Short-term joint effects of ambient PM2.5 and O3 on mortality in Beijing, China.

Introduction: In recent years, air pollution caused by co-occurring PM2.5 and O3, named combined air pollution (CAP), has been observed in Beijing, China, although the health effects of CAP on population mortality are unclear. Methods: We employed Poisson generalized additive models (GAMs) to evaluate the individual and joint effects of PM2.5 and O3 on mortality (nonaccidental, respiratory, and cardiovascular mortality) in Beijing, China, during the whole period (2014-2016) and the CAP period. Adverse health effects were assessed for percentage increases (%) in the three mortality categories with each 10-µg/m3 increase in PM2.5 and O3. The cumulative risk index (CRI) was adopted as a novel approach to quantify the joint effects. Results: The results suggested that both PM2.5 and O3 exhibited the greatest individual effects on the three mortality categories with cumulative lag day 01. Increases in the nonaccidental, cardiovascular, and respiratory mortality categories were 0.32%, 0.36%, and 0.43% for PM2.5 (lag day 01) and 0.22%, 0.37%, and 0.25% for O3 (lag day 01), respectively. There were remarkably synergistic interactions between PM2.5 and O3 on the three mortality categories. The study showed that the combined effects of PM2.5 and O3 on nonaccidental, cardiovascular, and respiratory mortality were 0.34%, 0.43%, and 0.46%, respectively, during the whole period and 0.58%, 0.79%, and 0.75%, respectively, during the CAP period. Our findings suggest that combined exposure to PM2.5 and O3, particularly during CAP periods, could further exacerbate their single-pollutant health risks. Conclusion: These findings provide essential scientific evidence for the possible creation and implementation of environmental protection strategies by policymakers.

Protocatechuic acid prevents isoproterenol-induced heart failure in mice by downregulating kynurenine-3-monooxygenase.

Protocatechuic acid (3,4-dihydroxybenzoic acid) prevents oxidative stress, inflammation and cardiac hypertrophy. This study aimed to investigate the therapeutic effects of protocatechuic acid in an isoproterenol-induced heart failure mouse model and to identify the underlying mechanisms. To establish the heart failure model, C57BL/6NTac mice were given high-dose isoproterenol (80 mg/kg body weight) for 14 days. Echocardiography revealed that protocatechuic acid reversed the isoproterenol-induced downregulation of fractional shortening and ejection fraction. Protocatechuic acid attenuated cardiac hypertrophy as evidenced by the decreased heart-weight-to-body-weight ratio and the expression of Nppb. RNA sequencing analysis identified kynurenine-3-monooxygenase (Kmo) as a potential target of protocatechuic acid. Protocatechuic acid treatment or transfection with short-interfering RNA against Kmo ameliorated transforming growth factor ß1-induced upregulation of Kmo, Col1a1, Col1a2 and Fn1 in vivo or in neonatal rat cardiac fibroblasts. Kmo knockdown attenuated the isoproterenol-induced increase in cardiomyocyte size, as well as Nppb and Col1a1 expression in H9c2 cells or primary neonatal rat cardiomyocytes. Moreover, protocatechuic acid attenuated Kmo overexpression-induced increases in Nppb mRNA levels. Protocatechuic acid or Kmo knockdown decreased isoproterenol-induced ROS generation in vivo and in vitro. Thus, protocatechuic acid prevents heart failure by downregulating Kmo. Therefore, protocatechuic acid and Kmo constitute a potential novel therapeutic agent and target, respectively, against heart failure.

AFM is used to study the biophysics of hypertension-induced tachyarrhythmia.

Patients with long-lasting hypertension often suffer from atrial or ventricular arrhythmias. Evidence suggests that mechanical stimulation can change the refractory period and dispersion of the ventricular myocyte action potential through stretch-activated ion channels (SACs) and influence cellular calcium transients, thus increasing susceptibility to ventricular arrhythmias. However, the specific pathogenesis of hypertension-induced arrhythmias is unknown. In this study, through clinical data, we found that a short-term increase in blood pressure leads to a rise in tachyarrhythmias in patients with clinical hypertension. We investigated the mechanism of this phenomenon using a combined imaging system(AC) of atomic force microscopy (AFM) and laser scanning confocal microscopy. After mechanical distraction to stimulate ventricular myocytes isolated from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), we synchronously monitored cardiomyocyte stiffness and intracellular calcium changes. This method can reasonably simulate cardiomyocytes' mechanics and ion changes when blood pressure rises rapidly. Our results indicated that the stiffness value of cardiomyocytes in SHR was significantly more extensive than that of normal controls, and cardiomyocytes were more sensitive to mechanical stress; In addition, intracellular calcium increased rapidly and briefly in rats with spontaneous hypertension. After intervention with streptomycin, a SAC blocker, ventricular myocytes are significantly less sensitive to mechanical stimuli. Thus, SAC is involved in developing and maintaining ventricular arrhythmias induced by hypertension. The increased stiffness of ventricular myocytes caused by hypertension leads to hypersensitivity of cellular calcium flow to mechanical stimuli is one of the mechanisms that cause arrhythmias. The AC system is a new research method to study the mechanical properties of cardiomyocytes. This study provides new techniques and ideas for developing new anti-arrhythmic drugs. HIGHLIGHT: The mechanism of hypertension-induced tachyarrhythmia is not precise. Through this study, it is found that the biophysical properties of myocardial abnormalities, the myocardium is excessively sensitive to mechanical stimulation, and the calcium flow appears to transient explosive changes, leading to tachyarrhythmia.

Spatiotemporal effects of meteorological conditions on global influenza peaks.

BACKGROUND: Numerous studies have suggested that meteorological conditions such as temperature and absolute humidity are highly indicative of influenza outbreaks. However, the explanatory power of meteorological factors on the seasonal influenza peaks varied widely between countries at different latitudes. OBJECTIVES: We aimed to explore the modification effects of meteorological factors on the seasonal influenza peaks in multi-countries. METHODS: Data on influenza positive rate (IPR) were collected across 57 countries and data on meteorological factors were collected from ECMWF Reanalysis v5 (ERA5). We used linear regression and generalized additive models to investigate the spatiotemporal associations between meteorological conditions and influenza peaks in cold and warm seasons. RESULTS: Influenza peaks were significantly correlated with months with both lower and higher temperatures. In temperate countries, the average intensity of cold season peaks was stronger than that of warm season peaks. However, the average intensity of warm season peaks was stronfger than of cold season peaks in tropical countries. Temperature and specific humidity had synergistic effects on influenza peaks at different latitudes, stronger in temperate countries (cold season: R2=0.90; warm season: R2=0.84) and weaker in tropical countries (cold season: R2=0.64; warm season: R2=0.03). Furthermore, the effects could be divided into cold-dry and warm-humid modes. The temperature transition threshold between the two modes was 16.5-19.5 °C. During the transition from cold-dry mode to warm-humid mode, the average 2 m specific humidity increased by 2.15 times, illustrating that transporting a large amount of water vapor may compensate for the negative effect of rising temperatures on the spread of the influenza virus. CONCLUSION: Differences in the global influenza peaks were related to the synergistic influence of temperature and specific humidity. The global influenza peaks could be divided into cold-dry and warm-humid modes, and specific thresholds of meteorological conditions were needed for the transition of the two modes.

Transformer-Based High-Frequency Oscillation Signal Detection on Magnetoencephalography From Epileptic Patients.

High-frequency oscillations (HFOs), observed within 80-500 Hz of magnetoencephalography (MEG) data, are putative biomarkers to localize epileptogenic zones that are critical for the success of surgical epilepsy treatment. It is crucial to accurately detect HFOs for improving the surgical outcome of patients with epilepsy. However, in clinical practices, detecting HFOs in MEG signals mainly depends on visual inspection by clinicians, which is very time-consuming, labor-intensive, subjective, and error-prone. To accurately and automatically detect HFOs, machine learning approaches have been developed and have demonstrated the promising results of automated HFO detection. More recently, the transformer-based model has attracted wide attention and achieved state-of-the-art performance on many machine learning tasks. In this paper, we are investigating the suitability of transformer-based models on the detection of HFOs. Specifically, we propose a transformer-based HFO detection framework for biomedical MEG one-dimensional signal data. For signal classification, we develop a transformer-based HFO (TransHFO) classification model. Then, we investigate the relationship between depth of deep learning models and classification performance. The experimental results show that the proposed framework outperforms the state-of-the-art HFO classifiers, increasing classification accuracy by 7%. Furthermore, we find that shallow TransHFO ( < 10 layers) outperforms deep TransHFO models (≥10 layers) on most data augmented factors.

Cross-Lingual Knowledge Transferring by Structural Correspondence and Space Transfer.

The cross-lingual sentiment analysis (CLSA) aims to leverage label-rich resources in the source language to improve the models of a resource-scarce domain in the target language, where monolingual approaches based on machine learning usually suffer from the unavailability of sentiment knowledge. Recently, the transfer learning paradigm that can transfer sentiment knowledge from resource-rich languages, for example, English, to resource-poor languages, for example, Chinese, has gained particular interest. Along this line, in this article, we propose semisupervised learning with SCL and space transfer (ssSCL-ST), a semisupervised transfer learning approach that makes use of structural correspondence learning as well as space transfer for cross-lingual sentiment analysis. The key idea behind ssSCL-ST, at a high level, is to explore the intrinsic sentiment knowledge in the target-lingual domain and to reduce the loss of valuable knowledge due to the knowledge transfer via semisupervised learning. ssSCL-ST also features in pivot set extension and space transfer, which helps to enhance the efficiency of knowledge transfer and improve the classification accuracy in the target language domain. Extensive experimental results demonstrate the superiority of ssSCL-ST to the state-of-the-art approaches without using any parallel corpora.

Polycyclic aromatic hydrocarbons induce endothelial injury through miR-155 to promote atherosclerosis.

Polycyclic aromatic hydrocarbons (PAHs) are considered as an external factor that induces atherosclerotic cardiovascular disease. Although miR-155 is known to be involved in cardiovascular disease, whether it is involved in PAH-induced arteriosclerosis remains unclear. We evaluated the effects of PAHs on vascularization, permeability, and miR-155 expression in HUVECs. We found that PAHs-induced sclerosis of HUVECs was characterized by increasing permeability, decreasing proliferation, and vascular lumen number. The expression of miR-155 was upregulated by PAHs treatment, and transfection with miR-155 inhibitor could reverse above effect of PAHs-induced sclerosis. Meanwhile, transcriptome sequencing revealed that 63 genes were downregulated in the group of PAHs treatment alone, and were then upregulated in the miR-155 inhibitor group. These genes were mainly involved in complement and coagulation cascades, cytokine-cytokine receptor interaction, TNF signaling pathway, and NF-kappa B signaling pathway. Among these 63 genes, SERPIND1 was directly targeted and regulated by miR-155. Further in vivo experiments in ApoE-/- mice confirmed that PAH accelerates the development of arteriosclerosis by promoting the expression of miR-155 to downregulate the SERPIND1. Therefore, PAH exaggerates atherosclerosis by activating miR-155-dependent endothelial injury. This study provides a fundamental insight on the miR-155 mechanism for PAHs enhancing atherosclerosis and miR-155 potentially serving as a novel drug target.

Effect of Air Quality on the Risk of Emergency Room Visits in Patients With Atrial Fibrillation.

Background: We investigated the effect of particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and meteorological conditions on the risk of emergency room visits in patients with atrial fibrillation (AF) in Beijing, which is considered as a monsoon climate region. Methods: In this case-crossover design study, medical records from patients with AF who visited the Critical Care Center in the Emergency Department of Anzhen Hospital from January 2011 through December 2014 and air quality and meteorological data of Beijing during the same period were collected and analyzed using Cox regression and time-series autocorrelation analyses. Results: A total of 8,241 patients were included. When the average PM2.5 concentration was >430 µg/m3, the risk of emergency room visits for patients with uncomplicated AF, AF combined with cardiac insufficiency, and AF combined with rheumatic heart disease increased by 12, 12, and 40%, respectively. When the average PM2.5 concentration was >420 µg/m3, patients with AF combined with diabetes mellitus had a 75% increased risk of emergency room visits, which was the largest increase in risk among all types of patients with AF. When the average PM2.5 concentration was >390 µg/m3, patients with AF combined with acute coronary syndrome had an approximately 30% increased risk of emergency room visits, which was the highest and fastest increase in risk among all types of patients with AF. The risk of emergency room visits for patients with AF was positively correlated with air quality as the time lag proceeded, with an autocorrelation coefficient of 0.223 between the risk of emergency room visits and air quality in patients with AF on day 6 of the time lag. Conclusion: Exposure to certain concentrations of PM2.5 in a monsoon climate region significantly increased the risk of emergency room visits in patients with AF.

Clinical Manifestation, Timing Course, Precipitating Factors, and Protective Factors of Ventricular Free Wall Rupture Following ST-Segment Elevation Myocardial Infarction.

Ventricular free wall rupture (FWR) is a catastrophic complication of that occurs after acute myocardial infarction (AMI), and at present, its clinical characteristics are unclear. We analyzed a total of 6,712 consecutive patients who presented with ST-segment elevation myocardial infarction (STEMI), and 78 patients with FWR after STEMI were enrolled in the study. Patients' demographic data, clinical manifestation, laboratory test results, and angiographic features were then collected and analyzed. FWR occurred in 78 cases (1.16%), and the inhospital mortality of FWR was up to 92.3%. Among the 78 FWR patients, 72 obtained accurate rupture time. FWR typically occurred within the first week after the infarct. Compared to late-phase FWR (more than 48 hours after STEMI) patients, early-phase FWR (during 48 hours after STEMI) patients showed significantly higher random glucose and higher percentage of anterior myocardial infarction. Besides, dual antiplatelet therapy (DAPT), ß-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (ACEI/ARB) were used less frequently in early-phase FWR patients. Moreover, we first reported the precipitating factors of FWR. Defecating, transporting, acute emotional upset, diets, and invasive treatment turned out to be the main triggers for FWR. Furthermore, we found that patients who survived from FWR were younger, had higher ß-blocker coverage in the inhospital treatment, and had a higher frequency of primary PCI. FWR remains an infrequent but devastating complication of STEMI. We have found several factors related to the occurrence and prognosis of FWR. This study provides evidence for a better understanding of FWR.

A Long-Term Cost-Effectiveness Analysis Comparing Radiofrequency Catheter Ablation with Antiarrhythmic Drugs in Treatment of Chinese Patients with Atrial Fibrillation.

INTRODUCTION: Radiofrequency catheter ablation (RFCA) is widely used to treat atrial fibrillation (AF) in China. OBJECTIVE: We aimed to determine the long-term cost effectiveness of RFCA versus antiarrhythmic drugs (AADs) in treating AF from the perspective of third-party payers. METHODS: The model was structured as a 12-month decision tree leading to a Markov model that simulated the follow-up treatment outcomes and costs with time horizons of 8, 15, and 20 years. Comparators were standard-of-care AADs. Clinical parameters captured normal sinus rhythm, AF, stroke, post-stroke, intracranial hemorrhage (ICH), gastrointestinal bleeding, post-ICH, and death. The risk of operative death, procedural complications, and adverse drug toxicity were also considered. The model output was quality-adjusted life-years (QALYs) and incremental cost per QALY gained. RESULTS: RFCA incurred more costs than the AADs but resulted in more QALYs gained than did AADs. The incremental cost per QALY gained with RFCA versus AADs was ¥66,764, ¥36,280, and ¥29,359 at 8, 15, and 20 years, respectively. The sensitivity analyses showed that the results were most sensitive to the changes in RFCA cost and CHADS2 score (clinical prediction rule for assessing the risk of stroke in patients with non-rheumatic AF). CONCLUSION: Compared with AADs, RFCA significantly improves clinical outcomes and QALYs among patients with paroxysmal or persistent AF. From the Chinese payer's perspective, RFCA is a cost-effective therapy over long-term horizons.

Polycyclic Aromatic Hydrocarbons from Particulate Matter 2.5 (PM2.5) in Polluted Air Changes miRNA Profile Related to Cardiovascular Disease.

BACKGROUND Particulate matter 2.5 (PM2.5) in air pollution is regarded as a risk factor for cardiovascular disease (CVDs). Recently, it has become well accepted that polycyclic aromatic hydrocarbons (PAHs) in PM2.5 impacts human CVDs. However, few studies have shown miRNAs affected by PAHs play a critical role in transcriptional regulation related to cardiovascular development and disease. MATERIAL AND METHODS Human umbilical cord vein cells (HUVECs) incubated prior to treatment with PAHs at various concentrations (0, 100, 200, 300, 400, and 500 µg/ml) of PAHs particle solutions were added to the culture medium for 24 h. We performed isolation and sequencing of small RNAs and analysis of small RNA sequences and differential expression. The M3RNA database was used to predict miRNA-miRNA interactions. Tools from the DAVID database were used to perform the GO functional analysis of predicted miRNA target genes. A First-Strand cDNA Synthesis Kit was used to synthesis cDNA. RESULTS miRNA155 was revealed as a key regulator in PAHs treatment. The putative targets of upregulated miRNA in PAHs treatment indicated that the downregulated genes were enriched in biological pathways such as Wnt signaling and ErbB signaling, which are crucial for the development of vasculature. CONCLUSIONS In general, our results suggest that PAHs taken by PM2.5 can decrease cardiovascular-related gene expression through upregulating miRNA, which may be a new target for therapy in the future.

Impact of meteorological conditions and PM2.5 on the onset of acute aortic dissection in monsoonal climate.

OBJECTIVE: To investigate the impact of meteorological conditions and PM2.5 on the onset of acute aortic dissection in monsoonal climate. METHODS: A linear regression analysis was performed in monsoonal climate epidemiological survey for a period of four years on the impact of meteorological factors (minimal temperature, mean temperature, maximal temperature, average daily surface temperature, day temperature range, relative humidity, mean wind speed, and atmospheric pressure) and PM2.5 concentration on the daily incidences of acute aortic dissections. Meteorological variables and PM2.5 concentration were retrieved on a daily basis from Beijing Regional Climate Center and the Ministry of Environmental Protection of the People's Republic of China's website, and the daily incidences of acute aortic dissections were retrieved from the Clinical Data Analysis and Reporting System in the Emergency and Critical Care Center of Beijing Anzhen Hospital. RESULTS: During the study period (from January 2011 to December 2014), 1164 patients were identified as having acute aortic dissections. The corresponding incidences in spring and autumn were 0.96 and 1.00, respectively, which significantly higher than that in summer and winter. The incidences of acute aortic dissection in a day could be predicted by diurnal temperature range (DTR) using the following linear multiple regression models: incidences of acute aortic dissection = 0.543 + 0.025 × DTR. CONCLUSION: This is the first study to show an attributable effect of DTR on acute aortic events in monsoonal climate. Our study confirms that meteorological variables were important factors influencing the incidence of acute aortic dissection.

A comparison of the real world effectiveness of catheter ablation and drug therapy in atrial fibrillation patients in a Chinese setting.

BACKGROUND: Studies have demonstrated that catheter ablation of atrial fibrillation is associated with better rhythm control than drug therapy. The present study aimed to assess the clinical outcomes and health-related quality of life of ablation therapy in a real world setting. METHODS: A prospective, non-randomized, single center study in a real-world clinical setting in China was conducted. Patients were followed up at 3, 6, and 9 months after baseline encounter. Propensity score matched patients receiving ablation or anti-arrhythmic drug therapy were compared. Incidence rate of atrial fibrillation recurrence and quality of life outcomes were measured and analyzed using log-rank test, multivariate logistic regression and mixed-effects linear regression respectively. RESULTS: In this study, 151 atrial fibrillation patients treated by ablation therapy and 318 patients treated by anti-arrhythmic drugs were enrolled. During follow up, 82.0% in the ablation arm and 22.4% in the drug arm had no documented atrial fibrillation recurrence [HR for atrial fibrillation recurrence 0.07 (95%CI: 0.02-0.21, p < 0.0001)] among paroxysmal atrial fibrillation patients. The corresponding no recurrent rate were 66.7% and 18.5% [0.21 (0.05-0.95, p = 0.04)] respectively among persistent atrial fibrillation patients. Improvement in Short Form-36 physical component scores, Short Form-36 mental component scores and total Atrial Fibrillation Effect on Quality-of-life scores were 16.33 (14.05-18.61, p < 0.001), 8.10 (6.11-10.09, p < 0.001) and 18.28 (16.11-20.45, p < 0.001) respectively among paroxysmal AF patients and 6.32 (3.15-9.49, p < 0.001), 3.99 (1.82-6.16, p < 0.001) and 13.97 (10.89-17.05, p < 0.001) respectively among persistent AF patients. Improvements in total Atrial Fibrillation Effect on Quality-of-life score were also significant in ablation arm while no significant improvement of total Atrial Fibrillation Effect on Quality-of-life score in the drug arm. CONCLUSION: Compared with drug therapy, catheter ablation is associated with significant lower AF recurrence and improved overall quality of life. TRIAL REGISTRATION: The present study has been registered on clinicaltrials.gov. The ClinicalTrials.gov ID is NCT01878981 . The registration date is May 29, 2013.

A modified HEART risk score in chest pain patients with suspected non-ST-segment elevation acute coronary syndrome.

OBJECTIVE: To validate a modified HEART [History, Electrocardiograph (ECG), Age, Risk factors and Troponin] risk score in chest pain patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in the emergency department (ED). METHODS: This retrospective cohort study used a prospectively acquired database and chest pain patients admitted to the emergency department with suspected NSTE-ACS were enrolled. Data recorded on arrival at the ED were used. The serum sample of high-sensitivity cardiac Troponin I other than conventional cardiac Troponin I used in the HEART risk score was tested. The modified HEART risk score was calculated. The end point was the occurrence of major adverse cardiac events (MACE) defined as a composite of acute myocardial infarction (AMI), percutaneous intervention (PCI), coronary artery bypass graft (CABG), or all-cause death, within three months after initial presentation. RESULTS: A total of 1,300 patients were enrolled. A total of 606 patients (46.6%) had a MACE within three months: 205 patients (15.8%) were diagnosed with AMI, 465 patients (35.8%) underwent PCI, and 119 patients (9.2%) underwent CABG. There were 10 (0.8%) deaths. A progressive, significant pattern of increasing event rate was observed as the score increased (P < 0.001 by χ (2) for trend). The area under the receiver operating characteristic curve was 0.84. All patients were classified into three groups: low risk (score 0-2), intermediate risk (score 3-4), and high risk (score 5-10). Event rates were 1.1%, 18.5%, and 67.0%, respectively (P < 0.001). CONCLUSIONS: The modified HEART risk score was validated in chest pain patients with suspected NSTE-ACS and may complement MACE risk assessment and patients triage in the ED. A prospective study of the score is warranted.

RanGTP aids anaphase entry through Ubr5-mediated protein turnover.

RanGTP is known to regulate the spindle assembly checkpoint (SAC), but the underlying molecular mechanism is unclear. BuGZ stabilizes SAC protein Bub3 through direct interaction and facilitates its mitotic function. Here we show that RanGTP promotes the turnover of BuGZ and Bub3 in metaphase, which in turn facilitates metaphase-to-anaphase transition. BuGZ and Bub3 interact with either importin-ß or an E3 ubiquitin ligase, Ubr5. RanGTP promotes the dissociation of importin-ß from BuGZ and Bub3 in metaphase. This results in increased binding of BuGZ and Bub3 to Ubr5, leading to ubiquitination and subsequent turnover of both proteins. We propose that elevated metaphase RanGTP levels use Ubr5 to couple overall chromosome congression to SAC silencing.

Phase transition of spindle-associated protein regulate spindle apparatus assembly.

Spindle assembly required during mitosis depends on microtubule polymerization. We demonstrate that the evolutionarily conserved low-complexity protein, BuGZ, undergoes phase transition or coacervation to promote assembly of both spindles and their associated components. BuGZ forms temperature-dependent liquid droplets alone or on microtubules in physiological buffers. Coacervation in vitro or in spindle and spindle matrix depends on hydrophobic residues in BuGZ. BuGZ coacervation and its binding to microtubules and tubulin are required to promote assembly of spindle and spindle matrix in Xenopus egg extract and in mammalian cells. Since several previously identified spindle-associated components also contain low-complexity regions, we propose that coacervating proteins may be a hallmark of proteins that comprise a spindle matrix that functions to promote assembly of spindles by concentrating its building blocks.

Splicing function of mitotic regulators links R-loop-mediated DNA damage to tumor cell killing.

Although studies suggest that perturbing mitotic progression leads to DNA damage and p53 activation, which in turn lead to either cell apoptosis or senescence, it remains unclear how mitotic defects trigger p53 activation. We show that BuGZ and Bub3, which are two mitotic regulators localized in the interphase nucleus, interact with the splicing machinery and are required for pre-mRNA splicing. Similar to inhibition of RNA splicing by pladienolide B, depletion of either BuGZ or Bub3 led to increased formation of RNA-DNA hybrids (R-loops), which led to DNA damage and p53 activation in both human tumor cells and primary cells. Thus, R-loop-mediated DNA damage and p53 activation offer a mechanistic explanation for apoptosis of cancer cells and senescence of primary cells upon disruption of the dual-function mitotic regulators. This demonstrates the importance of understanding the full range of functions of mitotic regulators to develop antitumor drugs.

A microtubule-associated zinc finger protein, BuGZ, regulates mitotic chromosome alignment by ensuring Bub3 stability and kinetochore targeting.

Equal chromosome segregation requires proper assembly of many proteins, including Bub3, onto kinetochores to promote kinetochore-microtubule interactions. By screening for mitotic regulators in the spindle envelope and matrix (Spemix), we identify a conserved Bub3 interacting and GLE-2-binding sequence (GLEBS) containing ZNF207 (BuGZ) that associates with spindle microtubules and regulates chromosome alignment. Using its conserved GLEBS, BuGZ directly binds and stabilizes Bub3. BuGZ also uses its microtubule-binding domain to enhance the loading of Bub3 to kinetochores that have assumed initial interactions with microtubules in prometaphase. This enhanced Bub3 loading is required for proper chromosome alignment and metaphase to anaphase progression. Interestingly, we show that microtubules are required for the highest kinetochore loading of Bub3, BubR1, and CENP-E during prometaphase. These findings suggest that BuGZ not only serves as a molecular chaperone for Bub3 but also enhances its loading onto kinetochores during prometaphase in a microtubule-dependent manner to promote chromosome alignment.

Impact of the origin of sinus node artery on recurrence after pulmonary vein isolation in patients with paroxysmal atrial fibrillation.

BACKGROUND: Major atrial coronary arteries, including the sinus node artery (SNA), were commonly found in the areas involved in atrial fibrillation (AF) ablation and could cause difficulties in achieving linear block at the left atrial (LA) roof. The SNA is a major atrial coronary artery of the atrial coronary circulation. This study aimed to determine impact of the origin of SNA on recurrence of AF after pulmonary vein isolation (PVI) in patients with paroxysmal AF. METHODS: Seventy-eight patients underwent coronary angiography for suspected coronary heart disease, followed by catheter ablation for paroxysmal AF. According to the origin of SNA from angiographic findings, they were divided into right SNA group (SNA originating from the right coronary artery) and left SNA group (SNA originating from the left circumflex artery). Guided by an electroanatomic mapping system, circumferential pulmonary vein ablation (CPVA) was performed in both groups and PVI was the procedural endpoint. All patients were followed up at 1, 3, 6, 9 and 12 months post-ablation. Recurrence was defined as any episode of atrial tachyarrhythmias (ATAs), including AF, atrial flutter or atrial tachycardia, that lasted longer than 30 seconds after a blanking period of 3 months. RESULTS: The SNA originated from the right coronary artery in 34 patients (43.6%) and the left circumflex artery in 44 patients (56.4%). Freedom from AF and antiarrhythmic drugs (AADs) at 1 year was 67.9% (53/78) for all patients. After 1 year follow-up, 79.4% (27/34) in right SNA group and 59.1% (26/44) in left SNA group (P = 0.042) were in sinus rhythm. On multivariate analysis, left atrium size (HR = 1.451, 95%CI: 1.240 - 1.697, P < 0.001) and a left SNA (HR = 6.22, 95%CI: 2.01 - 19.25, P = 0.002) were the independent predictors of AF recurrence. CONCLUSIONS: The left SNA is more frequent in the patients with paroxysmal AF. After one year follow-up, the presence of a left SNA was identified as an independent predictor of AF recurrence after CPVA in paroxysmal AF.

Outcome of catheter ablation of atrial fibrillation in patients with prior ischemic stroke.

BACKGROUND: Catheter ablation for atrial fibrillation (AF) has been demonstrated to be effective in a subsets of patients with AF. However, very few data are available in regard to patients with prior history of stroke undergoing catheter ablation. This study aimed to investigate the outcome of catheter ablation in AF patients with prior ischemic stroke. METHODS: Between January 2008 and December 2011, of 1897 consecutive patients who presented at Beijing An Zhen Hospital for treatment of drug-refractory AF, 172 (9.1%) patients in the study population had a history of ischemic stroke. All patients underwent catheter ablation and were followed up to assess maintenance of sinus rhythm and recurrence of symptomatic stroke. RESULTS: Among these 1897 patients, 1768 (93.2%) who had complete follow-up information for a minimum of six months were included in the final analysis. Patients in the stroke group (group I) and the no-stroke group (group II) were similar in regards to gender, body mass index (BMI), history of diabetes, type of AF, and left atrial size. The patients in group I were older than those in group II, and had a higher incidence of hypertension, chronic heart failure, lower left ventricular ejection fraction (LVEF), and higher CHADS2 scores. Six months after ablation, 107 (68.6%) patients in group I and 1403 (87.1%) in group II had discontinued warfarin treatment (P < 0.001). During a median follow-up of (633 ± 415) days, 65 patients in the group I and 638 in group II experienced AF recurrence, and five patients in group I and 28 in group II developed symptomatic stroke. The rates of AF recurrence and recurrent stroke were similar between group I and group II (41.7% vs. 39.6%, P = 0.611; 3.2% vs. 1.7%, P = 0.219; respectively). CONCLUSION: Catheter ablation of AF in patients with prior stroke is feasible and efficient.