Although many studies document the role of propositional truth-value in human psychological reading behavior, there is a relative paucity of research examining the role of differential propositional truth-value in processing Chinese counterfactual conditionals. This study is to investigate the role of differential propositional value in processing Chinese counterfactual conditionals by means of ERPs (event-related potentials). The study is based on comprehending two types of Chinese counterfactual conditionals, which is propositional truth value introduced by two different markers of conditional conjunctions in the protasis and apodosis, such as true counterfactual conditional markers jiaru (if) & jiu (so) in the sentence wo xiang yu jiaru you tui jiu keyi zai shuixia zhixi (I think if fish had legs so they could stifle under water), and false counterfactual conditional markers ruguo (if) & namo (then) in the sentence wo xiang gou ruguo you lin namo keyi zai shuixia huxi (I think if dogs had scales, then they could breathe under water). Two counterfactual propositional values (i.e. true and false propositional values) are constructed through manipulating sentence counterfactuality between the true and false counterfactual conditional markers in the protasis and the apodosis. Twenty-four full-time Chinese college students participated in the ERP study. The results demonstrated that processing the true counterfactual propositional sentences with conditional markers jiaru (if) & jiu (so) elicited the N400 effect relative to false propositional sentences with conditional markers ruguo (if) & namo (then). Moreover, the counterfactual sentences with true propositional conditions varied from the elicitation of the N400 effect in the protasis and absence of the N400 effect in the apodosis, showing that semantic roles may gradually disappear under the impact of truth value of propositional counterfactual condition, and/or the roles of semantic anomaly was eliminated in the accumulated sentence processing. While for the false counterfactual conditional sentences, elicitations of P300 in the protasis and robust N400 effect in the apodosis were shown, indicating the increasing semantic role in the processing. Interestingly, there was the absence of the P600 effect for processing sentences with syntactic violation, suggesting little extra syntactic cost in processing sentences with false propositional condition.

BACKGROUND: Studies suggest that the components of brain-evoked potentials (EPs) may serve as biomarkers of the post-traumatic stress disorder (PTSD) caused by participation in combat operations; however, to date, research remains fragmented, with no studies that have attempted to combine different paradigms. In addition, the mismatch negativity component has not been studied in a Russian sample of veterans with PTSD.
OBJECTIVE: To identify objective neurophysiological markers of combat-related PTSD using the method of auditory-evoked potentials in active and passive listening paradigms.
METHODS: The study included a recording of auditory EPs in an oddball paradigm in three settings: 1) directed attention to auditory stimuli, 2) passive listening while viewing a neutral video sequence, and 3) viewing a video sequence associated with a traumatic event. Combatants diagnosed with PTSD (18 people) were compared with mentally healthy civilian volunteers (22 people).
RESULTS: An increase in the latency period of the early components of auditory EP (N100 and P200), an increase in the amplitude of the P200 component to a deviant stimulus, and a decrease to a standard one in the active listening paradigm were established in the PTSD group. There were no significant differences in the parameters of the P300 component. The characteristics of mismatch negativity in the passive paradigm were revealed: an increase in the phenomenon amplitude, both when shown a video sequence associated with a traumatic event and when shown a neutral video sequence. A binary logistic regression model constructed using the selected parameters showed that the identified characteristics can potentially be considered as diagnostic markers of PTSD in combatants, as the classification accuracy stood at 87% (sensitivity - 81%, specificity - 91%).
CONCLUSIONS: Potential neurophysiological markers of PTSD are the following: the amplitude and latency of early components of auditory EPs in the paradigm of directed attention to stimuli and the amplitude of mismatch negativity during passive attention.
UNASSIGNED: Исследования показывают, что компоненты вызванных потенциалов головного мозга (ВП) могут являться биомаркерами посттравматического стрессового расстройства (ПТСР) вследствие участия в боевых действиях, однако на сегодняшний день исследования фрагментарны, не представлены исследования, сочетающие различные парадигмы. На русской выборке ветеранов с ПТСР не изучался компонент негативности рассогласования.
UNASSIGNED: Выявление объективных нейрофизиологических маркеров ПТСР вследствие участия в боевых действиях методом слуховых вызванных потенциалов в парадигмах активного и пассивного слушания.
UNASSIGNED: Исследование включало регистрацию слуховых ВП в парадигме вероятностного предъявления (oddball) в трех состояниях: 1) направленное внимание на слуховые стимулы; 2) пассивное слушание при просмотре нейтрального видеоряда; 3) при просмотре видеоряда, связанного с травматическим событием. Обследованы комбатанты с диагнозом ПТСР (18 человек) в сравнении с психически здоровыми гражданскими добровольцами (22 человека).
UNASSIGNED: В группе лиц с ПТСР обнаружено увеличение латентного периода ранних компонентов слухового ВП (N100 и Р200), увеличение амплитуды компонента Р200 на девиантный стимул и снижение на стандартный в парадигме активного слушания. Не выявлено значимых различий в показателях компонента Р300. Выявлены особенности негативности рассогласования в пассивной парадигме: увеличение амплитуды феномена как при предъявлении видеоряда, связанного с травматическим событием, так и при предъявлении нейтрального видеоряда. Построенная с использованием выделенных показателей модель бинарной логистической регрессии показала, что выявленные особенности потенциально можно рассматривать как диагностические маркеры ПТСР у комбатантов — точность классификации составила 87% (чувствительность — 81%, специфичность — 91%).
UNASSIGNED: Потенциальными нейрофизиологическими маркерами ПТСР являются амплитуда и латентный период ранних компонентов слуховых ВП в парадигме направленного внимания на стимулы, а также амплитуда негативности рассогласования при пассивном внимании.

Macroautophagy, the mainly regulated form of autophagy, maintains the cellular homeostasis and degrades the transported cargoes. It is initiated by the protein kinase complex regulating by two signals pathway Mammalian target of rapamycin complex 1 (mTORC1)-Adenosine 5\' monophosphate activated protein kinase (AMPK)-Unc 51 like kinase 1(ULK1) and ULK1-PI3K- phosphatidylinositol 3-phosphate (PI3P). Currently, autolysosomes are accumulated during the aging process of CD8+T cells in vitro and may participate in inducing death sensitization of senescent cells. The main mechanism of aplastic anemia, a hyperimmune disease, is the T cells subsets imbalance such as CD8+T cells abnormal activation and hyperfunction. Therefore, the role of autophagy in the CD8+T cells and supposed whether some immunosuppress drugs induced the cells autophagic death to treat the hyperimmune diseases were focused. It was decided found that the acetyltransferase p300 obviously increased in the aplastic anemia patients and was related with the severity of disease. Previous studies have reported that canonical autophagy is regulated by the mTORC1-p300 axis. p300 is a critical bridge in the p300-VPS34 axis mediated non-canonical autophagy. There is the deficiency of autophagy and acetylation in the CD8+T cells. The expression of p300 also decreased notably after the immunosuppressive drugs therapy. Our findings provide a framework for understanding how immunosuppressive drugs effect on the AA autophagy deficiency mechanism and proved that immunosuppressive drugs negatively regulated the function of CD8+T cells by p300-mediated canonical autophagy pathway and non-canonical autophagy pathway.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

The decision-making of soccer referees is one of the typical forms influenced by factors such as environmental pressure and individual emotions. While previous studies have explored how common factors like personal anxiety and on-field pressure affect the decisions of soccer referees, the mechanisms by which anxiety influences decision-making under pressure remain unclear. This study developed a penalty task based on real soccer match scenarios and recruited 76 experienced soccer referees. These referees were divided into two groups, high anxiety and low anxiety, based on their anxiety levels, to perform decision-making tasks under different pressure environments simulated to mimic real matches. Additionally, this research employed Event-Related Potential (ERP) technology to compare the brain signals of soccer referees with different levels of anxiety when facing foul play under various pressure environments. It was found that referees with high levels of anxiety displayed larger P300 and N400 amplitudes in a low-pressure environment (p = 0.0059, t = 2.9437). However, no significant differences in P300 and N400 amplitudes were observed between referees with high and low levels of anxiety under high-pressure conditions (p = 0.1890, t = 1.3411). This study not only reveals the complex mechanisms of anxiety in the decision-making process of referees but also emphasizes the importance of understanding and managing the psychological state of referees in competitive sports to improve the quality of their decisions. Our findings provide an empirical basis for future efforts to mitigate the impact of anxiety and optimize the decision-making process in similar high-pressure environments.

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.

BACKGROUND: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC.
METHODS: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system.
RESULTS: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression.
CONCLUSIONS: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC.
BACKGROUND: The funding details can be found in the Acknowledgements section.

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.

Earlier research has suggested gender differences in event-related potentials/oscillations (ERPs/EROs). Yet, the alteration in event-related oscillations (EROs) in the delta and theta frequency bands have not been explored between genders across the three age groups of adulthood, i.e., 18-50, 51-65, and >65 years. Data from 155 healthy elderly participants who underwent a neurological examination, comprehensive neuropsychological assessment (including attention, memory, executive function, language, and visuospatial skills), and magnetic resonance imaging (MRI) from past studies were used. The delta and theta ERO powers across the age groups and between genders were compared and correlational analyses among the ERO power, age, and neuropsychological tests were performed. The results indicated that females displayed higher theta ERO responses than males in the frontal, central, and parietal regions but not in the occipital location between 18 and 50 years of adulthood. The declining theta power of EROs in women reached that of men after the age of 50 while the theta ERO power was more stable across the age groups in men. Our results imply that the cohorts must be recruited at specified age ranges across genders, and clinical trials using neurophysiological biomarkers as an intervention endpoint should take gender into account in the future.