SOX2 represses c-MYC transcription by altering the co-activator landscape of the c-MYC super-enhancer and promoter regions.

Our previous studies determined that elevating SOX2 in a wide range of tumor cells leads to a reversible state of tumor growth arrest. Efforts to understand how tumor cell growth is inhibited led to the discovery of a SOX2:MYC axis that is responsible for downregulating c-MYC (MYC) when SOX2 is elevated. Although we had determined that elevating SOX2 downregulates MYC transcription, the mechanism responsible was not determined. Given the challenges of targeting MYC clinically, we set out to identify how elevating SOX2 downregulates MYC transcription. In this study, we focused on the MYC promoter region and an upstream region of the MYC locus that contains a MYC super-enhancer encompassing five MYC enhancers and which is associated with several cancers. Here we report that BRD4 and p300 associate with each of the MYC enhancers in the upstream MYC super-enhancer as well as the MYC promoter region and that elevating SOX2 decreases the recruitment of BRD4 and p300 to these sites. Additionally, we determined that elevating SOX2 leads to increases in the association of SOX2 and H3K27me3 within the MYC super-enhancer and the promoter region of MYC. Importantly, we conclude that the increases in SOX2 within the MYC super-enhancer precipitate a cascade of events that culminates in the repression of MYC transcription. Together, our studies identify a novel molecular mechanism able to regulate MYC transcription in two distinctly different tumor types and provide new mechanistic insights into the molecular interrelationships between two master regulators, SOX2 and MYC, widely involved in multiple cancers.

Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates the ZNF334 gene to inhibit the growth of colorectal cancer.

Although therapeutic targets for colorectal cancer (CRC) treatment have been developed, the treatment outcomes are not ideal and survival rates for CRC patients remain low. It is critical to identify a specific target and develop an effective CRC treatment system. The ZNF334 gene is a newly identified member of Zinc-finger proteins (ZNFs), which is essential for key biological processes associated with tumorigenesis. Abnormal epigenetic reprogramming of the ZNF334 gene promoter region decreases its expression in CRC and further induces the occurrence of CRC. Here, we clarified that P300 in CRC can regulate the H3K9/27 ac in the ZNF334 promoter. Furthermore, histone acetylation of the ZNF334 promoter region was increased by dCas9-P300 to normalize the deficiency of ZNF334 expression, thereby inhibiting the growth of CRC. Collectively, our findings enable a facile way to affect gene expression using CRISPR/Cas9-based epigenome editing and further determine the causal link between histone acetylation and gene activation, providing a promising gene therapy strategy for the CRC treatment.

Epstein-Barr virus nuclear antigen EBNA3A modulates IRF3-dependent IFNß expression.

Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, persistently infects over 90% of the human adult population and is associated with several human cancers. To establish life-long infection, EBV tampers with the induction of type I interferon (IFN I)-dependent antiviral immunity in the host. How various EBV genes help orchestrate this crucial strategy is incompletely defined. Here, we reveal a mechanism by which the EBV nuclear antigen 3A (EBNA3A) may inhibit IFNß induction. Using proximity biotinylation we identify the histone acetyltransferase P300, a member of the IFNß transcriptional complex, as a binding partner of EBNA3A. We further show that EBNA3A also interacts with the activated IFN-inducing transcription factor IRF3 that collaborates with P300 in the nucleus. Both events are mediated by the N-terminal domain of EBNA3A. We propose that EBNA3A limits binding of IRF3 to the IFNß promoter, thereby hampering downstream IFN I signaling. Collectively, our findings suggest a new mechanism of immune evasion by EBV, affected by its latency gene EBNA3A.

Neurophysiological Correlates of Near-Wins in Gambling: A Systematic Literature Review.

Identification of specific patterns of brain activity related to problem gambling may provide a deeper understanding of its underlying mechanisms, highlighting the importance of neurophysiological studies to better understand development and persistence of gambling behavior. The patterns of cognitive functioning have been investigated through electroencephalography (EEG) studies based on the near-win/near-miss (NW) effect. The main goal of the present study was to evaluate the neurophysiological basis of NWs and their modulation by gambling problems through a systematic review of event-related potentials (ERP) studies elicited by feedback events. The review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA). A total of 15 studies were included, 12 comprising non-problem gamblers (NPGs) and three comparing problem gamblers (PGs) with matched controls. For the P300 component, the win outcome elicited a larger amplitude than the other outcomes (NW and loss), followed by the NW outcome, which elicited a larger amplitude than loss in some studies. For feedback-related negativity (FRN), the loss outcome evoked a more negative amplitude in several studies, despite eliciting a similar amplitude to NW outcomes in others. For PGs, the NW outcome evoked a higher amplitude of P300 than loss, while NPGs showed a similar amplitude to both outcomes. The present review gathered information from different sources and provides a consistent view of the different studies. However, studies lack systematic and robust methodologies, leading to inconsistent results and making it difficult to reach any definitive conclusions.

Habituation of Central and Electrodermal Responses to an Auditory Two-Stimulus Oddball Paradigm.

The orienting reaction (OR) towards a new stimulus is subject to habituation, i.e., progressively attenuates with stimulus repetition. The skin conductance responses (SCRs) are known to represent a reliable measure of OR at the peripheral level. Yet, it is still a matter of debate which of the P3 subcomponents is the most likely to represent the central counterpart of the OR. The aim of the present work was to study habituation, recovery, and dishabituation phenomena intrinsic to a two-stimulus auditory oddball paradigm, one of the most-used paradigms both in research and clinic, by simultaneously recording SCRs and P3 in twenty healthy volunteers. Our findings show that the target stimulus was capable of triggering a more marked OR, as indexed by both SCRs and P3, compared to the standard stimulus, that could be due to its affective saliency and relevance for task completion; the application of temporal principal components analysis (PCA) to the P3 complex allowed us to identify several subcomponents including both early and late P3a (eP3a; lP3a), P3b, novelty P3 (nP3), and both a positive and a negative Slow Wave (+SW; -SW). Particularly, lP3a and P3b subcomponents showed a similar behavior to that observed for SCRs , suggesting them as central counterparts of OR. Finally, the P3 evoked by the first standard stimulus after the target showed a significant dishabituation phenomenon which could represent a sign of the local stimulus change. However, it did not reach a sufficient level to trigger an SCR/OR since it did not represent a salient event in the context of the task.

Effects of daily listening to 6 Hz binaural beats over one month: an event-related potentials study.

The aim of the present study was to identify cognitive alterations, as indicated by event-related potentials (ERPs), after one month of daily exposure to theta binaural beats (BBs) for 10 minutes. The recruited healthy subjects (n = 60) were equally divided into experimental and control groups. For a month, the experimental group was required to practice BBs listening daily, while the control group did not. ERPs were assessed at three separate visits over a span of one month, with a two-week interval between each visit. At each visit, ERPs were measured before and after listening. The auditory and visual ERPs significantly increased the auditory and visual P300 amplitudes consistently at each visit. BBs enhanced the auditory N200 amplitude consistently across all visits, but the visual N200 amplitude increased only at the second and third visits. Compared to the healthy controls, daily exposure to BBs for two weeks resulted in increased auditory P300 amplitude. Additionally, four weeks of BBs exposure not only increased auditory P300 amplitude but also reduced P300 latency. These preliminary findings suggest that listening to BBs at 6 Hz for 10 minutes daily may enhance certain aspects of cognitive function. However, further research is needed to confirm these effects and to understand the underlying mechanisms. Identifying the optimal duration and practice of listening to 6 Hz BBs could potentially contribute to cognitive enhancement strategies in healthy individuals.

Zinc-finger CCHC-type containing protein 8 promotes RNA virus replication by suppressing the type-I interferon responses.

Host cells have evolved an intricate regulatory network to fine tune the type-I interferon responses. However, the full picture of this regulatory network remains to be depicted. In this study, we found that knock out of zinc-finger CCHC-type containing protein 8 (ZCCHC8) impairs the replication of influenza A virus (IAV), Sendai virus (Sev), Japanese encephalitis virus (JEV), and vesicular stomatitis virus (VSV). Further investigation unveiled that ZCCHC8 suppresses the type-I interferon responses by targeting the interferon regulatory factor 3 (IRF3) signaling pathway. Mechanistically, ZCCHC8 associates with phosphorylated IRF3 and disrupts the interaction of IRF3 with the co-activator CREB-binding protein (CBP). Additionally, the direct binding of ZCCHC8 with the IFN-stimulated response element (ISRE) impairs the ISRE-binding of IRF3. Our study contributes to the comprehensive understanding for the negative regulatory network of the type-I interferon responses and provides valuable insights for the control of multiple viruses from a host-centric perspective.IMPORTANCEThe innate immune responses serve as the initial line of defense against invading pathogens and harmful substances. Negative regulation of the innate immune responses plays an essential role in avoiding auto-immune diseases and over-activated immune responses. Hence, the comprehensive understanding of the negative regulation network for innate immune responses could provide novel therapeutic insights for the control of viral infections and immune dysfunction. In this study, we report that ZCCHC8 negatively regulates the type-I interferon responses. We illustrate that ZCCHC8 impedes the IRF3-CBP association by interacting with phosphorylated IRF3 and competes with IRF3 for binding to ISRE. Our study demonstrates the role of ZCCHC8 in the replication of multiple RNA viruses and contributes to a deeper understanding of the negative regulation system for the type-I interferon responses.

Identification of Methamphetamine Abusers Can Be Supported by EEG-Based Wavelet Transform and BiLSTM Networks.

Methamphetamine (MA) is a neurological drug, which is harmful to the overall brain cognitive function when abused. Based on this property of MA, people can be divided into those with MA abuse and healthy people. However, few studies to date have investigated automatic detection of MA abusers based on the neural activity. For this reason, the purpose of this research was to investigate the difference in the neural activity between MA abusers and healthy persons and accordingly discriminate MA abusers. First, we performed event-related potential (ERP) analysis to determine the time range of P300. Then, the wavelet coefficients of the P300 component were extracted as the main features, along with the time and frequency domain features within the selected P300 range to classify. To optimize the feature set, F_score was used to remove features below the average score. Finally, a Bidirectional Long Short-term Memory (BiLSTM) network was performed for classification. The experimental result showed that the detection accuracy of BiLSTM could reach 83.85%. In conclusion, the P300 component of EEG signals of MA abusers is different from that in normal persons. Based on this difference, this study proposes a novel way for the prevention and diagnosis of MA abuse.

Cortical Generators and Connections Underlying Phoneme Perception: A Mismatch Negativity and P300 Investigation.

The cortical generators of the pure tone MMN and P300 have been thoroughly studied. Their nature and interaction with respect to phoneme perception, however, is poorly understood. Accordingly, the cortical sources and functional connections that underlie the MMN and P300 in relation to passive and active speech sound perception were identified. An inattentive and attentive phonemic oddball paradigm, eliciting a MMN and P300 respectively, were administered in 60 healthy adults during simultaneous high-density EEG recording. For both the MMN and P300, eLORETA source reconstruction was performed. The maximal cross-correlation was calculated between ROI-pairs to investigate inter-regional functional connectivity specific to passive and active deviant processing. MMN activation clusters were identified in the temporal (insula, superior temporal gyrus and temporal pole), frontal (rostral middle frontal and pars opercularis) and parietal (postcentral and supramarginal gyrus) cortex. Passive discrimination of deviant phonemes was aided by a network connecting right temporoparietal cortices to left frontal areas. For the P300, clusters with significantly higher activity were found in the frontal (caudal middle frontal and precentral), parietal (precuneus) and cingulate (posterior and isthmus) cortex. Significant intra- and interhemispheric connections between parietal, cingulate and occipital regions constituted the network governing active phonemic target detection. A predominantly bilateral network was found to underly both the MMN and P300. While passive phoneme discrimination is aided by a fronto-temporo-parietal network, active categorization calls on a network entailing fronto-parieto-cingulate cortices. Neural processing of phonemic contrasts, as reflected by the MMN and P300, does not appear to show pronounced lateralization to the language-dominant hemisphere.

Recording the tactile P300 with the cEEGrid for potential use in a brain-computer interface.

Brain-computer interfaces (BCIs) are scientifically well established, but they rarely arrive in the daily lives of potential end-users. This could be in part because electroencephalography (EEG), a prevalent method to acquire brain activity for BCI operation, is considered too impractical to be applied in daily life of end-users with physical impairment as an assistive device. Hence, miniaturized EEG systems such as the cEEGrid have been developed. While they promise to be a step toward bridging the gap between BCI development, lab demonstrations, and home use, they still require further validation. Encouragingly, the cEEGrid has already demonstrated its ability to record visually and auditorily evoked event-related potentials (ERP), which are important as input signal for many BCIs. With this study, we aimed at evaluating the cEEGrid in the context of a BCI based on tactually evoked ERPs. To compare the cEEGrid with a conventional scalp EEG, we recorded brain activity with both systems simultaneously. Forty healthy participants were recruited to perform a P300 oddball task based on vibrotactile stimulation at four different positions. This tactile paradigm has been shown to be feasible for BCI repeatedly but has never been tested with the cEEGrid. We found distinct P300 deflections in the cEEGrid data, particularly at vertical bipolar channels. With an average of 63%, the cEEGrid classification accuracy was significantly above the chance level (25%) but significantly lower than the 81% reached with the EEG cap. Likewise, the P300 amplitude was significantly lower (cEEGrid R2-R7: 1.87 µV, Cap Cz: 3.53 µV). These results indicate that a tactile BCI using the cEEGrid could potentially be operated, albeit with lower efficiency. Additionally, participants' somatosensory sensitivity was assessed, but no correlation to the accuracy of either EEG system was shown. Our research contributes to the growing amount of literature comparing the cEEGrid to conventional EEG systems and provides first evidence that the tactile P300 can be recorded behind the ear. A BCI based on a thus simplified EEG system might be more readily accepted by potential end-users, provided the accuracy can be substantially increased, e.g., by training and improved classification.

Differences in Children and Adolescents with Depression before and after a Remediation Program: An Event-Related Potential Study.

Depression is clinically diagnosed when a defined constellation of symptoms manifests over a specific duration with notable severity. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Major Depressive Disorder (MDD) is characterized by the presence of five or more symptoms persisting for at least two weeks. As a profound mental health condition affecting millions globally, depression presents a considerable challenge for researchers and clinicians alike. In pediatric and adolescent populations, depression can precipitate adverse outcomes, including substance abuse, academic difficulties, risky sexual behaviors, physical health problems, impaired social relationships, and a markedly elevated risk of suicide-up to thirty times higher than the general population. This paper details a study that evaluated the efficacy of Cognitive Behavioral Therapy (CBT) alone vs. CBT combined with selective serotonin reuptake inhibitors (SSRIs) in a treatment program. The study cohort comprised sixteen (16) children and adolescents diagnosed with depression (eight males and eight females) and sixteen (16) typically developing peers (eight males and eight females) aged from 9 to 15 years (Mean age = 11.94, standard deviation = 2.02). Initial assessments employed Event-Related Potentials (ERPs), the Children's Depression Inventory (CDI), and reaction time measurements. The results reveal that participants with depression exhibit cognitive deficits in attention and memory, as evidenced by prolonged P300 latencies. Following intervention with either CBT alone or CBT combined with medication, the depressed participants demonstrated significant improvements, evidenced by lower CDI scores, reduced P300 latencies, and faster reaction times, both compared to their pre-treatment status and relative to the control group.

Effects of Transcutaneous Auricular Vagus Nerve Stimulation on the P300: Do Stimulation Duration and Stimulation Type Matter?

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has attracted increasing interest as a neurostimulation tool with potential applications in modulating cognitive processes such as attention and memory, possibly through the modulation of the locus-coeruleus noradrenaline system. Studies examining the P300 brain-related component as a correlate of noradrenergic activity, however, have yielded inconsistent findings, possibly due to differences in stimulation parameters, thus necessitating further investigation. In this event-related potential study involving 61 participants, therefore, we examined how changes in taVNS parameters, specifically stimulation type (interval vs. continuous stimulation) and duration, influence P300 amplitudes during a visual novelty oddball task. Although no effects of stimulation were found over the whole cluster and time window of the P300, cluster-based permutation tests revealed a distinct impact of taVNS on the P300 response for a small electrode cluster, characterized by larger amplitudes observed for easy targets (i.e., stimuli that are easily discernible from standards) following taVNS compared to sham stimulation. Notably, our findings suggested that the type of stimulation significantly modulated taVNS effects on the P300, with continuous stimulation showing larger P300 differences (taVNS vs. sham) for hard targets and standards compared to interval stimulation. We observed no interaction effects of stimulation duration on the target-related P300. While our findings align with previous research, further investigation is warranted to fully elucidate the influence of taVNS on the P300 component and its potential utility as a reliable marker for neuromodulation in this field.

Mismatch Negativity and P300 in the Diagnosis and Prognostic Assessment of Coma and Other Disorders of Consciousness.

BACKGROUND: The objective of this study was to investigate the value of mismatch negativity (MMN) and P300 event-related potentials for discriminating the consciousness state and predicting improvement of consciousness at 6 months in patients with coma and other disorders of consciousness (DOC). METHODS: We performed MMN and P300 on 42 patients with DOC with a mean onset time of 40.21 ± 19.43 days. These patients with DOC were categorized into coma, unresponsive wakefulness syndrome (UWS), minimal consciousness minus (MCS-), and minimal consciousness plus (MCS +) groups according to neurobehavioral assessment and the Coma Recovery Scale-Revised score. The primary outcome was the improvement of consciousness at 6 months in patients with DOC. We assessed the efficacy of MMN and P300 in quantitatively predicting the prognosis at 6 months and the capability of MMN and P300 parameters to differentiate between DOC. RESULTS: At least one significant difference in either MMN or P300 parameters was displayed among the DOC groups, but not between the MCS- and MCS+ groups (significance level: 0.05). Both MMN and P300 amplitudes showed desirable predictive accuracy at 6 months, with areas under the curve (AUCs) of 0.859 and 0.856, respectively. The optimal thresholds for MMN and P300 amplitudes were 2.044 and 1.095 µV. However, the combined MMN-P300 amplitude showed better 6-month predictive accuracy (AUC 0.934, 95% confidence interval 0.860-1.000), with a sensitivity of 85% and a specificity of 90.9%. CONCLUSIONS: MMN and P300 may help discriminate among coma, UWS, and MCS, but not between patients with MCS- and patients with MCS+ . The MMN amplitude, P300 amplitude, and especially combined MMN-P300 amplitude at 6 months may be interesting predictors of consciousness improvement at 6 months in patients with DOC. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier ChiCTR2400083798.

Application of hybrid SSVEP + P300 brain computer interface to control avatar movement in mobile virtual reality gaming environment.

INTRODUCTION: This research evaluated the feasibility of a hybrid SSVEP + P300 brain computer interface (BCI) for controlling the movement of an avatar in a virtual reality (VR) gaming environment (VR + BCI). Existing VR + BCI gaming environments have limitations, such as visual fatigue, a lower communication rate, minimum accuracy, and poor system comfort. Hence, there is a need for an optimized hybrid BCI system that can simultaneously evoke the strongest P300 and SSVEP potentials in the cortex. METHODS: A BCI headset was coupled with a VR headset to generate a VR + BCI environment. The author developed a VR game in which the avatar's movement is controlled using the user's cortical responses with the help of a BCI headset. Specifically designed visual stimuli were used in the proposed system to elicit the strongest possible responses from the user's brain. The proposed system also includes an auditory feedback mechanism to facilitate precise avatar movement. RESULTS AND CONCLUSIONS: Conventional P300 BCI and SSVEP BCI were also used to control the movements of the avatar, and their performance metrics were compared to those of the proposed system. The results demonstrated that the hybrid SSVEP + P300 BCI system was superior to the other systems for controlling avatar movement.

Aerobic training attenuates cardiac remodeling in mice post-myocardial infarction by inhibiting the p300/CBP-associated factor.

Aerobic training (AT), an effective form of cardiac rehabilitation, has been shown to be beneficial for cardiac repair and remodeling after myocardial infarction (MI). The p300/CBP-associated factor (PCAF) is one of the most important lysine acetyltransferases and is involved in various biological processes. However, the role of PCAF in AT and AT-mediated cardiac remodeling post-MI has not been determined. Here, we found that the PCAF protein level was significantly increased after MI, while AT blocked the increase in PCAF. AT markedly improved cardiac remodeling in mice after MI by reducing endoplasmic reticulum stress (ERS). In vivo, similar to AT, pharmacological inhibition of PCAF by Embelin improved cardiac recovery and attenuated ERS in MI mice. Furthermore, we observed that both IGF-1, a simulated exercise environment, and Embelin protected from H2O2-induced cardiomyocyte injury, while PCAF overexpression by viruses or the sirtuin inhibitor nicotinamide eliminated the protective effect of IGF-1 in H9C2 cells. Thus, our data indicate that maintaining low PCAF levels plays an essential role in AT-mediated cardiac protection, and PCAF inhibition represents a promising therapeutic target for attenuating cardiac remodeling after MI.

Investigating the mechanism of tricyclic decyl benzoxazole -induced apoptosis in liver Cancer cells through p300-mediated FOXO3 activation.

OBJECTIVE: To investigate whether tricyclic decylbenzoxazole (TDB) regulates liver cancer cell proliferation and apoptosis through p300-mediated FOXO acetylation. METHODS: Sequencing, adenovirus, and lentivirus transfection were performed in human liver cancer cell line SMMC-7721 and apoptosis was detected by Tunel, Hoechst, and flow cytometry. TEM for mitochondrial morphology, MTT for cell proliferation ability, Western blot, and PCR were used to detect protein levels and mRNA changes. RESULTS: Sequencing analysis and cell experiments confirmed that TDB can promote the up-regulation of FOXO3 expression. TDB induced FOXO3 up-regulation in a dose-dependent manner, promoted the expression of p300 and Bim, and enhanced the acetylation and dephosphorylation of FOXO3, thus promoting apoptosis. p300 promotes apoptosis of cancer cells through Bim and other proteins, while HAT enhances the phosphorylation of FOXO3 and inhibits apoptosis. Overexpression of FOXO3 can increase the expression of exo-apoptotic pathways (FasL, TRAIL), endo-apoptotic pathways (Bim), and acetylation at the protein level and inhibit cell proliferation and apoptotic ability, while FOXO3 silencing or p300 mutation can partially reverse apoptosis. In tumor tissues with overexpression of FOXO3, TDB intervention can further increase the expression of p53 and caspase-9 proteins in tumor cells, resulting in loss of mitochondrial membrane integrity during apoptosis, the release of cytoplasm during signal transduction, activation of caspase-9 and synergistic inhibition of growth. CONCLUSION: TDB induces proliferation inhibition and promotes apoptosis of SMMC-7721 cells by activating p300-mediated FOXO3 acetylation.

Mecp2 promotes the anti-inflammatory effect of alpinetin via epigenetic modification crosstalk.

In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.

Extracellular C1qbp inhibits myogenesis by suppressing NFATc1.

Aging and lack of exercise are the most important etiological factors for muscle loss. We hypothesized that new factors that contribute to muscle loss could be identified from ones commonly altered in expression in aged and exercise-limited skeletal muscles. Mouse gastrocnemius muscles were subjected to mass spectrometry-based proteomic analysis. The muscle proteomes of hindlimb-unloaded and aged mice were compared to those of exercised and young mice, respectively. C1qbp expression was significantly upregulated in the muscles of both hindlimb-unloaded and aged mice. In vitro myogenic differentiation was not affected by altering intracellular C1qbp expression but was significantly suppressed upon recombinant C1qbp treatment. Additionally, recombinant C1qbp repressed the protein level but not the mRNA level of NFATc1. NFATc1 recruited the transcriptional coactivator p300, leading to the upregulation of acetylated histone H3 levels. Furthermore, NFATc1 silencing inhibited p300 recruitment, downregulated acetylated histone H3 levels, and consequently suppressed myogenic differentiation. The expression of C1qbp was inversely correlated with that of NFATc1 in the gastrocnemius muscles of exercised or hindlimb-unloaded, and young or aged mice. These findings demonstrate a novel role of extracellular C1qbp in suppressing myogenesis by inhibiting the NFATc1/p300 complex. Thus, C1qbp can serve as a novel therapeutic target for muscle loss.

Epigenetic control of SOX9 gene by the histone acetyltransferase P300 in human Sertoli cells.

Background: The transcription factor SOX9 is a key regulator of male sexual development and Sertoli cell differentiation. Altered SOX9 expression has been implicated in the pathogenesis of disorders of sexual development (DSD) in mammals. However, limited information exists regarding the epigenetic mechanisms governing its transcriptional control during sexual development. Methods: This study employed real-time PCR (qPCR), immunofluorescence (IIF), and chromatin immunoprecipitation (ChIP) assays to investigate the epigenetic mechanisms associated with SOX9 gene transcriptional control in human and mouse Sertoli cell lines. To identify the specific epigenetic enzymes involved in SOX9 epigenetic control, functional assays using siRNAs for P300, GCN5, and WDR5 were performed. Results: The transcriptional activation of SOX9 was associated with selective deposition of active histone modifications, such as H3K4me3 and H3K27ac, at its enhancer and promoter regions. Importantly, the histone acetyltransferase P300 was found to be significantly enriched at the SOX9 enhancers, co-localizing with the H3K27ac and the SOX9 transcription factor. Silencing of P300 led to decreased SOX9 expression and reduced H3K27ac levels at the eSR-A and e-ALDI enhancers, demonstrating the crucial role of P300-mediated histone acetylation in SOX9 transcriptional activation. Interestingly, another histone lysine acetyltransferases like GNC5 and methyltransferases as the Trithorax/COMPASS-like may also have a relevant role in male sexual differentiation. Conclusions: Histone acetylation by P300 at SOX9 enhancers, is a key mechanism governing the transcriptional control of this essential regulator of male sexual development. These findings provide important insights into the epigenetic basis of sexual differentiation and the potential pathogenesis of DSDs.

RSVP-based BCI for inconspicuous targets: detection, localization, and modulation of attention.

OBJECTIVE: While Brain-Computer Interface (BCI) based on Rapid Serial Visual Presentation (RSVP) is widely used in target detection, patterns of Event-Related Potential (ERP), as well as the performance on detecting inconspicuous targets remain unknown. Moreover, participant-screening methods to excluded 'BCI-blind' users are still lacking. APPROACH: A RSVP paradigm was designed with targets of varied concealment, size, and location. ERPs (e.g. P300 and N2pc) and target detection accuracy were compared among these conditions. The relationship between participants' attention scores and target detection accuracy was also analyzed to test attention level as a criterion for participant screening. MAIN RESULTS: Statistical analysis showed conditions of target concealment and size had significant influences on ERP. In particular, ERP for inconspicuous targets, such as concealed and small targets, had lower amplitude and longer latency. In consistent, the accuracy of detection in inconspicuous condition was significantly lower than that of conspicuous condition. In addition, a significant association was found between attention scores and target detection accuracy for camouflaged targets. SIGNIFICANCE: The study was the first to address ERP features among multiple dimensions of concealment, size, and location. The conclusion provided insights into the relationship between ERP decoding and properties of targets. In addition, the association between attention scores and detection accuracy implied a promising method in screening well-behaved participants for camouflaged target detection.