Inhibition of ERN1 affects the expression of TGIF1 and other homeobox gene expressions in U87MG glioblastoma cells.

BACKGROUND: The ERN1 (endoplasmic reticulum to nucleus signaling 1) pathway plays an important role in the regulation of gene expression in glioblastoma, but molecular mechanism has not yet been fully elucidated. The aim of this study was to evaluate the relative relevance of ERN1 activity as a kinase in comparison to its endoribonuclease activity in the regulation of homeobox gene expression. METHODS: Two sublines of U87MG glioblastoma cells with different ways of ERN1 inhibition were used: dnERN1 (overexpressed transgene without protein kinase and endoribonuclease) and dnrERN1 (overexpressed transgene with mutation in endoribonuclease). ERN1 suppression was also done using siRNA for ERN1. Silencing of XBP1 mRNA by specific siRNA was used for suppression of ERN1 endoribonuclease function mediated by XBP1s. The expression levels of homeobox genes and microRNAs were evaluated by qPCR. RESULTS: The expression of TGIF1 and ZEB2 genes was downregulated in both types of glioblastoma cells with inhibition of ERN1 showing the ERN1 endoribonuclease-dependent mechanism of their regulation. However, the expression of PBX3 and PRPRX1 genes did not change significantly in dnrERN1 glioblastoma cells but was upregulated in dnERN1 cells indicating the dependence of these gene expressions on the ERN1 protein kinase. At the same time, the changes in PAX6 and PBXIP1 gene expressions introduced in glioblastoma cells by dnrERN1 and dnERN1 were different in direction and magnitude indicating the interaction of ERN1 protein kinase and endoribonuclease activities in regulation of these gene expressions. The impact of ERN1 and XBP1 silencing on the expression of studied homeobox genes is similar to that observed in dnERN1 and dnrERN1 glioblastoma cells, correspondingly. CONCLUSION: The expression of TGIF1 and other homeobox genes is dependent on the ern1 signaling pathways by diverse mechanisms because inhibition of ERN1 endoribonuclease and both ERN1 enzymatic activities had dissimilar impacts on the expression of most studied genes showing that ERN1 protein kinase plays an important role in controlling homeobox gene expression associated with glioblastoma cell invasion.

Knockdown of ERN1 disturbs the expression of phosphoserine aminotransferase 1 and related genes in glioblastoma cells.

BACKGROUND: Endoplasmic reticulum stress and synthesis of serine are essential for tumor growth, but the mechanism of their interaction is not clarified yet. The overarching goal of this work was to investigate the impact of ERN1 (endoplasmic reticulum to nucleus signaling 1) inhibition on the expression of serine synthesis genes in U87MG glioblastoma cells concerning the suppression of cell proliferation. METHODS: Wild type U87MG glioblastoma cells and their clones with overexpression of transgenes dnERN1 (without cytoplasmic domain of ERN1) and dnrERN1 (with mutation in endoribonuclease of ERN1), and empty vector (as control) were used. The silencing of ERN1 and XBP1 was also used to inhibition of ERN1 and its function. Gene expression was measured by qPCR. RESULTS: We show that the expression of PSAT1 and several other related to serine synthesis genes is suppressed in cells with ERN1 inhibition by dissimilar mechanisms: PHGDH gene through ERN1 protein kinase, because its expression was resistant to inhibition of ERN1 endoribonuclease, but ATF4 gene via endoribonuclease of ERN1. However, in the control of PSAT1 and PSPH genes both enzymatic activities of ERN1 signaling protein are involved. At the same time, ERN1 knockdown strongly increased SHMT1 expression, which controls serine metabolism and enhances the proliferation and invasiveness of glioma cells. The level of microRNAs, which have binding sites in PSAT1, SHMT1, and PSPH mRNAs, was also changed in cells harboring dnERN1 transgene. Inhibition of ERN1 suppressed cell proliferation and enzymatic activity of PHGDH, a rate-limiting enzyme for serine synthesis. CONCLUSION: Changes in the expression of phosphoserine aminotransferase 1 and other genes related to serine synthesis are mediated by diverse ERN1-dependent mechanisms and contributed to suppressed proliferation and enhanced invasiveness of ERN1 knockdown glioblastoma cell.

The Role of the European Reference Network for Rare Bone Diseases (ERN BOND) and European Registries for Rare Bone and Mineral Conditions (EuRR-Bone) in the Governance of the Management of Rare Bone and Mineral Diseases.

Rare diseases (RDs) bear a significant challenge to individuals, healthcare systems, and societies. The European reference network on Rare BONe diseases (ERN BOND) is committed to improving multidisciplinary, patient-centred care for individuals with rare bone and mineral diseases (RBMDs). Its affiliated project, the European registries for rare bone and mineral conditions (EuRR-Bone) collects data using two different platforms, an electronic surveillance system (e-REC) that captures the occurrence of RBMDs and the Core Registry, a platform with the infrastructure for collecting Core data fields and longitudinal generic and condition-specific information. With emerging registries and the overlap with other ERNs, it is key to maintain the capability of the platforms to adapt to the needs of the network and the community whilst adhering to quality and FAIR (findable, accessible, interoperable, and reusable) principles. This binomial ensures long-term sustainability and potential advances in the care pathway of RBMDs whilst promoting good practice standards within Europe and beyond.

No association between error-related ERPs and trait anxiety in a nonclinical sample: Convergence across analytical methods including mass-univariate statistics.

Enhanced error monitoring, as indexed by increased amplitude of the error-related negativity (ERN) event-related potential (ERP) component, has been suggested to reflect a vulnerability neuro-marker of anxiety disorders. Another error-related ERP component is the error positivity (Pe), which reflects late-stage error processing. The associations between heightened ERN and Pe amplitudes and anxiety levels in the nonclinical population have been inconsistent. In this preregistered study, we examined the association between anxiety, ERN, and Pe, using different analytical methods (mass-univariate analyses, MUAs and conventional analyses), self-reported anxiety scales (STAI and STICSA), and trial numbers (all correct trials and equal numbers of correct and error trials). In a sample of 82 healthy adults, both conventional and MUAs demonstrated a robust enhancement of the ERN and Pe to errors relative to the correct-response ERPs. However, the mass-univariate approach additionally unveiled a wider array of electrodes and a longer effect duration for this error enhancement. Across the analytic methods, the results showed a lack of consistent correlation between trait anxiety and error-related ERPs. Findings were not modulated by trial numbers, analyses, or anxiety scales. The present results suggest a lack of enhancement of error monitoring by anxious traits in individuals with subclinical anxiety and those with clinical anxiety but without a clinical diagnosis. Importantly, the absence of such correlation questions the validity of the ERN as a neural marker for anxiety disorders. Future studies that investigate neuro-markers of anxiety may explore alternative task designs and employ robust statistics to provide a more comprehensive understanding of anxiety vulnerability.

Domain specificity of error monitoring: An ERP study in young and older adults.

Metacognition refers to the ability to monitor and control one's cognitive processes, which plays an important role in decision-making throughout the lifespan. It is still debated whether metacognitive abilities decline with age. Neuroimaging evidence suggests that metacognition is served by domain-specific mechanisms. These domains may differentially decline with increasing age. The current investigates whether the error-related negativity (ERN) and the error positivity (Pe) which reflect error detection and error awareness, respectively, differ across perceptual and memory domains in young and older adults. In total, 38 young adults and 37 older adults completed a classic Flanker Task (perceptual) and an adapted memory-based version. No difference in ERN amplitude was found between young and older adults and across domains. Perceptual ERN peaked earlier than Memory ERN. Memory ΔERN was larger than Perceptual ΔERN. Pe was smaller in older adults and ΔPe was larger for perceptual than memory flanker. Memory Pe peaked earlier in young as compared to older adults. Multivariate analyses of whole scalp data supported cross-domain differences. During the task, ERN decreased in young but not in older adults. Memory Pe decreased in young adults but increased in older adults while no significant change in perceptual Pe was found. The study's findings suggest that neural correlates of error monitoring differ across cognitive domains. Moreover, it was shown that error awareness declines in old age but its within-task dynamics vary across cognitive domains. Possible mechanisms underlying metacognition impairments in aging are discussed.

Disentangling associations between impulsivity, compulsivity, and performance monitoring.

Disorders marked by high levels of impulsivity and compulsivity have been linked to changes in performance monitoring, specifically the error-related negativity (ERN). We investigated the relationship between performance monitoring and individual differences in impulsivity and compulsivity. A total of 142 participants were recruited into four groups, each with different combinations of impulsivity and compulsivity, and they performed a flanker task to assess error-related brain activity. We defined error-related brain activity as ERN amplitude and theta power. Single-trial regression was employed to analyze the amplitude differences between incorrect and correct trials within the ERN time window. The findings revealed that impulsivity, compulsivity, and different measures of response processing exhibited distinct interactions, which were influenced by the configuration of impulsivity and compulsivity, but also depended on the measure of response processing. Specifically, high compulsivity predicted larger ERN amplitudes in individuals with low impulsivity, whereas high impulsivity had no significant effect on ERN amplitude in individuals with low compulsivity. Furthermore, when both impulsivity and compulsivity were high, no significant increase in ERN amplitude was observed; instead, there was a reduced difference between incorrect and correct trials. No significant differences were found for theta power. While the association between error-related brain activity and transdiagnostic markers or psychopathology may be smaller than generally assumed, considering the interaction between different transdiagnostic markers and their facets can enhance our understanding of the complex associations that arise during the investigation of neural correlates of performance monitoring, specifically the ERN.

Error monitoring under working memory load: An electrocortical investigation.

Error monitoring is essential for detecting errors and may facilitate behavioral adjustments that can reduce or prevent future errors. At times, error monitoring must occur while individuals are engaged in other, cognitively demanding tasks that might consume processing resources necessary for error monitoring. Here, we set out to determine whether concurrent working memory (WM) load interferes with error monitoring, as measured using event-related potentials, the error-related negativity (Ne/ERN), and error positivity (Pe). Fifty-four participants (n = 33 female) completed an arrowhead flanker task, with trials presented under low (2 letter) or high (6 letter) WM load. Participants were required to hold letter strings in memory and to recall these letters at the end of a set of flanker trials. Results showed that WM load reduced the Pe but did not affect the Ne/ERN. Therefore, WM load appeared to attenuate later, more elaborated stages of error processing, though initial error detection was unaffected. Additionally, high WM load slowed reaction times overall, but did not lead to a significant increase in errors. As such, slower responses may have helped participants maintain comparable accuracy for low-load versus high-load trials. Overall, results indicate that WM load interferes with the evaluation of error significance, which could interfere with behavioral adaptations over time.

Beyond peaks and troughs: Multiplexed performance monitoring signals in the EEG.

With the discovery of event-related potentials elicited by errors more than 30 years ago, a new avenue of research on performance monitoring, cognitive control, and decision making emerged. Since then, the field has developed and expanded fulminantly. After a brief overview on the EEG correlates of performance monitoring, this article reviews recent advancements based on single-trial analyses using independent component analysis, multiple regression, and multivariate pattern classification. Given the close interconnection between performance monitoring and reinforcement learning, computational modeling and model-based EEG analyses have made a particularly strong impact. The reviewed findings demonstrate that error- and feedback-related EEG dynamics represent variables reflecting how performance-monitoring signals are weighted and transformed into an adaptation signal that guides future decisions and actions. The model-based single-trial analysis approach goes far beyond conventional peak-and-trough analyses of event-related potentials and enables testing mechanistic theories of performance monitoring, cognitive control, and decision making.

Electrophysiological correlates of cognitive control and performance monitoring in risk propensity: An event-related potential study.

Investigating the cognitive control processes and error detection mechanisms involved in risk-taking behaviors is essential for understanding risk propensity. This study investigated the relationship between risk propensity and cognitive control processes using an event-related potentials (ERP) approach. The study employed a Cued Go/Nogo paradigm to elicit ERP components related to cognitive control processes, including contingent negative variation (CNV), P300, error-related negativity (ERN), and error positivity (Pe). Healthy participants were categorized into high-risk and low-risk groups based on their performance in the Balloon Analogue Risk Task (BART). The results revealed risk-taking behavior influenced CNV amplitudes, indicating heightened response preparation and inhibition for the high-risk group. In contrast, the P300 component showed no group differences but revealed enhanced amplitudes in Nogo trials, particularly in high-risk group. Furthermore, despite the lack of difference in the Pe component, the high-risk group exhibited smaller ERN amplitudes compared to the low-risk group, suggesting reduced sensitivity to error detection. These findings imply that risk-taking behaviors may be associated with a hypoactive avoidance system rather than impaired response inhibition. Understanding the neural mechanisms underlying risk propensity and cognitive control processes can contribute to the development of interventions aimed at reducing risky behaviors and promoting better decision-making.

Cortical origin of theta error signals.

A multi-scale approach elucidated the origin of the error-related-negativity (ERN), with its associated theta-rhythm, and the post-error-positivity (Pe) in macaque supplementary eye field (SEF). Using biophysical modeling, synaptic inputs to a subpopulation of layer-3 (L3) and layer-5 (L5) pyramidal cells (PCs) were optimized to reproduce error-related spiking modulation and inter-spike intervals. The intrinsic dynamics of dendrites in L5 but not L3 error PCs generate theta rhythmicity with random phases. Saccades synchronized the phases of the theta-rhythm, which was magnified on errors. Contributions from error PCs to the laminar current source density (CSD) observed in SEF were negligible and could not explain the observed association between error-related spiking modulation in L3 PCs and scalp-EEG. CSD from recorded laminar field potentials in SEF was comprised of multipolar components, with monopoles indicating strong electro-diffusion, dendritic/axonal electrotonic current leakage outside SEF, or violations of the model assumptions. Our results also demonstrate the involvement of secondary cortical regions, in addition to SEF, particularly for the later Pe component. The dipolar component from the observed CSD paralleled the ERN dynamics, while the quadrupolar component paralleled the Pe. These results provide the most advanced explanation to date of the cellular mechanisms generating the ERN.

Endoplasmic reticulum stress-dependent regulation of carboxypeptidase E expression in glioblastoma cells.

Objective. Carboxypeptidase E (CPE) plays an important role in the biosynthesis of neurotransmitters and peptide hormones including insulin. It also promotes cell proliferation, survival, and invasion of tumor cells. The endoplasmic reticulum stress, hypoxia, and nutrient supply are significant factors of malignant tumor growth including glioblastoma. There are data indicating that the knockdown of the endoplasmic reticulum to nucleus signaling 1 (ERN1) suppressed glioblastoma cell proliferation and increased invasiveness of these cells. The present study aims to investigate the regulation of the CPE gene in U87MG glioblastoma cells by ERN1 knockdown, hypoxia, and glucose or glutamine deprivations with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in tumorigenesis. Methods. Human glioblastoma cells U87MG (transfected by an empty vector; control) and ERN1 knockdown cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Hypoxia was introduced by dimethyloxalylglycine; for glucose and glutamine deprivations, the cells were cultured in DMEM medium without glucose or glutamine for 16 h, respectively. The expression level of the CPE gene was studied by quantitative RT-PCR and normalized to ACTB. Results. It was found that inhibition of endoribonuclease and protein kinase activities of ERN1 led to a strong up-regulation of CPE gene expression in glioblastoma cells. The expression of this gene also increased in glioblastoma cells after silencing ERN1. At the same time, the expression of this gene did not significantly change in cells with inhibited ERN1 endoribonuclease only. The expression of the CPE gene was resistant to hypoxia in control U87MG cells, but increased in cells with ERN1 knockdown. The expression of this gene was up-regulated under glutamine deprivation in control glioblastoma cells, but decreased upon ERN1 knockdown. However, glucose deprivation decreased the expression of CPE gene in both types of used cells, but ERN1 inhibition enhanced this effect. Conclusion. The results of the present study demonstrate that inhibition of ERN1 strongly up-regulated the expression of pro-oncogenic CPE gene through protein kinase activity of ERN1 and that increased CPE gene expression possibly participates in ERN1 knockdown-mediated invasiveness of glioblastoma cells.

Endoplasmic reticulum stress-dependent regulation of the expression of serine hydroxymethyltransferase 2 in glioblastoma cells.

Objective. Serine hydroxymethyltransferase (SHMT2) plays a multifunctional role in mitochondria (folate-dependent tRNA methylation, translation, and thymidylate synthesis). The endoplasmic reticulum stress, hypoxia, and glucose and glutamine supply are significant factors of malignant tumor growth including glioblastoma. Previous studies have shown that the knockdown of the endoplasmic reticulum to nucleus signaling 1 (ERN1) pathway of endoplasmic reticulum stress strongly suppressed glioblastoma cell proliferation and modified the sensitivity of these cells to hypoxia and glucose or glutamine deprivations. The present study aimed to investigate the regulation of the SHMT2 gene in U87MG glioblastoma cells by ERN1 knockdown, hypoxia, and glucose or glutamine deprivations with the intent to reveal the role of ERN1 signaling in sensitivity of this gene expression to hypoxia and nutrient supply. Methods. The control U87MG glioblastoma cells (transfected by an empty vector) and ERN1 knockdown cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Hypoxia was introduced by dimethyloxalylglycine (500 ng/ml for 4 h). For glucose and glutamine deprivations, cells were exposed in DMEM without glucose and glutamine, respectively for 16 h. RNA was extracted from cells and reverse transcribed. The expression level of the SHMT2 gene was studied by real-time qPCR and normalized to ACTB. Results. It was found that inhibition of ERN1 endoribonuclease and protein kinase in glioblastoma cells led to a down-regulation of SHMT2 gene expression in U87MG cells. At the same time, the expression of this gene did not significantly change in cells with inhibited ERN1 endoribonuclease, but tunicamycin strongly increased its expression. Moreover, the expression of the SHMT2 gene was not affected in U87MG cells after silencing of XBP1. Hypoxia up-regulated the expression level of the SHMT2 gene in both control and ERN1 knockdown U87MG cells. The expression of this gene was significantly up-regulated in glioblastoma cells under glucose and glutamine deprivations and ERN1 knockdown significantly increased the sensitivity of the SHMT2 gene to these nutrient deprivation conditions. Conclusion. The results of the present study demonstrate that the expression of the SHMT2 gene responsible for serine metabolism and formation of folate one-carbon is controlled by ERN1 protein kinase and induced by hypoxia as well as glutamine and glucose deprivation conditions in glioblastoma cells and reflects the ERN1-mediated reprogramming of sensitivity this gene expression to nutrient deprivation.

ERN1 knockdown modifies the hypoxic regulation of homeobox gene expression in U87MG glioblastoma cells.

OBJECTIVE.: Homeobox genes play an important role in health and disease including oncogenesis. The present investigation aimed to study ERN1-dependent hypoxic regulation of the expression of genes encoding homeobox proteins MEIS (zinc finger E-box binding homeobox 2) and LIM homeobox 1 family, SPAG4 (sperm associated antigen 4) and NKX3-1 (NK3 homeobox 1) in U87MG glioblastoma cells in response to inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioblastoma growth. METHODS.: The expression level of homeobox genes was studied in control (transfected by vector) and ERN1 knockdown U87MG glioblastoma cells under hypoxia induced by dimethyloxalylglycine (0.5 mM for 4 h) by quantitative polymerase chain reaction and normalized to ACTB. RESULTS.: It was found that hypoxia down-regulated the expression level of LHX2, LHX6, MEIS2, and NKX3-1 genes but up-regulated the expression level of MEIS1, LHX1, MEIS3, and SPAG4 genes in control glioblastoma cells. At the same time, ERN1 knockdown of glioblastoma cells significantly modified the sensitivity of all studied genes to a hypoxic condition. Thus, ERN1 knockdown of glioblastoma cells removed the effect of hypoxia on the expression of MEIS1 and LHX1 genes, but increased the sensitivity of MEIS2, LHX2, and LHX6 genes to hypoxia. However, the expression of MEIS3, NKX3-1, and SPAG4 genes had decreased sensitivity to hypoxia in ERN1 knockdown glioblastoma cells. Moreover, more pronounced changes under the conditions of ERN1 inhibition were detected for the pro-oncogenic gene SPAG4. CONCLUSION.: The results of the present study demonstrate that hypoxia affected the expression of homeobox genes MEIS1, MEIS2, MEIS3, LHX1, LHX2, LHX6, SPAG4, and NKX3-1 in U87MG glioblastoma cells in gene-specific manner and that the sensitivity of all studied genes to hypoxia condition is mediated by ERN1, the major pathway of the endoplasmic reticulum stress signaling, and possibly contributed to the control of glioblastoma growth. A fundamentally new results of this work is the establishment of the fact regarding the dependence of hypoxic regulation of SPAG4 gene expression on ER stress, in particular ERN1, which is associated with suppression of cell proliferation and tumor growth.

Inhibition of signaling protein ERN1 increases the sensitivity of serine synthesis gene expressions to glucose and glutamine deprivations in U87MG glioblastoma cells.

Objective. Glucose and glutamine supply as well as serine synthesis and endoplasmic reticulum (ER) stress are important factors of glioblastoma growth. Previous studies showed that the knockdown of ERN1 (ER to nucleus signaling 1) suppressed glioblastoma cell proliferation and modified the sensitivity of numerous gene expressions to nutrient deprivations. The present study is aimed to investigate the impact of glucose and glutamine deprivations on the expression of serine synthesis genes in U87MG glioblastoma cells in relation to ERN1 knockdown with the intent to reveal the role of ERN1 signaling pathway on the ER stress-dependent regulation of these gene expressions. Clarification of the regulatory mechanisms of serine synthesis is a great significance for glioblastoma therapy. Methods. The control U87MG glioblastoma cells (transfected by empty vector) and ERN1 knockdown cells (transfected by dominant-negative ERN1) were exposed under glucose and glutamine deprivation conditions for 16 h. RNA was extracted from cells and reverse transcribed. The expression level of PHGDH (phosphoglycerate dehydrogenase), PSAT1 (phosphoserine amino-transferase 1), PSPH (phosphoserine phosphatase), ATF4 (activating transcription factor 4), and SHMT1 (serine hydroxymethyltransferase 1) genes was studied by real-time qPCR and normalized to ACTB. Results. It was found that the expression level of genes responsible for serine synthesis such as PHGDH, PSAT1, PSPH, and transcription factor ATF4 was up-regulated in U87MG glioblastoma cells under glucose and glutamine deprivations. Furthermore, inhibition of ERN1 significantly enhances the impact of glucose and especially glutamine deprivations on these gene expressions. At the same time, the expression of the SHMT1 gene, which is responsible for serine conversion to glycine, was down-regulated in both nutrient deprivation conditions with more significant changes in ERN1 knockdown glioblastoma cells. Conclusion. Taken together, the results of present study indicate that the expression of genes responsible for serine synthesis is sensitive to glucose and glutamine deprivations in gene-specific manner and that suppression of ERN1 signaling significantly modifies the impact of both glucose and glutamine deprivations on PHGDH, PSAT1, PSPH, ATF4, and SHMT1 gene expressions and reflects the ERN1-mediated genome reprograming introduced by nutrient deprivation condition.

Variation in coupling across neural and cardiac systems of regulation is linked to markers of anxiety risk in preschool.

Both cortical and parasympathetic systems are believed to regulate emotional arousal in the service of healthy development. Systemic coordination, or coupling, between putative regulatory functions begins in early childhood. Yet the degree of coupling between cortical and parasympathetic systems in young children remains unclear, particularly in relation to the development of typical or atypical emotion function. We tested whether cortical (ERN) and parasympathetic (respiratory sinus arrhythmia [RSA]) markers of regulation were coupled during cognitive challenge in preschoolers (N = 121). We found no main effect of RSA predicting ERN. We then tested children's typical and atypical emotion behavior (context-appropriate/context-inappropriate fear, anxiety symptoms, neuroendocrine reactivity) as moderators of early coupling in an effort to link patterns of coupling to adaptive emotional development. Negative coupling (i.e., smaller ERN, more RSA suppression or larger ERN, less RSA suppression) at age 3 was associated with greater atypical and less typical emotion behaviors, indicative of greater risk. Negative age 3 coupling was also visible for children who had greater Generalized Anxiety Disorder symptoms and blunted cortisol reactivity at age 5. Results suggest that negative coupling may reflect a maladaptive pattern across regulatory systems that is identifiable during the preschool years.

TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by a number of variables, including endoplasmic reticulum stress (ER). Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family and acts as an endoplasmic reticulum (ER) chaperone. Nevertheless, the function of TXNDC5 in hepatocytes under ER stress remains largely uncharacterized. In order to identify the role of TXNDC5 in hepatic wild-type (WT) and TXNDC5-deficient (KO) AML12 cell lines, tunicamycin, palmitic acid, and thapsigargin were employed as stressors. Cell viability, mRNA, protein levels, and mRNA splicing were then assayed. The protein expression results of prominent ER stress markers indicated that the ERN1 and EIF2AK3 proteins were downregulated, while the HSPA5 protein was upregulated. Furthermore, the ATF6 protein demonstrated no significant alterations in the absence of TXNDC5 at the protein level. The knockout of TXNDC5 has been demonstrated to increase cellular ROS production and its activity is required to maintain normal mitochondrial function during tunicamycin-induced ER stress. Tunicamycin has been observed to disrupt the protein levels of HSPA5, ERN1, and EIF2AK3 in TXNDC5-deficient cells. However, palmitic acid has been observed to disrupt the protein levels of ATF6, HSPA5, and EIF2AK3. In conclusion, TXNDC5 can selectively activate distinct ER stress pathways via HSPA5, contingent on the origin of ER stress. Conversely, the absence of TXNDC5 can disrupt the EIF2AK3 cascade.

Deconstructing the functional significance of the error-related negativity (ERN) and midline frontal theta oscillations using stepwise time-locking and single-trial response dynamics.

Error-related electroencephalographic potentials have been used for decades to develop theoretical models of response monitoring processes, study altered cognitive functioning in clinical populations, and more recently, to improve the performance of brain-computer interfaces. However, the vast majority of this research relies on discrete behavioral responses that confound error detection, response cancelation, error correction, and post-error cognitive and affective processes. By contrast, the present study demonstrates a novel, complementary method for isolating the functional correlates of error-related electroencephalographic responses using single-trial kinematic analyses of cursor trajectories and a stepwise time-locking analysis. The results reveal that the latency of the ERN, Pe, and medial-frontal theta oscillations are all strongly positively correlated with the latency at which an initiated error response is canceled, as indicated by the peak deceleration of the initiated movement prior to a corrective response. Results are discussed with respect to current theoretical models of error-related brain potentials and potential relevance to clinical applications.

Getting off track: Cortical feedback processing network modulated by continuous error signal during target-feedback mismatch.

Performance monitoring and feedback processing - especially in the wake of erroneous outcomes - represent a crucial aspect of everyday life, allowing us to deal with imminent threats in the short term but also promoting necessary behavioral adjustments in the long term to avoid future conflicts. Over the last thirty years, research extensively analyzed the neural correlates of processing discrete error stimuli, unveiling the error-related negativity (ERN) and error positivity (Pe) as two main components of the cognitive response. However, the connection between the ERN/Pe and distinct stages of error processing, ranging from action monitoring to subsequent corrective behavior, remains ambiguous. Furthermore, mundane actions such as steering a vehicle already transgress the scope of discrete erroneous events and demand fine-tuned feedback control, and thus, the processing of continuous error signals - a topic scarcely researched at present. We analyzed two electroencephalography datasets to investigate the processing of continuous erroneous signals during a target tracking task, employing feedback in various levels and modalities. We observed significant differences between correct (slightly delayed) and erroneous feedback conditions in the larger one of the two datasets that we analyzed, both in sensor and source space. Furthermore, we found strong error-induced modulations that appeared consistent across datasets and error conditions, indicating a clear order of engagement of specific brain regions that correspond to individual components of error processing.

Slip or fallacy? Effects of error severity on own and observed pitch error processing in pianists.

Errors elicit a negative, mediofrontal, event-related potential (ERP), for both own errors (error-related negativity; ERN) and observed errors (here referred to as observer mediofrontal negativity; oMN). It is unclear, however, if the action-monitoring system codes action valence as an all-or-nothing phenomenon or if the system differentiates between errors of different severity. We investigated this question by recording electroencephalography (EEG) data of pianists playing themselves (Experiment 1) or watching others playing (Experiment 2). Piano pieces designed to elicit large errors were used. While active participants' ERN amplitudes differed between small and large errors, observers' oMN amplitudes did not. The different pattern in the two groups of participants was confirmed in an exploratory analysis comparing ERN and oMN directly. We suspect that both prediction and action mismatches can be coded in action monitoring systems, depending on the task, and a need-to-adapt signal is sent whenever mismatches happen to indicate the magnitude of the needed adaptation.

12th European Hidradenitis Suppurativa (EHSF) e.V. Conference-Facing HS according to the Renessaince style.

The-first hybrid-12th Conference of the European Hidradenitis Suppurativa Foundation (EHSF) e.V. took place on 8-10 February 2023 in Florence, Italy. With 198 high level scientific contributions and 757 participants from 45 countries, this 12th EHSF e.V. Conference has already been added to the EHSF's most unforgettable scientific activities. Twenty two active contributors were scientists and students under the age of 30 years and concurred for the three Young Investigator Awards. This special issue of Experimental Dermatology includes extended abstracts of the majority of the scientific lectures and posters. The 13th EHSF Conference will take place on February 7-9, 2024, as a physical presence event in Lyon, France. Dr. Philippe Guillem, Prof. Axel Villani and their team are glad to become your hosts.