MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Effect of supplemental Ca2+ on NaCl-stressed castor plants (Ricinus communis L.)

Greenhouse experiments were conducted to assess the effects of supplemental Ca2+ in salinised soil on germination and plant growth response of castor plant (Ricinus communis L. Var. Avani-31, Euphorbiaceae). NaCl amounting to 390 g was thoroughly mixed with soil of seven lots, of 100 kg each, to give electrical conductivity of 4.1 dS m–1. Further, Ca(NO3)2 × 4H20 to the quantity of 97.5, 195, 292.5, 390, 487.5, and 585 g was separately mixed with soil of six lots to give 1:0.25, 1:0.50, 1:0.75, 1:1, 1:1.25, and 1:1.50 Na+/Ca2+ ratios, respectively. The soil of the seventh lot contained only NaCl and its Na+/Ca2+ ratio was 1:0. Soil without addition of NaCl and Ca (NO3)2 × 4H20 served as control, with a 0:0 Na+/Ca2+ ratio. Salinity significantly retarded seed germination and plant growth, but the deleterious effects of NaCl on seed germination were ameliorated and plant growth was restored with Ca2+ supply at the critical level (1:0.25 Na+/Ca2+ ratio) to salinised soil. Supply of Ca2+ above the critical level further retarded seed germination and plant growth due to the increased soil salinity. Salt stress reduced N, P, K+ and Ca2+ content in plant tissues, but these nutrients were restored by addition of Ca2+ at the critical level to saline soil. In contrast, Na+ content in plant tissues significantly increased in response to salinity, but significantly decreased with increasing Ca2+ supply to saline soil. The results are discussed in terms of the beneficial effects of Ca2+ supply on the plant growth of Ricinus communis grown under saline conditions

Illusions of Visual Motion Elicited by Electrical Stimulation of Human MT Complex

Human cortical area MT+ (hMT+) is known to respond to visual motion stimuli, but its causal role in the conscious experience of motion remains largely unexplored. Studies in non-human primates demonstrate that altering activity in area MT can influence motion perception judgments, but animal studies are inherently limited in assessing subjective conscious experience. In the current study, we use functional magnetic resonance imaging (fMRI), intracranial electrocorticography (ECoG), and electrical brain stimulation (EBS) in three patients implanted with intracranial electrodes to address the role of area hMT+ in conscious visual motion perception. We show that in conscious human subjects, reproducible illusory motion can be elicited by electrical stimulation of hMT+. These visual motion percepts only occurred when the site of stimulation overlapped directly with the region of the brain that had increased fMRI and electrophysiological activity during moving compared to static visual stimuli in the same individual subjects. Electrical stimulation in neighboring regions failed to produce illusory motion. Our study provides evidence for the sufficient causal link between the hMT+ network and the human conscious experience of visual motion. It also suggests a clear spatial relationship between fMRI signal and ECoG activity in the human brain

Neurodevelopment of the visual system in typically developing children.

A central question in developmental psychology is how a child acquires knowledge about the surrounding world. Is it important for learning to know what an object represents, before a child knows how to deal with it? Or does a child learn because it is improving haptic skills to act upon an object, to follow its actions and predict how it behaves? Behavioral research investigating such questions distinguished the role of dorsal and ventral visual streams in learning to "know how" and "know what" about objects, but these studies did not unequivocally resolve how these functions mature. Recent functional, structural, and microstructural neuroimaging research has shed a novel light on the normal development of the human visual system, particularly during later stages of child development. This chapter reviews these neuroimaging studies and interrogates them on the question of whether dorsal and ventral visual streams mature at different rates. Structural gray matter properties within the ventral visual stream show prolonged development compared to the dorsal stream, whereas white matter connectivity within dorsal visual stream structures matures later. Functionally specialized areas in the ventral visual stream show increased size during development, whereas parietal dorsal stream areas show increasing activity associated with high-order visual perception. Such results emphasize the importance of neuroimaging techniques for research on visual cognitive development. They suggest that high-order visual functions mature late and that dorsal and ventral visual streams follow different neurodevelopmental trajectories

Neurodevelopment of the visual system in typically developing children

A central question in developmental psychology is how a child acquires knowledge about the surrounding world. Is it important for learning to know what an object represents, before a child knows how to deal with it? Or does a child learn because it is improving haptic skills to act upon an object, to follow its actions and predict how it behaves? Behavioral research investigating such questions distinguished the role of dorsal and ventral visual streams in learning to “know how” and “know what” about objects, but these studies did not unequivocally resolve how these functions mature. Recent functional, structural, and microstructural neuroimaging research has shed a novel light on the normal development of the human visual system, particularly during later stages of child development. This chapter reviews these neuroimaging studies and interrogates them on the question of whether dorsal and ventral visual streams mature at different rates. Structural gray matter properties within the ventral visual stream show prolonged development compared to the dorsal stream, whereas white matter connectivity within dorsal visual stream structures matures later. Functionally specialized areas in the ventral visual stream show increased size during development, whereas parietal dorsal stream areas show increasing activity associated with high-order visual perception. Such results emphasize the importance of neuroimaging techniques for research on visual cognitive development. They suggest that high-order visual functions mature late and that dorsal and ventral visual streams follow different neurodevelopmental trajectories

Spatial distribution of the antagonistic surround of MT/V5 neurons

The majority (217/325, 66%) of the neurons in the middle temporal (MT) area/V5 show strong antagonistic surrounds, defined here by a decrease of at least 50% in the summation curve. We mapped the antagonistic surround in 145 such cells, using eight circularly distributed surround stimulus patches (Surround Asymmetry Test, SAT) and also mapped the surround in 51 of these 145 cells using a grid consisting of 25 square patches (Surround Mapping Test, SMT). Both tests showed that the angular surround distribution was non-uniform in the majority of these neurons. In half the neurons, the antagonistic surround was asymmetric, and arose from a single region on one side of the excitatory receptive field (ERF). In another quarter of the sample the surround was bilaterally symmetric, and arose from a pair of regions on opposite sides of the ERF. Only the remaining 20% showed a circularly symmetric surround distribution. These three groups differed in their laminar distribution. The SMT showed that, radially, the surround antagonism reached a maximum, on average, at 1.5 times the ERF radius, Detailed comparisons of the spatial relationships of excitatory and inhibitory regions of the RF components shows that non-homogeneity of the surround influence appears to be an intrinsic property of the surround. Such a property may underly the extraction of the surface orientation and curvature from speed patterns

Parallel processing in human visual cortex revealed through the influence of their neural responses on the visual evoked potential

The neural response in the human visual system is composed of magno-, parvo- and koniocellular input from the retina. Signal differences from functional imaging between health and individuals with a cognitive weakness are attributed to a dysfunction of a specific retinal input. Yet, anatomical interconnections within the human visual system obscure individual contribution to the neural response in V1. Deflections in the visual evoked potential (VEP) arise from an interaction between electric dipoles, their strength determined by the size of the neural population active during temporal - and spatial luminance contrast processing. To investigate interaction between these neural responses, we recorded the VEP over visual cortex of 14 healthy adults viewing four series of windmill patterns. Within a series, the relative area white in a pattern varied systematically. Between series, the number of sectors across which this area was distributed doubled. These patterns were viewed as pattern alternating and on-/off stimuli. P100/P1 amplitude increased linearly with the relative area white in the pattern, while N135/N1 and P240/P2 amplitude increased with the number of sectors of which the area white was distributed. The decreases P100 amplitude with increasing number of sectors is attributed to an interaction between electric dipoles located in granular and supragranular layers of V1. Differences between the VEP components obtained during a pattern reversing display and following pattern onset are accounted for by the transient and sustained nature of neural responses processing temporal - and spatial luminance contrast and ability of these responses to manifest in the VEP

Cross-Frequency Coupling Between Brain and Body Biosignals: A Systemic Physiology Augmented Functional Near-Infrared Spectroscopy Hyperscanning Study.

BACKGROUND Understanding the brain and body processes during interaction or cooperation between two or more subjects is an important topic in current neuroscientific research. In a previous study, we introduced a novel approach that enables investigation of the coupling of biosignals (brain and systemic physiology, SP) from two subjects: systemic physiology augmented functional near-infrared spectroscopy (SPA-fNIRS) hyperscanning. AIM The aim was to extend our signal analysis approach by the cross-frequency time-dependent wavelet transform coherence (WTC) of the fNIRS and SP biosignals to gain new insights into the nature and cause of functional hyperconnectivity. SUBJECTS AND METHODS 24 pairs of adults took part in a closed-eye versus prolonged eye-contact task of 10 min each. Brain and body activity was measured continuously by SPA-fNIRS hyperscanning. We calculated the time-dependent WTC of the biosignals for four different frequency bands: very low-frequency band (VLF, 0.002-0.08 Hz), low-frequency band 1 (LF1, 0.015-0.15 Hz), low-frequency band 2 (LF2, 0.08-0.15 Hz) and heart rate band (HR, 1-2 Hz). We then performed the cross-frequency correlated-coherence coupling analysis. RESULTS A stronger cross-frequency coupling during the eye-contact condition (between 99 pairs of biosignals) was found than during the eye-closed condition (between 50 pairs of biosignals). Prolonged eye contact led to entrainment of the brain and body between different frequency bands and two subjects. The strongest hyperconnectivity was between the LF1-VLF frequency band. DISCUSSION AND CONCLUSION With this exploratory study, we reveal further benefits of the SPA-fNIRS approach for future hyperscanning studies