymal Stem Cells Instruct Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF.

PubMed

Deng, Yinan; Zhang, Yingcai; Ye, Linsen; Zhang, Tong; Cheng, Jintao; Chen, Guihua; Zhang, Qi; Yang, Yang

2016-12-05

Human UC-MSCs are regarded as an attractive alternative to BM-MSCs for clinical applications due to their easy preparation, higher proliferation and lower immunogenicity. However, the mechanisms underlying immune suppression by UC-MSCs are still unclear. We studied the mechanism of inhibition by UC-MSCs during the differentiation of monocytes into DCs and focused on the specific source and the role of the involved cytokines. We found that UC-MSCs suppressed monocyte differentiation into DCs and instructed monocytes towards other cell types, with clear decreases in the expression of co-stimulatory molecules, in the secretion of inflammatory factors and in allostimulatory capacity. IL6, HGF and IL10 might be involved in this process because they were detected at higher levels in a coculture system. UC-MSCs produce IL-6 and HGF, and neutralization of IL-6 and HGF reversed the suppressive effect of UC-MSCs. IL10 was not produced by UC-MSCs but was exclusively produced by monocytes after exposure to UC-MSCs, IL-6 or HGF. In summary, we found that the UC-MSC-mediated inhibitory effect was dependent on IL6 and HGF secreted by UC-MSCs and that this effect induced monocyte-derived cells to produce IL10, which might indirectly strengthen the suppressive effect of UC-MSCs.

Chromatic and achromatic monocular deprivation produce separable changes of eye dominance in adults.

PubMed

Zhou, Jiawei; Reynaud, Alexandre; Kim, Yeon Jin; Mullen, Kathy T; Hess, Robert F

2017-11-29

Temporarily depriving one eye of its input, in whole or in part, results in a transient shift in eye dominance in human adults, with the patched eye becoming stronger and the unpatched eye weaker. However, little is known about the role of colour contrast in these behavioural changes. Here, we first show that the changes in eye dominance and contrast sensitivity induced by monocular eye patching affect colour and achromatic contrast sensitivity equally. We next use dichoptic movies, customized and filtered to stimulate the two eyes differentially. We show that a strong imbalance in achromatic contrast between the eyes, with no colour content, also produces similar, unselective shifts in eye dominance for both colour and achromatic contrast sensitivity. Interestingly, if this achromatic imbalance is paired with similar colour contrast in both eyes, the shift in eye dominance is selective, affecting achromatic but not chromatic contrast sensitivity and revealing a dissociation in eye dominance for colour and achromatic image content. On the other hand, a strong imbalance in chromatic contrast between the eyes, with no achromatic content, produces small, unselective changes in eye dominance, but if paired with similar achromatic contrast in both eyes, no changes occur. We conclude that perceptual changes in eye dominance are strongly driven by interocular imbalances in achromatic contrast, with colour contrast having a significant counter balancing effect. In the short term, eyes can have different dominances for achromatic and chromatic contrast, suggesting separate pathways at the site of these neuroplastic changes. © 2017 The Author(s).

Design and validation of a method for evaluation of interocular interaction.

PubMed

Lai, Xin Jie Angela; Alexander, Jack; Ho, Arthur; Yang, Zhikuan; He, Mingguang; Suttle, Catherine

2012-02-01

To design a simple viewing system allowing dichoptic masking, and to validate this system in adults and children with normal vision. A Trial Frame Apparatus (TFA) was designed to evaluate interocular interaction. This device consists of a trial frame, a 1 mm pinhole in front of the tested eye and a full or partial occluder in front of the non-tested eye. The difference in visual function in one eye between the full- and partial-occlusion conditions was termed the Interaction Index. In experiment 1, low-contrast acuity was measured in six adults using five types of partial occluder. Interaction Index was compared between these five, and the occluder showing the highest Index was used in experiment 2. In experiment 2, low-contrast acuity, contrast sensitivity, and alignment sensitivity were measured in the non-dominant eye of 45 subjects (15 older adults, 15 young adults, and 15 children), using the TFA and an existing well-validated device (shutter goggles) with full and partial occlusion of the dominant eye. These measurements were repeated on 11 subjects of each group using TFA in the partial-occlusion condition only. Repeatability of visual function measurements using TFA was assessed using the Bland-Altman method and agreement between TFA and goggles in terms of visual functions and interactions was assessed using the Bland-Altman method and t-test. In all three subject groups, the TFA showed a high level of repeatability in all visual function measurements. Contrast sensitivity was significantly poorer when measured using TFA than using goggles (p < 0.05). However, Interaction Index of all three visual functions showed acceptable agreement between TFA and goggles (p > 0.05). The TFA may provide an acceptable method for the study of some forms of dichoptic masking in populations where more complex devices (e.g., shutter goggles) cannot be used.

Repeatability, interocular correlation and agreement of quantitative swept-source optical coherence tomography angiography macular metrics in healthy subjects.

PubMed

Fang, Danqi; Tang, Fang Yao; Huang, Haifan; Cheung, Carol Y; Chen, Haoyu

2018-05-29

To investigate the repeatability, interocular correlation and agreement of quantitative swept-source optical coherence tomography angiography (SS-OCTA) metrics in healthy subjects. Thirty-three healthy normal subjects were enrolled. The macula was scanned four times by an SS-OCTA system using the 3 mm×3 mm mode. The superficial capillary map images were analysed using a MATLAB program. A series of parameters were measured: foveal avascular zone (FAZ) area, FAZ perimeter, FAZ circularity, parafoveal vessel density, fractal dimension and vessel diameter index (VDI). The repeatability of four scans was determined by intraclass correlation coefficient (ICC). Then the averaged results were analysed for intereye difference, correlation and agreement using paired t-test, Pearson's correlation coefficient (r), ICC and Bland-Altman plot. The repeatability assessment of the macular metrics exported high ICC values (ranged from 0.853 to 0.996). There is no statistically significant difference in the OCTA metrics between the two eyes. FAZ area (ICC=0.961, r=0.929) and FAZ perimeter (ICC=0.884, r=0.802) showed excellent binocular correlation. Fractal dimension (ICC=0.732, r=0.578) and VDI (ICC=0.707, r=0.547) showed moderate binocular correlation, while parafoveal vessel density had poor binocular correlation. Bland-Altman plots showed the range of agreement was from -0.0763 to 0.0954 mm 2 for FAZ area and from -0.0491 to 0.1136 for parafoveal vessel density. The macular metrics obtained using SS-OCTA showed excellent repeatability in healthy subjects. We showed high intereye correlation in FAZ area and perimeter, moderate correlation in fractal dimension and VDI, while vessel density had poor correlation in normal healthy subjects. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of Ocular Optics on Perceived Visual Direction and Depth

NASA Astrophysics Data System (ADS)

Ye, Ming

Most studies of human retinal image quality have specifically addressed the issues of image contrast, few have examined the problem of image location. However, one of the most impressive properties of human vision involves the location of objects. We are able to identify object location with great accuracy (less than 5 arcsec). The sensitivity we exhibit for image location indicates that any optical errors, such as refractive error, ocular aberrations, pupil decentration, etc., may have noticeable effects on perceived visual direction and distance of objects. The most easily observed effects of these optical factors is a binocular depth illusion called chromostereopsis in which equidistance colored objects appear to lie at the different distances. This dissertation covers a series of theoretical and experimental studies that examined the effects of ocular optics on perceived monocular visual direction and binocular chromostereopsis. Theoretical studies included development of an adequate eye model for predicting chromatic aberration, a major ocular aberration, using geometric optics. Also, a wave optical analysis is used to model the effects of defocus, optical aberrations, Stiles-Crawford effect (SCE) and pupil location on retinal image profiles. Experimental studies used psychophysical methods such as monocular vernier alignment tests, binocular stereoscopic tests, etc. This dissertation concludes: (1) With a decentered large pupil, the SCE reduces defocused image shifts compare to an eye without the SCE. (2) The blurred image location can be predicted by the centroid of the image profile. (3) Chromostereopsis with small pupils can be precisely accounted for by the interocular difference in monocular transverse chromatic aberration. (4) The SCE also plays an important role in the effect of pupil size on chromostereopsis. The reduction of chromostereopsis with large pupils can be accurately predicted by the interocular difference in monocular chromatic diplopia which is also reduced with large pupils. This supports the hypothesis that the effect of pupil size on chromostereopsis is due to monocular mechanisms.

High-power flexible AlGaN/GaN heterostructure field-effect transistors with suppression of negative differential conductance

NASA Astrophysics Data System (ADS)

Oh, Seung Kyu; Cho, Moon Uk; Dallas, James; Jang, Taehoon; Lee, Dong Gyu; Pouladi, Sara; Chen, Jie; Wang, Weijie; Shervin, Shahab; Kim, Hyunsoo; Shin, Seungha; Choi, Sukwon; Kwak, Joon Seop; Ryou, Jae-Hyun

2017-09-01

We investigate thermo-electronic behaviors of flexible AlGaN/GaN heterostructure field-effect transistors (HFETs) for high-power operation of the devices using Raman thermometry, infrared imaging, and current-voltage characteristics. A large negative differential conductance observed in HFETs on polymeric flexible substrates is confirmed to originate from the decreasing mobility of the two-dimensional electron gas channel caused by the self-heating effect. We develop high-power transistors by suppressing the negative differential conductance in the flexible HFETs using chemical lift-off and modified Ti/Au/In metal bonding processes with copper (Cu) tapes for high thermal conductivity and low thermal interfacial resistance in the flexible hybrid structures. Among different flexible HFETs, the ID of the HFETs on Cu with Ni/Au/In structures decreases only by 11.3% with increasing drain bias from the peak current to the current at VDS = 20 V, which is close to that of the HFETs on Si (9.6%), solving the problem of previous flexible AlGaN/GaN transistors.

Rho differentially regulates the Hippo pathway by modulating the interaction between Amot and Nf2 in the blastocyst.

PubMed

Shi, Xianle; Yin, Zixi; Ling, Bin; Wang, Lingling; Liu, Chang; Ruan, Xianhui; Zhang, Weiyu; Chen, Lingyi

2017-11-01

The Hippo pathway modulates the transcriptional activity of Yap to regulate the differentiation of the inner cell mass (ICM) and the trophectoderm (TE) in blastocysts. Yet how Hippo signaling is differentially regulated in ICM and TE cells is poorly understood. Through an inhibitor/activator screen, we have identified Rho as a negative regulator of Hippo in TE cells, and PKA as a positive regulator of Hippo in ICM cells. We further elucidated a novel mechanism by which Rho suppresses Hippo, distinct from the prevailing view that Rho inhibits Hippo signaling through modulating cytoskeleton remodeling and/or cell polarity. Active Rho prevents the phosphorylation of Amot Ser176, thus stabilizing the interaction between Amot and F-actin, and restricting the binding between Amot and Nf2. Moreover, Rho attenuates the interaction between Amot and Nf2 by binding to the coiled-coil domain of Amot. By blocking the association of Nf2 and Amot, Rho suppresses Hippo in TE cells. © 2017. Published by The Company of Biologists Ltd.

The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

PubMed Central

Krah, Nathan M; De La O, Jean-Paul; Swift, Galvin H; Hoang, Chinh Q; Willet, Spencer G; Chen Pan, Fong; Cash, Gabriela M; Bronner, Mary P; Wright, Christopher VE; MacDonald, Raymond J; Murtaugh, L Charles

2015-01-01

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas. DOI: http://dx.doi.org/10.7554/eLife.07125.001 PMID:26151762

Top-down enhancement and suppression of activity in category-selective extrastriate cortex from an act of reflective attention.

PubMed

Johnson, Matthew R; Johnson, Marcia K

2009-12-01

Recent research has demonstrated top-down attentional modulation of activity in extrastriate category-selective visual areas while stimuli are in view (perceptual attention) and after they are removed from view (reflective attention). Perceptual attention is capable of both enhancing and suppressing activity in category-selective areas relative to a passive viewing baseline. In this study, we demonstrate that a brief, simple act of reflective attention ("refreshing") is also capable of both enhancing and suppressing activity in some scene-selective areas (the parahippocampal place area [PPA]) but not others (refreshing resulted in enhancement but not in suppression in the middle occipital gyrus [MOG]). This suggests that different category-selective extrastriate areas preferring the same class of stimuli may contribute differentially to reflective processing of one's internal representations of such stimuli.

The Needs of the Highly Able and the Needs of Society: A Multidisciplinary Analysis of Talent Differentiation and Its Significance to Gifted Education and Issues of Societal Inequality

ERIC Educational Resources Information Center

Persson, Roland S.

2014-01-01

Does gifted education affect societal inequality, and does societal inequality suppress and/or distort the development of high ability? Drawing from several academic disciplines and current political discourse, a differentiated use of terms used to describe the highly able is explored in this article. A social evolutionary framework is proposed as…

PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity

PubMed Central

Rattanakorn, Kirk; Gadi, Abhilash; Verma, Narendra; Maurizi, Giulia; Gunaratne, Preethi H.; Coarfa, Cristian; Kennedy, Oran D.; Garabedian, Michael J.; Basilico, Claudio; Mansukhani, Alka

2016-01-01

Osteosarcoma (OS) is a highly aggressive pediatric bone cancer in which most tumor cells remain immature and fail to differentiate into bone-forming osteoblasts. However, OS cells readily respond to adipogenic stimuli suggesting they retain mesenchymal stem cell-like properties. Here we demonstrate that nuclear receptor PPARγ agonists such as the anti-diabetic, thiazolidinedione (TZD) drugs induce growth arrest and cause adipogenic differentiation in human, mouse and canine OS cells as well as in tumors in mice. Gene expression analysis reveals that TZDs induce lipid metabolism pathways while suppressing targets of the Hippo-YAP pathway, Wnt signaling and cancer-related proliferation pathways. Significantly, TZD action appears to be restricted to the high Sox2 expressing cancer stem cell population and is dependent on PPARγ expression. TZDs also affect growth and cell fate by causing the cytoplasmic sequestration of the transcription factors SOX2 and YAP that are required for tumorigenicity. Finally, we identify a TZD-regulated gene signature based on Wnt/Hippo target genes and PPARγ that predicts patient outcomes. Together, this work highlights a novel connection between PPARγ agonist in inducing adipogenesis and mimicking the tumor suppressive hippo pathway. It also illustrates the potential of drug repurposing for TZD-based differentiation therapy for osteosarcoma. PMID:27528232

Suppression subtractive hybridization and comparative expression analysis to identify developmentally regulated genes in filamentous fungi.

PubMed

Gesing, Stefan; Schindler, Daniel; Nowrousian, Minou

2013-09-01

Ascomycetes differentiate four major morphological types of fruiting bodies (apothecia, perithecia, pseudothecia and cleistothecia) that are derived from an ancestral fruiting body. Thus, fruiting body differentiation is most likely controlled by a set of common core genes. One way to identify such genes is to search for genes with evolutionary conserved expression patterns. Using suppression subtractive hybridization (SSH), we selected differentially expressed transcripts in Pyronema confluens (Pezizales) by comparing two cDNA libraries specific for sexual and for vegetative development, respectively. The expression patterns of selected genes from both libraries were verified by quantitative real time PCR. Expression of several corresponding homologous genes was found to be conserved in two members of the Sordariales (Sordaria macrospora and Neurospora crassa), a derived group of ascomycetes that is only distantly related to the Pezizales. Knockout studies with N. crassa orthologues of differentially regulated genes revealed a functional role during fruiting body development for the gene NCU05079, encoding a putative MFS peptide transporter. These data indicate conserved gene expression patterns and a functional role of the corresponding genes during fruiting body development; such genes are candidates of choice for further functional analysis. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Painless thyroiditis].

PubMed

Okamura, Ken; Fujikawa, Megumi; Bandai, Sachiko

2006-12-01

Painless thyroiditis is characterized by painless low-uptake thyrotoxicosis (thyrotoxicosis without hyperthyroidism). Destructive damage of the thyroid has been thought to be the mechanism for self-limited thyrotoxicosis. However, hydrolysis of thyroglobulin must be responsible for the release of excessive thyroid hormone. Low-uptake of iodine and excessive release of thyroid hormone suggest the uncoupling of hormone synthesis and hormone secretion in the thyroid gland. Suppressed serum TSH level, various cytokines or growth factors including TGFbeta1, and thyroglobulin itself may be responsible for the suppressed hormone synthesis. The mechanism for persistent hormone release despite suppressed hormone synthesis should be clarified. Quantitative TSH binding inhibitor immunoglobulin assay is helpful for the differential diagnosis of painless thyroiditis and Graves' hyperthyroidism.

Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

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

Liu, Qi; Wan, Qilong; Yang, Rongtao

Highlights: Black-Right-Pointing-Pointer Different PTH administration exerts different effects on condylar chondrocyte. Black-Right-Pointing-Pointer Intermittent PTH administration suppresses condylar chondrocyte proliferation. Black-Right-Pointing-Pointer Continuous PTH administration maintains condylar chondrocyte proliferating. Black-Right-Pointing-Pointer Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presentedmore » enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular asymmetry.« less

Low Intensity Pulsed Ultrasound (LIPUS) Influences the Multilineage Differentiation of Mesenchymal Stem and Progenitor Cell Lines through ROCK-Cot/Tpl2-MEK-ERK Signaling Pathway*

PubMed Central

Kusuyama, Joji; Bandow, Kenjiro; Shamoto, Mitsuo; Kakimoto, Kyoko; Ohnishi, Tomokazu; Matsuguchi, Tetsuya

2014-01-01

Mesenchymal stem cells (MSCs) are pluripotent cells that can differentiate into multilineage cell types, including adipocytes and osteoblasts. Mechanical stimulus is one of the crucial factors in regulating MSC differentiation. However, it remains unknown how mechanical stimulus affects the balance between adipogenesis and osteogenesis. Low intensity pulsed ultrasound (LIPUS) therapy is a clinical application of mechanical stimulus and facilitates bone fracture healing. Here, we applied LIPUS to adipogenic progenitor cell and MSC lines to analyze how multilineage cell differentiation was affected. We found that LIPUS suppressed adipogenic differentiation of both cell types, represented by impaired lipid droplet appearance and decreased gene expression of peroxisome proliferator-activated receptor γ2 (Pparg2) and fatty acid-binding protein 4 (Fabp4). LIPUS also down-regulated the phosphorylation level of peroxisome proliferator-activated receptor γ2 protein, inhibiting its transcriptional activity. In contrast, LIPUS promoted osteogenic differentiation of the MSC line, characterized by increased cell calcification as well as inductions of runt-related transcription factor 2 (Runx2) and Osteocalcin mRNAs. LIPUS induced phosphorylation of cancer Osaka thyroid oncogene/tumor progression locus 2 (Cot/Tpl2) kinase, which was essential for the phosphorylation of mitogen-activated kinase kinase 1 (MEK1) and p44/p42 extracellular signal-regulated kinases (ERKs). Notably, effects of LIPUS on both adipogenesis and osteogenesis were prevented by a Cot/Tpl2-specific inhibitor. Furthermore, effects of LIPUS on MSC differentiation as well as Cot/Tpl2 phosphorylation were attenuated by the inhibition of Rho-associated kinase. Taken together, these results indicate that mechanical stimulus with LIPUS suppresses adipogenesis and promotes osteogenesis of MSCs through Rho-associated kinase-Cot/Tpl2-MEK-ERK signaling pathway. PMID:24550383

Low intensity pulsed ultrasound (LIPUS) influences the multilineage differentiation of mesenchymal stem and progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway.

PubMed

Kusuyama, Joji; Bandow, Kenjiro; Shamoto, Mitsuo; Kakimoto, Kyoko; Ohnishi, Tomokazu; Matsuguchi, Tetsuya

2014-04-11

Mesenchymal stem cells (MSCs) are pluripotent cells that can differentiate into multilineage cell types, including adipocytes and osteoblasts. Mechanical stimulus is one of the crucial factors in regulating MSC differentiation. However, it remains unknown how mechanical stimulus affects the balance between adipogenesis and osteogenesis. Low intensity pulsed ultrasound (LIPUS) therapy is a clinical application of mechanical stimulus and facilitates bone fracture healing. Here, we applied LIPUS to adipogenic progenitor cell and MSC lines to analyze how multilineage cell differentiation was affected. We found that LIPUS suppressed adipogenic differentiation of both cell types, represented by impaired lipid droplet appearance and decreased gene expression of peroxisome proliferator-activated receptor γ2 (Pparg2) and fatty acid-binding protein 4 (Fabp4). LIPUS also down-regulated the phosphorylation level of peroxisome proliferator-activated receptor γ2 protein, inhibiting its transcriptional activity. In contrast, LIPUS promoted osteogenic differentiation of the MSC line, characterized by increased cell calcification as well as inductions of runt-related transcription factor 2 (Runx2) and Osteocalcin mRNAs. LIPUS induced phosphorylation of cancer Osaka thyroid oncogene/tumor progression locus 2 (Cot/Tpl2) kinase, which was essential for the phosphorylation of mitogen-activated kinase kinase 1 (MEK1) and p44/p42 extracellular signal-regulated kinases (ERKs). Notably, effects of LIPUS on both adipogenesis and osteogenesis were prevented by a Cot/Tpl2-specific inhibitor. Furthermore, effects of LIPUS on MSC differentiation as well as Cot/Tpl2 phosphorylation were attenuated by the inhibition of Rho-associated kinase. Taken together, these results indicate that mechanical stimulus with LIPUS suppresses adipogenesis and promotes osteogenesis of MSCs through Rho-associated kinase-Cot/Tpl2-MEK-ERK signaling pathway.

P50 suppression in children with selective mutism: a preliminary report.

PubMed

Henkin, Yael; Feinholz, Maya; Arie, Miri; Bar-Haim, Yair

2010-01-01

Evidence suggests that children with selective mutism (SM) display significant aberrations in auditory efferent activity at the brainstem level that may underlie inefficient auditory processing during vocalization, and lead to speech avoidance. The objective of the present study was to explore auditory filtering processes at the cortical level in children with SM. The classic paired-click paradigm was utilized to assess suppression of the P50 event-related potential to the second, of two sequentially-presented clicks, in ten children with SM and 10 control children. A significant suppression of P50 to the second click was evident in the SM group, whereas no suppression effect was observed in controls. Suppression was evident in 90% of the SM group and in 40% of controls, whereas augmentation was found in 10% and 60%, respectively, yielding a significant association between group and suppression of P50. P50 to the first click was comparable in children with SM and controls. The adult-like, mature P50 suppression effect exhibited by children with SM may reflect a cortical mechanism of compensatory inhibition of irrelevant repetitive information that was not properly suppressed at lower levels of their auditory system. The current data extends our previous findings suggesting that differential auditory processing may be involved in speech selectivity in SM.

Greater magnocellular saccadic suppression in high versus low autistic tendency suggests a causal path to local perceptual style.

PubMed

Crewther, David P; Crewther, Daniel; Bevan, Stephanie; Goodale, Melvyn A; Crewther, Sheila G

2015-12-01

Saccadic suppression-the reduction of visual sensitivity during rapid eye movements-has previously been proposed to reflect a specific suppression of the magnocellular visual system, with the initial neural site of that suppression at or prior to afferent visual information reaching striate cortex. Dysfunction in the magnocellular visual pathway has also been associated with perceptual and physiological anomalies in individuals with autism spectrum disorder or high autistic tendency, leading us to question whether saccadic suppression is altered in the broader autism phenotype. Here we show that individuals with high autistic tendency show greater saccadic suppression of low versus high spatial frequency gratings while those with low autistic tendency do not. In addition, those with high but not low autism spectrum quotient (AQ) demonstrated pre-cortical (35-45 ms) evoked potential differences (saccade versus fixation) to a large, low contrast, pseudo-randomly flashing bar. Both AQ groups showed similar differential visual evoked potential effects in later epochs (80-160 ms) at high contrast. Thus, the magnocellular theory of saccadic suppression appears untenable as a general description for the typically developing population. Our results also suggest that the bias towards local perceptual style reported in autism may be due to selective suppression of low spatial frequency information accompanying every saccadic eye movement.

Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells.

PubMed

Luz-Crawford, Patricia; Kurte, Monica; Bravo-Alegría, Javiera; Contreras, Rafael; Nova-Lamperti, Estefania; Tejedor, Gautier; Noël, Danièle; Jorgensen, Christian; Figueroa, Fernando; Djouad, Farida; Carrión, Flavio

2013-06-04

Mesenchymal stem cells (MSCs) are adult, multipotent, stem cells with immunomodulatory properties. The mechanisms involved in the capacity of MSCs to inhibit the proliferation of proinflammatory T lymphocytes, which appear responsible for causing autoimmune disease, have yet to be fully elucidated. One of the underlying mechanisms studied recently is the ability of MSCs to generate T regulatory (Treg) cells in vitro and in vivo from activated peripheral blood mononuclear cells (PBMC), T-CD4+ and also T-CD8(+) cells. In the present work we investigated the capacity of MSCs to generate Treg cells using T-CD4(+) cells induced to differentiate toward the proinflammatory Th1 and Th17 lineages. MSCs were obtained from mouse bone marrow and characterized according to their surface antigen expression and their multilineage differentiation potential. CD4(+) T cells isolated from mouse spleens were induced to differentiate into Th1 or Th17 cells and co-cultured with MSCs added at day 0, 2 or 4 of the differentiation processes. After six days, CD25, Foxp3, IL-17 and IFN-γ expression was assessed by flow cytometry and helios and neuropilin 1 mRNA levels were assessed by RT-qPCR. For the functional assays, the 'conditioned' subpopulation generated in the presence of MSCs was cultured with concanavalin A-activated CD4(+) T cells labeled with carboxyfluorescein succinimidyl ester. Finally, we used the encephalomyelitis autoimmune diseases (EAE) mouse model, in which mice were injected with MSCs at day 18 and 30 after immunization. At day 50, the mice were euthanized and draining lymph nodes were extracted for Th1, Th17 and Treg detection by flow cytometry. MSCs were able to suppress the proliferation, activation and differentiation of CD4(+) T cells induced to differentiate into Th1 and Th17 cells. This substantial suppressive effect was associated with an increase of the percentage of functional induced CD4(+)CD25(+)Foxp3(+) regulatory T cells and IL-10 secretion. However, using mature Th1 or Th17 cells our results demonstrated that while MSCs suppress the proliferation and phenotype of mature Th1 and Th17 cells they did not generate Treg cells. Finally, we showed that the beneficial effect observed following MSC injection in an EAE mouse model was associated with the suppression of Th17 cells and an increase in the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes when administrated at early stages of the disease. This study demonstrated that MSCs contribute to the generation of an immunosuppressive environment via the inhibition of proinflammatory T cells and the induction of T cells with a regulatory phenotype. Together, these results might have important clinical implications for inflammatory and autoimmune diseases.

Sound Waves Induce Neural Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells via Ryanodine Receptor-Induced Calcium Release and Pyk2 Activation.

PubMed

Choi, Yura; Park, Jeong-Eun; Jeong, Jong Seob; Park, Jung-Keug; Kim, Jongpil; Jeon, Songhee

2016-10-01

Mesenchymal stem cells (MSCs) have shown considerable promise as an adaptable cell source for use in tissue engineering and other therapeutic applications. The aims of this study were to develop methods to test the hypothesis that human MSCs could be differentiated using sound wave stimulation alone and to find the underlying mechanism. Human bone marrow (hBM)-MSCs were stimulated with sound waves (1 kHz, 81 dB) for 7 days and the expression of neural markers were analyzed. Sound waves induced neural differentiation of hBM-MSC at 1 kHz and 81 dB but not at 1 kHz and 100 dB. To determine the signaling pathways involved in the neural differentiation of hBM-MSCs by sound wave stimulation, we examined the Pyk2 and CREB phosphorylation. Sound wave induced an increase in the phosphorylation of Pyk2 and CREB at 45 min and 90 min, respectively, in hBM-MSCs. To find out the upstream activator of Pyk2, we examined the intracellular calcium source that was released by sound wave stimulation. When we used ryanodine as a ryanodine receptor antagonist, sound wave-induced calcium release was suppressed. Moreover, pre-treatment with a Pyk2 inhibitor, PF431396, prevented the phosphorylation of Pyk2 and suppressed sound wave-induced neural differentiation in hBM-MSCs. These results suggest that specific sound wave stimulation could be used as a neural differentiation inducer of hBM-MSCs.

Curcumin inhibits cellular condensation and alters microfilament organization during chondrogenic differentiation of limb bud mesenchymal cells.

PubMed

Kim, Dong Kyun; Kim, Song Ja; Kang, Shin Sung; Jin, Eun Jung

2009-09-30

Curcumin is a well known natural polyphenol product isolated from the rhizome of the plant Curcuma longa, anti-inflammatory agent for arthritis by inhibiting synthesis of inflammatory prostaglandins. However, the mechanisms by which curcumin regulates the functions of chondroprogenitor, such as proliferation, precartilage condensation, cytoskeletal organization or overall chondrogenic behavior, are largely unknown. In the present report, we investigated the effects and signaling mechanism of curcumin on the regulation of chondrogenesis. Treating chick limb bud mesenchymal cells with curcumin suppressed chondrogenesis by stimulating apoptotic cell death. It also inhibited reorganization of the actin cytoskeleton into a cortical pattern concomitant with rounding of chondrogenic competent cells and down-regulation of integrin beta1 and focal adhesion kinase (FAK) phosphorylation. Curcumin suppressed the phosphorylation of Akt leading to Akt inactivation. Activation of Akt by introducing a myristoylated, constitutively active form of Akt reversed the inhibitory actions of curcumin during chondrogenesis. In summary, for the first time, we describe biological properties of curcumin during chondrogenic differentiation of chick limb bud mesenchymal cells. Curcumin suppressed chondrogenesis by stimulating apoptotic cell death and down-regulating integrin-mediated reorganization of actin cytoskeleton via modulation of Akt signaling.

Tumor exosomes block dendritic cells maturation to decrease the T cell immune response.

PubMed

Ning, Yongling; Shen, Kai; Wu, Qiyong; Sun, Xiao; Bai, Yu; Xie, Yewen; Pan, Jie; Qi, Chunjian

2018-07-01

Tumors can induce the generation and accumulation of immunosuppression in a tumor microenvironment, contributing to the tumor's escape from immunological surveillance. Although tumor antigen-pulsed dendritic cell can improve anti-tumor immune responses, tumor associated regulatory dendritic cells are involved in the induction of immune tolerance. The current study sought to investigate whether exosomes produced by tumor cells had any effect on DCs in immune suppression. In this study, we examined the effect of tumor exosomes on DCs and found that exosomes from LLC Lewis lung carcinoma or 4T1 breast cancer cell blocked the differentiation of myeloid precursor cells into CD11c + DCs and induced cell apoptosis. Tumor exosome treatment inhibited the maturation and migration of DCs and promoted the immune suppression of DCs. The treatment of tumor exosomes drastically decreased CD4 + IFN-γ + Th1 differentiation but increased the rates of regulatory T (Treg) cells. The immunosuppressive ability of tumor exosome-treated DCs were partially restored with PD-L1 blockage. These data suggested that PD-L1 played a role in tumor exosome-induced DC-associated immune suppression. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

The novel 19q13 KRAB zinc-finger tumour suppressor ZNF382 is frequently methylated in oesophageal squamous cell carcinoma and antagonises Wnt/β-catenin signalling.

PubMed

Zhang, Chong; Xiang, Tingxiu; Li, Shuman; Ye, Lin; Feng, Yixiao; Pei, Lijiao; Li, Lili; Wang, Xiangyu; Sun, Ran; Tao, Qian; Ren, Guosheng

2018-05-14

Zinc finger proteins (ZFPs) are the largest transcription factor family in mammals. About one-third of ZFPs are Krüppel-associated box domain (KRAB)-ZFPs and involved in the regulation of cell differentiation/proliferation/apoptosis and neoplastic transformation. We recently identified ZNF382 as a novel KRAB-ZFP epigenetically inactivated in multiple cancers due to frequent promoter CpG methylation. However, its epigenetic alterations, biological functions/mechanism and clinical significance in oesophageal squamous cell carcinoma (ESCC) are still unknown. Here, we demonstrate that ZNF382 expression was suppressed in ESCC due to aberrant promoter methylation, but highly expressed in normal oesophagus tissues. ZNF382 promoter methylation is correlated with ESCC differentiation levels. Restoration of ZNF382 expression in silenced ESCC cells suppressed tumour cell proliferation and metastasis through inducing cell apoptosis. Importantly, ZNF382 suppressed Wnt/β-catenin signalling and downstream target gene expression, likely through binding directly to FZD1 and DVL2 promoters. In summary, our findings demonstrate that ZNF382 functions as a bona fide tumour suppressor inhibiting ESCC pathogenesis through inhibiting the Wnt/β-catenin signalling pathway.

β₂ adrenergic receptor activation suppresses bone morphogenetic protein (BMP)-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells.

PubMed

Yamada, Takayuki; Ezura, Yoichi; Hayata, Tadayoshi; Moriya, Shuichi; Shirakawa, Jumpei; Notomi, Takuya; Arayal, Smriti; Kawasaki, Makiri; Izu, Yayoi; Harada, Kiyoshi; Noda, Masaki

2015-06-01

β adrenergic stimulation suppresses bone formation in vivo while its actions in osteoblastic differentiation are still incompletely understood. We therefore examined the effects of β2 adrenergic stimulation on osteoblast-like MC3T3-E1 cells focusing on BMP-induced alkaline phosphatase expression. Morphologically, isoproterenol treatment suppresses BMP-induced increase in the numbers of alkaline phosphatase-positive small foci in the cultures of MC3T3-E1 cells. Biochemically, isoproterenol treatment suppresses BMP-induced enzymatic activity of alkaline phosphatase in a dose-dependent manner. Isoproterenol suppression of alkaline phosphatase activity is observed even when the cells are treated with high concentrations of BMP. With respect to cell density, isoproterenol treatment tends to suppress BMP-induced increase in alkaline phosphatase expression more in osteoblasts cultured at higher cell density. In terms of treatment protocol, continuous isoproterenol treatment is compared to cyclic treatment. Continuous isoproterenol treatment is more suppressive against BMP-induced increase in alkaline phosphatase expression than cyclic regimen. At molecular level, isoproterenol treatment suppresses BMP-induced enhancement of alkaline phosphatase mRNA expression. Regarding the mode of isoproterenol action, isoproterenol suppresses BMP-induced BRE-luciferase activity. These data indicate that isoproterenol regulates BMP-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells. © 2014 Wiley Periodicals, Inc.

Language choice in bimodal bilingual development.

PubMed

Lillo-Martin, Diane; de Quadros, Ronice M; Chen Pichler, Deborah; Fieldsteel, Zoe

2014-01-01

Bilingual children develop sensitivity to the language used by their interlocutors at an early age, reflected in differential use of each language by the child depending on their interlocutor. Factors such as discourse context and relative language dominance in the community may mediate the degree of language differentiation in preschool age children. Bimodal bilingual children, acquiring both a sign language and a spoken language, have an even more complex situation. Their Deaf parents vary considerably in access to the spoken language. Furthermore, in addition to code-mixing and code-switching, they use code-blending-expressions in both speech and sign simultaneously-an option uniquely available to bimodal bilinguals. Code-blending is analogous to code-switching sociolinguistically, but is also a way to communicate without suppressing one language. For adult bimodal bilinguals, complete suppression of the non-selected language is cognitively demanding. We expect that bimodal bilingual children also find suppression difficult, and use blending rather than suppression in some contexts. We also expect relative community language dominance to be a factor in children's language choices. This study analyzes longitudinal spontaneous production data from four bimodal bilingual children and their Deaf and hearing interlocutors. Even at the earliest observations, the children produced more signed utterances with Deaf interlocutors and more speech with hearing interlocutors. However, while three of the four children produced >75% speech alone in speech target sessions, they produced <25% sign alone in sign target sessions. All four produced bimodal utterances in both, but more frequently in the sign sessions, potentially because they find suppression of the dominant language more difficult. Our results indicate that these children are sensitive to the language used by their interlocutors, while showing considerable influence from the dominant community language.

An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients.

PubMed

Wei, Ping; Hu, Guo-Hua; Kang, Hou-Yong; Yao, Hong-Bing; Kou, Wei; Liu, Hong; Zhang, Cheng; Hong, Su-Ling

2014-05-01

A predominant Th17 population is a marker of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR) exhibits strong immunomodulation potential via regulation of the differentiation of T lymphocytes and dendritic cells (DCs) after activation by its ligand, such as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). The aim of this study was to analyze the effect of AhR on Th17 differentiation by investigating the action of ITE on DCs and CD4(+) T cells from patients with AR. In all, 26 AR patients and 12 healthy controls were included in this study. The expression of interleukin (IL)-1β, IL-6, IL-10, and IL-17 in the culture supernatant and the presence of Th17 cells in CD4(+) T cells and DC-CD4(+) T-cell co-culture system were measured before and after treatment with ITE. We show that ITE significantly induced cell secretion of IL-10 and inhibited IL-1β and IL-6 production in DCs, and promoted IL-10 production and suppressed IL-17 expression in CD4(+) T cells in vitro. It also suppressed the expansion of Th17 cells in vitro. Our work demonstrates that ITE acts on DCs and CD4(+) T cells to inhibit the Th17 response that suppresses AR; the AhR-DC-Th17 axis may be an important pathway in the treatment of AR. ITE, a nontoxic AhR ligand, attenuated the Th17 response; thus, it appears to be a promising therapeutic candidate for suppressing the inflammatory responses associated with AR.

Language choice in bimodal bilingual development

PubMed Central

Lillo-Martin, Diane; de Quadros, Ronice M.; Chen Pichler, Deborah; Fieldsteel, Zoe

2014-01-01

Bilingual children develop sensitivity to the language used by their interlocutors at an early age, reflected in differential use of each language by the child depending on their interlocutor. Factors such as discourse context and relative language dominance in the community may mediate the degree of language differentiation in preschool age children. Bimodal bilingual children, acquiring both a sign language and a spoken language, have an even more complex situation. Their Deaf parents vary considerably in access to the spoken language. Furthermore, in addition to code-mixing and code-switching, they use code-blending—expressions in both speech and sign simultaneously—an option uniquely available to bimodal bilinguals. Code-blending is analogous to code-switching sociolinguistically, but is also a way to communicate without suppressing one language. For adult bimodal bilinguals, complete suppression of the non-selected language is cognitively demanding. We expect that bimodal bilingual children also find suppression difficult, and use blending rather than suppression in some contexts. We also expect relative community language dominance to be a factor in children's language choices. This study analyzes longitudinal spontaneous production data from four bimodal bilingual children and their Deaf and hearing interlocutors. Even at the earliest observations, the children produced more signed utterances with Deaf interlocutors and more speech with hearing interlocutors. However, while three of the four children produced >75% speech alone in speech target sessions, they produced <25% sign alone in sign target sessions. All four produced bimodal utterances in both, but more frequently in the sign sessions, potentially because they find suppression of the dominant language more difficult. Our results indicate that these children are sensitive to the language used by their interlocutors, while showing considerable influence from the dominant community language. PMID:25368591

Dense-HOG-based drift-reduced 3D face tracking for infant pain monitoring

NASA Astrophysics Data System (ADS)

Saeijs, Ronald W. J. J.; Tjon A Ten, Walther E.; de With, Peter H. N.

2017-03-01

This paper presents a new algorithm for 3D face tracking intended for clinical infant pain monitoring. The algorithm uses a cylinder head model and 3D head pose recovery by alignment of dynamically extracted templates based on dense-HOG features. The algorithm includes extensions for drift reduction, using re-registration in combination with multi-pose state estimation by means of a square-root unscented Kalman filter. The paper reports experimental results on videos of moving infants in hospital who are relaxed or in pain. Results show good tracking behavior for poses up to 50 degrees from upright-frontal. In terms of eye location error relative to inter-ocular distance, the mean tracking error is below 9%.

Repressive effects of a capacitive-resistive electric transfer (CRet) hyperthermic apparatus combined with provitamin C on intracellular lipid-droplets formation in adipocytes.

PubMed

Kato, Shinya; Saitoh, Yasukazu; Miwa, Nobuhiko

2013-01-01

The aim of this study was to evaluate inhibitory effects of L-ascorbic acid-2-O-phosphate-Na(2) (APS), a pro-vitamin C, combined with hyperthermia on adipogenic differentiation of mouse stromal cells, OP9. OP9 preadipocytes were differentiated with serum replacement, administered with APS, and simultaneously treated with hyperthermia using a capacitive-resistive electric transfer (CRet) apparatus, which was conducted repeatedly twice a day. After 2 days, intracellular lipid droplets were stained with Oil Red O, then observed by microscopy and assessed spectrophotometrically. After stimulation by serum replacement for 2 days, lipid droplets were accumulated surrounding nucleus of OP9 cells. When APS of 0.15-0.6 mM was administered without hyperthermia, the amount of lipid droplets was markedly suppressed to 50.5%∼-11.3% versus the undifferentiated control, and diminished huge aggregates of lipid droplets. In OP9 cells treated by hyperthermia at 42°C for 0.5 min, 1 min or 3 min in the absence of APS, adipogenesis was suppressed abruptly in a time-dependent manner to 95.4%, 18.7% or -5.5%, respectively. Whereas, the percentage of adipogenesis was 96.8% in OP9 cells treated by mild hyperthermia alone at 41°C for 1 min. The simultaneous application of APS and hyperthermia at 41°C for 1 min markedly suppressed the accumulation of lipid droplets to 25.7%∼-66.2%. By scanning electron microscopy (SEM) observation, the surface of OP9 cells treated with APS and hyperthermia appeared to have the morphological property of undifferentiated OP9 cells. Combined treatment of APS and mild hyperthermia suppresses adipogenesis in OP9 cells, particularly in lipid droplets accumulation during spontaneous differentiation of OP9 preadipocytes.

REV-ERBs agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

PubMed

Song, Chao; Tan, Peng; Zhang, Zheng; Wu, Wei; Dong, Yonghui; Zhao, Liming; Liu, Huiyong; Guan, Hanfeng; Li, Feng

2018-01-22

REV-ERBs (REV-ERBα and REV-ERBβ) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBα knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBβ knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-κB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up-regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERBs agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

Inhibition of bone resorption by Tanshinone VI isolated from Salvia miltiorrhiza Bunge.

PubMed

Nicolin, V; Dal Piaz, F; Nori, S L; Narducci, P; De Tommasi, N

2010-05-10

During the last decade, a more detailed knowledge of molecular mechanisms involved in osteoclastogenesis has driven research efforts in the development and screening of compound libraries of several small molecules that specifically inhibit the pathway involved in the commitment of the osteoclast precursor cells. Natural compounds that suppress osteoclast differentiation may have therapeutic value in treating osteoporosis and other bone erosive diseases such as rheumatoid arthritis or metastasis associated with bone loss. In ongoing investigation into anti-osteoporotic compounds from natural products we have analyzed the effect of Tanshinone VI on osteoclasts differentiation, using a physiologic three-dimensional osteoblast/bone marrow model of cell co-culture. Tanshinone VI is an abietane diterpene extracted from the root of Salvia miltiorrhiza Bunge (Labiatae), a Chinese traditional crude drug, "Tan-Shen". Tashinone has been widely used in clinical practice for the prevention of cardiac diseases, arthritis and other inflammation-related disorders based on its pharmacological actions in multiple tissues. Although Tanshinone VI A has been used as a medicinal agent in the treatment of many diseases, its role in osteoclast-related bone diseases remains unknown. We showed previously that Tanshinone VI greatly inhibits osteoclast differentiation and suppresses bone resorption through disruption of the actin ring; subsequently, we intended to examine the precise inhibitory mechanism of Tanshinone VI on osteoclast differentiating factor. This study shows, for the first time, that Tanshinone VI prevents osteoclast differentiation by inhibiting RANKL expression and NFkB induction.

Diminished potential for B-lymphoid differentiation after murine leukemia virus infection in vivo and in EML hematopoietic progenitor cells.

PubMed

Finstad, Samantha L; Rosenberg, Naomi; Levy, Laura S

2007-07-01

Infection with a recombinant murine-feline gammaretrovirus, MoFe2, or with the parent virus, Moloney murine leukemia virus, caused significant reduction in B-lymphoid differentiation of bone marrow at 2 to 8 weeks postinfection. The suppression was selective, in that myeloid potential was significantly increased by infection. Analysis of cell surface markers and immunoglobulin H gene rearrangements in an in vitro model demonstrated normal B-lymphoid differentiation after infection but significantly reduced viability of differentiating cells. This reduction in viability may confer a selective advantage on undifferentiated lymphoid progenitors in the bone marrow of gammaretrovirus-infected animals and thereby contribute to the establishment of a premalignant state.

Fat suppression with short inversion time inversion-recovery and chemical-shift selective saturation: a dual STIR-CHESS combination prepulse for turbo spin echo pulse sequences.

PubMed

Tanabe, Koji; Nishikawa, Keiichi; Sano, Tsukasa; Sakai, Osamu; Jara, Hernán

2010-05-01

To test a newly developed fat suppression magnetic resonance imaging (MRI) prepulse that synergistically uses the principles of fat suppression via inversion recovery (STIR) and spectral fat saturation (CHESS), relative to pure CHESS and STIR. This new technique is termed dual fat suppression (Dual-FS). To determine if Dual-FS could be chemically specific for fat, the phantom consisted of the fat-mimicking NiCl(2) aqueous solution, porcine fat, porcine muscle, and water was imaged with the three fat-suppression techniques. For Dual-FS and STIR, several inversion times were used. Signal intensities of each image obtained with each technique were compared. To determine if Dual-FS could be robust to magnetic field inhomogeneities, the phantom consisting of different NiCl(2) aqueous solutions, porcine fat, porcine muscle, and water was imaged with Dual-FS and CHESS at the several off-resonance frequencies. To compare fat suppression efficiency in vivo, 10 volunteer subjects were also imaged with the three fat-suppression techniques. Dual-FS could suppress fat sufficiently within the inversion time of 110-140 msec, thus enabling differentiation between fat and fat-mimicking aqueous structures. Dual-FS was as robust to magnetic field inhomogeneities as STIR and less vulnerable than CHESS. The same results for fat suppression were obtained in volunteers. The Dual-FS-STIR-CHESS is an alternative and promising fat suppression technique for turbo spin echo MRI. Copyright 2010 Wiley-Liss, Inc.

Pressure suppression containment system for boiling water reactor

DOEpatents

Gluntz, Douglas M.; Nesbitt, Loyd B.

1997-01-01

A system for suppressing the pressure inside the containment of a BWR following a postulated accident. A piping subsystem is provided which features a main process pipe that communicates the wetwell airspace to a connection point downstream of the guard charcoal bed in an offgas system and upstream of the main bank of delay charcoal beds which give extensive holdup to offgases. The main process pipe is fitted with both inboard and outboard containment isolation valves. Also incorporated in the main process pipe is a low-differential-pressure rupture disk which prevents any gas outflow in this piping whatsoever until or unless rupture occurs by virtue of pressure inside this main process pipe on the wetwell airspace side of the disk exceeding the design opening (rupture) pressure differential. The charcoal holds up the radioactive species in the noncondensable gas from the wetwell plenum by adsorption, allowing time for radioactive decay before the gas is vented to the environs.

EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation

PubMed Central

Béguelin, Wendy; Popovic, Relja; Teater, Matt; Jiang, Yanwen; Bunting, Karen L.; Rosen, Monica; Shen, Hao; Yang, Shao Ning; Wang, Ling; Ezponda, Teresa; Martinez-Garcia, Eva; Zhang, Haikuo; Zhang, Yupeng; Verma, Sharad K.; McCabe, Michael T.; Ott, Heidi M.; Van Aller, Glenn S.; Kruger, Ryan G.; Liu, Yan; McHugh, Charles F.; Scott, David W.; Chung, Young Rock; Kelleher, Neil; Shaknovich, Rita; Creasy, Caretha L.; Gascoyne, Randy D.; Wong, Kwok-Kin; Cerchietti, Leandro C.; Levine, Ross L.; Abdel-Wahab, Omar; Licht, Jonathan D.; Elemento, Olivier; Melnick, Ari M.

2013-01-01

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. PMID:23680150

The polysaccharides from fermented Ganoderma lucidum mycelia induced miRNAs regulation in suppressed HepG2 cells.

PubMed

Shen, Jie; Park, Hyeon-soo; Xia, Yong-mei; Kim, Gon-sup; Cui, Steve W

2014-03-15

Medicinal mushroom polysaccharides such as Ganoderma lucidum polysaccharides (GLPs) have been commonly hypothesized to suppress tumor cells proliferation through immune effects. To verify this hypothesis through investigating comprehensive miRNA expression in polysaccharide treated cancer cells, an anticancer mycelia GLP was employed to disclose miRNA differential expression of human hepatocarcinoma cells (HepG2), by using a miRNA microarray assay based on Sanger miR-Base Release 16. The experiment and the analysis result indicates that among the 61 differential expressed miRNAs (p ≤ 0.01), 17 of them were regulated significantly. GLP can inhibit HepG2 cells directly through regulation of hepatocarcinoma genes. A newly found miR-3131 exhibited the strongest upregulation (92-folds, Log2 = 6.53, p = 0.000016). The miRNAs responded synergistically in both hepatocarcinoma and immune-related aspects. Copyright © 2014 Elsevier Ltd. All rights reserved.

Photonic ultra-wideband pulse generation, hybrid modulation and dispersion-compensation-free transmission in multi-access communication systems.

PubMed

Tan, Kang; Shao, Jing; Sun, Junqiang; Wang, Jian

2012-01-16

We propose and demonstrate a scheme for optical ultrawideband (UWB) pulse generation by exploiting a half-carrier-suppressed Mach-Zehnder modulator (MZM) and a delay-interferometer- and wavelength-division-multiplexer-based, reconfigurable and multi-channel differentiator (DWRMD). Multi-wavelength, polarity- and shape-switchable UWB pulses of monocycle, doublet, triplet, and quadruplet are experimentally generated simply by tuning two bias voltages to modify the carrier-suppression ratio of MZM and the differential order of DWRMD respectively. The pulse position modulation, pulse shape modulation, pulse amplitude modulation and binary phase-shift keying modulation of UWB pulses can also be conveniently realized with the same scheme structure, which indicates that the hybrid modulation of those four formats can be achieved. Consequently, the proposed approach has potential applications in multi-shape, multi-modulation and multi-access UWB-over-fiber communication systems.

Multi-spectral endogenous fluorescence imaging for bacterial differentiation

NASA Astrophysics Data System (ADS)

Chernomyrdin, Nikita V.; Babayants, Margarita V.; Korotkov, Oleg V.; Kudrin, Konstantin G.; Rimskaya, Elena N.; Shikunova, Irina A.; Kurlov, Vladimir N.; Cherkasova, Olga P.; Komandin, Gennady A.; Reshetov, Igor V.; Zaytsev, Kirill I.

2017-07-01

In this paper, the multi-spectral endogenous fluorescence imaging was implemented for bacterial differentiation. The fluorescence imaging was performed using a digital camera equipped with a set of visual bandpass filters. Narrowband 365 nm ultraviolet radiation passed through a beam homogenizer was used to excite the sample fluorescence. In order to increase a signal-to-noise ratio and suppress a non-fluorescence background in images, the intensity of the UV excitation was modulated using a mechanical chopper. The principal components were introduced for differentiating the samples of bacteria based on the multi-spectral endogenous fluorescence images.

The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation

PubMed Central

Wang, Xiao; Bi, Yujing; Xue, Lixiang; Liao, Jiongbo; Chen, Xi; Lu, Yun; Zhang, Zhengguo; Wang, Jian; Liu, Huanrong; Yang, Hui

2014-01-01

While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-γ)-producing CD8+ T cells and CD4+ T cells (TH1 T helper cells) and more interleukin 4 (IL-4)-producing CD4+ T cells (TH2) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b+ Gr1+ MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation. PMID:25452304

Endoplasmic reticulum stress suppresses lipin-1 expression in 3T3-L1 adipocytes

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

Takahashi, Nobuhiko, E-mail: ntkhs@hoku-iryo-u.ac.jp; Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510; Yoshizaki, Takayuki

Highlights: ► Lipin-1 involves lipid metabolism, adipocyte differentiation, and inflammation. ► Adipose lipin-1 expression is reduced in obesity. ► ER stress suppresses lipin-1 expression in 3T3-L1 adipocytes. ► Activation of PPAR-γ recovers ER stress-induced lipin-1 reduction. -- Abstract: Lipin-1 plays crucial roles in the regulation of lipid metabolism and cell differentiation in adipocytes. In obesity, adipose lipin-1 mRNA expression is decreased and positively correlated with systemic insulin sensitivity. Amelioration of the lipin-1 depletion might be improved dysmetabolism. Although some cytokines such as TNF-α and interleukin-1β reduces adipose lipin-1 expression, the mechanism of decreased adipose lipin-1 expression in obesity remains unclear.more » Recently, endoplasmic reticulum (ER) stress is implicated in the pathogenesis of obesity. Here we investigated the role of ER stress on the lipin-1 expression in 3T3-L1 adipocytes. We demonstrated that lipin-1 expression was suppressed by the treatment with ER stress inducers (tunicamycin and thapsigargin) at transcriptional level. We also showed that constitutive lipin-1 expression could be maintained by peroxisome proliferator-activated receptor-γ in 3T3-L1 adipocytes. Activation of peroxisome proliferator-activated receptor-γ recovered the ER stress-induced lipin-1 suppression. These results suggested that ER stress might be involved in the pathogenesis of obesity through lipin-1 depletion.« less

Arctigenin Inhibits Osteoclast Differentiation and Function by Suppressing Both Calcineurin-Dependent and Osteoblastic Cell-Dependent NFATc1 Pathways

PubMed Central

Yamashita, Teruhito; Uehara, Shunsuke; Udagawa, Nobuyuki; Li, Feng; Kadota, Shigetoshi; Esumi, Hiroyasu; Kobayashi, Yasuhiro; Takahashi, Naoyuki

2014-01-01

Arctigenin, a lignan-derived compound, is a constituent of the seeds of Arctium lappa. Arctigenin was previously shown to inhibit osteoclastogenesis; however, this inhibitory mechanism has yet to be elucidated. Here, we showed that arctigenin inhibited the action of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key transcription factor for osteoclastogenesis. NFATc1 in osteoclast precursors was activated through two distinct pathways: the calcineurin-dependent and osteoblastic cell-dependent pathways. Among the several lignan-derived compounds examined, arctigenin most strongly inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast-like cell formation in mouse bone marrow macrophage (BMM) cultures, in which the calcineurin-dependent NFATc1 pathway was activated. Arctigenin suppressed neither the activation of nuclear factor κB and mitogen-activated protein kinases nor the up-regulation of c-Fos expression in BMMs treated with RANKL. However, arctigenin suppressed RANKL-induced NFATc1 expression. Interestingly, the treatment of osteoclast-like cells with arctigenin converted NFATc1 into a lower molecular weight species, which was translocated into the nucleus even in the absence of RANKL. Nevertheless, arctigenin as well as cyclosporin A (CsA), a calcineurin inhibitor, suppressed the NFAT-luciferase reporter activity induced by ionomycin and phorbol 12-myristate 13-acetate in BMMs. Chromatin immunoprecipitation analysis confirmed that arctigenin inhibited the recruitment of NFATc1 to the promoter region of the NFATc1 target gene. Arctigenin, but not CsA suppressed osteoclast-like cell formation in co-cultures of osteoblastic cells and bone marrow cells, in which the osteoblastic cell-dependent NFATc1 pathway was activated. The forced expression of constitutively active NFATc1 rescued osteoclastogenesis in BMM cultures treated with CsA, but not that treated with arctigenin. Arctigenin also suppressed the pit-forming activity of osteoclast-like cells cultured on dentin slices. These results suggest that arctigenin induces a dominant negative species of NFATc1, which inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways. PMID:24465763

Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways.

PubMed

Yamashita, Teruhito; Uehara, Shunsuke; Udagawa, Nobuyuki; Li, Feng; Kadota, Shigetoshi; Esumi, Hiroyasu; Kobayashi, Yasuhiro; Takahashi, Naoyuki

2014-01-01

Arctigenin, a lignan-derived compound, is a constituent of the seeds of Arctium lappa. Arctigenin was previously shown to inhibit osteoclastogenesis; however, this inhibitory mechanism has yet to be elucidated. Here, we showed that arctigenin inhibited the action of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key transcription factor for osteoclastogenesis. NFATc1 in osteoclast precursors was activated through two distinct pathways: the calcineurin-dependent and osteoblastic cell-dependent pathways. Among the several lignan-derived compounds examined, arctigenin most strongly inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast-like cell formation in mouse bone marrow macrophage (BMM) cultures, in which the calcineurin-dependent NFATc1 pathway was activated. Arctigenin suppressed neither the activation of nuclear factor κB and mitogen-activated protein kinases nor the up-regulation of c-Fos expression in BMMs treated with RANKL. However, arctigenin suppressed RANKL-induced NFATc1 expression. Interestingly, the treatment of osteoclast-like cells with arctigenin converted NFATc1 into a lower molecular weight species, which was translocated into the nucleus even in the absence of RANKL. Nevertheless, arctigenin as well as cyclosporin A (CsA), a calcineurin inhibitor, suppressed the NFAT-luciferase reporter activity induced by ionomycin and phorbol 12-myristate 13-acetate in BMMs. Chromatin immunoprecipitation analysis confirmed that arctigenin inhibited the recruitment of NFATc1 to the promoter region of the NFATc1 target gene. Arctigenin, but not CsA suppressed osteoclast-like cell formation in co-cultures of osteoblastic cells and bone marrow cells, in which the osteoblastic cell-dependent NFATc1 pathway was activated. The forced expression of constitutively active NFATc1 rescued osteoclastogenesis in BMM cultures treated with CsA, but not that treated with arctigenin. Arctigenin also suppressed the pit-forming activity of osteoclast-like cells cultured on dentin slices. These results suggest that arctigenin induces a dominant negative species of NFATc1, which inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways.

Ebselen Is a Potential Anti-Osteoporosis Agent by Suppressing Receptor Activator of Nuclear Factor Kappa-B Ligand-Induced Osteoclast Differentiation In vitro and Lipopolysaccharide-Induced Inflammatory Bone Destruction In vivo.

PubMed

Baek, Jong Min; Kim, Ju-Young; Yoon, Kwon-Ha; Oh, Jaemin; Lee, Myeung Su

2016-01-01

Ebselen is a non-toxic seleno-organic drug with anti-inflammatory and antioxidant properties that is currently being examined in clinical trials to prevent and treat various diseases, including atherosclerosis, stroke, and cancer. However, no reports are available for verifying the pharmacological effects of ebselen on major metabolic bone diseases such as osteoporosis. In this study, we observed that ebselen suppressed the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells in an osteoblast/osteoclast co-culture by regulating the ratio of receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin secreted by osteoblasts. In addition, ebselen treatment in the early stage of osteoclast differentiation inhibited RANKL-dependent osteoclastogenesis by decreasing the phosphorylation of IκB, PI3K, and Akt in early signaling pathways and by subsequently inducing c-Fos and nuclear factor of activated T-cells c1. Further, ebselen induced apoptosis of osteoclasts in the late stage of osteoclast differentiation. In addition, ebselen treatment suppressed filamentous actin ring formation and bone resorption activity of mature osteoclasts. Reflecting these in vitro effects, administration of ebselen recovered bone loss and its µ-CT parameters in lipopolysaccharide-mediated mouse model. Histological analysis confirmed that ebselen prevented trabecular bone matrix degradation and osteoclast formation in the bone tissues. Finally, it was proved that the anti-osteoclastogenic action of ebselen is achieved through targeting N-methyl-D-aspartate (NMDA) receptor. These results indicate that ebselen is a potentially safe drug for treating metabolic bone diseases such as osteoporosis.

The role of growth factors in maintenance of stemness in bone marrow-derived mesenchymal stem cells

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

Eom, Young Woo; Oh, Ji-Eun; Lee, Jong In

2014-02-28

Highlights: • Expression of FGF-2, FGF-4, EGF, and HGF decreased during long-term culture of BMSCs. • Loss of growth factors induced autophagy, senescence and decrease of stemness. • FGF-2 increased proliferation potential via AKT and ERK activation in BMSCs. • FGF-2 suppressed LC3-II expression and down-regulated senescence of BMSCs. • HGF was important in maintenance of the differentiation potential of BMSCs. - Abstract: Mesenchymal stem cells (MSCs) are an active topic of research in regenerative medicine due to their ability to secrete a variety of growth factors and cytokines that promote healing of damaged tissues and organs. In addition, thesemore » secreted growth factors and cytokines have been shown to exert an autocrine effect by regulating MSC proliferation and differentiation. We found that expression of EGF, FGF-4 and HGF were down-regulated during serial passage of bone marrow-derived mesenchymal stem cells (BMSCs). Proliferation and differentiation potentials of BMSCs treated with these growth factors for 2 months were evaluated and compared to BMSCs treated with FGF-2, which increased proliferation of BMSCs. FGF-2 and -4 increased proliferation potentials at high levels, about 76- and 26-fold, respectively, for 2 months, while EGF and HGF increased proliferation of BMSCs by less than 2.8-fold. Interestingly, differentiation potential, especially adipogenesis, was maintained only by HGF treatment. Treatment with FGF-2 rapidly induced activation of AKT and later induced ERK activation. The basal level of phosphorylated ERK increased during serial passage of BMSCs treated with FGF-2. The expression of LC3-II, an autophagy marker, was gradually increased and the population of senescent cells was increased dramatically at passage 7 in non-treated controls. But FGF-2 and FGF-4 suppressed LC3-II expression and down-regulated senescent cells during long-term (i.e. 2 month) cultures. Taken together, depletion of growth factors during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF) through suppression of AKT and ERK signaling.« less

Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) blocks differentiation and maintains the expression of pluripotency markers in human embryonic stem cells.

PubMed

Burton, Peter; Adams, David R; Abraham, Achamma; Allcock, Robert W; Jiang, Zhong; McCahill, Angela; Gilmour, Jane; McAbney, John; Kaupisch, Alexandra; Kane, Nicole M; Baillie, George S; Baker, Andrew H; Milligan, Graeme; Houslay, Miles D; Mountford, Joanne C

2010-12-15

hESCs (human embryonic stem cells) have enormous potential for use in pharmaceutical development and therapeutics; however, to realize this potential, there is a requirement for simple and reproducible cell culture methods that provide adequate numbers of cells of suitable quality. We have discovered a novel way of blocking the spontaneous differentiation of hESCs in the absence of exogenous cytokines by supplementing feeder-free conditions with EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine], an established inhibitor of ADA (adenosine deaminase) and cyclic nucleotide PDE2 (phosphodiesterase 2). hESCs maintained in feeder-free conditions with EHNA for more than ten passages showed no reduction in hESC-associated markers including NANOG, POU5F1 (POU domain class 5 transcription factor 1, also known as Oct-4) and SSEA4 (stage-specific embryonic antigen 4) compared with cells maintained in feeder-free conditions containing bFGF (basic fibroblast growth factor). Spontaneous differentiation was reversibly suppressed by the addition of EHNA, but, upon removing EHNA, hESC populations underwent efficient spontaneous, multi-lineage and directed differentiation. EHNA also acts as a strong blocker of directed neuronal differentiation. Chemically distinct inhibitors of ADA and PDE2 lacked the capacity of EHNA to suppress hESC differentiation, suggesting that the effect is not driven by inhibition of either ADA or PDE2. Preliminary structure-activity relationship analysis found the differentiation-blocking properties of EHNA to reside in a pharmacophore comprising a close adenine mimetic with an extended hydrophobic substituent in the 8- or 9-position. We conclude that EHNA and simple 9-alkyladenines can block directed neuronal and spontaneous differentiation in the absence of exogenous cytokine addition, and may provide a useful replacement for bFGF in large-scale or cGMP-compliant processes.

Effect of ECM2 expression on bovine skeletal muscle-derived satellite cell differentiation.

PubMed

Liu, Chang; Tong, Huili; Li, Shufeng; Yan, Yunqin

2018-05-01

Extracellular matrix components have important regulatory functions during cell proliferation and differentiation. In recent study, extracellular matrix were shown to have a strong effect on skeletal muscle differentiation. Here, we aimed to elucidate the effects of extracellular matrix protein 2 (ECM2), an extracellular matrix component, on the differentiation of bovine skeletal muscle-derived satellite cells (MDSCs). Western blot and immunofluorescence analyses were used to elucidate the ECM2 expression pattern in bovine MDSCs during differentiation in vitro. CRISPR/Cas9 technology was used to activate or inhibit ECM2 expression to study its effects on the in vitro differentiation of bovine MDSCs. ECM2 expression was shown to increase gradually during bovine MDSC differentiation, and the levels of this protein were higher in more highly differentiated myotubes. ECM2 activation promoted MDSC differentiation, whereas its suppression inhibited the differentiation of these cells. Here, for the first time, we demonstrated the importance of ECM2 expression during bovine MDSC differentiation; these results could lead to treatments that help to increase beef cattle muscularity. © 2018 International Federation for Cell Biology.

Objective assessment of subjective tinnitus through contralateral suppression of otoacoustic emissions by white noise; suggested cut-off points.

PubMed

Riga, M; Komis, A; Maragkoudakis, P; Korres, G; Danielides, V

2016-12-01

Normative otoacoustic emission (OAE) suppression values are currently lacking and the role of cochlear efferent innervation in tinnitus is controversial. The aim of this study was to investigate the association between tinnitus and medial olivocochlear bundle (MOCB) malfunction. Potential suppression amplitude cut-off criteria that could differentiate participants with tinnitus from those without were sought. Mean suppression amplitudes of transient evoked OAEs and distortion product OAEs by contralateral white noise (50 dBSL) were recorded. Six mean suppression amplitudes criteria were validated as possible cut-off points. The population consisted of normal hearing (n = 78) or presbycusic adults (n = 19) with tinnitus or without (n = 28 and 13, respectively) chronic tinnitus (in total, n = 138 78 females/60males, aged 49 ± 14 years). Participants with mean suppression values lower than 0.5-1 dBSPL seem to present a high probability to report tinnitus (specificity 88-97%). On the other hand, participants with mean suppression values larger than 2-2.5dBSPL seem to present a high probability of the absence of tinnitus (sensitivity 87-99%). Correlations were stronger among participants with bilateral presence or absence of tinnitus. This study seem to confirm an association between tinnitus and low suppression amplitudes (<1 dBSPL), which might evolve into an objective examination tool, supplementary to conventional audiological testing.

Suppressive subtractive hybridization approach revealed differential expression of hypersensitive response and reactive oxygen species production genes in tea (Camellia sinensis (L.) O. Kuntze) leaves during Pestalotiopsis thea infection.

PubMed

Senthilkumar, Palanisamy; Thirugnanasambantham, Krishnaraj; Mandal, Abul Kalam Azad

2012-12-01

Tea (Camellia sinensis (L.) O. Kuntze) is an economically important plant cultivated for its leaves. Infection of Pestalotiopsis theae in leaves causes gray blight disease and enormous loss to the tea industry. We used suppressive subtractive hybridization (SSH) technique to unravel the differential gene expression pattern during gray blight disease development in tea. Complementary DNA from P. theae-infected and uninfected leaves of disease tolerant cultivar UPASI-10 was used as tester and driver populations respectively. Subtraction efficiency was confirmed by comparing abundance of β-actin gene. A total of 377 and 720 clones with insert size >250 bp from forward and reverse library respectively were sequenced and analyzed. Basic Local Alignment Search Tool analysis revealed 17 sequences in forward SSH library have high degree of similarity with disease and hypersensitive response related genes and 20 sequences with hypothetical proteins while in reverse SSH library, 23 sequences have high degree of similarity with disease and stress response-related genes and 15 sequences with hypothetical proteins. Functional analysis indicated unknown (61 and 59 %) or hypothetical functions (23 and 18 %) for most of the differentially regulated genes in forward and reverse SSH library, respectively, while others have important role in different cellular activities. Majority of the upregulated genes are related to hypersensitive response and reactive oxygen species production. Based on these expressed sequence tag data, putative role of differentially expressed genes were discussed in relation to disease. We also demonstrated the efficiency of SSH as a tool in enriching gray blight disease related up- and downregulated genes in tea. The present study revealed that many genes related to disease resistance were suppressed during P. theae infection and enhancing these genes by the application of inducers may impart better disease tolerance to the plants.

Antibiosis functions during interactions of Trichoderma afroharzianum and Trichoderma gamsii with plant pathogenic Rhizoctonia and Pythium.

PubMed

Zhang, Xinjian; Harvey, Paul R; Stummer, Belinda E; Warren, Rosemary A; Zhang, Guangzhi; Guo, Kai; Li, Jishun; Yang, Hetong

2015-09-01

Trichoderma afroharzianum is one of the best characterized Trichoderma species, and strains have been utilized as plant disease suppressive inoculants. In contrast, Trichoderma gamsii has only recently been described, and there is limited knowledge of its disease suppressive efficacies. Comparative studies of changes in gene expression during interactions of these species with their target plant pathogens will provide fundamental information on pathogen antibiosis functions. In the present study, we used complementary DNA amplified fragment length polymorphism (cDNA-AFLP) analysis to investigate changes in transcript profiling of T. afroharzianum strain LTR-2 and T. gamsii strain Tk7a during in vitro interactions with plant pathogenic Rhizoctonia solani and Pythium irregulare. Considerable differences were resolved in the overall expression profiles of strains LTR-2 and Tk7a when challenged with either plant pathogen. In strain LTR-2, previously reported mycoparasitism-related genes such as chitinase, polyketide synthase, and non-ribosomal peptide synthetase were found to be differentially expressed. This was not so for strain Tk7a, with the only previously reported antibiosis-associated genes being small secreted cysteine-rich proteins. Although only one differentially expressed gene was common to both strains LTR-2 and Tk7a, numerous genes reportedly associated with pathogen antibiosis processes were differentially expressed in both strains, including degradative enzymes and membrane transport proteins. A number of novel potential antibiosis-related transcripts were found from strains LTR-2 and Tk7a and remain to be identified. The expression kinetics of 20 Trichoderma (10 from strain LTR-2, 10 from strain Tk7a) transcript-derived fragments (TDFs) were quantified by quantitative reverse transcription PCR (RT-qPCR) at pre- and post-mycelia contact stages of Trichoderma-prey interactions, thereby confirming differential gene expression. Collectively, this research is providing information to elucidate the antibiosis mechanisms and disease suppressive activities of T. afroharzianum and T. gamsii against soilborne fungal and oomycete plant pathogens.

Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

PubMed Central

Schroeder, Barbara; Park, Cheol Hong; Chandra Mohan, KVP; Khurana, Ashwani; Corominas-Faja, Bruna; Cuyàs, Elisabet; Alarcón, Tomás; Kleer, Celina; Menendez, Javier A.; Lupu, Ruth

2016-01-01

The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies. PMID:27223424

The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

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

Yu, Haitao; Du, Yuxuan; Zhang, Xulong

Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity ofmore » Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.« less

Transonic Flutter Suppression Control Law Design, Analysis and Wind-Tunnel Results

NASA Technical Reports Server (NTRS)

Mukhopadhyay, Vivek

1999-01-01

The benchmark active controls technology and wind tunnel test program at NASA Langley Research Center was started with the objective to investigate the nonlinear, unsteady aerodynamics and active flutter suppression of wings in transonic flow. The paper will present the flutter suppression control law design process, numerical nonlinear simulation and wind tunnel test results for the NACA 0012 benchmark active control wing model. The flutter suppression control law design processes using classical, and minimax techniques are described. A unified general formulation and solution for the minimax approach, based on the steady state differential game theory is presented. Design considerations for improving the control law robustness and digital implementation are outlined. It was shown that simple control laws when properly designed based on physical principles, can suppress flutter with limited control power even in the presence of transonic shocks and flow separation. In wind tunnel tests in air and heavy gas medium, the closed-loop flutter dynamic pressure was increased to the tunnel upper limit of 200 psf. The control law robustness and performance predictions were verified in highly nonlinear flow conditions, gain and phase perturbations, and spoiler deployment. A non-design plunge instability condition was also successfully suppressed.

Cognitive and neural consequences of memory suppression in major depressive disorder.

PubMed

Sacchet, Matthew D; Levy, Benjamin J; Hamilton, J Paul; Maksimovskiy, Arkadiy; Hertel, Paula T; Joormann, Jutta; Anderson, Michael C; Wagner, Anthony D; Gotlib, Ian H

2017-02-01

Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD.

2,4,5-TMBA, a natural inhibitor of cyclooxygenase-2, suppresses adipogenesis and promotes lipolysis in 3T3-L1 adipocytes.

PubMed

Wu, Man-Ru; Hou, Ming-Hon; Lin, Ya-Lin; Kuo, Chia-Feng

2012-07-25

Obesity is a global health problem. Because of the high costs and side effects of obesity-treatment drugs, the potential of natural products as alternatives for treating obesity is under exploration. 2,4,5-Trimethoxybenzaldehyde (2,4,5-TMBA) present in plant roots, seeds, and leaves was reported to be a significant inhibitor of cyclooxygenase-2 (COX-2) activity at the concentration of 100 μg/mL. Because COX-2 is associated with differentiation of preadipocytes, the murine 3T3-L1 cells were cultured with 100 μg/mL of 2,4,5-TMBA during differentiation and after the cells were fully differentiated to study the effect of 2,4,5-TMBA on adipogenesis and lipolysis. Oil Red O staining and triglyceride assay revealed that 2,4,5-TMBA inhibited the formation of lipid droplets during differentiation; moreover, 2,4,5-TMBA down-regulated the protein levels of adipogenic signaling molecules and transcription factors MAP kinase kinase (MEK), extracellular signal-regulated kinase (ERK), CCAAT/enhancer binding protein (C/EBP)α, β, and δ, peroxisome proliferator-activated receptor (PPAR)γ, adipocyte determination and differentiation-dependent factor 1 (ADD1), and the rate-limiting enzyme for lipid synthesis acetyl-CoA carboxylase (ACC). In fully differentiated adipocytes, treatment with 2,4,5-TMBA for 72 h significantly decreased lipid accumulation by increasing the hydrolysis of triglyceride through suppression of perilipin A (lipid droplet coating protein) and up-regulation of hormone-sensitive lipase (HSL). The results of this in vitro study will pioneer future in vivo studies on antiobesity effects of 2,4,5-TMBA and selective COX-2 inhibitors.

Restoration of miR-1305 relieves the inhibitory effect of nicotine on periodontal ligament-derived stem cell proliferation, migration, and osteogenic differentiation.

PubMed

Chen, Zhuo; Liu, Hui-Li

2017-04-01

Nicotine hinders the regenerative potentials of human periodontal ligament-derived stem cells (PDLSCs) and delays the healing process of periodontal diseases, but the underlying mechanism remains unclear. miR-1305 upregulation and its potential target RUNX2 downregulation exist in the PDLSCs exposed to nicotine. In this study, we aimed to investigate whether nicotine inhibits PDLSC proliferation, migration, and osteogenic differentiation by increasing miR-1305 level and decreasing RUNX2 level. Quantitative real-time PCR (qRT-PCR) and Western blot assays were performed to detect the expression levels of miR-1305 and RUNX2 in the PDLSCs exposed to nicotine, respectively. PDLSCs with miR-1305 overexpression, low expression, or RUNX2 overexpression were constructed by lipofectin transfection. MTT, migration, and Western blot assays were applied to assess the effect of miR-1305 on PDLSC proliferation, migration, and osteogenic differentiation, respectively. Target prediction and luciferase reporter assays were performed to investigate the targets of miR-1305. Nicotine promoted miR-1305 expression and inhibited RUNX2 expression in PDLSCs. Cell proliferation, migration, and differentiation detection showed that nicotine suppressed proliferation, migration, and osteogenic differentiation of PDLSCs, and restoration of miR-1305 relieved the inhibitory effect of nicotine on PDLSCs. Moreover, we identified and validated that RUNX2 was a direct target of miR-1305, and upregulation of RUNX2 had similar effects with the downregulation of miR-1305 on relieving the inhibitory effect of nicotine on PDLSCs. Nicotine suppresses proliferation, migration, and osteogenic differentiation of PDLSCs, and restoration of miR-1305 relieves the inhibitory effect of nicotine on PDLSCs depending on its target RUNX2. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Inhibition of T Helper Cell Type 2 Cell Differentiation and Immunoglobulin E Response by Ligand-Activated Vα14 Natural Killer T Cells

PubMed Central

Cui, Junqing; Watanabe, Naohiro; Kawano, Tetsu; Yamashita, Masakatsu; Kamata, Tohru; Shimizu, Chiori; Kimura, Motoko; Shimizu, Eiko; Koike, Jyunzo; Koseki, Haruhiko; Tanaka, Yujiro; Taniguchi, Masaru; Nakayama, Toshinori

1999-01-01

Murine Vα14 natural killer T (NKT) cells are thought to play a crucial role in various immune responses, including infectious, allergic, and autoimmune diseases. Because Vα14 NKT cells produce large amounts of both interleukin (IL)-4 and interferon (IFN)-γ upon in vivo stimulation with a specific ligand, α-galactosylceramide (α-GalCer), or after treatment with anti-CD3 antibody, a regulatory role on helper T (Th) cell differentiation has been proposed for these cells. However, the identity of the cytokine produced by Vα14 NKT cells that play a dominant role on the Th cell differentiation still remains controversial. Here, we demonstrate by using Vα14 NKT-deficient mice that Vα14 NKT cells are dispensable for the induction of antigen-specific immunoglobulin (Ig)E responses induced by ovalbumin immunization or Nippostrongylus brasiliensis infection. However, upon in vivo activation with α-GalCer, Vα14 NKT cells are found to suppress antigen-specific IgE production. The suppression appeared to be IgE specific, and was not detected in either Vα14 NKT– or IFN-γ–deficient mice. Consistent with these results, we also found that ligand-activated Vα14 NKT cells inhibited Th2 cell differentiation in an in vitro induction culture system. Thus, it is likely that activated Vα14 NKT cells exert a potent inhibitory effect on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In marked contrast, our studies have revealed that IL-4 produced by Vα14 NKT cells has only a minor effect on Th2 cell differentiation. PMID:10499917

Identification of differentially expressed genes of brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss) in response to Tetracapsuloides bryosalmonae (Myxozoa).

PubMed

Kumar, Gokhlesh; Abd-Elfattah, Ahmed; El-Matbouli, Mansour

2015-03-01

Tetracapsuloides bryosalmonae Canning et al., 1999 (Myxozoa) is the causative agent of proliferative kidney disease in various species of salmonids in Europe and North America. We have shown previously that the development and distribution of the European strain of T. bryosalmonae differs in the kidney of brown trout (Salmo trutta) Linnaeus, 1758 and rainbow trout (Oncorhynchus mykiss) Walbaum, 1792, and that intra-luminal sporogonic stages were found in brown trout but not in rainbow trout. We have now compared transcriptomes from kidneys of brown trout and rainbow trout infected with T. bryosalmonae using suppressive subtractive hybridization (SSH). The differentially expressed transcripts produced by SSH were cloned, transformed, and tested by colony PCR. Differential expression screening of PCR products was validated using dot blot, and positive clones having different signal intensities were sequenced. Differential screening and a subsequent NCBI-BLAST analysis of expressed sequence tags revealed nine clones expressed differently between both fish species. These differentially expressed genes were validated by quantitative real-time PCR of kidney samples from both fish species at different time points of infection. Expression of anti-inflammatory (TSC22 domain family protein 3) and cell proliferation (Prothymin alpha) genes were upregulated significantly in brown trout but downregulated in rainbow trout. The expression of humoral immune response (immunoglobulin mu) and endocytic pathway (Ras-related protein Rab-11b) genes were significantly upregulated in rainbow trout but downregulated in brown trout. This study suggests that differential expression of host anti-inflammatory, humoral immune and endocytic pathway responses, cell proliferation, and cell growth processes do not inhibit the development of intra-luminal sporogonic stages of the European strain of T. bryosalmonae in brown trout but may suppress it in rainbow trout.

Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.

PubMed

Garcia, I; Crowther, A J; Gama, V; Miller, C R; Miller, C Ryan; Deshmukh, M; Gershon, T R

2013-05-02

Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.

Nitric Oxide Modulates TGF-β–Directive Signals To Suppress Foxp3+ Regulatory T Cell Differentiation and Potentiate Th1 Development

PubMed Central

Lee, Seung-Woo; Choi, Heonsik; Eun, So-Young; Fukuyama, Satoshi; Croft, Michael

2011-01-01

TGF-β can induce Foxp3+ inducible regulatory T cells (Treg) and also synergize with IL-6 and IL-4 to induce Th17 and Th9 cells. We now report that NO modulates TGF-β activity away from Treg but toward the Th1 lineage. NO potentiated Th1 differentiation in the presence of TGF-β in both IL-12–independent and –dependent fashions by augmenting IFN-γ–activated STAT-1 and T-bet. Differentiation into Treg, Th1, and Th17 lineages could be modulated by NO competing with other cofactors, such as IL-6 and retinoic acid. NO antagonized IL-6 to block TGF-β–directed Th17 differentiation, and together with IL-6, NO suppressed Treg development induced by TGF-β and retinoic acid. Furthermore, we show that physiologically produced NO from TNF and inducible NO synthase-producing dendritic cells can contribute to Th1 development predominating over Treg development through a synergistic activity induced when these cells cocluster with conventional dendritic cells presenting Ag to naive Th cells. This illustrates that NO is another cofactor allowing TGF-β to participate in development of multiple Th lineages and suggests a new mechanism by which NO, which is associated with protection against intracellular pathogens, might maintain effective Th1 immunity. PMID:21555530

TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

PubMed Central

Cammareri, Patrizia; Vincent, David F; Hodder, Michael C; Ridgway, Rachel A; Murgia, Claudio; Nobis, Max; Campbell, Andrew D; Varga, Julia; Huels, David J; Subramani, Chithra; Prescott, Katie L H; Nixon, Colin; Hedley, Ann; Barry, Simon T; Greten, Florian R; Inman, Gareth J; Sansom, Owen J

2017-01-01

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment. PMID:28622298

Identification of differentially expressed genes in the oviduct of two rabbit lines divergently selected for uterine capacity using suppression subtractive hybridization.

PubMed

Ballester, M; Castelló, A; Peiró, R; Argente, M J; Santacreu, M A; Folch, J M

2013-06-01

Suppressive subtractive hybridization libraries from oviduct at 62 h post-mating of two lines of rabbits divergently selected for uterine capacity were generated to identify differentially expressed genes. A total of 438 singletons and 126 contigs were obtained by cluster assembly and sequence alignment of 704 expressed sequence tags (ESTs), of which 54% showed homology to known proteins of the non-redundant NCBI databases. Differential screening by dot blot validated 71 ESTs, of which 47 showed similarity to known genes. Transcripts of genes were functionally annotated in the molecular function and the biological process gene ontology categories using the BLAST2GO software and were assigned to reproductive developmental process, immune response, amino acid metabolism and degradation, response to stress and apoptosis terms. Finally, three interesting genes, PGR, HSD17B4 and ERO1L, were identified as overexpressed in the low line using RT-qPCR. Our study provides a list of candidate genes that can be useful to understanding the molecular mechanisms underlying the phenotypic differences observed in early embryo survival and development traits. © 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics.

Rapamycin promotes differentiation increasing βIII-tubulin, NeuN, and NeuroD while suppressing nestin expression in glioblastoma cells

PubMed Central

Lenzi, Paola; Gambardella, Stefano; Ferese, Rosangela; Calierno, Maria Teresa; Falleni, Alessandra; Grimaldi, Alfonso; Frati, Alessandro; Esposito, Vincenzo; Limatola, Cristina; Fornai, Francesco

2017-01-01

Glioblastoma cells feature mammalian target of rapamycin (mTOR) up-regulation which relates to a variety of effects such as: lower survival, higher infiltration, high stemness and radio- and chemo-resistance. Recently, it was demonstrated that mTOR may produce a gene shift leading to altered protein expression. Therefore, in the present study we administered different doses of the mTOR inhibitor rapamycin to explore whether the transcription of specific genes are modified. By using a variety of methods we demonstrate that rapamycin stimulates gene transcription related to neuronal differentiation while inhibiting stemness related genes such as nestin. In these experimental conditions, cell phenotype shifts towards a pyramidal neuron-like shape owing long branches. Rapamycin suppressed cell migration when exposed to fetal bovine serum (FBS) while increasing the cell adhesion protein phospho-FAK (pFAK). The present study improves our awareness of basic mechanisms which relate mTOR activity to the biology of glioblastoma cells. These findings apply to a variety of effects which can be induced by mTOR regulation in the brain. In fact, the ability to promote neuronal differentiation might be viewed as a novel therapeutic pathway to approach neuronal regeneration. PMID:28418837

Rapamycin promotes differentiation increasing βIII-tubulin, NeuN, and NeuroD while suppressing nestin expression in glioblastoma cells.

PubMed

Ferrucci, Michela; Biagioni, Francesca; Lenzi, Paola; Gambardella, Stefano; Ferese, Rosangela; Calierno, Maria Teresa; Falleni, Alessandra; Grimaldi, Alfonso; Frati, Alessandro; Esposito, Vincenzo; Limatola, Cristina; Fornai, Francesco

2017-05-02

Glioblastoma cells feature mammalian target of rapamycin (mTOR) up-regulation which relates to a variety of effects such as: lower survival, higher infiltration, high stemness and radio- and chemo-resistance. Recently, it was demonstrated that mTOR may produce a gene shift leading to altered protein expression. Therefore, in the present study we administered different doses of the mTOR inhibitor rapamycin to explore whether the transcription of specific genes are modified. By using a variety of methods we demonstrate that rapamycin stimulates gene transcription related to neuronal differentiation while inhibiting stemness related genes such as nestin. In these experimental conditions, cell phenotype shifts towards a pyramidal neuron-like shape owing long branches. Rapamycin suppressed cell migration when exposed to fetal bovine serum (FBS) while increasing the cell adhesion protein phospho-FAK (pFAK). The present study improves our awareness of basic mechanisms which relate mTOR activity to the biology of glioblastoma cells. These findings apply to a variety of effects which can be induced by mTOR regulation in the brain. In fact, the ability to promote neuronal differentiation might be viewed as a novel therapeutic pathway to approach neuronal regeneration.

Time-delayed feedback control of diffusion in random walkers.

PubMed

Ando, Hiroyasu; Takehara, Kohta; Kobayashi, Miki U

2017-07-01

Time delay in general leads to instability in some systems, while specific feedback with delay can control fluctuated motion in nonlinear deterministic systems to a stable state. In this paper, we consider a stochastic process, i.e., a random walk, and observe its diffusion phenomenon with time-delayed feedback. As a result, the diffusion coefficient decreases with increasing delay time. We analytically illustrate this suppression of diffusion by using stochastic delay differential equations and justify the feasibility of this suppression by applying time-delayed feedback to a molecular dynamics model.

Halenaquinone inhibits RANKL-induced osteoclastogenesis.

PubMed

Tsukamoto, Sachiko; Takeuchi, Tomoharu; Kawabata, Tetsuro; Kato, Hikaru; Yamakuma, Michiko; Matsuo, Kanae; El-Desoky, Ahmed H; Losung, Fitje; Mangindaan, Remy E P; de Voogd, Nicole J; Arata, Yoichiro; Yokosawa, Hideyoshi

2014-11-15

Halenaquinone was isolated from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells. It inhibited the RANKL (receptor activator of nuclear factor-κB ligand)-induced upregulation of TRAP (tartrate-resistant acid phosphatase) activity as well as the formation of multinuclear osteoclasts. In addition, halenaquinone substantially suppressed RANKL-induced IκB degradation and Akt phosphorylation. Thus, these results suggest that halenaquinone inhibits RANKL-induced osteoclastogenesis at least by suppressing the NF-κB and Akt signaling pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation

PubMed Central

Azimova, Dinara R.

2016-01-01

Despite extensive knowledge about the transcriptional regulation of stem cell differentiation, less is known about the role of dynamic cytosolic cues. We report that an increase in intracellular pH (pHi) is necessary for the efficient differentiation of Drosophila adult follicle stem cells (FSCs) and mouse embryonic stem cells (mESCs). We show that pHi increases with differentiation from FSCs to prefollicle cells (pFCs) and follicle cells. Loss of the Drosophila Na+–H+ exchanger DNhe2 lowers pHi in differentiating cells, impairs pFC differentiation, disrupts germarium morphology, and decreases fecundity. In contrast, increasing pHi promotes excess pFC cell differentiation toward a polar/stalk cell fate through suppressing Hedgehog pathway activity. Increased pHi also occurs with mESC differentiation and, when prevented, attenuates spontaneous differentiation of naive cells, as determined by expression of microRNA clusters and stage-specific markers. Our findings reveal a previously unrecognized role of pHi dynamics for the differentiation of two distinct types of stem cell lineages, which opens new directions for understanding conserved regulatory mechanisms. PMID:27821494

Caffeic acid phenethyl ester suppresses monocyte adhesion to the endothelium by inhibiting NF-κB/NOX2-derived ROS signaling

PubMed Central

Nakahara, Risa; Makino, Junya; Kamiya, Tetsuro; Hara, Hirokazu; Adachi, Tetsuo

2016-01-01

Caffeic acid phenethyl ester (CAPE), one of the major polyphenols, exhibits anti-oxidative, anti-bacterial, and anti-cancer properties. Atherosclerosis is a chronic inflammatory disease, the progression of which is closely related to the accumulated adhesion of inflammatory monocytes/macrophages to the endothelium. We herein determined whether CAPE and its derivatives suppressed THP-1 cell adhesion to human umbilical vein endothelial cells (HUVEC). Of the four polyphenols tested, CAPE significantly suppressed the 12-O-tetradecanoylphorbol 13-acetate (TPA)-elicited expression of cluster for differentiation (CD) 11b, 14, and 36, and this was accompanied by the inhibition of THP-1 cell adhesion to HUVEC. CAPE also suppressed the activation of TPA-elicited nuclear factor-κB (NF-κB) and accumulation of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS), but did not affect extracellular signal-regulated kinase (ERK) phosphorylation. Taken together, these results demonstrated that CAPE suppressed THP-1 cell adhesion to HUVEC through, at least in part, the NF-κB, NOX2, and ROS-derived signaling axis. PMID:27257341

The histone methyltransferase Smyd2 is a negative regulator of macrophage activation by suppressing interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) production.

PubMed

Xu, Guiliang; Liu, Guilin; Xiong, Sidong; Liu, Haiyan; Chen, Xi; Zheng, Biao

2015-02-27

SET and MYND domain-containing 2 (Smyd2), a histone 3 lysine 4- and histone 3 lysine 36 (H3K36)-specific methyltransferase, plays critical roles in cardiac development and tumorigenesis. However, the role of Smyd2 in immunity and inflammation remains poorly understood. In this study, we report that Smyd2 is a novel negative regulator for macrophage activation and M1 polarization. Elevated Smyd2 expression suppresses the production of proinflammatory cytokines, including IL-6 and TNF, and inhibits the expression of important cell surface molecules, including major MHC-II and costimulatory molecules. Furthermore, macrophages with high Smyd2 expression inhibit Th-17 cell differentiation but promote regulatory T cell differentiation as a result of increased TGF-β production and decreased IL-6 secretion. In macrophages, Smyd2 specifically facilitates H3K36 dimethylation at Tnf and Il6 promoters to suppress their transcription and inhibits NF-κB and ERK signaling. Therefore, our data demonstrate that epigenetic modification by Smyd2-mediated H3K36 dimethylation at Tnf and Il6 promoters plays an important role in the regulation of macrophage activation during inflammation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Leptin Directly Promotes T Cell Glycolytic Metabolism to Drive Effector T cell Differentiation in Autoimmunity

PubMed Central

Gerriets, Valerie A.; Danzaki, Keiko; Kishton, Rigel J.; Eisner, William; Nichols, Amanda G.; Saucillo, Donte C.; Shinohara, Mari L.; MacIver, Nancie J.

2016-01-01

Upon activation, T cells require energy for growth, proliferation and function. Effector T cells (Teff), such as Th1 and Th17, utilize high levels of glucose uptake and glycolysis to fuel proliferation and function. In contrast, Treg instead require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg metabolism is altered in settings of malnutrition, when nutrients are limited and circulating leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg. We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff number, function, and glucose metabolism, but did not alter Treg metabolism or suppressive function. Using the autoimmune model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff, but not Treg, glucose metabolism and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of Th17 differentiation and Teff glucose metabolism, and found HIF-1α expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg. PMID:27222115

Novel genetic factors involved in resistance to Bacillus thuringiensis in Plutella xylostella.

PubMed

Ayra-Pardo, C; Raymond, B; Gulzar, A; Rodríguez-Cabrera, L; Morán-Bertot, I; Crickmore, N; Wright, D J

2015-12-01

The widespread and sustainable exploitation of the entomopathogen Bacillus thuringiensis (Bt) in pest control is threatened by the evolution of resistance. Although resistance is often associated with loss of binding of the Bt toxins to the insect midgut cells, other factors have been implicated. Here we used suppressive subtractive hybridization and gene expression suppression to identify additional molecular components involved in Bt-resistance in Plutella xylostella. We isolated transcripts from genes that were differentially expressed in the midgut of larvae from a resistant population, following ingestion of a Bt kurstaki HD1 strain-based commercial formulation (DiPel), and compared with a genetically similar susceptible population. Quantitative real-time polymerase-chain reaction (RT-PCR) analysis confirmed the differential basal expression of a subset of these genes. Gene expression suppression of three of these genes (P. xylostella cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1, stromal cell-derived factor 2-like 1 and hatching enzyme-like 1) significantly increased the pathogenicity of HD1 to the resistant population. In an attempt to link the multitude of factors reportedly influencing resistance to Bt with the well-characterized loss of toxin binding, we also considered Bt-resistance models in P. xylostella and other insects. © 2015 The Royal Entomological Society.

Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

PubMed

Endo, Toyoshi; Kobayashi, Tetsuro

2013-09-01

Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were severely hypothyroid and had similar serum Ca(2+) and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in the growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate compared with that of wild-type mice. Expressions of chondrocyte differentiation marker genes Sox-9 and type IIa collagen in growth plate from THYx mice were 52 and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

Runx2- and histone deacetylase 3-mediated repression is relieved in differentiating human osteoblast cells to allow high bone sialoprotein expression.

PubMed

Lamour, Virginie; Detry, Cédric; Sanchez, Christelle; Henrotin, Yves; Castronovo, Vincent; Bellahcène, Akeila

2007-12-14

Bone sialoprotein (BSP) is a bone matrix glycoprotein whose expression coincides with terminal osteoblastic differentiation and the onset of mineralization. In this study we show that BSP expression is considerably increased in confluent Saos-2 human osteosarcoma cells and in differentiating normal human osteoblasts, concomitantly with the decrease of Runx2, a key transcription factor controlling bone formation. Therefore, we investigated the role of Runx2 in the regulation of BSP expression in Saos-2 cells. Using a mobility shift assay, we demonstrated that Runx2 binds to the BSP promoter only in preconfluent cells. Histone deacetylase 3 (HDAC3) has been recently shown to act as a Runx2 co-repressor. Chromatin immunoprecipitation assays demonstrated that both Runx2 and HDAC3 are detectable at the BSP promoter in preconfluent Saos-2 cells but not when they are confluent and overexpress BSP. Consistently, nuclear Runx2 protein level is down-regulated, whereas Saos-2 cells became increasingly confluent. Finally, the suppression of HDAC3, Runx2, or both by RNA interference induced the expression of BSP at both mRNA and protein levels in Saos-2 cells. Our data demonstrate that Runx2 and HDAC3 repress BSP gene expression and that this repression is suspended upon osteoblastic cell differentiation. Both the nuclear disappearance of Runx2 and the non-recruitment of HDAC3 represent new means to relieve Runx2-mediated suppression of BSP expression, thus allowing the acquisition of a fully differentiated and mineralization-competent phenotype by osteoblast cells.

Effects of genistein, a soybean-derived isoflavone, on proliferation and differentiation of B16-BL6 mouse melanoma cells.

PubMed

Yan, C H; Chen, X G; Li, Y; Han, R

1999-01-01

Genistein, a soybean-derived isoflavone, may contribute to the lower cancer incidence in South Asian countries. In this study, the effects and molecular mechanisms of genistein on growth and differentiation of B16-BL6 mouse melanoma cells were investigated. Genistein suppressed the growth of these melanoma cells. The IC50 value is 15.5 microM. On the other hand, genistein induced the changes of cell shape and cytoskeletal network. The cytoskeletal filaments were induced to form a bundle along the direction of elongation of the cells. Moreover, tyrosine phosphorylation levels of cytoskeleton-associated proteins decreased after the cells were exposed to 20 or 30 microM of genistein for 3 days. All these morphological and molecular changes were accompanied by appearance of the differentiated phenotypes. Genistein induced the increase of cellular melanin content, enhancement of tyrosinase activity, and decrease of colonization potentials in soft agar in a time-dependent and dose-dependent manner. The effective concentration was no more than 10 microM after 3 days' exposure. The tumorigenic potentials of B16-BL6 cells in C57BL/6 mouse also decreased after exposure to 20 or 30 microM of genistein for 3 days. When expressions of tumor-related genes were investigated in the differentiation-induced cells, the content of P53 dramatically increased while that of c-Myc protein decreased. Therefore, due to its ability to induce cellular and molecular changes, genistein suppressed the growth and induced differentiated phenotypes in B16-BL6 melanoma cells.

A suppression of differential rotation in Jupiter’s deep interior

NASA Astrophysics Data System (ADS)

Guillot, T.; Miguel, Y.; Militzer, B.; Hubbard, W. B.; Kaspi, Y.; Galanti, E.; Cao, H.; Helled, R.; Wahl, S. M.; Iess, L.; Folkner, W. M.; Stevenson, D. J.; Lunine, J. I.; Reese, D. R.; Biekman, A.; Parisi, M.; Durante, D.; Connerney, J. E. P.; Levin, S. M.; Bolton, S. J.

2018-03-01

Jupiter’s atmosphere is rotating differentially, with zones and belts rotating at speeds that differ by up to 100 metres per second. Whether this is also true of the gas giant’s interior has been unknown, limiting our ability to probe the structure and composition of the planet. The discovery by the Juno spacecraft that Jupiter’s gravity field is north–south asymmetric and the determination of its non-zero odd gravitational harmonics J3, J5, J7 and J9 demonstrates that the observed zonal cloud flow must persist to a depth of about 3,000 kilometres from the cloud tops. Here we report an analysis of Jupiter’s even gravitational harmonics J4, J6, J8 and J10 as observed by Juno and compared to the predictions of interior models. We find that the deep interior of the planet rotates nearly as a rigid body, with differential rotation decreasing by at least an order of magnitude compared to the atmosphere. Moreover, we find that the atmospheric zonal flow extends to more than 2,000 kilometres and to less than 3,500 kilometres, making it fully consistent with the constraints obtained independently from the odd gravitational harmonics. This depth corresponds to the point at which the electric conductivity becomes large and magnetic drag should suppress differential rotation. Given that electric conductivity is dependent on planetary mass, we expect the outer, differentially rotating region to be at least three times deeper in Saturn and to be shallower in massive giant planets and brown dwarfs.

Myostatin inhibits myosatellite cell proliferation and consequently activates differentiation: evidence for endocrine-regulated transcript processing.

PubMed

Garikipati, Dilip K; Rodgers, Buel D

2012-10-01

Myostatin is a potent negative regulator of muscle growth in mammals. Despite high structural conservation, functional conservation in nonmammalian species is only assumed. This is particularly true for fish due to the presence of several myostatin paralogs: two in most species and four in salmonids (MSTN-1a, -1b, -2a, and -2b). Rainbow trout are a rich source of primary myosatellite cells as hyperplastic muscle growth occurs even in adult fish. These cells were therefore used to determine myostatin's effects on proliferation whereas our earlier studies reported its effects on quiescent cells. As in mammals, recombinant myostatin suppressed proliferation with no changes in cell morphology. Expression of MSTN-1a was several fold higher than the other paralogs and was autoregulated by myostatin, which also upregulated the expression of key differentiation markers: Myf5, MyoD1, myogenin, and myosin light chain. Thus, myostatin-stimulated cellular growth inhibition activates rather than represses differentiation. IGF-1 stimulated proliferation but had minimal and delayed effects on differentiation and its actions were suppressed by myostatin. However, IGF-1 upregulated MSTN-2a expression and the processing of its transcript, which is normally unprocessed. Myostatin therefore appears to partly mediate IGF-stimulated myosatellite differentiation in rainbow trout. This also occurs in mammals, although the IGF-stimulated processing of MSTN-2a transcripts is highly unique and is indicative of subfunctionalization within the gene family. These studies also suggest that the myokine's actions, including its antagonistic relationship with IGF-1, are conserved and that the salmonid gene family is functionally diverging.

Three-dimensional OCT based guinea pig eye model: relating morphology and optics.

PubMed

Pérez-Merino, Pablo; Velasco-Ocana, Miriam; Martinez-Enriquez, Eduardo; Revuelta, Luis; McFadden, Sally A; Marcos, Susana

2017-04-01

Custom Spectral Optical Coherence Tomography (SOCT) provided with automatic quantification and distortion correction algorithms was used to measure the 3-D morphology in guinea pig eyes (n = 8, 30 days; n = 5, 40 days). Animals were measured awake in vivo under cyclopegia. Measurements showed low intraocular variability (<4% in corneal and anterior lens radii and <8% in the posterior lens radii, <1% interocular distances). The repeatability of the surface elevation was less than 2 µm. Surface astigmatism was the individual dominant term in all surfaces. Higher-order RMS surface elevation was largest in the posterior lens. Individual surface elevation Zernike terms correlated significantly across corneal and anterior lens surfaces. Higher-order-aberrations (except spherical aberration) were comparable with those predicted by OCT-based eye models.

ING4 Loss in Prostate Cancer Progression

DTIC Science & Technology

2016-10-01

proper transitioning from late stage pregnancy to early lactation [12]. ING4 expres- sion is also lost in some breast cancers [13] where it may suppress...differentiation, Pten is elevated early (Fig. 6a), but decreases after ING4 is induced and CREB becomes active (after day 10). In EMP cells, CREB/ATF1 is...constitutive CREB/ATF1 activation (Fig. 6c) as early as 4 days after differentiation, before it is detected in normal PrECs. We observed a

Measurement of the Diphoton Differential Cross Section in p anti-p Collisions at √s = 1.96-TeV

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

Dyer, Joshua Marc

The diphoton differential cross-section as a function of mass up to 300 GeV/c 2, q T up to 100 GeV/c, and opening angle over a range of 0 to π radians is measured. The measurement is performed using 1046.19 pb -1 of data collected at Fermi National Accelerator Laboratory using the D0 detector. This analysis considers all direct diphoton states but attempts to suppress contributions due to fragmentation.

Frequency-noise cancellation in semiconductor lasers by nonlinear heterodyne detection.

PubMed

Bondurant, R S; Welford, D; Alexander, S B; Chan, V W

1986-12-01

The bit-error-rate (BER) performance of conventional noncoherent, heterodyne frequency-shift-keyed (FSK) optical communications systems can be surpassed by the use of a differential FSK modulation format and nonlinear postdetection processing at the receiver. A BER floor exists for conventional frequency-shift keying because of the frequency noise of the transmitter and local oscillator. The use of differential frequency-shift keying with nonlinear postdetection processing suppresses this BER floor for the semiconductor laser system considered here.

Development of the updating executive function: From 7-year-olds to young adults.

PubMed

Carriedo, Nuria; Corral, Antonio; Montoro, Pedro R; Herrero, Laura; Rucián, Mercedes

2016-04-01

Updating information in working memory (WM) is a critical executive function responsible both for continuously replacing outdated information with new relevant data and to suppress or inhibit content that is no longer relevant according to task demands. The goal of the present research is twofold: First, we aimed to study updating development in 548 participants of 4 different age ranges--7-, 11-, and 15-year-olds and young adults--using the updating task devised by R. De Beni and P. Palladino (2004), which allows differentiating maintenance and inhibition processes. Second, we attempted to determine the relation between these processes across development as well as the differentiation among different types of inhibition processes tapped by this task. Results showed that there was an improvement of memory performance with age along with an upgrading of inhibitory efficiency. However, whereas in memory performance, a progressive increase was observed until the age of 15 years followed by stabilization, in inhibition, a continuous progressive increase was observed until young adulthood. Importantly, results showed that development of the different inhibitory mechanisms does not progress equally. All the groups committed more errors related to inefficient suppression mechanisms in WM than errors related to control of long-term memory interference. Principal component analysis showed that updating implies different subprocesses: active maintenance/suppression of information in WM and control of proactive interference. Developmental trajectories showed that the maintenance/suppression of information in the WM component continues to develop far beyond adolescence but that proactive interference control is responsible for variations in updating across development. (c) 2016 APA, all rights reserved).

MiR-29-mediated elastin down-regulation contributes to inorganic phosphorus-induced osteoblastic differentiation in vascular smooth muscle cells.

PubMed

Sudo, Ryo; Sato, Fumiaki; Azechi, Takuya; Wachi, Hiroshi

2015-12-01

Vascular calcification increases the risk of cardiovascular mortality. We previously reported that expression of elastin decreases with progression of inorganic phosphorus (Pi)-induced vascular smooth muscle cell (VSMC) calcification. However, the regulatory mechanisms of elastin mRNA expression during vascular calcification remain unclear. MicroRNA-29 family members (miR-29a, b and c) are reported to mediate elastin mRNA expression. Therefore, we aimed to determine the effect of miR-29 on elastin expression and Pi-induced vascular calcification. Calcification of human VSMCs was induced by Pi and evaluated measuring calcium deposition. Pi stimulation promoted Ca deposition and suppressed elastin expression in VSMCs. Knockdown of elastin expression by shRNA also promoted Pi-induced VSMC calcification. Elastin pre-mRNA measurements indicated that Pi stimulation suppressed elastin expression without changing transcriptional activity. Conversely, Pi stimulation increased miR-29a and miR-29b expression. Inhibition of miR-29 recovered elastin expression and suppressed calcification in Pi-treated VSMCs. Furthermore, over-expression of miR-29b promoted Pi-induced VSMC calcification. RT-qPCR analysis showed knockdown of elastin expression in VSMCs induced expression of osteoblast-related genes, similar to Pi stimulation, and recovery of elastin expression by miR-29 inhibition reduced their expression. Our study shows that miR-29-mediated suppression of elastin expression in VSMCs plays a pivotal role in osteoblastic differentiation leading to vascular calcification. © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

IL-33 inhibits RANKL-induced osteoclast formation through the regulation of Blimp-1 and IRF-8 expression

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

Kiyomiya, Hiroyasu; Division of Oral and Maxillofacial Surgery, Department of Science of Physical Functions, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580; Ariyoshi, Wataru

2015-05-01

Interleukin (IL)-33 is a recently discovered proinflammatory cytokine that belongs to the IL-1 family. Several studies have reported that IL-33 inhibits osteoclast differentiation. However, the mechanism of IL-33 regulation of osteoclastogenesis remains unclear. In the present study, we examined the effect of IL-33 on osteoclast formation in vitro. IL-33 suppressed osteoclast formation in both mouse bone marrow cells and monocyte/macrophage cell line RAW264.7 cells induced by receptor activator of NF-κB ligand (RANKL) and/or macrophage stimulating factor (M-CSF). IL-33 also inhibited the expression of RANKL-induced nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), thereby decreasing the expression of osteoclastogenesis-related marker genes, includingmore » Cathepsin K, Osteoclast stimulatory transmembrane protein (Oc-stamp) and Tartrate-resistant acid phosphatase (Trap). Blockage of IL-33-ST2 binding suppressed the IL-33-mediated inhibition of NFATc1. RANKL-induced B-lymphocyte-induced maturation protein-1 (Blimp-1) expression was also suppressed by IL-33, which was followed by the stimulation of anti-osteoclastic genes such as interferon regulatory factor-8 (IRF-8). These results suggest that IL-33-ST2 interactions down-regulate both RANKL-induced NFATc1 activation and osteoclast differentiation via the regulation of Blimp-1 and IRF-8 expression. - Highlights: • IL-33 inhibits RANKL-induced osteoclast formation. • IL-33 has inhibitory effect on the RANKL-induced NFATc1 expression. • IL-33-induced NFATc1 suppression depends on the regulation of Blimp-1 and IRF-8.« less

Laser pumped 4He magnetometer with light shift suppression

NASA Astrophysics Data System (ADS)

Lin, Zaisheng; Wang, He; Peng, Xiang; Wu, Teng; Guo, Hong

2016-11-01

We report a laser-pumped 4He atomic magnetometer with light shift suppression through the atomic sensor itself. A linearly polarized light is used to optically align the 4He metastable atoms and we monitor the magneto-optical double resonance (MODR) signals produced by the left- and right-circularly orthogonal components. It is shown that light shift leads to the atomic alignment to orientation conversion effect, and thus, the difference between the two MODR signals. One of these two MODR signals is locked at the Larmor frequency and is used to measure the ambient magnetic field, while the differential signal is, simultaneously, fed back to suppress the light shift. The scheme could be of the advantage to the design of compact magnetometers by reducing the systematic errors due to light shift.

Tunneling probe of fluctuating superconductivity in disordered thin films

NASA Astrophysics Data System (ADS)

Dentelski, David; Frydman, Aviad; Shimshoni, Efrat; Dalla Torre, Emanuele G.

2018-03-01

Disordered thin films close to the superconductor-insulator phase transition (SIT) hold the key to understanding quantum phase transition in strongly correlated materials. The SIT is governed by superconducting quantum fluctuations, which can be revealed, for example, by tunneling measurements. These experiments detect a spectral gap, accompanied by suppressed coherence peaks, on both sides of the transition. Here we describe the insulating side in terms of a fluctuating superconducting field with finite-range correlations. We perform a controlled diagrammatic resummation and derive analytic expressions for the tunneling differential conductance. We find that short-range superconducting fluctuations suppress the coherence peaks even in the presence of long-range correlations. Our approach offers a quantitative description of existing measurements on disordered thin films and accounts for tunneling spectra with suppressed coherence peaks.

Pluripotency factors in embryonic stem cells regulate differentiation into germ layers.

PubMed

Thomson, Matt; Liu, Siyuan John; Zou, Ling-Nan; Smith, Zack; Meissner, Alexander; Ramanathan, Sharad

2011-06-10

Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells. Copyright © 2011 Elsevier Inc. All rights reserved.

The Drosophila Sp8 transcription factor Buttonhead prevents premature differentiation of intermediate neural progenitors

PubMed Central

Xie, Yonggang; Li, Xiaosu; Zhang, Xian; Mei, Shaolin; Li, Hongyu; Urso, Andreacarola; Zhu, Sijun

2014-01-01

Intermediate neural progenitor cells (INPs) need to avoid differentiation and cell cycle exit while maintaining restricted developmental potential, but mechanisms preventing differentiation and cell cycle exit of INPs are not well understood. In this study, we report that the Drosophila homolog of mammalian Sp8 transcription factor Buttonhead (Btd) prevents premature differentiation and cell cycle exit of INPs in Drosophila larval type II neuroblast (NB) lineages. We show that the loss of Btd leads to elimination of mature INPs due to premature differentiation of INPs into terminally dividing ganglion mother cells. We provide evidence to demonstrate that Btd prevents the premature differentiation by suppressing the expression of the homeodomain protein Prospero in immature INPs. We further show that Btd functions cooperatively with the Ets transcription factor Pointed P1 to promote the generation of INPs. Thus, our work reveals a critical mechanism that prevents premature differentiation and cell cycle exit of Drosophila INPs. DOI: http://dx.doi.org/10.7554/eLife.03596.001 PMID:25285448

Inactivation of EGFR/AKT signaling enhances TSA-induced ovarian cancer cell differentiation.

PubMed

Shao, Genbao; Lai, Wensheng; Wan, Xiaolei; Xue, Jing; Wei, Ye; Jin, Jie; Zhang, Liuping; Lin, Qiong; Shao, Qixiang; Zou, Shengqiang

2017-05-01

Ovarian tumor is one of the most lethal gynecologic cancers, but differentiation therapy for this cancer is poorly characterized. Here, we show that thrichostatin A (TSA), the well known inhibitor of histone deacetylases (HDACs), can induce cell differentiation in HO8910 ovarian cancer cells. TSA-induced cell differentiation is characterized by typical morphological change, increased expression of the differentiation marker FOXA2, decreased expression of the pluripotency markers SOX2 and OCT4, suppressing cell proliferation, and cell cycle arrest in the G1 phase. TSA also induces an elevated expression of cell cycle inhibitory protein p21Cip1 along with a decrease in cell cycle regulatory protein cyclin D1. Significantly, blockage of epidermal growth factor receptor (EGFR) signaling pathway with specific inhibitors of this signaling cascade promotes the TSA-induced differentiation of HO8910 cells. These results imply that the EGFR cascade inhibitors in combination with TSA may represent a promising differentiation therapy strategy for ovarian cancer.

Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice

PubMed Central

Xue, Yansong; Zhang, Hanying; Sun, Xiaofei; Zhu, Mei-Jun

2016-01-01

Background and aims The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. Methods Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro. Results Compared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1β, TNF-α and IFN-γ expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-α-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation. Conclusions Metformin supplementation promotes secretory cell lineage differentiation, suppresses inflammation and improves epithelial barrier function in IL10KO mice likely through activation of AMPK, showing its beneficial effects on gut epithelial. PMID:28002460

Calreticulin Regulates VEGF-A in Neuroblastoma Cells.

PubMed

Weng, Wen-Chin; Lin, Kuan-Hung; Wu, Pei-Yi; Lu, Yi-Chien; Weng, Yi-Cheng; Wang, Bo-Jeng; Liao, Yung-Feng; Hsu, Wen-Ming; Lee, Wang-Tso; Lee, Hsinyu

2015-08-01

Calreticulin (CRT) has been previously correlated with the differentiation of neuroblastoma (NB), implying a favorable prognostic factor. Vascular endothelial growth factor (VEGF) has been reported to participate in the behavior of NB. This study investigated the association of CRT and VEGF-A in NB cells. The expressions of VEGF-A and HIF-1α, with overexpression or knockdown of CRT, were measured in three NB cells (SH-SY5Y, SK-N-DZ, and stNB-V1). An inducible CRT NB cell line and knockdown CRT stable cell lines were also established. The impacts of CRT overexpression on NB cell apoptosis, proliferation, and differentiation were also evaluated. We further examined the role of VEGF-A in the NB cell differentiation via VEGF receptor blockade. Constitutive overexpression of CRT led to NB cell differentiation without proliferation. Thus, an inducible CRT stNB-V1 cell line was generated by a tetracycline-regulated gene system. CRT overexpression increased VEGF-A and HIF-1α messenger RNA (mRNA) expressions in SH-SY5Y, SK-N-DZ, and stNB-V1 cells. CRT overexpression also enhanced VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. Knockdown of CRT decreased VEGF-A and HIF-1α mRNA expressions and lowered VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. We further demonstrated that NB cell apoptosis was not affected by CRT overexpression in stNB-V1 cells. Nevertheless, overexpression of CRT suppressed cell proliferation and enhanced cell differentiation in stNB-V1 cells, whereas blockage of VEGFR-1 markedly suppressed the expression of neuron-specific markers including GAP43, NSE2, and NFH, as well as TrkA, a molecular marker indicative of NB cell differentiation. Our findings suggest that VEGF-A is involved in CRT-related neuronal differentiation in NB. Our work may provide important information for developing a new therapeutic strategy to improve the outcome of NB patients.

Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells.

PubMed

Zogovic, Nevena; Tovilovic-Kovacevic, Gordana; Misirkic-Marjanovic, Maja; Vucicevic, Ljubica; Janjetovic, Kristina; Harhaji-Trajkovic, Ljubica; Trajkovic, Vladimir

2015-04-01

We explored the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), and autophagy in phorbol myristate acetate (PMA)-induced neuronal differentiation of SH-SY5Y human neuroblastoma cells. PMA-triggered expression of neuronal markers (dopamine transporter, microtubule-associated protein 2, β-tubulin) was associated with an autophagic response, measured by the conversion of microtubule-associated protein light chain 3 (LC3)-I to autophagosome-bound LC3-II, increase in autophagic flux, and expression of autophagy-related (Atg) proteins Atg7 and beclin-1. This coincided with the transient activation of AMPK and sustained activation of ERK. Pharmacological inhibition or RNA interference-mediated silencing of AMPK suppressed PMA-induced expression of neuronal markers, as well as ERK activation and autophagy. A selective pharmacological blockade of ERK prevented PMA-induced neuronal differentiation and autophagy induction without affecting AMPK phosphorylation. Conversely, the inhibition of autophagy downstream of AMPK/ERK, either by pharmacological agents or LC3 knockdown, promoted the expression of neuronal markers, thus indicating a role of autophagy in the suppression of PMA-induced differentiation of SH-SY5Y cells. Therefore, PMA-induced neuronal differentiation of SH-SY5Y cells depends on a complex interplay between AMPK, ERK, and autophagy, in which the stimulatory effects of AMPK/ERK signaling are counteracted by the coinciding autophagic response. Phorbol myristate acetate (PMA) induces the expression of dopamine transporter, microtubule-associated protein 2, and β-tubulin, and subsequent neuronal differentiation of SH-SY5Y neuroblastoma cells through AMP-activated protein kinase (AMPK)-dependent activation of extracellular signal-regulated kinase (ERK). The activation of AMPK/ERK axis also induces the expression of beclin-1 and Atg7, and increases LC3 conversion, thereby triggering the autophagic response that counteracts differentiation process. © 2014 International Society for Neurochemistry.

Microtubule actin crosslinking factor 1 promotes osteoblast differentiation by promoting β-catenin/TCF1/Runx2 signaling axis.

PubMed

Hu, Lifang; Su, Peihong; Yin, Chong; Zhang, Yan; Li, Runzhi; Yan, Kun; Chen, Zhihao; Li, Dijie; Zhang, Ge; Wang, Liping; Miao, Zhiping; Qian, Airong; Xian, Cory J

2018-02-01

Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key cytoskeletal linker, has been shown to play key roles in signal transduction and in diverse cellular processes; however, its role in regulating osteoblast differentiation is still needed to be elucidated. To further uncover the functions and mechanisms of action of MACF1 in osteoblast differentiation, we examined effects of MACF1 knockdown (MACF1-KD) in MC3T3-E1 osteoblastic cells on their osteoblast differentiation and associated molecular mechanisms. The results showed that knockdown of MACF1 significantly suppressed mineralization of MC3T3-E1 cells, down-regulated the expression of key osteogenic genes alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and type I collagen α1 (Col Iα1). Knockdown of MACF1 dramatically reduced the nuclear translocation of β-catenin, decreased the transcriptional activation of T cell factor 1 (TCF1), and down-regulated the expression of TCF1, lymphoid enhancer-binding factor 1 (LEF1), and Runx2, a target gene of β-catenin/TCF1. In addition, MACF1-KD increased the active level of glycogen synthase kinase-3β (GSK-3β), which is a key regulator for β-catenin signal transduction. Moreover, the reduction of nuclear β-catenin amount and decreased expression of TCF1 and Runx2 were significantly reversed in MACF1-KD cells when treated with lithium chloride, an agonist for β-catenin by inhibiting GSK-3β activity. Taken together, these findings suggest that knockdown of MACF1 in osteoblastic cells inhibits osteoblast differentiation through suppressing the β-catenin/TCF1-Runx2 axis. Thus, a novel role of MACF1 in and a new mechanistic insight of osteoblast differentiation are uncovered. © 2017 Wiley Periodicals, Inc.

Bufalin inhibits the differentiation and proliferation of human osteosarcoma cell line hMG63-derived cancer stem cells.

PubMed

Chang, Yuewen; Zhao, Yongfang; Zhan, Hongsheng; Wei, Xiaoen; Liu, Tianjin; Zheng, Bo

2014-02-01

Cancer stem cells (CSCs) play an important role in drug resistance of tumor and are responsible for high recurrence rates. Agents that can suppress the proliferation and differentiation of CSCs would provide new opportunity to fight against tumor recurrence. In this study, we developed a new strategy to enrich CSCs in human osteosarcoma cell line hMG63. Using these CSCs as model, we tested the effect of bufalin, a traditional Chinese medicine, on the proliferation and differentiation of CSCs. hMG63 cells were cultured in poly-HEMA-treated dish and cancer stem cell-specific medium. In this nonadhesive culture system, hMG63 formed spheres, which were then collected and injected into the immunodeficient mice. Cisplatin was administered every 3 days for five times. The enriched xenograft tumors were cultured in cancer stem cell-specific medium again to form tumor spheres. Expression of cancer stem cell markers of these cells was measured by flow cytometry. These cells were then treated with bufalin, and the proliferation and differentiation ability were indicated by the expression level of molecular markers and the formation of sphere again in vitro. We obtained a low CD133+/CD44 cell population with high-level stem cell marker. When treated with bufalin, the sphere could not get attached to the flask and failed to differentiate, which was indicated by the stable expression of stem cell marker CD133 and OCT-4 in the condition permissive to differentiation. Treatment of bufalin also suppressed the single cells isolated from the sphere to form sphere again in the nonadhesive culture system, and a decreased expression of proliferation marker Ki67 was also detected in these cells. Sphere-formed and chemoresistant colon xenograft tumors in immunodeficient mice could enrich cancer stem cell population. Bufalin could inhibit proliferation and differentiation of CSCs.

MicroRNA hsa-let-7b suppresses the odonto/osteogenic differentiation capacity of stem cells from apical papilla by targeting MMP1.

PubMed

Wang, Yanqiu; Pang, Xiyao; Wu, Jintao; Jin, Lin; Yu, Yan; Gobin, Romila; Yu, Jinhua

2018-01-31

MicroRNA let-7 family acts as the key regulator of the differentiation of mesenchymal stem cells (MSCs). However, the influence of let-7b on biological characteristics of stem cells from apical papilla (SCAPs) is still controversial. In this study, the expression of hsa-let-7b was obviously downregulated during the osteogenic differentiation of SCAPs. SCAPs were then infected with hsa-let-7b or hsa-let-7b inhibitor lentiviruses. The proliferation ability was determined by CCK-8 and flow cytometry. The odonto/osteogenic differentiation capacity was analyzed by alkaline phosphatase (ALP) activity, alizarin red staining, Western blot assay, and real-time RT-PCR. Bioinformatics analysis was used to screen out the target of hsa-let-7b and the target relationship was confirmed by dual luciferase reporter assay. Hsa-let-7b was of no influence on the proliferation of SCAPs. Interferential expression of hsa-let-7b increased the ALP activity as well as the formation of calcified nodules of SCAPs. Moreover, the mRNA levels of osteoblastic markers (ALP, RUNX2, OSX, OPN, and OCN) were upregulated while the protein levels of DSPP, ALP, RUNX2, OSX, OPN, and OCN also increased considerably. Conversely, overexpression of hsa-let-7b inhibited the odonto/osteogenic differentiation capacity of SCAPs. Bioinformatics analysis revealed a putative binding site of hsa-let-7b in the matrix metalloproteinase 1 (MMP1) 3'-untranslated region (3'-UTR). Dual luciferase reporter assay confirmed that hsa-let-7b targets MMP1. The odonto/osteogenic differentiation ability of SCAPs ascended after repression of hsa-let-7b, which was then reversed after co-transfection with siMMP1. Together, hsa-let-7b can suppress the odonto/osteogenic differentiation capacity of SCAPs by targeting MMP1. © 2018 Wiley Periodicals, Inc.

Smurf1 plays a role in EGF inhibition of BMP2-induced osteogenic differentiation

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

Lee, Hye-Lim; Park, Hyun-Jung; Kwon, Arang

2014-05-01

It has been demonstrated that epidermal growth factor (EGF) plays a role in supporting the proliferation of bone marrow stromal cells in bone but inhibits their osteogenic differentiation. However, the mechanism underlying EGF inhibition of osteoblast differentiation remains unclear. Smurf1 is an E3 ubiquitin ligase that targets Smad1/5 and Runx2, which are critical transcription factors for bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation. In this study, we investigated the effect of EGF on the expression of Smurf1, and the role of Smurf1 in EGF inhibition of osteogenic differentiation using C2C12 cells, a murine myoblast cell line. EGF increased Smurf1 expression,more » which was blocked by inhibiting the activity of either JNK or ERK. Chromatin immunoprecipitation and Smurf1 promoter assays demonstrated that c-Jun and Runx2 play roles in the EGF induction of Smurf1 transcription. EGF suppressed BMP2-induced expression of osteogenic marker genes, which were rescued by Smurf1 knockdown. EGF downregulated the protein levels of Runx2 and Smad1 in a proteasome-dependent manner. EGF decreased the transcriptional activity of Runx2 and Smurf1, which was partially rescued by Smurf1 silencing. Taken together, these results suggest that EGF increases Smurf1 expression via the activation of JNK and ERK and the subsequent binding of c-Jun and Runx2 to the Smurf1 promoter and that Smurf1 mediates the inhibitory effect of EGF on BMP2-induced osteoblast differentiation. - Highlights: • EGF increases the expression level of Smurf1 in mesenchymal precursor cells. • EGF reduces the protein levels and transcriptional activity of Runx2 and Smad1. • EGF suppresses BMP2-induced osteogenic differentiation, which is rescued by Smurf1 knockdown.« less

Curcumin suppresses transforming growth factor-β1-induced cardiac fibroblast differentiation via inhibition of Smad-2 and p38 MAPK signaling pathways

PubMed Central

LIU, HUZI; LIU, AIJUN; SHI, CHUNLI; LI, BAO

2016-01-01

The differentiation of cardiac fibroblasts (CFs) into myofibroblasts and the subsequent deposition of the extracellular matrix is associated with myocardial fibrosis following various types of myocardial injury. In the present study, the effect of curcumin, which is a pharmacologically-safe natural compound from the Curcuma longa herb, on transforming growth factor (TGF)-β1-induced CFs was investigated, and the underlying molecular mechanisms were examined. The expression levels of α-smooth muscle actin (SMA) stress fibers were investigated using western blotting and immunofluorescence in cultured neonatal rat CFs. Protein and mRNA expression levels of α-SMA and collagen type I (ColI) were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. In addition, the activation of Smad2 and p38 was examined using western blotting. Curcumin, SB431542 (a TGF-βR-Smad2 inhibitor) and SB203580 (a p38 inhibitor) were used to inhibit the stimulation by TGF-β1. The results demonstrated that the TGF-β1-induced expression of α-SMA and ColI was suppressed by curcumin at the mRNA and protein levels, while SB431542 and SB203580 induced similar effects. Furthermore, phosphorylated Smad-2 and p38 were upregulated in TGF-β1-induced CFs, and these effects were substantially inhibited by curcumin administration. In conclusion, the results of the present study demonstrated that treatment with curcumin effectively suppresses TGF-β1-induced CF differentiation via Smad-2 and p38 signaling pathways. Thus, curcumin may be a potential therapeutic agent for the treatment of cardiac fibrosis. PMID:26998027

Effects of Inteferons on Human B-cell Differentiation in vitro

PubMed Central

Kim, Samyong; Stoetter, Hans; Heimpel, Herrman

1987-01-01

The effects of interferons (IFN) on in vitro differentiation of B-lymphocytes were studied. Peripheral lymphocytes from normal subjects were cultivated under polyclonal activator pokeweed mitogen (PWN) or Epstein-Barr virus (EBV) stimulation. The secreted Ig in the culture supernatants were measured for IgM by ELISA method. To determine the cellular level of IFN action T-cell enriched fraction (Te) or B-cell enriched fraction (Be) were preincubated with IFN prior to recombination culture. IFN had modulatory activities on Ig production; at low to moderately high doses (10–1000 U/ml of IFN-alpha or 12–120 U/ml of IFN-gamma) stimulating when IFN was added until 48 hr after the start of the culture, while after 72 hr from culture start IFN suppressed Ig production. Preincubation of Be-cells with moderately high doses of IFN (120 U/ml of IFN-gamma or 1000 U/ml of IFN-alpha) prior to PWM-stimulation suppressed Ig production. Likewise, in EBV-stimulated culture, high dose IFN suppressed Ig production. But low dose of IFN enhanced ig production in EBV-stimulated culture. Preincubation of Te-cells with IFN prior to PWM-stimulation with Be-cells enhanced the Ig production. The T-cell subset analysis at the end of these culture showed enhanced ratio of T-helper cell relative to T-suppressor cells, suggesting increased T-helper cell proliferation after incubation with IFN. Thus, it is concluded that IFNs have modulatory activities on B-cell differentiation. The mechanism seems to be direct effects on B-cells (in PWM and EBV system) as well as through T-helper cell mediation (PWM system). The IFN-gamma showed more potent (2-to 6-fold) stimulatory activities than IFN-alpha. PMID:2484953

A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization

PubMed Central

Mestre-Citrinovitz, Ana C.; Kleff, Veronika; Vallejo, Griselda

2015-01-01

Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone) and estrogen receptor (ICI182780) antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets. PMID:25897495

Aggregatibacter actinomycetemcomitans-Induced AIM2 Inflammasome Activation Is Suppressed by Xylitol in Differentiated THP-1 Macrophages.

PubMed

Kim, Seyeon; Park, Mi Hee; Song, Yu Ri; Na, Hee Sam; Chung, Jin

2016-06-01

Aggressive periodontitis is characterized by rapid destruction of periodontal tissue caused by Aggregatibacter actinomycetemcomitans. Interleukin (IL)-1β is a proinflammatory cytokine, and its production is tightly regulated by inflammasome activation. Xylitol, an anticaries agent, is anti-inflammatory, but its effect on inflammasome activation has not been researched. This study investigates the effect of xylitol on inflammasome activation induced by A. actinomycetemcomitans. The differentiated THP-1 macrophages were stimulated by A. actinomycetemcomitans with or without xylitol and the expressions of IL-1β and inflammasome components were detected by real time PCR, ELISA, confocal microscopy and Immunoblot analysis. The effects of xylitol on the adhesion and invasion of A. actinomycetemcomitans to cells were measured by viable cell count. A. actinomycetemcomitans increased pro IL-1β synthesis and IL-1β secretion in a multiplicity of infection- and time-dependent manner. A. actinomycetemcomitans also stimulated caspase-1 activation. Among inflammasome components, apoptosis-associated speck-like protein containing a CARD (ASC) and absent in melanoma 2 (AIM2) proteins were upregulated by A. actinomycetemcomitans infection. When cells were pretreated with xylitol, proIL-1β and IL-1β production by A. actinomycetemcomitans infection was significantly decreased. Xylitol also inhibited ASC and AIM2 proteins and formation of ASC puncta. Furthermore, xylitol suppressed internalization of A. actinomycetemcomitans into differentiated THP-1 macrophages without affecting viability of A. actinomycetemcomitans within cells. A. actinomycetemcomitans induced IL-1β production and AIM2 inflammasome activation. Xylitol inhibited these effects, possibly by suppressing internalization of A. actinomycetemcomitans into cells. Thus, this study proposes a mechanism for IL-1β production via inflammasome activation and discusses a possible use for xylitol in periodontal inflammation caused by A. actinomycetemcomitans.

Ebselen Is a Potential Anti-Osteoporosis Agent by Suppressing Receptor Activator of Nuclear Factor Kappa-B Ligand-Induced Osteoclast Differentiation In vitro and Lipopolysaccharide-Induced Inflammatory Bone Destruction In vivo

PubMed Central

Baek, Jong Min; Kim, Ju-Young; Yoon, Kwon-Ha; Oh, Jaemin; Lee, Myeung Su

2016-01-01

Ebselen is a non-toxic seleno-organic drug with anti-inflammatory and antioxidant properties that is currently being examined in clinical trials to prevent and treat various diseases, including atherosclerosis, stroke, and cancer. However, no reports are available for verifying the pharmacological effects of ebselen on major metabolic bone diseases such as osteoporosis. In this study, we observed that ebselen suppressed the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells in an osteoblast/osteoclast co-culture by regulating the ratio of receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin secreted by osteoblasts. In addition, ebselen treatment in the early stage of osteoclast differentiation inhibited RANKL-dependent osteoclastogenesis by decreasing the phosphorylation of IκB, PI3K, and Akt in early signaling pathways and by subsequently inducing c-Fos and nuclear factor of activated T-cells c1. Further, ebselen induced apoptosis of osteoclasts in the late stage of osteoclast differentiation. In addition, ebselen treatment suppressed filamentous actin ring formation and bone resorption activity of mature osteoclasts. Reflecting these in vitro effects, administration of ebselen recovered bone loss and its µ-CT parameters in lipopolysaccharide-mediated mouse model. Histological analysis confirmed that ebselen prevented trabecular bone matrix degradation and osteoclast formation in the bone tissues. Finally, it was proved that the anti-osteoclastogenic action of ebselen is achieved through targeting N-methyl-D-aspartate (NMDA) receptor. These results indicate that ebselen is a potentially safe drug for treating metabolic bone diseases such as osteoporosis. PMID:27019631

Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response.

PubMed

Park, Jeongho; Lee, Jang-Won; Cooper, Scott C; Broxmeyer, Hal E; Cannon, Jason R; Kim, Chang H

2017-10-01

Parkinson's disease (PD) is a neurodegenerative disease, whereas Crohn's disease is an inflammatory bowel disease. Interestingly, polymorphisms in the LRRK2 gene have been identified as risk factors for both diseases. LRRK2 G2019S is the most prevalent mutation found in PD. To gain insights into the role of the LRRK2 G2019S gene on the development and activation of the immune system in the brain-gut axis, we investigated the effect of LRRK2 G2019S on bone marrow myeloid progenitors and myeloid cell function in the periphery. We used bacterial artificial chromosome transgenic rats harboring the human LRRK2 G2019S gene. LRRK2 G2019S transgene decreased the numbers of monocytic and granulocytic progenitors in the bone marrow. However, the numbers of peripheral, immature myeloid cells with suppressive activity were increased in the gut and blood circulation of LRRK2 G2019S compared with control rats in various acute and chronic inflammatory responses. In inflammatory conditions, Th17 cell activity was suppressed, but tissue-associated phylum Bacteroidetes was abnormally increased in the intestine of LRRK2 G2019S rats. The abnormally expanded myeloid cells because of the LRRK2 G2019S gene were highly suppressive on Th17 cell differentiation. Moreover, we found that inhibition of LRRK2 kinase affects myeloid progenitors and myeloid cell differentiation. Taken together, the results indicate that abnormal LRRK2 activity can alter bone marrow myelopoiesis, peripheral myeloid cell differentiation, and intestinal immune homeostasis. These findings may have ramifications in immune and inflammatory responses in patients with LRRK2 abnormalities. © Society for Leukocyte Biology.

Measurement of the production of high-pT electrons from heavy-flavour hadron decays in Pb-Pb collisions at √{sNN} = 2.76 TeV

NASA Astrophysics Data System (ADS)

Adam, J.; Adamová, D.; Aggarwal, M. M.; Aglieri Rinella, G.; Agnello, M.; Agrawal, N.; Ahammed, Z.; Ahmad, S.; Ahn, S. U.; Aiola, S.; Akindinov, A.; Alam, S. N.; Albuquerque, D. S. D.; Aleksandrov, D.; Alessandro, B.; Alexandre, D.; Alfaro Molina, R.; Alici, A.; Alkin, A.; Alme, J.; Alt, T.; Altinpinar, S.; Altsybeev, I.; Alves Garcia Prado, C.; An, M.; Andrei, C.; Andrews, H. A.; Andronic, A.; Anguelov, V.; Anson, C.; Antičić, T.; Antinori, F.; Antonioli, P.; Anwar, R.; Aphecetche, L.; Appelshäuser, H.; Arcelli, S.; Arnaldi, R.; Arnold, O. W.; Arsene, I. C.; Arslandok, M.; Audurier, B.; Augustinus, A.; Averbeck, R.; Azmi, M. D.; Badalà, A.; Baek, Y. W.; Bagnasco, S.; Bailhache, R.; Bala, R.; Balasubramanian, S.; Baldisseri, A.; Baral, R. C.; Barbano, A. M.; Barbera, R.; Barile, F.; Barnaföldi, G. G.; Barnby, L. S.; Barret, V.; Bartalini, P.; Barth, K.; Bartke, J.; Bartsch, E.; Basile, M.; Bastid, N.; Basu, S.; Bathen, B.; Batigne, G.; Batista Camejo, A.; Batyunya, B.; Batzing, P. C.; Bearden, I. G.; Beck, H.; Bedda, C.; Behera, N. K.; Belikov, I.; Bellini, F.; Bello Martinez, H.; Bellwied, R.; Beltran, L. G. E.; Belyaev, V.; Bencedi, G.; Beole, S.; Bercuci, A.; Berdnikov, Y.; Berenyi, D.; Bertens, R. A.; Berzano, D.; Betev, L.; Bhasin, A.; Bhat, I. R.; Bhati, A. K.; Bhattacharjee, B.; Bhom, J.; Bianchi, L.; Bianchi, N.; Bianchin, C.; Bielčík, J.; Bielčíková, J.; Bilandzic, A.; Biro, G.; Biswas, R.; Biswas, S.; Bjelogrlic, S.; Blair, J. T.; Blau, D.; Blume, C.; Bock, F.; Bogdanov, A.; Boldizsár, L.; Bombara, M.; Bonora, M.; Book, J.; Borel, H.; Borissov, A.; Borri, M.; Botta, E.; Bourjau, C.; Braun-Munzinger, P.; Bregant, M.; Broker, T. A.; Browning, T. A.; Broz, M.; Brucken, E. J.; Bruna, E.; Bruno, G. E.; Budnikov, D.; Buesching, H.; Bufalino, S.; Buhler, P.; Buitron, S. A. I.; Buncic, P.; Busch, O.; Buthelezi, Z.; Butt, J. B.; Buxton, J. T.; Cabala, J.; Caffarri, D.; Caines, H.; Caliva, A.; Calvo Villar, E.; Camerini, P.; Carena, F.; Carena, W.; Carnesecchi, F.; Castillo Castellanos, J.; Castro, A. J.; Casula, E. A. R.; Ceballos Sanchez, C.; Cepila, J.; Cerello, P.; Cerkala, J.; Chang, B.; Chapeland, S.; Chartier, M.; Charvet, J. L.; Chattopadhyay, S.; Chattopadhyay, S.; Chauvin, A.; Chelnokov, V.; Cherney, M.; Cheshkov, C.; Cheynis, B.; Chibante Barroso, V.; Chinellato, D. D.; Cho, S.; Chochula, P.; Choi, K.; Chojnacki, M.; Choudhury, S.; Christakoglou, P.; Christensen, C. H.; Christiansen, P.; Chujo, T.; Chung, S. U.; Cicalo, C.; Cifarelli, L.; Cindolo, F.; Cleymans, J.; Colamaria, F.; Colella, D.; Collu, A.; Colocci, M.; Conesa Balbastre, G.; Conesa Del Valle, Z.; Connors, M. E.; Contreras, J. G.; Cormier, T. M.; Corrales Morales, Y.; Cortés Maldonado, I.; Cortese, P.; Cosentino, M. R.; Costa, F.; Crkovská, J.; Crochet, P.; Cruz Albino, R.; Cuautle, E.; Cunqueiro, L.; Dahms, T.; Dainese, A.; Danisch, M. C.; Danu, A.; Das, D.; Das, I.; Das, S.; Dash, A.; Dash, S.; de, S.; de Caro, A.; de Cataldo, G.; de Conti, C.; de Cuveland, J.; de Falco, A.; de Gruttola, D.; De Marco, N.; de Pasquale, S.; de Souza, R. D.; Deisting, A.; Deloff, A.; Deplano, C.; Dhankher, P.; di Bari, D.; di Mauro, A.; di Nezza, P.; di Ruzza, B.; Diaz Corchero, M. A.; Dietel, T.; Dillenseger, P.; Divià, R.; Djuvsland, Ø.; Dobrin, A.; Domenicis Gimenez, D.; Dönigus, B.; Dordic, O.; Drozhzhova, T.; Dubey, A. K.; Dubla, A.; Ducroux, L.; Duggal, A. K.; Dupieux, P.; Ehlers, R. J.; Elia, D.; Endress, E.; Engel, H.; Epple, E.; Erazmus, B.; Erhardt, F.; Espagnon, B.; Esumi, S.; Eulisse, G.; Eum, J.; Evans, D.; Evdokimov, S.; Eyyubova, G.; Fabbietti, L.; Fabris, D.; Faivre, J.; Fantoni, A.; Fasel, M.; Feldkamp, L.; Feliciello, A.; Feofilov, G.; Ferencei, J.; Fernández Téllez, A.; Ferreiro, E. G.; Ferretti, A.; Festanti, A.; Feuillard, V. J. G.; Figiel, J.; Figueredo, M. A. S.; Filchagin, S.; Finogeev, D.; Fionda, F. M.; Fiore, E. M.; Floris, M.; Foertsch, S.; Foka, P.; Fokin, S.; Fragiacomo, E.; Francescon, A.; Francisco, A.; Frankenfeld, U.; Fronze, G. G.; Fuchs, U.; Furget, C.; Furs, A.; Fusco Girard, M.; Gaardhøje, J. J.; Gagliardi, M.; Gago, A. M.; Gajdosova, K.; Gallio, M.; Galvan, C. D.; Gangadharan, D. R.; Ganoti, P.; Gao, C.; Garabatos, C.; Garcia-Solis, E.; Garg, K.; Garg, P.; Gargiulo, C.; Gasik, P.; Gauger, E. F.; Gay Ducati, M. B.; Germain, M.; Ghosh, P.; Ghosh, S. K.; Gianotti, P.; Giubellino, P.; Giubilato, P.; Gladysz-Dziadus, E.; Glässel, P.; Goméz Coral, D. M.; Gomez Ramirez, A.; Gonzalez, A. S.; Gonzalez, V.; González-Zamora, P.; Gorbunov, S.; Görlich, L.; Gotovac, S.; Grabski, V.; Graczykowski, L. K.; Graham, K. L.; Greiner, L.; Grelli, A.; Grigoras, C.; Grigoriev, V.; Grigoryan, A.; Grigoryan, S.; Grion, N.; Gronefeld, J. M.; Grosse-Oetringhaus, J. F.; Grosso, R.; Gruber, L.; Guber, F.; Guernane, R.; Guerzoni, B.; Gulbrandsen, K.; Gunji, T.; Gupta, A.; Gupta, R.; Guzman, I. B.; Haake, R.; Hadjidakis, C.; Hamagaki, H.; Hamar, G.; Hamon, J. C.; Harris, J. W.; Harton, A.; Hatzifotiadou, D.; Hayashi, S.; Heckel, S. T.; Hellbär, E.; Helstrup, H.; Herghelegiu, A.; Herrera Corral, G.; Herrmann, F.; Hess, B. A.; Hetland, K. F.; Hillemanns, H.; Hippolyte, B.; Hladky, J.; Horak, D.; Hosokawa, R.; Hristov, P.; Hughes, C.; Humanic, T. J.; Hussain, N.; Hussain, T.; Hutter, D.; Hwang, D. S.; Ilkaev, R.; Inaba, M.; Ippolitov, M.; Irfan, M.; Isakov, V.; Islam, M. S.; Ivanov, M.; Ivanov, V.; Izucheev, V.; Jacak, B.; Jacazio, N.; Jacobs, P. M.; Jadhav, M. B.; Jadlovska, S.; Jadlovsky, J.; Jahnke, C.; Jakubowska, M. J.; Janik, M. A.; Jayarathna, P. H. S. Y.; Jena, C.; Jena, S.; Jimenez Bustamante, R. T.; Jones, P. G.; Jusko, A.; Kalinak, P.; Kalweit, A.; Kang, J. H.; Kaplin, V.; Kar, S.; Karasu Uysal, A.; Karavichev, O.; Karavicheva, T.; Karayan, L.; Karpechev, E.; Kebschull, U.; Keidel, R.; Keijdener, D. L. D.; Keil, M.; Mohisin Khan, M.; Khan, P.; Khan, S. A.; Khanzadeev, A.; Kharlov, Y.; Khatun, A.; Khuntia, A.; Kileng, B.; Kim, D. W.; Kim, D. J.; Kim, D.; Kim, H.; Kim, J. S.; Kim, J.; Kim, M.; Kim, M.; Kim, S.; Kim, T.; Kirsch, S.; Kisel, I.; Kiselev, S.; Kisiel, A.; Kiss, G.; Klay, J. L.; Klein, C.; Klein, J.; Klein-Bösing, C.; Klewin, S.; Kluge, A.; Knichel, M. L.; Knospe, A. G.; Kobdaj, C.; Kofarago, M.; Kollegger, T.; Kolojvari, A.; Kondratiev, V.; Kondratyeva, N.; Kondratyuk, E.; Konevskikh, A.; Kopcik, M.; Kour, M.; Kouzinopoulos, C.; Kovalenko, O.; Kovalenko, V.; Kowalski, M.; Koyithatta Meethaleveedu, G.; Králik, I.; Kravčáková, A.; Krivda, M.; Krizek, F.; Kryshen, E.; Krzewicki, M.; Kubera, A. M.; Kučera, V.; Kuhn, C.; Kuijer, P. G.; Kumar, A.; Kumar, J.; Kumar, L.; Kumar, S.; Kundu, S.; Kurashvili, P.; Kurepin, A.; Kurepin, A. B.; Kuryakin, A.; Kushpil, S.; Kweon, M. J.; Kwon, Y.; La Pointe, S. L.; La Rocca, P.; Lagana Fernandes, C.; Lakomov, I.; Langoy, R.; Lapidus, K.; Lara, C.; Lardeux, A.; Lattuca, A.; Laudi, E.; Lazaridis, L.; Lea, R.; Leardini, L.; Lee, S.; Lehas, F.; Lehner, S.; Lehrbach, J.; Lemmon, R. C.; Lenti, V.; Leogrande, E.; León Monzón, I.; Lévai, P.; Li, S.; Li, X.; Lien, J.; Lietava, R.; Lindal, S.; Lindenstruth, V.; Lippmann, C.; Lisa, M. A.; Ljunggren, H. M.; Llope, W.; Lodato, D. F.; Loenne, P. I.; Loginov, V.; Loizides, C.; Lopez, X.; López Torres, E.; Lowe, A.; Luettig, P.; Lunardon, M.; Luparello, G.; Lupi, M.; Lutz, T. H.; Maevskaya, A.; Mager, M.; Mahajan, S.; Mahmood, S. M.; Maire, A.; Majka, R. D.; Malaev, M.; Maldonado Cervantes, I.; Malinina, L.; Mal'Kevich, D.; Malzacher, P.; Mamonov, A.; Manko, V.; Manso, F.; Manzari, V.; Mao, Y.; Marchisone, M.; Mareš, J.; Margagliotti, G. V.; Margotti, A.; Margutti, J.; Marín, A.; Markert, C.; Marquard, M.; Martin, N. A.; Martinengo, P.; Martínez, M. I.; Martínez García, G.; Martinez Pedreira, M.; Mas, A.; Masciocchi, S.; Masera, M.; Masoni, A.; Mastroserio, A.; Matyja, A.; Mayer, C.; Mazer, J.; Mazzilli, M.; Mazzoni, M. A.; Meddi, F.; Melikyan, Y.; Menchaca-Rocha, A.; Meninno, E.; Mercado Pérez, J.; Meres, M.; Mhlanga, S.; Miake, Y.; Mieskolainen, M. M.; Mikhaylov, K.; Milano, L.; Milosevic, J.; Mischke, A.; Mishra, A. N.; Mishra, T.; Miśkowiec, D.; Mitra, J.; Mitu, C. M.; Mohammadi, N.; Mohanty, B.; Molnar, L.; Montes, E.; Moreira de Godoy, D. A.; Moreno, L. A. P.; Moretto, S.; Morreale, A.; Morsch, A.; Muccifora, V.; Mudnic, E.; Mühlheim, D.; Muhuri, S.; Mukherjee, M.; Mulligan, J. D.; Munhoz, M. G.; Münning, K.; Munzer, R. H.; Murakami, H.; Murray, S.; Musa, L.; Musinsky, J.; Myers, C. J.; Naik, B.; Nair, R.; Nandi, B. K.; Nania, R.; Nappi, E.; Naru, M. U.; Natal da Luz, H.; Nattrass, C.; Navarro, S. R.; Nayak, K.; Nayak, R.; Nayak, T. K.; Nazarenko, S.; Nedosekin, A.; Negrao de Oliveira, R. A.; Nellen, L.; Ng, F.; Nicassio, M.; Niculescu, M.; Niedziela, J.; Nielsen, B. S.; Nikolaev, S.; Nikulin, S.; Nikulin, V.; Noferini, F.; Nomokonov, P.; Nooren, G.; Noris, J. C. C.; Norman, J.; Nyanin, A.; Nystrand, J.; Oeschler, H.; Oh, S.; Ohlson, A.; Okubo, T.; Olah, L.; Oleniacz, J.; Oliveira da Silva, A. C.; Oliver, M. H.; Onderwaater, J.; Oppedisano, C.; Orava, R.; Oravec, M.; Ortiz Velasquez, A.; Oskarsson, A.; Otwinowski, J.; Oyama, K.; Ozdemir, M.; Pachmayer, Y.; Pacik, V.; Pagano, D.; Pagano, P.; Paić, G.; Pal, S. K.; Palni, P.; Pan, J.; Pandey, A. K.; Papikyan, V.; Pappalardo, G. S.; Pareek, P.; Park, J.; Park, W. J.; Parmar, S.; Passfeld, A.; Paticchio, V.; Patra, R. N.; Paul, B.; Pei, H.; Peitzmann, T.; Peng, X.; Pereira da Costa, H.; Peresunko, D.; Perez Lezama, E.; Peskov, V.; Pestov, Y.; Petráček, V.; Petrov, V.; Petrovici, M.; Petta, C.; Piano, S.; Pikna, M.; Pillot, P.; Pimentel, L. O. D. L.; Pinazza, O.; Pinsky, L.; Piyarathna, D. B.; Płoskoń, M.; Planinic, M.; Pluta, J.; Pochybova, S.; Podesta-Lerma, P. L. M.; Poghosyan, M. G.; Polichtchouk, B.; Poljak, N.; Poonsawat, W.; Pop, A.; Poppenborg, H.; Porteboeuf-Houssais, S.; Porter, J.; Pospisil, J.; Pozdniakov, V.; Prasad, S. K.; Preghenella, R.; Prino, F.; Pruneau, C. A.; Pshenichnov, I.; Puccio, M.; Puddu, G.; Pujahari, P.; Punin, V.; Putschke, J.; Qvigstad, H.; Rachevski, A.; Raha, S.; Rajput, S.; Rak, J.; Rakotozafindrabe, A.; Ramello, L.; Rami, F.; Rana, D. B.; Raniwala, R.; Raniwala, S.; Räsänen, S. S.; Rascanu, B. T.; Rathee, D.; Ratza, V.; Ravasenga, I.; Read, K. F.; Redlich, K.; Rehman, A.; Reichelt, P.; Reidt, F.; Ren, X.; Renfordt, R.; Reolon, A. R.; Reshetin, A.; Reygers, K.; Riabov, V.; Ricci, R. A.; Richert, T.; Richter, M.; Riedler, P.; Riegler, W.; Riggi, F.; Ristea, C.; Rodríguez Cahuantzi, M.; Røed, K.; Rogochaya, E.; Rohr, D.; Röhrich, D.; Ronchetti, F.; Ronflette, L.; Rosnet, P.; Rossi, A.; Roukoutakis, F.; Roy, A.; Roy, C.; Roy, P.; Rubio Montero, A. J.; Rui, R.; Russo, R.; Ryabinkin, E.; Ryabov, Y.; Rybicki, A.; Saarinen, S.; Sadhu, S.; Sadovsky, S.; Šafařík, K.; Sahlmuller, B.; Sahoo, B.; Sahoo, P.; Sahoo, R.; Sahoo, S.; Sahu, P. K.; Saini, J.; Sakai, S.; Saleh, M. A.; Salzwedel, J.; Sambyal, S.; Samsonov, V.; Sandoval, A.; Sano, M.; Sarkar, D.; Sarkar, N.; Sarma, P.; Sas, M. H. P.; Scapparone, E.; Scarlassara, F.; Scharenberg, R. P.; Schiaua, C.; Schicker, R.; Schmidt, C.; Schmidt, H. R.; Schmidt, M.; Schukraft, J.; Schutz, Y.; Schwarz, K.; Schweda, K.; Scioli, G.; Scomparin, E.; Scott, R.; Šefčík, M.; Seger, J. E.; Sekiguchi, Y.; Sekihata, D.; Selyuzhenkov, I.; Senosi, K.; Senyukov, S.; Serradilla, E.; Sett, P.; Sevcenco, A.; Shabanov, A.; Shabetai, A.; Shadura, O.; Shahoyan, R.; Shangaraev, A.; Sharma, A.; Sharma, A.; Sharma, M.; Sharma, M.; Sharma, N.; Sheikh, A. I.; Shigaki, K.; Shou, Q.; Shtejer, K.; Sibiriak, Y.; Siddhanta, S.; Sielewicz, K. M.; Siemiarczuk, T.; Silvermyr, D.; Silvestre, C.; Simatovic, G.; Simonetti, G.; Singaraju, R.; Singh, R.; Singhal, V.; Sinha, T.; Sitar, B.; Sitta, M.; Skaali, T. B.; Slupecki, M.; Smirnov, N.; Snellings, R. J. M.; Snellman, T. W.; Song, J.; Song, M.; Song, Z.; Soramel, F.; Sorensen, S.; Sozzi, F.; Spiriti, E.; Sputowska, I.; Srivastava, B. K.; Stachel, J.; Stan, I.; Stankus, P.; Stenlund, E.; Steyn, G.; Stiller, J. H.; Stocco, D.; Strmen, P.; Suaide, A. A. P.; Sugitate, T.; Suire, C.; Suleymanov, M.; Suljic, M.; Sultanov, R.; Šumbera, M.; Sumowidagdo, S.; Suzuki, K.; Swain, S.; Szabo, A.; Szarka, I.; Szczepankiewicz, A.; Szymanski, M.; Tabassam, U.; Takahashi, J.; Tambave, G. J.; Tanaka, N.; Tarhini, M.; Tariq, M.; Tarzila, M. G.; Tauro, A.; Tejeda Muñoz, G.; Telesca, A.; Terasaki, K.; Terrevoli, C.; Teyssier, B.; Thakur, D.; Thomas, D.; Tieulent, R.; Tikhonov, A.; Timmins, A. R.; Toia, A.; Tripathy, S.; Trogolo, S.; Trombetta, G.; Trubnikov, V.; Trzaska, W. H.; Tsuji, T.; Tumkin, A.; Turrisi, R.; Tveter, T. S.; Ullaland, K.; Umaka, E. N.; Uras, A.; Usai, G. L.; Utrobicic, A.; Vala, M.; van der Maarel, J.; van Hoorne, J. W.; van Leeuwen, M.; Vanat, T.; Vande Vyvre, P.; Varga, D.; Vargas, A.; Vargyas, M.; Varma, R.; Vasileiou, M.; Vasiliev, A.; Vauthier, A.; Vázquez Doce, O.; Vechernin, V.; Veen, A. M.; Velure, A.; Vercellin, E.; Vergara Limón, S.; Vernet, R.; Vértesi, R.; Vickovic, L.; Vigolo, S.; Viinikainen, J.; Vilakazi, Z.; Villalobos Baillie, O.; Villatoro Tello, A.; Vinogradov, A.; Vinogradov, L.; Virgili, T.; Vislavicius, V.; Vodopyanov, A.; Völkl, M. A.; Voloshin, K.; Voloshin, S. A.; Volpe, G.; von Haller, B.; Vorobyev, I.; Voscek, D.; Vranic, D.; Vrláková, J.; Wagner, B.; Wagner, J.; Wang, H.; Wang, M.; Watanabe, D.; Watanabe, Y.; Weber, M.; Weber, S. G.; Weiser, D. F.; Wessels, J. P.; Westerhoff, U.; Whitehead, A. M.; Wiechula, J.; Wikne, J.; Wilk, G.; Wilkinson, J.; Willems, G. A.; Williams, M. C. S.; Windelband, B.; Winn, M.; Witt, W. E.; Yalcin, S.; Yang, P.; Yano, S.; Yin, Z.; Yokoyama, H.; Yoo, I.-K.; Yoon, J. H.; Yurchenko, V.; Zaccolo, V.; Zaman, A.; Zampolli, C.; Zanoli, H. J. C.; Zaporozhets, S.; Zardoshti, N.; Zarochentsev, A.; Závada, P.; Zaviyalov, N.; Zbroszczyk, H.; Zhalov, M.; Zhang, H.; Zhang, X.; Zhang, Y.; Zhang, C.; Zhang, Z.; Zhao, C.; Zhigareva, N.; Zhou, D.; Zhou, Y.; Zhou, Z.; Zhu, H.; Zhu, J.; Zichichi, A.; Zimmermann, A.; Zimmermann, M. B.; Zinovjev, G.; Zmeskal, J.; Alice Collaboration

2017-08-01

Electrons from heavy-flavour hadron decays (charm and beauty) were measured with the ALICE detector in Pb-Pb collisions at a centre-of-mass of energy √{sNN} = 2.76 TeV. The transverse momentum (pT) differential production yields at mid-rapidity were used to calculate the nuclear modification factor RAA in the interval 3

Greater magnocellular saccadic suppression in high versus low autistic tendency suggests a causal path to local perceptual style

PubMed Central

Crewther, David P.; Crewther, Daniel; Bevan, Stephanie; Goodale, Melvyn A.; Crewther, Sheila G.

2015-01-01

Saccadic suppression—the reduction of visual sensitivity during rapid eye movements—has previously been proposed to reflect a specific suppression of the magnocellular visual system, with the initial neural site of that suppression at or prior to afferent visual information reaching striate cortex. Dysfunction in the magnocellular visual pathway has also been associated with perceptual and physiological anomalies in individuals with autism spectrum disorder or high autistic tendency, leading us to question whether saccadic suppression is altered in the broader autism phenotype. Here we show that individuals with high autistic tendency show greater saccadic suppression of low versus high spatial frequency gratings while those with low autistic tendency do not. In addition, those with high but not low autism spectrum quotient (AQ) demonstrated pre-cortical (35–45 ms) evoked potential differences (saccade versus fixation) to a large, low contrast, pseudo-randomly flashing bar. Both AQ groups showed similar differential visual evoked potential effects in later epochs (80–160 ms) at high contrast. Thus, the magnocellular theory of saccadic suppression appears untenable as a general description for the typically developing population. Our results also suggest that the bias towards local perceptual style reported in autism may be due to selective suppression of low spatial frequency information accompanying every saccadic eye movement. PMID:27019719

Lithospermum erythrorhizon suppresses high-fat diet-induced obesity, and acetylshikonin, a main compound of Lithospermum erythrorhizon, inhibits adipocyte differentiation.

PubMed

Gwon, So Young; Ahn, Ji Yun; Chung, Chang Hwa; Moon, BoKyung; Ha, Tae Youl

2012-09-12

Lithospermum erythrorhizon, which has traditionally been used as a vegetable and to make the liquor Jindo Hongju, contains several naphthoquinone pigments, including shikonin. This study aimed to evaluate the antiobesity effects of Lithospermum erythrorhizon ethanol extract (LE) and elucidate the underlying mechanism. C57BL/6J mice were fed a normal or high-fat diet with or without LE supplementation for 8 weeks. LE reduced high-fat diet-induced increases in body weight, white adipose tissue mass, serum triglyceride and total cholesterol levels, and hepatic lipid levels while decreasing lipogenic and adipogenic gene expression. Furthermore, acetylshikonin suppressed adipocyte differentiation in a dose-dependent manner and significantly attenuated adipogenic transcription factor expression in 3T3-L1 cells. These findings suggest that Lithospermum erythrorhizon prevents obesity by inhibiting adipogenesis through downregulation of genes involved in the adipogenesis pathway and may be a useful dietary supplement for the prevention of obesity.

Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins

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

Edwards, Megan R.; Liu, Gai; Mire, Chad E.

2016-02-11

Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitorymore » domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.« less

Differential suppression of glial nitric oxide synthase induction by structurally related tyrosine kinase inhibitors.

PubMed

Galea, E; Reddi, J; Feinstein, D L

1995-11-24

Incubation of C6 astrocytoma cells with bacterial endotoxin (lipopolysaccharide; LPS) plus interferon-gamma (IFN-gamma), or with a combination of cytokines (TNF-alpha, IL1-beta, and IFN-gamma) leads to high levels of inducible nitric oxide synthase (iNOS) expression. Previous results demonstrated a requirement for tyrosine kinase (TK) activities for iNOS induction. In the present study, a set of structurally related TK inhibitors, the tyrphostins (TYRs), were used to characterize possible differences between LPS and cytokine iNOS induction. All TYRs tested suppressed both types of induction. However, dose-response curves revealed significant differences in the IC50 values obtained for some TYRs (T25 and T56), and significant differences in the IC50 potency rank order when comparing inhibition of LPS versus cytokine-dependent iNOS induction. These results are consistent with differential TK utilization by the LPS versus cytokine pathways of iNOS induction, and establish a basis for developing further selective inhibitors of iNOS expression.

Regulatory T-cell stability and plasticity in mucosal and systemic immune systems.

PubMed

Murai, M; Krause, P; Cheroutre, H; Kronenberg, M

2010-09-01

Regulatory T cells (Treg) express the forkhead box p3 (Foxp3) transcription factor and suppress pathological immune responses against self and foreign antigens, including commensal microorganisms. Foxp3 has been proposed as a master key regulator for Treg, required for their differentiation, maintenance, and suppressive functions. Two types of Treg have been defined. Natural Treg (nTreg) are usually considered to be a separate sublineage arising during thymus differentiation. Induced Treg (iTreg) originate upon T cell receptor (TCR) stimulation in the presence of tumor growth factor beta. Although under homeostatic conditions most Treg in the periphery are nTreg, special immune challenges in the intestine promote more frequently the generation of iTreg. Furthermore, recent observations have challenged the notion that Treg are a stable sublineage, and they suggest that, particularly under lymphopenic and/or inflammatory conditions, Treg may lose Foxp3 and/or acquire diverse effector functions, especially in the intestine, which may contribute to uncontrolled inflammation.

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

PubMed Central

Yeste, Ada; Nadeau, Meghan; Burns, Evan J.; Weiner, Howard L.; Quintana, Francisco J.

2012-01-01

The immune response is normally controlled by regulatory T cells (Tregs). However, Treg deficits are found in autoimmune diseases, and therefore the induction of functional Tregs is considered a potential therapeutic approach for autoimmune disorders. The activation of the ligand-activated transcription factor aryl hydrocarbon receptor by 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) or other ligands induces dendritic cells (DCs) that promote FoxP3+ Treg differentiation. Here we report the use of nanoparticles (NPs) to coadminister ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG)35–55 to promote the generation of Tregs by DCs. NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Tregs in vitro. Moreover, NPs carrying ITE and MOG35–55 expanded the FoxP3+ Treg compartment and suppressed the development of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis. Thus, NPs are potential new tools to induce functional Tregs in autoimmune disorders. PMID:22745170

Pressure suppression containment system for boiling water reactor

DOEpatents

Gluntz, D.M.; Nesbitt, L.B.

1997-01-21

A system is disclosed for suppressing the pressure inside the containment of a BWR following a postulated accident. A piping subsystem is provided which features a main process pipe that communicates the wetwell airspace to a connection point downstream of the guard charcoal bed in an offgas system and upstream of the main bank of delay charcoal beds which give extensive holdup to offgases. The main process pipe is fitted with both inboard and outboard containment isolation valves. Also incorporated in the main process pipe is a low-differential-pressure rupture disk which prevents any gas outflow in this piping whatsoever until or unless rupture occurs by virtue of pressure inside this main process pipe on the wetwell airspace side of the disk exceeding the design opening (rupture) pressure differential. The charcoal holds up the radioactive species in the noncondensable gas from the wetwell plenum by adsorption, allowing time for radioactive decay before the gas is vented to the environs. 3 figs.

Differentially expressed genes of Tetrahymena thermophila in response to tributyltin (TBT) identified by suppression subtractive hybridization and real time quantitative PCR.

PubMed

Feng, Lifang; Miao, Wei; Wu, Yuxuan

2007-02-15

Tributyltin (TBT) is widely used as antifouling paints, agriculture biocides, and plastic stabilizers around the world, resulting in great pollution problem in aquatic environments. However, it has been short of the biomonitor to detect TBT in freshwater. We constructed the suppression subtractive hybridization library of Tetrahymena thermophila exposed to TBT, and screened out 101 Expressed Sequence Tags whose expressions were significantly up- or down-regulated with TBT treatment. From this, a series of genes related to the TBT toxicity were discovered, such as glutathione-S-transferase gene (down-regulated), plasma membrane Ca2+ ATPase isoforms 3 gene (up-regulated) and NgoA (up-regulated). Furthermore, their expressions under different concentrations of TBT treatment (0.5-40 ppb) were detected by real time fluorescent quantitative PCR. The differentially expressed genes of T. thermophila in response to TBT were identified, which provide the basic to make Tetrahymena as a sensitive, rapid and convenient TBT biomonitor in freshwater based on rDNA inducible expression system.

Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.

PubMed

Li, Ningning; Zhang, Ying; Sidlauskas, Kastytis; Ellis, Matthew; Evans, Ian; Frankel, Paul; Lau, Joanne; El-Hassan, Tedani; Guglielmi, Loredana; Broni, Jessica; Richard-Loendt, Angela; Brandner, Sebastian

2018-05-03

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

Schedules of electric shock presentation in the behavioral control of imprinted ducklings.

PubMed

Barrett, J E

1972-09-01

The behavioral effects of various schedules of electric shock presentation were investigated during and after the imprinting of Peking ducklings to moving stimuli. The behavior of following a moving imprinted stimulus was differentially controlled by a multiple schedule of punishment and avoidance that respectively suppressed and maintained following behavior. Pole-pecking, reinforced by presentations of the imprinted stimulus, was suppressed by response-produced shock (punishment); various schedules of response-independent shock and delayed punishment had an overall minimal effect. The delivery of response-independent shock in the presence of one of two stimuli, both during and after imprinting, resulted in a marked reduction in choice of the stimulus paired with shock. The experiments provide no support for a differentiation of imprinting from learning on the basis of the behavioral effects of aversive stimuli. Instead, as is the case with other organisms, the schedule under which shock is delivered to imprinted ducklings appears to be an important determinant of the temporal patterning of subsequent behavior.

Lactobacillus gasseri OLL2809 and its RNA suppress proliferation of CD4(+) T cells through a MyD88-dependent signalling pathway.

PubMed

Yoshida, Ayako; Yamada, Kiyoshi; Yamazaki, Yasumasa; Sashihara, Toshihiro; Ikegami, Shuuji; Shimizu, Makoto; Totsuka, Mamoru

2011-08-01

Recent studies have shown that probiotics are beneficial in prevention and improvement of inflammatory diseases. Accumulating evidence indicates that probiotics can modulate immune cell responses, although the specific molecular mechanism by which probiotics work remains elusive. Because T cells express receptors for microbial components, we examined whether the probiotic strain Lactobacillus gasseri OLL2809 (LG2809) and its components regulate murine CD4(+) T-cell activation. LG2809, as well as two other Lactobacillus strains, inhibited proliferation of CD4(+) T cells; LG2809 had the strongest suppressive activity among them. RNA isolated from LG2809 was also shown to have suppressive activity. We observed this suppressive effect in the culture of CD4(+) T cells stimulated with anti-CD3/CD28 treatment, suggesting a direct effect on CD4(+) T cells. In contrast, the suppressive effect was not observed for CD4(+) T cells from myeloid differentiation primary response gene 88 (MyD88) protein-deficient mice, and was abrogated in the presence of an anti-oxidant reagent, N-acetyl-cysteine (NAC). These results demonstrate that the suppressive effect of LG2809 and its RNA occurred through a MyD88-dependent signalling pathway and suggest involvement of a reactive oxygen species-dependent mechanism. LG2809 RNA injected subcutaneously suppressed delayed-type-hypersensitivity response in DO11.10 mice, and the suppression was abrogated by treatment with NAC. Collectively, these results suggest that suppression of T-cell proliferation by RNA may be one of the mechanisms when a probiotic bacterial strain exerts suppressive effects on inflammatory responses. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

Primary dedifferentiated liposarcoma of the axilla arising in a mixed, well-differentiated and myxoid liposarcoma.

PubMed

Campbell, Garth S; Lawrence, Thomas J; Porter, Scott E; Rezeanu, Luminita

2012-01-01

We describe a case of mixed liposarcoma of the axilla presenting as a high grade undifferentiated sarcoma with areas of well-differentiated and myxoid liposarcoma. MRI demonstrated a lobulated, septated intermuscular mass with marked heterogeneous gadolinium enhancement. A small focus of the tumor demonstrated fat suppressed signal more characteristic of well-differentiated liposarcoma. Pathologic analysis following wide local excision revealed a large, high grade sarcomatous component with highly pleomorphic cells with a thin rim of well-differentiated and myxoid liposarcoma on histologic examination. Dedifferentiated liposarcomas arising outside of the retroperitoneum are very rare, as are dedifferentiated liposarcomas arising from a histologically mixed liposarcoma. In this regard, this case illustrates an unusual combination of tumor location and histology which, to our knowledge, has not previously been reported.

Primary Dedifferentiated Liposarcoma of the Axilla Arising in a Mixed, Well-differentiated and Myxoid Liposarcoma

PubMed Central

Campbell, Garth S.; Lawrence, Thomas J.; Porter, Scott E.; Rezeanu, Luminita

2012-01-01

We describe a case of mixed liposarcoma of the axilla presenting as a high grade undifferentiated sarcoma with areas of well-differentiated and myxoid liposarcoma. MRI demonstrated a lobulated, septated intermuscular mass with marked heterogeneous gadolinium enhancement. A small focus of the tumor demonstrated fat suppressed signal more characteristic of well-differentiated liposarcoma. Pathologic analysis following wide local excision revealed a large, high grade sarcomatous component with highly pleomorphic cells with a thin rim of well-differentiated and myxoid liposarcoma on histologic examination. Dedifferentiated liposarcomas arising outside of the retroperitoneum are very rare, as are dedifferentiated liposarcomas arising from a histologically mixed liposarcoma. In this regard, this case illustrates an unusual combination of tumor location and histology which, to our knowledge, has not previously been reported. PMID:22690275

Methods to Control EMI Noises Produced in Power Converter Systems

NASA Astrophysics Data System (ADS)

Mutoh, Nobuyoshi; Ogata, Mitukatu

A new method to control EMI noises produced in power converters (rectifier and inverter) composed of IPMs (Intelligent Power Modules) is studied especially focusing on differential mode noises. The differential mode noises are occurred due to switching operations of the PWM control. As they are diffused into the ground through stray capacitors distributed between the ground and the power transmission lines and machine frames, differential mode noises should be confined and suppressed within the smallest area where power converters are laid out. It is impossible to control differential mode noises easily occurring diffusion by the conventional methods like filtering techniques. So, a new EMI noise control method using a multi-power circuit technique is proposed. The proposed method of the effectiveness has been verified through simulations and experiments.

Not All Attention Orienting is Created Equal: Recognition Memory is Enhanced When Attention Orienting Involves Distractor Suppression

PubMed Central

Markant, Julie; Worden, Michael S.; Amso, Dima

2015-01-01

Learning through visual exploration often requires orienting of attention to meaningful information in a cluttered world. Previous work has shown that attention modulates visual cortex activity, with enhanced activity for attended targets and suppressed activity for competing inputs, thus enhancing the visual experience. Here we examined the idea that learning may be engaged differentially with variations in attention orienting mechanisms that drive driving eye movements during visual search and exploration. We hypothesized that attention orienting mechanisms that engaged suppression of a previously attended location will boost memory encoding of the currently attended target objects to a greater extent than those that involve target enhancement alone To test this hypothesis we capitalized on the classic spatial cueing task and the inhibition of return (IOR) mechanism (Posner, Rafal, & Choate, 1985; Posner, 1980) to demonstrate that object images encoded in the context of concurrent suppression at a previously attended location were encoded more effectively and remembered better than those encoded without concurrent suppression. Furthermore, fMRI analyses revealed that this memory benefit was driven by attention modulation of visual cortex activity, as increased suppression of the previously attended location in visual cortex during target object encoding predicted better subsequent recognition memory performance. These results suggest that not all attention orienting impacts learning and memory equally. PMID:25701278

Transonic Flutter Suppression Control Law Design, Analysis and Wind Tunnel Results

NASA Technical Reports Server (NTRS)

Mukhopadhyay, Vivek

1999-01-01

The benchmark active controls technology and wind tunnel test program at NASA Langley Research Center was started with the objective to investigate the nonlinear, unsteady aerodynamics and active flutter suppression of wings in transonic flow. The paper will present the flutter suppression control law design process, numerical nonlinear simulation and wind tunnel test results for the NACA 0012 benchmark active control wing model. The flutter suppression control law design processes using (1) classical, (2) linear quadratic Gaussian (LQG), and (3) minimax techniques are described. A unified general formulation and solution for the LQG and minimax approaches, based on the steady state differential game theory is presented. Design considerations for improving the control law robustness and digital implementation are outlined. It was shown that simple control laws when properly designed based on physical principles, can suppress flutter with limited control power even in the presence of transonic shocks and flow separation. In wind tunnel tests in air and heavy gas medium, the closed-loop flutter dynamic pressure was increased to the tunnel upper limit of 200 psf The control law robustness and performance predictions were verified in highly nonlinear flow conditions, gain and phase perturbations, and spoiler deployment. A non-design plunge instability condition was also successfully suppressed.

Transonic Flutter Suppression Control Law Design, Analysis and Wind-Tunnel Results

NASA Technical Reports Server (NTRS)

Mukhopadhyay, Vivek

1999-01-01

The benchmark active controls technology and wind tunnel test program at NASA Langley Research Center was started with the objective to investigate the nonlinear, unsteady aerodynamics and active flutter suppression of wings in transonic flow. The paper will present the flutter suppression control law design process, numerical nonlinear simulation and wind tunnel test results for the NACA 0012 benchmark active control wing model. The flutter suppression control law design processes using (1) classical, (2) linear quadratic Gaussian (LQG), and (3) minimax techniques are described. A unified general formulation and solution for the LQG and minimax approaches, based on the steady state differential game theory is presented. Design considerations for improving the control law robustness and digital implementation are outlined. It was shown that simple control laws when properly designed based on physical principles, can suppress flutter with limited control power even in the presence of transonic shocks and flow separation. In wind tunnel tests in air and heavy gas medium, the closed-loop flutter dynamic pressure was increased to the tunnel upper limit of 200 psf. The control law robustness and performance predictions were verified in highly nonlinear flow conditions, gain and phase perturbations, and spoiler deployment. A non-design plunge instability condition was also successfully suppressed.

Transonic Flutter Suppression Control Law Design Using Classical and Optimal Techniques with Wind-Tunnel Results

NASA Technical Reports Server (NTRS)

Mukhopadhyay, Vivek

1999-01-01

The benchmark active controls technology and wind tunnel test program at NASA Langley Research Center was started with the objective to investigate the nonlinear, unsteady aerodynamics and active flutter suppression of wings in transonic flow. The paper will present the flutter suppression control law design process, numerical nonlinear simulation and wind tunnel test results for the NACA 0012 benchmark active control wing model. The flutter suppression control law design processes using (1) classical, (2) linear quadratic Gaussian (LQG), and (3) minimax techniques are described. A unified general formulation and solution for the LQG and minimax approaches, based on the steady state differential game theory is presented. Design considerations for improving the control law robustness and digital implementation are outlined. It was shown that simple control laws when properly designed based on physical principles, can suppress flutter with limited control power even in the presence of transonic shocks and flow separation. In wind tunnel tests in air and heavy gas medium, the closed-loop flutter dynamic pressure was increased to the tunnel upper limit of 200 psf. The control law robustness and performance predictions were verified in highly nonlinear flow conditions, gain and phase perturbations, and spoiler deployment. A non-design plunge instability condition was also successfully suppressed.

Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin β-Receptor Signaling (LTβR) Originating from Splenic and Non-Splenic Tissues.

PubMed

Milićević, Novica M; Nohroudi, Klaus; Schmidt, Friederike; Schmidt, Hendrik; Ringer, Cornelia; Sorensen, Grith Lykke; Milićević, Živana; Westermann, Jürgen

2016-01-01

Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin β-receptor (LTβR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTβR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTβR signaling inside and outside of the implanted tissue. We show that LTβR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTβR expressing cells in the animal (regenerate weights of 115 ± 8 mg in LTβR deficient recipients and of 12 ± 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTβR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTβR dependent suppressive activity. Thus, LTβR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases.

Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin β-Receptor Signaling (LTβR) Originating from Splenic and Non-Splenic Tissues

PubMed Central

Schmidt, Friederike; Schmidt, Hendrik; Ringer, Cornelia; Sorensen, Grith Lykke; Milićević, Živana; Westermann, Jürgen

2016-01-01

Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin β-receptor (LTβR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTβR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTβR signaling inside and outside of the implanted tissue. We show that LTβR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTβR expressing cells in the animal (regenerate weights of 115 ± 8 mg in LTβR deficient recipients and of 12 ± 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTβR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTβR dependent suppressive activity. Thus, LTβR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases. PMID:27936003

Effects of suppression and acceptance of sadness on the urge for non-suicidal self-injury and self-punishment.

PubMed

Svaldi, Jennifer; Dorn, Christina; Matthies, Swantje; Philipsen, Alexandra

2012-12-30

The present study wanted to test the course of the urge for non-suicidal self-injury (UNSSI) and the urge for self-punishment (USP) when suppressing or accepting upcoming emotions in response to a sadness-inducing film clip in female participants with borderline personality disorder (BPD). Thirty-six women with BPD were allocated either to a condition in which they were asked to engage in expressive suppression or acceptance while watching a sadness-inducing film clip. Ratings of UNSSI, USP, and positive and negative emotions were assessed prior to the clip (baseline), immediately after it (t1) and after a 5min waiting period (t2), during which participants viewed landscape pictures. Additionally, physiological measures were obtained. Main results revealed a significant increase in UNSSI from baseline to t2 in the acceptance, but not in the suppression group. Furthermore, USP scores significantly increased from baseline to t2 in the acceptance, but not in the suppression condition. However, there was no differential impact on the sympathetic and parasympathetic branch depending on strategy. The results are in line with recent literature showing that expressive suppression in BPD may also have an adaptive function. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Functional characterization of the extraclassical receptive field in macaque V1: contrast, orientation, and temporal dynamics.

PubMed

Henry, Christopher A; Joshi, Siddhartha; Xing, Dajun; Shapley, Robert M; Hawken, Michael J

2013-04-03

Neurons in primary visual cortex, V1, very often have extraclassical receptive fields (eCRFs). The eCRF is defined as the region of visual space where stimuli cannot elicit a spiking response but can modulate the response of a stimulus in the classical receptive field (CRF). We investigated the dependence of the eCRF on stimulus contrast and orientation in macaque V1 cells for which the laminar location was determined. The eCRF was more sensitive to contrast than the CRF across the whole population of V1 cells with the greatest contrast differential in layer 2/3. We confirmed that many V1 cells experience stronger suppression for collinear than orthogonal stimuli in the eCRF. Laminar analysis revealed that the predominant bias for collinear suppression was found in layers 2/3 and 4b. The laminar pattern of contrast and orientation dependence suggests that eCRF suppression may derive from different neural circuits in different layers, and may be comprised of two distinct components: orientation-tuned and untuned suppression. On average tuned suppression was delayed by ∼25 ms compared with the onset of untuned suppression. Therefore, response modulation by the eCRF develops dynamically and rapidly in time.

Adipose Genes Down-Regulated During Experimental Endotoxemia Are Also Suppressed in Obesity

PubMed Central

Hinkle, Christine C.; Haris, Lalarukh; Shah, Rhia; Mehta, Nehal N.; Putt, Mary E.; Reilly, Muredach P.

2012-01-01

Context: Adipose inflammation is a crucial link between obesity and its metabolic complications. Human experimental endotoxemia is a controlled model for the study of inflammatory cardiometabolic responses in vivo. Objective: We hypothesized that adipose genes down-regulated during endotoxemia would approximate changes observed with obesity-related inflammation and reveal novel candidates in cardiometabolic disease. Design, Subjects, and Intervention: Healthy volunteers (n = 14) underwent a 3 ng/kg endotoxin challenge; adipose biopsies were taken at 0, 4, 12, and 24 h for mRNA microarray. A priority list of highly down-regulated and biologically relevant genes was validated by RT-PCR in an independent sample of adipose from healthy subjects (n = 7) undergoing a subclinical 0.6 ng/kg endotoxemia protocol. Expression of validated genes was screened in adipose of lean and severely obese individuals (n = 11 per group), and cellular source was probed in cultured adipocytes and macrophages. Results: Endotoxemia (3 ng/kg) suppressed expression of 353 genes (to <67% of baseline; P < 1 × 10−5) of which 68 candidates were prioritized for validation. In low-dose (0.6 ng/kg) endotoxin validation, 22 (32%) of these 68 genes were confirmed. Functional classification revealed that many of these genes are involved in cell development and differentiation. Of validated genes, 59% (13 of 22) were down-regulated more than 1.5-fold in primary human adipocytes after treatment with endotoxin. In human macrophages, 59% (13 of 22) were up-regulated during differentiation to inflammatory M1 macrophages whereas 64% (14 of 22) were down-regulated during transition to homeostatic M2 macrophages. Finally, in obese vs. lean adipose, 91% (20 of 22) tended to have reduced expression (χ2 = 10.72, P < 0.01) with 50% (11 of 22) reaching P < 0.05 (χ2 = 9.28, P < 0.01). Conclusions: Exploration of down-regulated mRNA in adipose during human endotoxemia revealed suppression of genes involved in cell development and differentiation. A majority of candidates were also suppressed in endogenous human obesity, suggesting a potential pathophysiological role in human obesity-related adipose inflammation. PMID:22893715

Adipose genes down-regulated during experimental endotoxemia are also suppressed in obesity.

PubMed

Shah, Rachana; Hinkle, Christine C; Haris, Lalarukh; Shah, Rhia; Mehta, Nehal N; Putt, Mary E; Reilly, Muredach P

2012-11-01

Adipose inflammation is a crucial link between obesity and its metabolic complications. Human experimental endotoxemia is a controlled model for the study of inflammatory cardiometabolic responses in vivo. We hypothesized that adipose genes down-regulated during endotoxemia would approximate changes observed with obesity-related inflammation and reveal novel candidates in cardiometabolic disease. Healthy volunteers (n = 14) underwent a 3 ng/kg endotoxin challenge; adipose biopsies were taken at 0, 4, 12, and 24 h for mRNA microarray. A priority list of highly down-regulated and biologically relevant genes was validated by RT-PCR in an independent sample of adipose from healthy subjects (n = 7) undergoing a subclinical 0.6 ng/kg endotoxemia protocol. Expression of validated genes was screened in adipose of lean and severely obese individuals (n = 11 per group), and cellular source was probed in cultured adipocytes and macrophages. Endotoxemia (3 ng/kg) suppressed expression of 353 genes (to <67% of baseline; P < 1 × 10(-5)) of which 68 candidates were prioritized for validation. In low-dose (0.6 ng/kg) endotoxin validation, 22 (32%) of these 68 genes were confirmed. Functional classification revealed that many of these genes are involved in cell development and differentiation. Of validated genes, 59% (13 of 22) were down-regulated more than 1.5-fold in primary human adipocytes after treatment with endotoxin. In human macrophages, 59% (13 of 22) were up-regulated during differentiation to inflammatory M1 macrophages whereas 64% (14 of 22) were down-regulated during transition to homeostatic M2 macrophages. Finally, in obese vs. lean adipose, 91% (20 of 22) tended to have reduced expression (χ(2) = 10.72, P < 0.01) with 50% (11 of 22) reaching P < 0.05 (χ(2) = 9.28, P < 0.01). Exploration of down-regulated mRNA in adipose during human endotoxemia revealed suppression of genes involved in cell development and differentiation. A majority of candidates were also suppressed in endogenous human obesity, suggesting a potential pathophysiological role in human obesity-related adipose inflammation.

Human colon tissue in organ culture: calcium and multi-mineral-induced mucosal differentiation

PubMed Central

Dame, Michael K.; Veerapaneni, Indiradevi; Bhagavathula, Narasimharao; Naik, Madhav; Varani, James

2011-01-01

We have recently shown that a multi-mineral extract from the marine red algae, Lithothamnion calcareum, suppresses colon polyp formation and inflammation in mice. In the present study, we used intact human colon tissue in organ culture to compare responses initiated by Ca2+ supplementation versus the multi-mineral extract. Normal human colon tissue was treated for 2 d in culture with various concentrations of calcium or the mineral-rich extract. The tissue was then prepared for histology/immunohistochemistry, and the culture supernatants were assayed for levels of type I procollagen and type I collagen. At higher Ca2+ concentrations or with the mineral-rich extract, proliferation of epithelial cells at the base and walls of the mucosal crypts was suppressed, as visualized by reduced Ki67 staining. E-cadherin, a marker of differentiation, was more strongly expressed at the upper third of the crypt and at the luminal surface. Treatment with Ca2+ or with the multi-mineral extract influenced collagen turnover, with decreased procollagen and increased type I collagen. These data suggest that calcium or mineral-rich extract has the capacity to (1) promote differentiation in human colon tissue in organ culture and (2) modulate stromal function as assessed by increased levels of type I collagen. Taken together, these data suggest that human colon tissue in organ culture (supporting in vivo finding in mice) will provide a valuable model for the preclinical assessment of agents that regulate growth and differentiation in the colonic mucosa. PMID:21104039

Alpinia officinarum Stimulates Osteoblast Mineralization and Inhibits Osteoclast Differentiation.

PubMed

Shim, Ki-Shuk; Lee, Chung-Jo; Yim, Nam-Hui; Gu, Min Jung; Ma, Jin Yeul

2016-01-01

Alpinia officinarum rhizome has been used as a traditional herbal remedy to treat inflammatory and internal diseases. Based on the previously observed inhibitory effect of A. officinarum rhizome in an arthritis model, we evaluated whether a water extract of A. officinarum rhizome (WEAO) would enhance in vitro osteoblast mineralization using calvarial osteoblast precursor cells or would inhibit in vitro osteoclast differentiation and bone resorption using bone marrow derived macrophages. In osteoblasts, WEAO enhanced the mRNA levels of transcription factor (runt-related transcription factor 2, smad1, smad5, and junB) and marker (bone morphogenetic protein-2, collagen type 1alpha1, and osteocalcin) genes related to osteoblast mineralization, consistent with increased alizarin red S staining intensity. WEAO markedly inhibited osteoclast differentiation by suppressing the receptor activator for nuclear factor-[Formula: see text]B ligand-induced downregulation of inhibitor of DNA binding 2 and V-maf musculoaponeurotic fibrosarcoma oncogene homolog B and the phosphorylation of c-Jun N-terminal kinase, p38, nuclear factor-[Formula: see text]B, c-Src, and Bruton's tyrosine kinase to induce nuclear factor of activated T cells cytoplasmic 1 expression. WEAO also suppressed the resorbing activity of mature osteoclasts by altering actin ring formation. Therefore, the results of this study demonstrate that WEAO stimulates osteoblast mineralization and inhibits osteoclast differentiation. Thus, WEAO may be a promising herbal candidate to treat or prevent pathological bone diseases by regulating the balance between osteoclast and osteoblast activity.

Screening differentially expressed genes in an amphipod (Hyalella azteca) exposed to fungicide vinclozolin by suppression subtractive hybridization.

PubMed

Wu, Yun H; Wu, Tsung M; Hong, Chwan Y; Wang, Yei S; Yen, Jui H

2014-01-01

Vinclozolin, a dicarboximide fungicide, is an endocrine disrupting chemical that competes with an androgenic endocrine disruptor compound. Most research has focused on the epigenetic effect of vinclozolin in humans. In terms of ecotoxicology, understanding the effect of vinclozolin on non-target organisms is important. The expression profile of a comprehensive set of genes in the amphipod Hyalella azteca exposed to vinclozolin was examined. The expressed sequence tags in low-dose vinclozolin-treated and -untreated amphipods were isolated and identified by suppression subtractive hybridization. DNA dot blotting was used to confirm the results and establish a subtracted cDNA library for comparing all differentially expressed sequences with and without vinclozolin treatment. In total, 494 differentially expressed genes, including hemocyanin, heatshock protein, cytochrome, cytochrome oxidase and NADH dehydrogenase were detected. Hemocyanin was the most abundant gene. DNA dot blotting revealed 55 genes with significant differential expression. These genes included larval serum protein 1 alpha, E3 ubiquitin-protein ligase, mitochondrial cytochrome c oxidase, mitochondrial protein, proteasome inhibitor, hemocyanin, zinc-finger-containing protein, mitochondrial NADH-ubiquinone oxidoreductase and epididymal sperm-binding protein. Vinclozolin appears to upregulate stress-related genes and hemocyanin, related to immunity. Moreover, vinclozolin downregulated NADH dehydrogenase, related to respiration. Thus, even a non-lethal concentration of vinclozolin still has an effect at the genetic level in H. azteca and presents a potential risk, especially as it would affect non-target organism hormone metabolism.

Phloretin and phlorizin promote lipolysis and inhibit inflammation in mouse 3T3-L1 cells and in macrophage-adipocyte co-cultures.

PubMed

Huang, Wen-Chung; Chang, Wei-Tien; Wu, Shu-Ju; Xu, Pei-Yin; Ting, Nai-Chun; Liou, Chian-Jiun

2013-10-01

Previous studies found that phloretin (PT) and phlorizin (PZ) could inhibit glucose transport, with PT being a better inhibitor of lipid peroxidation. This study aimed to evaluate the antiobesity effects of PT and PZ in 3T3-L1 cells and if they can modulate the relationship between adipocytes and macrophages. Differentiated 3T3-L1 cells were treated with PT or PZ. Subsequently, transcription factors of adipogenesis and lipolysis proteins were measured. In addition, RAW 264.7 macrophages treated with PT or PZ were cultured in differentiated media from 3T3-L1 cells to analyze inflammatory mediators and signaling pathways. PT significantly enhanced glycerol release and inhibited the adipogenesis-related transcription factors. PT also promoted phosphorylation of AMP-activated protein kinase and increased activity of adipose triglyceride lipase and hormone-sensitive lipase. PT suppressed the nuclear transcription factor kappa-B and mitogen-activated protein kinase pathways when RAW 264.7 cells were cultured in differentiated media from 3T3-L1 cells. PZ improved lipolysis and inhibited the macrophage inflammatory response less effectively than PT. This study suggests that PT is more effective than PZ at increasing lipolysis in adipocytes. In addition, PT also suppresses inflammatory response in macrophage that is stimulated by differentiated media from 3T3-L1 cells. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Arabidopsis and Tobacco SUPERMAN regulate hormone signalling and mediate cell proliferation and differentiation

PubMed Central

Nibau, Candida; Di Stilio, Verónica S.; Wu, Hen-ming; Cheung, Alice Y.

2011-01-01

Arabidopsis thaliana SUPERMAN (SUP) plays an important role during flower development by maintaining the boundary between stamens and carpels in the inner two whorls. It was proposed that SUP maintains this boundary by regulating cell proliferation in both whorls, as loss-of-function superman mutants produce more stamens at the expense of carpels. However, the cellular mechanism that underlies SUP function remains unknown. Here Arabidopsis or tobacco (Nicotiana tabacum) SUP was overexpressed in tobacco plants to substantiate SUP's role as a regulator of cell proliferation and boundary definition and provide evidence that its biological role may be mediated via hormonal changes. It was found that moderate levels of SUP stimulated cell growth and proliferation, whereas high levels were inhibitory. SUP stimulated auxin- and cytokinin-regulated processes, and cells overexpressing SUP displayed reduced hormone dependency for proliferation and regeneration into plants. SUP also induced proliferation of female traits in the second and third flower whorls and promoted differentiation of petaloid properties in sepals, further supporting a role for SUP as a boundary regulator. Moreover, cytokinin suppressed stamen development and promoted differentiation of carpeloid tissues, suggesting that SUP may regulate male and female development via its effect on cytokinin signalling. Taken together, these observations suggest a model whereby the effect of SUP on cell growth and proliferation involves the modulation of auxin- and cytokinin-regulated processes. Furthermore, differential SUP expression or different sensitivities of different cell types to SUP may determine whether SUP stimulates or suppresses their proliferation. PMID:20980362

The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy

PubMed Central

Ohsawa, Yutaka; Takayama, Kentaro; Nishimatsu, Shin-ichiro; Okada, Tadashi; Fujino, Masahiro; Fukai, Yuta; Murakami, Tatsufumi; Hagiwara, Hiroki; Itoh, Fumiko; Tsuchida, Kunihiro; Hayashi, Yoshio; Sunada, Yoshihide

2015-01-01

Myostatin, a muscle-specific transforming growth factor-β (TGF-β), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an α-helix that is evolutionarily conserved among other TGF-β family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF-β1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings. PMID:26226340

The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy.

PubMed

Ohsawa, Yutaka; Takayama, Kentaro; Nishimatsu, Shin-ichiro; Okada, Tadashi; Fujino, Masahiro; Fukai, Yuta; Murakami, Tatsufumi; Hagiwara, Hiroki; Itoh, Fumiko; Tsuchida, Kunihiro; Hayashi, Yoshio; Sunada, Yoshihide

2015-01-01

Myostatin, a muscle-specific transforming growth factor-β (TGF-β), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an α-helix that is evolutionarily conserved among other TGF-β family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF-β1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings.