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

How our hearts beat together: a study on physiological synchronization based on a self-paced joint motor task

Cardiac physiological synchrony is regarded as an important component of social interaction due to its putative role in prosocial behaviour. Yet, the processes underlying physiological synchrony remain unclear. We aim to investigate these processes. 20 dyads (19 men, 21 women, age range 18-35) engaged in a self-paced interpersonal tapping synchronization task under different levels of tapping synchrony due to blocking of sensory communication channels. Applying wavelet transform coherence analysis, significant increases in heart rate synchronization from baseline to task execution were found with no statistically significant difference across conditions. Furthermore, the control analysis, which assessed synchrony between randomly combined dyads of participants showed no difference from the original dyads' synchrony. We showed that interindividual cardiac physiological synchrony during self-paced synchronized finger tapping resulted from a task-related stimulus equally shared by all individuals. We hypothesize that by applying mental effort to the task, individuals changed into a similar mental state, altering their cardiac regulation. This so-called psychophysiological mode provoked more uniform, less variable fluctuation patterns across all individuals leading to similar heart rate coherence independent of subsequent pairings. With this study, we provide new insights into cardiac physiological synchrony and highlight the importance of appropriate study design and control analysis

Systemic physiology augmented functional near-infrared spectroscopy hyperscanning: a first evaluation investigating entrainment of spontaneous activity of brain and body physiology between subjects.

Significance: Functional near-infrared spectroscopy (fNIRS) enables measuring the brain activity of two subjects while they interact, i.e., the hyperscanning approach. Aim: In our exploratory study, we extended classical fNIRS hyperscanning by adding systemic physiological measures to obtain systemic physiology augmented fNIRS (SPA-fNIRS) hyperscanning while blocking and not blocking the visual communication between the subjects. This approach enables access brain-to-brain, brain-to-body, and body-to-body coupling between the subjects simultaneously. Approach: Twenty-four pairs of subjects participated in the experiment. The paradigm consisted of two subjects that sat in front of each other and had their eyes closed for 10 min, followed by a phase of 10 min where they made eye contact. Brain and body activity was measured continuously by SPA-fNIRS. Results: Our study shows that making eye contact for a prolonged time causes significant changes in brain-to-brain, brain-to-body, and body-to-body coupling, indicating that eye contact is followed by entrainment of the physiology between subjects. Subjects that knew each other generally showed a larger trend to change between the two conditions. Conclusions: The main point of this study is to introduce a new framework to investigate brain-to-brain, body-to-body, and brain-to-body coupling through a simple social experimental paradigm. The study revealed that eye contact leads to significant synchronization of spontaneous activity of the brain and body physiology. Our study is the first that employed the SPA-fNIRS approach and showed its usefulness to investigate complex interpersonal physiological changes

Effects of contact with a dog on prefrontal brain activity: A controlled trial

BACKGROUND There is a broad range of known effects of animal contact on human mental and physical health. Neurological correlates of human interaction with animals have been sparsely investigated. We investigated changes in frontal brain activity in the presence of and during contact with a dog. METHODS Twenty-one healthy individuals each participated in six sessions. In three sessions, participants had contact with a dog, and in three control sessions they interacted with a plush animal. Each session had five two-minute phases with increasing intensity of contact to the dog or plush animal from the first to the fourth phase. We measured oxygenated, deoxygenated, and total hemoglobin and oxygen saturation of the blood in the frontal lobe/frontopolar area with functional near-infrared spectroscopy (SenSmart Model X-100) to assess brain activity. FINDINGS In both conditions, the concentration of oxygenated hemoglobin increased significantly from the first to the fourth phase by 2.78 μmol/l (CI = 2.03-3.53, p < .001). Oxygenated hemoglobin concentration was 0.80 μmol/l higher in the dog condition compared to in the control condition (CI = 0.27-1.33, p = .004). Deoxygenated-hemoglobin concentration, total hemoglobin concentration, and oxygen saturation showed similar patterns. CONCLUSION Prefrontal brain activation in healthy subjects increased with the rise in interaction closeness with a dog or a plush animal. Moreover, interaction with a dog stimulated more brain activity compared to the control condition, suggesting that interactions with a dog can activate stronger attentional processes and elicit more emotional arousal than interacting with a nonliving stimulus

Effects of contact with a dog on prefrontal brain activity: a controlled trial

Background There is a broad range of known effects of animal contact on human mental and physical health. Neurological correlates of human interaction with animals have been sparsely inves- tigated. We investigated changes in frontal brain activity in the presence of and during con- tact with a dog. Methods Twenty-one healthy individuals each participated in six sessions. In three sessions, partici- pants had contact with a dog, and in three control sessions they interacted with a plush ani- mal. Each session had five two-minute phases with increasing intensity of contact to the dog or plush animal from the first to the fourth phase. We measured oxygenated, deoxygenated, and total hemoglobin and oxygen saturation of the blood in the frontal lobe/frontopolar area with functional near-infrared spectroscopy (SenSmart Model X-100) to assess brain activity. Findings In both conditions, the concentration of oxygenated hemoglobin increased significantly from the first to the fourth phase by 2.78 μmol/l (CI = 2.03-3.53, p < .001). Oxygenated hemoglo- bin concentration was 0.80 μmol/l higher in the dog condition compared to in the control con- dition (CI = 0.27-1.33, p = .004). Deoxygenated-hemoglobin concentration, total hemoglobin concentration, and oxygen saturation showed similar patterns. Conclusion Prefrontal brain activation in healthy subjects increased with the rise in interaction closeness with a dog or a plush animal. Moreover, interaction with a dog stimulated more brain activity compared to the control condition, suggesting that interactions with a dog can activate stron- ger attentional processes and elicit more emotional arousal than interacting with a nonliving stimulus

A functional SUMO-motif in the active site of PIM1 promotes its degradation via RNF4, and stimulates protein kinase activity

The PIM1 serine/threonine protein kinase mediates growth factor and survival signalling, and cooperates potently with c-MYC during tumorigenesis. PIM1 is overexpressed in many human cancers and is a promising target for drug development. PIM1 levels are regulated mainly through cytokine-induced transcription and protein degradation, but mechanisms regulating its activity and levels remain largely unexplored. Here, we show that PIM1 is modified in vitro and in cultured cells by the Small ubiquitin-like modifier (SUMO) on two independent sites: K169, within a consensus SUMOylation motif (IK169DE171) in the active site of PIM1, and also at a second promiscuous site. Alanine substitution of E171 (within the consensus motif) abolished SUMOylation, significantly increased the half-life of PIM1, and markedly reduced its ubiquitylation. Mechanistically, SUMOylation promoted ubiquitin-mediated degradation of PIM1 via recruitment of the SUMO-targeted ubiquitin ligase, RNF4. Additionally, SUMOylated PIM1 showed enhanced protein kinase activity in vitro. Interestingly, the E171A mutant was active in vitro but displayed altered substrate specificity in cultured cells, consistent with the idea that SUMOylation may govern PIM1 substrate specificity under certain contexts. Taken together, these data demonstrate that the protein kinase activity and levels of PIM1 can be regulated by covalent post-translational modification

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

Absolute Pitch—Functional Evidence of Speech-Relevant Auditory Acuity

Absolute pitch (AP) has been shown to be associated with morphological changes and neurophysiological adaptations in the planum temporale, a cortical area involved in higher-order auditory and speech perception processes. The direct link between speech processing and AP has hitherto not been addressed. We provide first evidence that AP compared with relative pitch (RP) ability is associated with significantly different hemodynamic responses to complex speech sounds. By systematically varying the lexical and/or prosodic information of speech stimuli, we demonstrated consistent activation differences in AP musicians compared with RP musicians and nonmusicians. These differences relate to stronger activations in the posterior part of the middle temporal gyrus and weaker activations in the anterior mid-part of the superior temporal gyrus. Furthermore, this pattern is considerably modulated by the auditory acuity of AP. Our results suggest that the neural underpinnings of pitch processing expertise exercise a strong influence on propositional speech perception (sentence meaning)

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