Left Atrial Strain Predicts Cardiovascular and All-Cause Mortality.

Background: Left atrial strain can usefully reflect left atrial function. The follow-up periods in previous studies assessing left atrial strain as a survival predictor have been relatively short, and few studies have examined the ability of left atrial strain to predict mortality in patients with borderline diastolic function. This study sought to investigate the survival predictive value of left atrial strain with a longer follow-up duration. In addition, we also evaluated the survival predictive value of left atrial strain in patients with borderline diastolic function. Methods: In total, 652 participants who received routine echocardiography underwent 2-D speckle tracking echocardiography to evaluate left atrial reservoir function by peak atrial longitudinal strain. The study endpoints were all-cause and cardiovascular mortality. Results: The mean left atrial strain was 27.6%, and the median follow-up duration was 92 months. During follow-up, 72 patients died of cardiovascular causes and 181 died of all causes. Univariable Cox regression analysis revealed that lower left atrial strain significantly predicted an increase in all-cause and cardiovascular mortality. After adjusting for common clinical and echocardiographic parameters, lower left atrial strain was still associated with a higher risk of all-cause mortality [hazard ratio (HR) = 0.942, p = 0.011] and cardiovascular mortality (HR = 0.915, p = 0.018) in multivariable Cox-regression analysis. In addition, 293 patients had borderline left ventricular diastolic function. Multivariable analysis still revealed that left atrial strain could predict cardiovascular mortality in this population. Conclusions: Our data showed that left atrial strain could predict all-cause and cardiovascular mortality, even after adjusting for general clinical and echocardiographic parameters.

Skin sympathetic nerve activity as a potential biomarker for overactive bladder.

PURPOSE: Abnormalities in autonomic function are associated with an overactive bladder (OAB). Heart rate variability is generally used as the sole assessment of autonomic activity; however, we utilized neuECG, a novel method of recording skin electrical signals, to assess autonomic nervous function in healthy controls and patients with OAB before and after treatment. METHODS: The prospective sample included 52 participants: 23 patients newly diagnosed with OAB and 29 controls. Autonomic function was assessed in all participants in the morning using neuECG, which analyzed the average skin sympathetic nerve activity (aSKNA) and electrocardiogram simultaneously. All patients with OAB were administered antimuscarinics; urodynamic parameters were assessed before treatments; autonomic and bladder functions using validated questionnaires for OAB symptoms were evaluated before and after OAB treatment. RESULTS: Patients with OAB had significantly higher baseline aSKNA (p = 0.003), lower standard deviation of the normal-to-normal beat intervals, lower root mean square of the successive differences, lower high-frequency, and higher low-frequency than did controls. Baseline aSKNA had the highest value in predicting OAB (AUROC = 0.783, p < 0.001). The aSKNA was negatively correlated with first desire and normal desire in urodynamic studies (both p = 0.025) and was significantly decreased after treatment at rest, stress, and recovery phases, as compared to those before treatment (p = 0.046, 0.017, and 0.017, respectively). CONCLUSION: Sympathetic activity increased significantly in patients with OAB compared to that in healthy controls, and decreased significantly post-treatment. Higher aSKNA is associated with decreased bladder volume at which voiding is desired. SKNA may be a potential biomarker for diagnosing OAB.

Exploring Key Factors Influencing Nursing Students' Cognitive Load and Willingness to Serve Older Adults: Cross-sectional Descriptive Correlational Study.

BACKGROUND: Virtual learning environments (VLEs) use a virtual environment to support learning activities. VLEs are commonly used to overcome the temporal and spatial restrictions of learning activities held in conventional face-to-face classrooms. In VLEs, students can participate in learning activities using the internet, and teachers can provide assistive learning tools during the process. OBJECTIVE: The purpose of this study was to investigate the relationships among nursing students' mental load, cognitive load, and affective learning outcomes in terms of their willingness to serve older adults in an interaction-based educational virtual reality (VR) learning environment. METHODS: This study used a cross-sectional method. A total of 130 students participated in interaction-based VR learning and completed related questionnaires. Descriptive and inferential statistics and stepwise regression for data analysis were used. RESULTS: The research results revealed that in the dimension of willingness to use VR learning materials, perceived usefulness received the highest score (mean 4.42, SD 0.45). In the dimension of nursing ability, students scored the highest in information management and application ability to care for case patients (mean 4.35, SD 0.54). Correlation analysis revealed that cognitive load during learning and willingness to serve older adults were negatively correlated, whereas willingness to use VR learning materials was positively correlated with nursing ability and willingness to serve older adults. Analyzing the regression coefficients of predictor variables revealed that willingness to use VR learning materials (ß=.23; t2=2.89, P=.005) and cognitive load during learning (ß=-.35; t2=-.4.30, P<.001) were predictive factors of nursing students' willingness to serve older adults. CONCLUSIONS: This study demonstrated that students' willingness to use VR learning materials and their cognitive load during learning affected their willingness to care for older adults. Therefore, the components of mental or cognitive load generate inconsistent predictive effects on affective variables and willingness to serve older adults.

Up-regulated small-conductance calcium-activated potassium currents contribute to atrial arrhythmogenesis in high-fat feeding mice.

AIMS: Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodelling. The small-conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. METHODS AND RESULTS: Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months. Electrocardiography and echocardiography were used to detect cardiac electrical and structure remodelling. Atrial action potential duration (APD) and calcium transient duration (CaTD) were measured by optical mapping of Langendorff-perfused mice hearts. Atrial fibrillation (AF) inducibility and duration were assessed by burst pacing. Whole-cell patch clamp was performed in primarily isolated atrial myocytes for SK current density. The SK current density is higher in atrial myocytes from HFD than in CTL mice (P ≤ 0.037). The RNA and protein expression of SK channels are increased in HFD mice (P ≤ 0.041 and P ≤ 0.011, respectively). Action potential duration is shortened in HFD compared with CTL (P ≤ 0.015). The shortening of the atrial APD in HFD is reversed by the application of 100 nM apamin (P ≤ 0.043). Compared with CTL, CaTD is greater in HFD atria (P ≤ 0.029). Calcium transient decay (Tau) is significantly higher in HFD than in CTL (P = 0.001). Both APD and CaTD alternans thresholds were higher in HFD (P ≤ 0.043), along with higher inducibility and longer duration of AF in HFD (P ≤ 0.023). CONCLUSION: Up-regulation of apamin-sensitive SK currents plays a partial role in the atrial arrhythmogenicity of HFD mice.

Do Personality Traits Matter? Exploring Anti-drug Behavioral Patterns in a Computer-Assisted Situated Learning Environment.

Drug abuse has been and continues to be, a common social issue worldwide, yet the efficiency of widely adopted sweeping speech for anti-drug campaigns has proven inefficient. To provide students with a safe and efficient learning situation related to drug refusal skills, we used a novel approach rooted in a serious learning game and concept map during a brief extracurricular period to help students understand drugs and their negative effects. The proposed game-based situational learning system allowed all students to participate simultaneously and individually in multiple scenarios of drug temptation posed by peers and classmates to practice responding and refusing drugs in school and community settings. Moreover, to explore whether different personality traits (such as the Big Five personality traits) result in different anti-drug responses, we used a serious game to conduct an anti-drug experiment on 53 junior middle school students aged 13-15. Each participant's decision-making process was recorded in the serious game as behavioral patterns for lag sequential analysis (LSA). The outcomes revealed seven behavioral patterns including differentiation (D), acceptance (A), effective (ER) and ineffective responses (IR), effective (ES) and ineffective solution-seeking (IS), and failure to refuse (F). The GSEQ (Generalized Sequential Querier) which is a computer program for analyzing sequential observational data was used. The results indicated the following: (1) Neuroticism was performed at a relatively low level under the guidance of a concept map. (2) "Neuroticism" was associated with the lowest risk of accepting drugs. (3) Students with "openness to experiences" were at high risk of accepting drugs. (4) Almost all personality behavioral transition diagrams showed that failure to refuse (F) drugs was followed by inefficient seeking of help (SI) and inefficient refusal (RI). These findings provide reference points for designing adaptive anti-drug education programs.

Skin sympathetic nerve activity and ventricular arrhythmias in acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) is major cause of ventricular arrhythmias (VAs) and sudden death. neuECG is a noninvasive method to simultaneously record skin sympathetic nerve activity (SKNA) and electrocardiogram. OBJECTIVE: The purpose of this study was to test the hypotheses that (1) ACS increases average SKNA (aSKNA), (2) the magnitude of aSKNA elevation is associated with VAs during ACS, and (3) there is a gender difference in aSKNA between patients without and with ACS. METHODS: We prospectively studied 128 ACS and 165 control participants. The neuECG was recorded with electrodes at Lead I configuration at baseline, during mental math stress, and during recovery (5 minutes for each phase). All recordings were done in the morning. RESULTS: In the control group, women have higher aSKNA than do men at baseline (0.82 ± 0.25 µV vs 0.73 ± 0.20 µV; P = .009) but not during mental stress (1.21 ± 0.36 µV vs 1.16 ± 0.36 µV; P = .394), suggesting women had lower sympathetic reserve. In comparison, ACS is associated with equally elevated aSKNA in women vs men at baseline (1.14 ± 0.33 µV vs 1.04 ± 0.35 µV; P = .531), during mental stress (1.46 ± 0.32 µV vs 1.33 ± 0.37 µV; P = .113), and during recovery (1.30 ± 0.33 µV vs 1.11 ± 0.30 µV; P = .075). After adjusting for age and gender, the adjusted odds ratio for VAs including ventricular tachycardia and ventricular fibrillation is 1.23 (95% confidence interval 1.05-1.44) for each 0.1 µV aSKNA elevation. aSKNA is positively correlated with plasma norepinephrine level. CONCLUSION: ACS is associated with elevated aSKNA, and the magnitude of aSKNA elevation is associated with the occurrence of VAs. Women have higher aSKNA and lower SKNA reserve than do men among controls but not among patients with ACS.

What Drives Internet Entrepreneurial Intention to Use Technology Products? An Investigation of Technology Product Imagination Disposition, Social Support, and Motivation.

Technological products such as computer, communication, and consumer electronic products, apps, smart wearables, and streaming services have become inseparable from people's lives. In technological fields of practice, imagination, creativity, innovation, and entrepreneurship may influence one another. A vivid imagination can generate creativity and trigger the entrepreneurial intention to "bring new things to the market." This study aims to understand the formation of internet entrepreneurial intention to use technology products. Drawing on social cognitive theory, this study explores and empirically tests how technology product imagination disposition and social support impact internet entrepreneurial intention to use technology products. Drawing from self-determination theory, this study proposes and examines the mediating role of intrinsic (challenge and enjoyment) and extrinsic motivation (compensation and outward motivation) in the relationship between technology product imagination disposition and internet entrepreneurial intention, as well as the relationship between social support and internet entrepreneurial intention. We conducted a survey of 568 adults in Taiwan and used partial least squares to test our hypotheses. The results show the following: (1) Technology product imagination disposition is positively associated with challenge, enjoyment, compensation, and outward motivation. (2) Social support is positively associated with challenge, enjoyment, compensation, and outward motivation. (3) Challenge, enjoyment, and outward motivation are positively associated with internet entrepreneurial intention to use technology products. (4) Technology product imagination disposition intensifies internet entrepreneurial intention to use technology products by strengthening challenge, enjoyment, and outward motivation. Social support intensifies internet entrepreneurial intention by increasing challenge, enjoyment, and outward motivation. The partial mediation model represents a significant improvement in the total effect over the direct effect. We discuss the implications of these results for research and internet entrepreneurship practices.

Automated ECG classification based on 1D deep learning network.

The standard 12-lead electrocardiogram (ECG) records the heart's electrical activity from electrodes on the skin, and is widely used in screening and diagnosis of the cardiac conditions due to its low price and non-invasive characteristics. Manual examination of ECGs requires professional medical skills, and is strenuous and time consuming. Recently, deep learning methodologies have been successfully applied in the analysis of medical images. In this paper, we present an automated system for the identification of normal and abnormal ECG signals. A multi-channel multi-scale deep neural network (DNN) model is proposed, which is an end-to-end structure to classify the ECG signals without any feature extraction. Convolutional layers are used to extract primary features, and long short-term memory (LSTM) and attention are incorporated to improve the performance of the DNN model. The system was developed with a 12-lead ECG dataset provided by the Kaohsiung Medical University Hospital (KMUH). Experimental results show that the proposed system can yield high recognition rates in classifying normal and abnormal ECG signals.

Sex-specific chromatin remodelling safeguards transcription in germ cells.

Stability of the epigenetic landscape underpins maintenance of the cell-type-specific transcriptional profile. As one of the main repressive epigenetic systems, DNA methylation has been shown to be important for long-term gene silencing; its loss leads to ectopic and aberrant transcription in differentiated cells and cancer1. The developing mouse germ line endures global changes in DNA methylation in the absence of widespread transcriptional activation. Here, using an ultra-low-input native chromatin immunoprecipitation approach, we show that following DNA demethylation the gonadal primordial germ cells undergo remodelling of repressive histone modifications, resulting in a sex-specific signature in mice. We further demonstrate that Polycomb has a central role in transcriptional control in the newly hypomethylated germline genome as the genetic loss of Ezh2 leads to aberrant transcriptional activation, retrotransposon derepression and dramatic loss of developing female germ cells. This sex-specific effect of Ezh2 deletion is explained by the distinct landscape of repressive modifications observed in male and female germ cells. Overall, our study provides insight into the dynamic interplay between repressive chromatin modifications in the context of a developmental reprogramming system.

High Skin Sympathetic Nerve Activity in Patients with Recurrent Syncope.

(1) Background: The autonomic imbalance plays a role in vasovagal syncope (VVS) diagnosed by head-up tilting test (HUT). neuECG is a new method of recording skin electrical signals to simultaneously analyze skin sympathetic nerve activity (SKNA) and electrocardiogram. We hypothesize that SKNA is higher in subjects with tilt-positive than tilt-negative and the SKNA surges before syncope. (2) Methods: We recorded neuECG in 41 subjects who received HUT (according to the "Italian protocol"), including rest, tilt-up, provocation and recovery phases. Data were analyzed to determine the average SKNA (aSKNA, µV) per digitized sample. Electrocardiogram was used to calculate standard deviation of normal-to-normal beat intervals (SDNN). The "SKNA-SDNN index" was calculated by rest aSKNA multiplied by the ratio of tilt-up to rest SDNN. (3) Results: 16 of 41 (39%) subjects developed syncope. The aSKNA at rest phase is significantly higher in the tilt-positive (1.21 ± 0.27 µV) than tilt-negative subjects (1.02 ± 0.29 µV) (p = 0.034). There are significant surges and withdraw of aSKNA 30 s before and after syncope (both p ≤ 0.006). SKNA-SDNN index is able to predict syncope (p < 0.001). (4) Conclusion: Higher SKNA at rest phase is associated with positive HUT. The SKNA-SDNN index is a novel marker to predict syncope during HUT.

Variants in Maternal Effect Genes and Relaxed Imprinting Control in a Special Placental Mesenchymal Dysplasia Case with Mild Trophoblast Hyperplasia.

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother's genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal-zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum.

Betel-Quid Chewing, Heart Failure, and Premature Ventricular Contractions in Patients with Cardiopulmonary Symptoms.

Betel-quid (BQ) is a commonly used psychoactive substance that renders a specific cardiotoxicity. The purpose of this study was to investigate the association between BQ chewing and premature ventricular contractions (PVC) in patients with cardiopulmonary symptoms, and examine the potential influences of cardiovascular and chronic diseases on such relationship. Participants were 146 patients with cardiopulmonary symptoms who participated in 24-h Holter electrocardiogram monitoring during 2012-2018 in a hospital serving residents that lived in a BQ high prevalence area. Data on substance uses and medical histories for cardiovascular and chronic diseases were collected. Baron-Kenny method was employed to evaluate possible mediation. In patients with cardiopulmonary symptoms, 36.3% were BQ users and 63.7% were nonusers. Adjusting for covariates, BQ chewing was significantly associated with heart failure and diabetes mellitus (adjusted odds ratio (aOR) = 3.4 and 2.3, respectively), but only heart failure was significantly correlated with a low and high level of PVC. Additionally controlling for the effect of heart failure, the risk of high PVC for BQ users reduced from 3.60 to 2.88; however, the risk for BQ chewers remained significant (95% CI: 1.06-7.84). Heart failure was found to explain 27.7% of the excessive effect of BQ use on high PVC. In conclusion, BQ use is directly associated with an elevated risk of high PVC in patients with cardiopulmonary symptoms. The higher risk might be elevated among patients who suffered heart failure. Given several research limitations, the findings from this study offer future opportunities for validation.

The Development of a Sustainability-Oriented Creativity, Innovation, and Entrepreneurship Education Framework: A Perspective Study.

Innovation can include creativity, innovation mechanisms, and entrepreneurship. The ability to innovate is an important indicator of economic and social development, and creativity is an educational indicator of learning effectiveness. This article explores creativity and innovation from an educational perspective and proposes a sustainability-oriented creativity, innovation, and entrepreneurship education framework that uses creative problem solving. This framework contains four layers and three dimensions. The first layer concerns the thinker and basic structure, and the second layer contains the catalyst of sustainable development goals (SDGs). The third layer is the advanced structure of cultivating SDG thinkers. The final layer is the generation of students who will attempt to start up social enterprises. The three aspects apply the creative nature of diffuse thinking to social innovation; apply demand expansion to extend individual needs to societal needs; and apply educational goal development to encourage sustainability. We expect this framework, which can turn thinkers into doers through creativity and social innovation, to apply to different disciplines. This article provides suggestions for (1) designing curriculum in creativity, innovation, and entrepreneurship education (CIE) for different education level and (2) transitioning technical and vocational education in developing economies on the road to sustainable development.

Resolution of left ventricular thrombus by edoxaban after failed treatment with warfarin overdose: A case report.

RATIONALE: Although novel oral-anticoagulants are widely used in patients with atrial fibrillation (AF) for stroke prevention, there was only limited evidence for their use in left ventricular (LV) thrombus. PATIENT CONCERNS: A 41-year-old man who presented with acute onset of right-hand clumsiness and aphasia even under high international normalized ratio (INR: 7.64) from warfarin use. He was previously treated with warfarin for the LV thrombus and non-valvular AF. Brain magnetic resonance imaging (MRI) showed multiple acute infarction in the cortex of the bilateral frontal lobes, left parietal lobe, and bilateral central semiovale, which highly suggested embolic stroke. DIAGNOSIS: The repeated transthoracic echocardiogram still revealed LV thrombus (1.27 × 0.90 cm), which failed to respond to warfarin therapy. INTERVENTIONS: Due to acute infarctions occurred under supratherapeutic range of INR, we switched warfarin to edoxaban (dose: 60 mg/day) after INR decreased to less than 2. OUTCOMES: The thrombus disappeared after receiving edoxaban for 23 days, and no more recurrent stroke was noted for more than 6 months. LESSONS: This is the first case demonstrates that while facing ineffective treatment of warfarin for LV thrombus, edoxaban could be safely and effectively used under this situation.

Periodic limb movements during sleep are associated with cardiovascular diseases: A systematic review and meta-analysis.

Periodic limb movements during sleep present with repetitive movements, typically in the lower limbs, during sleep. Periodic limb movements during sleep have been proposed to be associated with increased risk of heart diseases. The aim of this study was to examine the co-morbidity rates of heart disease, including acute myocardial infarction, coronary artery disease and cardiovascular disease, in subjects with or without periodic limb movements during sleep through a meta-analysis. An electronic review of PubMed, Embase, ScienceDirect, Cochrane Library, ProQuest, Web of Science, ClinicalKey and ClinicalTrials.gov was performed. Clinical studies, case-controlled trials and cohort studies were all included in the search. Case reports or series, and non-clinical studies were excluded. A meta-analysis of the results of six studies comparing the prevalence of coronary artery disease/acute myocardial infarction/cardiovascular disease in subjects with/without periodic limb movements during sleep was performed. There were significantly higher co-morbidity rates of coronary artery disease (odds ratio = 1.568, 95% confidence interval: 1.187-2.073, p = 0.002) and cardiovascular disease (odds ratio = 1.279, 95% confidence interval: 1.095-1.494, p = 0.002), but not acute myocardial infarction (odds ratio = 1.272, 95% confidence interval = 0.942-1.718, p = 0.117), in the periodic limb movements during sleep group than in the non-periodic limb movements during sleep group. This meta-analysis highlights the importance of a significantly high prevalence of coronary artery disease and cardiovascular disease in subjects with periodic limb movements during sleep. Further studies should be focused on the potential pathophysiology, and whether treatment for periodic limb movements during sleep can improve the outcome of heart disease.

Diffuse ST-Segment Depression with ST-Segment Elevation in Lead aVR in 12-Lead Electrocardiography May Indicate Ischemic Change of Severe Aortic Stenosis.

UNLABELLED: Diffuse ST-segment depression with ST-segment elevation in the lead augmented vector right (aVR) in 12-lead electrocardiography may indicate the possibility of coronary artery disease involving the left main coronary artery or proximal left anterior descending artery, pulmonary embolism or takotsubo cardiomyopathy. We report a 69-year-old female with severe aortic stenosis, who had similar electrocardiographic findings which indicated ischemic change and led to cardiogenic shock and ventricular tachycardia. Intubation and insertion of an intra- aortic balloon pump (IABP) were performed and the result of coronary angiography showed only less than 40% stenosis. Her blood pressure gradually stabilized, and diffuse ST-segment depression or ST-segment elevation in lead aVR was not noted in the 12-lead electrocardiography. However, we removed the IABP and after 6 hours, sudden profound shock refractory to combined vasopressors occurred. Electrocardiography again showed ST- segment elevation in aVR with and diffuse ST-segment depression. After several episodes of ventricular tachycardia, cardiopulmonary resuscitation was not successful and the patient expired in our hospital. KEY WORDS: Diffuse ST depression; Severe aortic stenosis; ST elevation in aVR.

Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response.

While numerous small ubiquitin-like modifier (SUMO) conjugated substrates have been identified, very little is known about the cellular signalling mechanisms that differentially regulate substrate sumoylation. Here, we show that acetylation of SUMO E2 conjugase Ubc9 selectively downregulates the sumoylation of substrates with negatively charged amino acid-dependent sumoylation motif (NDSM) consisting of clustered acidic residues located downstream from the core ψ-K-X-E/D consensus motif, such as CBP and Elk-1, but not substrates with core ψ-K-X-E/D motif alone or SUMO-interacting motif. Ubc9 is acetylated at residue K65 and K65 acetylation attenuates Ubc9 binding to NDSM substrates, causing a reduction in NDSM substrate sumoylation. Furthermore, Ubc9 K65 acetylation can be downregulated by hypoxia via SIRT1, and is correlated with hypoxia-elicited modulation of sumoylation and target gene expression of CBP and Elk-1 and cell survival. Our data suggest that Ubc9 acetylation/deacetylation serves as a dynamic switch for NDSM substrate sumoylation and we report a previously undescribed SIRT1/Ubc9 regulatory axis in the modulation of protein sumoylation and the hypoxia response.

Daxx interacts with and modulates the activity of CREB.

The phosphorylation of cAMP response element-binding protein (CREB) induced by the cAMP-dependent protein kinase A (PKA) elicits the recruitment of CREB-binding protein (CBP) for activating cAMP responsive gene expression. Several reports indicate that proteins binding to CREB and/or CBP play important roles in modulating the CREB-dependent transactivation. Here, we show that Daxx interacts with CREB and modulates CREB-mediated transcription. Daxx was identified as a CREB-interacting protein by a yeast two-hybrid screen. Depletion of endogenous Daxx by specific shRNA or overexpression of Daxx resulted in decreased or increased levels of the cAMP/PKA-induced reporter activity and target gene expression, respectively. In vitro and in vivo binding studies revealed that Daxx C-terminal domain binds to CREB basic leucine zipper domain. The binding of Daxx to CREB correlates with its repressive effect on a CRE-mediated reporter activity induced by forskolin or PKA. Furthermore, the results of electrophoresis mobility shift assays and chromatin immunoprecipitation experiments showed that Daxx attenuated the DNA binding potential of the CREB. Our study provides a previously undescribed role of Daxx in repressing cAMP-responsive gene expression and also a mechanism underlying the repressive effect of Daxx on CREB transcriptional potential.