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Abstract Background Hypertrophic cardiomyopathy (HCM) is frequently associated with atrial fibrillation (AF). We compared clinical, echocardiographic, and electrophysiological parameters between HCM subtypes and those without HCM at AF catheter ablation (AFCA) and analyzed post‐AFCA reverse remodeling and AF recurrence based on HCM presence and subtype. Methods Among 5161 consecutive patients who underwent de novo AFCA, we included HCM patients and control patients who were age‐, gender‐, and AF type‐matched. Between AF‐HCM patients and controls, we compared baseline values for left atrium (LA) wall thickness (LAWT), reverse remodeling at 1‐year follow‐up, and procedural outcomes over the course of follow‐up between two groups. Results A total of 122 AF‐HCM patients and 318 control patients were included. AF‐HCM patients had more frequent heart failure and higher LA diameter, E/Em, and LA pressure (all, p

Abstract Background and Objectives Although extra‐pulmonary vein (PV) triggers (ExPVTs) play a role in atrial fibrillation (AF) recurrence after catheter ablation (AFCA), the mechanism is unknown. We explored whether the locations of ExPVTs were associated with low‐voltage scar areas (LVAs). Methods Among 2255 consecutive patients who underwent a de novo AFCA, 1696 (male 72.1%, median 60 years old, paroxysmal 64.7%) were included who underwent isoproterenol provocation and voltage mapping of the left atrium (LA) during their procedures. We investigated the associations between ExPVTs and their mean LA voltage and colocalization of ExPVTs within LVAs (

Abstract Background High‐power short‐duration (HPSD) ablation creates wide, shallow lesions using radiofrequency (RF) heating. It is uncertain if adjusting RF energy based on atrial wall thickness provides extra benefits. We studied the safety and effectiveness of tailored HPSD energy based on left atrial (LA) wall thickness (LAWT) for circumferential pulmonary vein isolation (CPVI) in patients with paroxysmal atrial fibrillation (PAF). Methods We enrolled 212 patients (68.4% male, mean age: 59.5 ± 11.0 years) and randomly assigned them to two groups: LAWT‐guided CPVI (WT, n = 108) and conventional CPVI (control, n = 104). Both groups used an open irrigated‐tip deflectable catheter to apply 50 W for 10 s to the posterior LA, while controls used 60 W for 15 s on other LA regions. RF delivery time in WT was titrated (15 s at LAWT > 2.1 mm, 13 s at 1.4–2.1 mm, and 11 s at .999). The total procedure time, cardioversion rate, and post‐procedural AAD prescription rates did not significantly differ between the groups. Conclusions The LAWT‐guided energy titration strategy did not result in improved procedural safety and efficacy compared to the conventional 50–60 W‐HPSD CPVI in patients with PAF.

Abstract Background The muscular discontinuities or lack of myocardial extensions around the pulmonary veins (PVs) antrum were previously reported. The objective of our study was to compare the efficacy of a partial antral ablation for PV isolation (PVI) using ultra-high density (UHD) mapping with a conventional wide antral circumferential ablation (WACA) in atrial fibrillation (AF) patients. Methods A total of 119 patients medical records who received catheter ablation for AF in our hospital were analyzed. In one group of patients, detailed activation mapping of each PV was performed using a UHD mapping system. Each PV antral segment’s activation pattern was classified into “directly-activated from the LA” or “passively-activated from an adjacent PV segment” patterns. The ablation applications were performed at the directly-activated PV antral segment only for the PVI when the PV had “passively-activated segments” (partial antral ablation; PA-UHD group). Another patient group received a conventional WACA for the PVI (WACA group). Results Sixty patients received partial antral ablation (PA-UHD), and age/sex-matched 59 patients received WACA. In the PA-UHD group, passively-activated segments were observed in 58.3% of all PV segments. The success rate of a partial antral ablation for the PVI in PVs with passively-activated segments was 85%. The 1-year atrial tachyarrhythmia recurrence did not differ between the PA-UHD and WACA groups. Conclusions Our study revealed the presence of passively-activated PV segments, which could potentially indicate muscular discontinuity at the PV-LA junction. In most PVs with passively-activated segments, PVI was successfully achieved by ablation with only directly-activated segments. The 1-year recurrence rate of atrial tachyarrhythmia in PA-UHD group was comparable to that observed in the WACA group.

Background Although successful atrial fibrillation (AF) ablation can maintain sinus rhythm and reduce the left atrial (LA) dimension, blunted LA reverse remodeling can be observed in patients with atrial myopathy. We explored the potential mechanisms and long‐term outcomes in patients with blunted LA reverse remodeling after successful AF catheter ablation. Methods and Results We included 1685 patients who underwent baseline and 1‐year follow‐up echocardiograms, had a baseline LA dimension ≥40 mm, and did not have a recurrence of AF within a year. The patients were divided into tertile groups according to the delta value of the change in LA dimension on the preprocedure and 1‐year postprocedure echocardiography. After propensity score matching for age, sex, AF type, and LA dimension, 1272 patients were finally included in the analyses (424 in each group; the least/blunted, moderate, and the most reverse remodeling group). The patients in the T1 group (blunted LA reverse remodeling) were independently associated with higher left ventricular mass index (odds ratio [OR], 1.014 [95% CI, 1.005–1.022], P=0.001), change in ΔH2FPEF score (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder, filling pressure) score (OR, 1.445 [95% CI, 1.121–1.861], P=0.004), ventricular epicardial adipose tissue volume (OR, 1.010 [95% CI, 1.003–1.017], P=0.003), thinner LA wall thickness (OR, 0.461 [95% CI, 0.271–0.785], P=0.004), lower LA voltage (OR, 0.670 [95% CI, 0.499–0.899], P=0.008), and showed higher long‐term AF recurrence (log‐rank P

Background: The real-world safety profile of COVID-19 mRNA vaccines remains incompletely elucidated. Methods: We performed a nationwide post-market safety surveillance analysis in Singapore, on vacinees aged 5 years and older, through mid-September 2022. Observed-over-expected (O/E) analyses were performed to identify potential safety signals among eight shortlisted adverse events of special interest (AESIs): strokes, cerebral venous thrombosis (CVT), acute myocardial infarction, myocarditis/pericarditis, pulmonary embolism, immune thrombocytopenia, convulsions and appendicitis. Self-controlled case series analyses (SCCS) were performed to validate signals of concern, occurring within 42 days of vaccination. Findings: Elevated risks were observed on O/E analyses for the following AESIs: myocarditis/pericarditis, [rate ratio (RR): 3.66, 95 % confidence interval (95 % CI): 2.71 to 4.94], appendicitis [RR: 1.14 (1.02 to 1.27)] and CVT [RR: 2.11 (1.18 to 3.77)]. SCCS analyses generated corroborative findings: myocarditis/pericarditis, [relative incidence (RI): 6.96 (3.95 to 12.27) at 1 to 7 days post-dose 2], CVT [RI: 4.30 (1.30 to 14.20) at 22 to 42 days post-dose 1] and appendicitis [RI: 1.31 (1.03 to 1.67) at 1 to 7 days post-dose 1]. Booster dose 1 continued to be associated with higher rates of myocarditis/pericarditis on O/E analysis [RR: 2.30, (1.39 to 3.80) and 1.69, (1.11 to 2.59)] at 21- and 42-days post-booster dose 1, respectively. Males aged 12 to 17 exhibited highest risks of both myocarditis/pericarditis [RI: 6.31 (1.36 to 29.3)] and appendicitis [RI: 2.01 (1.12 to 3.64)] after primary vaccination. Similarly, CVT was also predominantly observed in males aged above 50 (11 out of 16 cases), within 42-days of vaccination. Interpretation: Our data suggest that myocarditis/pericarditis, appendicitis and CVT are associated with primary vaccination using COVID-19 mRNA vaccines. Males at specific ages exhibit higher risks for all three AEs identified. The risk of myocarditis/pericarditis continues to be elevated after booster dose 1.

BackgroundThe comparative efficacy, saftey, and heart rate variability (HRV) parameters after pulmonary vein isolation using cryoballoon (Cryo-PVI), high-power short-duration (HPSD-PVI), and conventional radiofrequency ablation (conventional-PVI) for atrial fibrillation (AF) is unclear.Materials and methodsIn this propensity score-weighted, retrospective analysis of a single-center cohort, we analyzed 3,395 patients (26.2% female, 74.5% paroxysmal AF) who underwent AF catheter ablation without an empirical left atrial ablation. Procedural factors, recurrence rates, complication rates, and the post-procedural HRV parameters were compared across the Cryo-PVI (n = 625), HPSD-PVI (n = 748), and conventional-PVI (n = 2,022) groups.ResultsDespite the shortest procedural time in the Cryo-PVI group (74 min for Cryo-PVI vs. 104 min for HPSD-PVI vs. 153 min for conventional-PVI, p

Abstract Background Ablation of idiopathic ventricular arrhythmias (VAs) in the cardiac crux region is one of the challenging procedures due to the complex anatomical structure where the four chambers of the heart are offset. Although this region is complex, the contiguous cardiac structures allow for the ablation of arrhythmias from adjacent sites. Case presentation We present different anatomical approaches in radiofrequency ablation and the ECG characteristics from a case series of VAs originated from the basal inferior ventricular septum, the corresponding endocardial aspect of the basal cardiac crux region. Conclusions Ablation of VAs originated from the basal cardiac crux region requires detailed mapping in the proximal coronary venous system and the adjacent structures including the RV, RA, and LV. In addition to the characteristic ECG of basal crux VAs, our three cases present an abrupt precordial transition in V2 with R wave amplitude greater than in V1 and V3.

Abstract The muscular discontinuities at the pulmonary vein (PV)–left atrial (LA) junction are known. The high-density mapping may help to find the muscular discontinuity. This study evaluated the efficacy of a partial antral ablation for a pulmonary vein (PV) isolation using high density (HD) mapping. A total of 60 drug-refractory atrial fibrillation (AF) patients undergoing catheter ablation were enrolled. The detailed activation mapping of each PV and LA junction was performed using an HD mapping system, and each PV segment’s activation pattern was classified into a “directly-activated from the LA” or “passively-activated from an adjacent PV segment” pattern. The antral ablations were performed at the directly-activated PV segments only when the PV had “passively-activated segments”. If the PV did not contain passively-activated segments, a circumferential antral ablation was performed on those PVs. A “successful partial antral ablation” was designated if the electrical isolation of targeted PV was achieved by ablation at the directly-activated segments only. If the isolation was not achieved even though all directly-activated segments were ablated, a “failed partial antral ablation” was designated, and then a circumferential ablation was performed. Among 240 PVs, passively-activated segments were observed in 140 (58.3%) PVs. Both inferior PVs had more passively-activated segments than superior PVs, and the posteroinferior segments had the highest proportion of passive activation. The overall rate of successful partial antral ablation was 85%. The atrial tachyarrhythmia recurrence was observed in 10 patients (16.7%) at 1-year. HD mapping allowed the evaluation of the detailed activation patterns of the PVs, and passively-activated segments may represent muscular discontinuity. Partial antral ablation of directly-activated antral segments only was feasible and effective for a PVI.

Summary: Post-translational modifications (PTMs), such as glycosylation and palmitoylation, are critical to protein folding, stability, intracellular trafficking, and function. Understanding regulation of PTMs of SARS-CoV-2 spike (S) protein could help the therapeutic drug design. Herein, the VSV vector was used to produce SARS-CoV-2 S pseudoviruses to examine the roles of the 611LYQD614 and cysteine-rich motifs in S protein maturation and virus infectivity. Our results show that 611LY612 mutation alters S protein intracellular trafficking and reduces cell surface expression level. It also changes S protein glycosylation pattern and decreases pseudovirus infectivity. The S protein contains four cysteine-rich clusters with clusters I and II as the main palmitoylation sites. Mutations of clusters I and II disrupt S protein trafficking from ER-to-Golgi, suppress pseudovirus production, and reduce spike-mediated membrane fusion activity. Taken together, glycosylation and palmitoylation orchestrate the S protein maturation processing and are critical for S protein-mediated membrane fusion and infection.

Abstract Background Atrioventricular (AV) node normally has decremental conduction property and a longer refractory period than His-Purkinje system (HPS). This results in AV conduction delay or block at the level of AV node in response to short-coupled atrial premature beats. Prolonged refractoriness in HPS can produce unusual physiological patterns of AV conduction such as conduction delay or infra-nodal block in the distal elements of HPS. Case presentation We present a case in which atrial premature stimulation produces infra-nodal Wenckebach conduction block which initiates long-short cycle sequence within the bundle branches resulted in alternating bundle branch block and atypical pattern of Ashman phenomenon. Conclusions This case highlights the importance of recognizing the unusual physiological AV conduction patterns of HPS. The long-short cycle sequence in the bundle branches of distal HPS and linking phenomenon can result in alternating bundle branch block without the presence of HPS disease.

Abstract Background Radiofrequency catheter ablation (RFCA) for accessory pathways (APs) at the site of prior valve surgery (VS) remains challenging. We aimed to clarify the factors associated with successful RFCA for such APs. Methods Upon reviewing a RFCA registry and previous case reports, we included nine patients who underwent RFCA of APs at the site of prior VS (total‐VS group; age, 34.0 [24.5‐45.0] years; men, 4/9) and 196 patients who underwent RFCA of APs with no history of VS (no‐VS group; age, 40.5 [23.0‐54.0] years; men, 114/196). Electrophysiological features, procedural details, and outcomes were examined. Results Accessory pathway exhibited decremental conduction in four of nine patients in the total‐VS group. The number of RFCA attempts was significantly higher in the total‐VS group than in the no‐VS group (10.0 [4.5‐14.5] vs 2.0 [1.0‐3.0]; P

Abstract Background Catheter ablation of para‐Hisian (PH) premature ventricular complexes (PVCs) has a high risk of heart block. This study aimed to find the electrocardiographic (ECG) predictors of PH‐PVCs. Methods We enrolled 47 patients who underwent an electrophysiologic study for catheter ablation of PVCs and analyzed the ECG characteristics, retrospectively. Results The PVC locations were the PH in 14, right ventricular (RV) outflow tract (OT) in 11, left ventricular (LV) OT in 16, LV septum in 5, and LV summit in 1. The QRS width of the PH‐PVCs was significantly narrower than that of the rest of PVCs (140.9 ± 17.1 ms vs. 158.9 ± 19.4 ms, P = 0.004). Precordial transition of the PH‐PVCs related to sinus rhythm was not helpful in predicting the location. Lead I had monophasic R waves in 100% and lead aVR QS waves in 100%. In aVL, 13 of 14 patients had monophasic R waves, and 1 had biphasic (rS) waves with an initial positive polarity. Among the study cohort, 15 patients had a QS in aVR and R in aVL, including 13 PH‐PVCs and 2 PVCs coming from the RVOT septum and LVOT septum, respectively. The QS in aVR and monophasic R in aVL had a sensitivity of 92.8%, specificity of 93.9%, positive predictive value of 86.7%, and negative predictive value of 96.9% for localizing PH‐PVCs. Conclusions A PVC morphology with a QS in aVR and monophasic R in aVL and QRS width

Cell-free DNA (cfDNA) is the major structural component of neutrophil extracellular traps (NETs), an innate immune response to infection. Antimicrobial proteins and peptides bound to cfDNA play a critical role in the bactericidal property of NETs. Recent studies have shown that NETs have procoagulant activity, wherein cfDNA triggers thrombin generation through activation of the intrinsic pathway of coagulation. We have recently shown that thrombin binds to NETs in vitro and consequently can alter the proteome of NETs. However, the effect of NETs on thrombin is still unknown. In this study, we report that DNA binding leads to thrombin autolysis and generation of multiple thrombin-derived C-terminal peptides (TCPs) in vitro. Employing a 25-residue prototypic TCP, GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), we show that TCPs bind NETs, thus conferring mutual protection against nuclease and protease degradation. Together, our results demonstrate the complex interplay between coagulation, NET formation, and thrombin cleavage and identify a previously undisclosed mechanism for formation of TCPs.

Background We previously reported the benefit of linear ablation from the superior vena cava to the right atrial septum (SVC‐L) within a year after circumferential pulmonary vein isolation (CPVI) in patients with paroxysmal atrial fibrillation (AF). We explored the long‐term effects of SVC‐L and its potential related mechanisms. Methods and Results Among 2140 consecutive patients with AF ablation, we included 614 patients (73.3% male, aged 57.8±10.7 years, 13.7% with persistent AF) who did not undergo an extra–pulmonary vein left atrial ablation after propensity score matching; of those, 307 had additional SVC‐L and 307 had CPVI alone. We evaluated the heart rate variability and computational modeling study to explore mechanisms. Although the procedure time was longer in the SVC‐L group than the CPVI group (P

We determined the effects of atmospheric temperature (10–30 ± 2°C in 5°C increments) and carbon dioxide (CO₂) levels (400 ± 50 ppm, 540 ± 50 ppm, and 940 ± 50 ppm) on the infection of Solanum tuberosum cv. Chubaek by Potato leafroll virus (PLRV). Below CO₂ levels of 400 ± 50 ppm, the PLRV infection rate and RNA content in plant tissues increased as the temperature increased to 20 ± 2°C, but declined at higher temperatures. At high CO₂ levels (940 ± 50 ppm), more plants were infected by PLRV at 30 ± 2°C than at 20 or 25 ± 2°C, whereas PLRV RNA content was unchanged in the 20–30 ± 2°C temperature range. The effects of atmospheric CO₂ concentration on the acquisition of PLRV by Myzus persicae and accumulation of PLRV RNA in plant tissues were investigated using a growth chamber at 20 ± 2°C. The M. persicae PLRV RNA content slightly increased at elevated CO₂ levels (940 ± 50 ppm), but this increase was not statistically significant. Transmission rates of PLRV by Physalis floridana increased as CO₂ concentration increased. More PLRV RNA accumulated in potato plants maintained at 540 or 940 ± 50 ppm CO₂, than in plants maintained at 400 ± 50 ppm. This is the first evidence of greater PLRV RNA accumulation and larger numbers of S. tuberosum plants infected by PLRV under conditions of combined high CO₂ levels (940 ± 50 ppm) and high temperature (30 ± 2°C).

We examined the effects of temperature on acquisition of Potato virus Y-O (PVY-O), Potato virus A (PVA), and Potato leafroll virus (PLRV) by Myzus persicae by performing transmission tests with aphids that acquired each virus at different temperatures. Infection by PVY-O/PVA and PLRV increased with increasing plant temperature in Nicotiana benthamiana and Physalis floridana, respectively, after being transmitted by aphids that acquired them within a temperature range of 10–20°C. However, infection rates subsequently decreased. Direct qRT-PCR of RNA extracted from a single aphid showed that PLRV infection increased in the 10–20°C range, but this trend also declined shortly thereafter. We examined the effect of temperature on establishment of virus infection. The greatest number of plants became infected when N. benthamiana was held at 20°C after inoculation with PVY-O or PVA. The largest number of P. floridana plants became infected with PLRV when the plants were maintained at 25°C. PLRV levels were highest in P. floridana kept at 20–25°C. These results indicate that the optimum temperatures for proliferation of PVY-O/PVA and PLRV differed. Western blot analysis showed that accumulations of PVY-O and PVA coat proteins (CPs) were lower at 10°C or 15°C than at 20°C during early infection. However, accumulation increased over time. At 25°C or 30°C, the CPs of both viruses accumulated during early infection but disappeared as time passed. Our results suggest that symptom attenuation and reduction of PVY-O and PVA CP accumulation at higher temperatures appear to be attributable to increased RNA silencing.

Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.

Neutrophil extracellular traps (NETs) consist of a decondensed DNA scaffold decorated with neutrophil-derived proteins. The proteome of NETs, or “NETome,” has been largely elucidated in vitro. However, components such as plasma and extracellular matrix proteins may affect the NETome under physiological conditions. Here, using a reductionistic approach, we explored the effects of two proteases active during injury and wounding, human thrombin and plasmin, on the NETome. Using high-resolution mass spectrometry, we identified a total of 164 proteins, including those previously not described in NETs. The serine proteases, particularly thrombin, were also found to interact with DNA and bound to NETs in vitro. Among the most abundant proteins were those identified previously, including histones, neutrophil elastase, and antimicrobial proteins. We observed reduced histone (H2B, H3, and H4) and neutrophil elastase levels upon the addition of the two proteases. Analyses of NET-derived tryptic peptides identified subtle changes upon protease treatments. Our results provide evidence that exogenous proteases, present during wounding and inflammation, influence the NETome. Taken together, regulation of NETs and their proteins under different physiological conditions may affect their roles in infection, inflammation, and the host response.

BackgroundEpicardial adipose tissue (EAT) is known to play an important role in atrial fibrillation substrate remodeling; however, the influence of sex on the association between EAT and left atrial (LA) transport function has not been elucidated. Methods and ResultsOf the 514 patients who underwent an index atrial fibrillation ablation procedure, 123 postmenopausal women with no history of hormone replacement therapy and 123 men who were matched for age, body mass index, type of atrial fibrillation, and CHADS2 score were enrolled. Before the procedure, LA volume, LA emptying fraction, and EAT volume were assessed using multislice computed tomography. Blood samples were obtained from a coronary sinus for analysis of serum adiponectin level before the ablation procedure. There were no differences in baseline demographics and laboratory findings between sexes. Compared with men, women had significantly less total EAT (P

Stiff left atrial (LA) syndrome was initially reported in post-cardiac surgery patients and known to be associated with low LA compliance. We investigated the physiological and clinical implications of LA compliance by estimating LA pulse pressure (LApp) among patients with atrial fibrillation (AF) and structurally and functionally normal heart. Among 1038 consecutive patients with LA pressure measurements before AF ablation, we included 334 patients with structurally and functionally normal heart (81.7% male, 54.1±10.6 years, 77.0% paroxysmal AF) after excluding those with hypertension, diabetes, and previous ablation or cardiac surgery. We measured LApp (peak-nadir LA pressure) at the beginning of the ablation procedure and compared the values with clinical parameters and the AF recurrence rate. AF patients with normal heart were younger and more frequently male and had paroxysmal AF, a lower body mass index, and a lower LApp compared to others (all p

We performed bias correction in future climate change scenarios to provide better accuracy of models through adaptation to future climate change. The proposed combination of the change factor (CF) and quantile mapping (QM) methods combines the individual advantages of both methods for adjusting the bias in global circulation models (GCMs) and regional circulation models (RCMs). We selected a study site in Songwol-dong, Seoul, Republic of Korea, to test and assess our proposed method. Our results show that the combined CF + QM method delivers better performance in terms of correcting the bias in GCMs/RCMs than when both methods are applied individually. In particular, our proposed method considerably improved the bias-corrected precipitation by capturing both the high peaks and amounts of precipitation as compared to that from the CF-only and QM-only methods. Thus, our proposed method can provide high-accuracy bias-corrected precipitation data, which could prove to be highly useful in interdisciplinary studies across the world.

G-protein coupled receptor 119 (GPR119) has emerged as a promising new target for the treatment of type 2 diabetes mellitus. The expression of GPR119 on the pancreatic B cells and intestinal L cells provides a unique opportunity for a single drug to promote insulin and GLP-1 secretion. In this study, we identified a novel small molecule GPR119 agonist, HD0471953, from our large library of synthetic compounds based on its ability to anti-hyperglycemic effects on T2DM murine models. We have tested the acute efficacy of HD0471953 by the oral glucose tolerance test (OGTT) with normal C57BL/6J mice. Then, chronic administrations of HD0471953 were performed to evaluate the efficacy on various diabetic rodent models. Single administration of HD0471953 showed improved glycemic control with a dose-dependent manner in OGTT with normal mice, and the insulin and GLP-1 were also increased. To identify chronic efficacy, we have observed a decline of blood glucose and fasting insulin in a dose-dependent manner of 10, 20, and 50 mpk in db/db mice. The results suggest that HD0471953 may be a potentially promising anti-hyperglycemic agent for the treatment of patients with type 2 diabetes mellitus.

In the recent era of information explosion, exploring event from social networks has recently been a crucial task for many applications. To derive valuable comprehensive and thorough insights on social events, visual analytics (VA) system have been broadly used as a promising solution. However, due to the enormous social data volume with highly diversity and complexity, the number of event exploration tasks which can be enabled in a conventional real-time visual analytics systems has been limited. In this article, we introduce SocioPedia+, a real-time visual analytics system for social event exploration in time and space domains. By introducing the dimension of social knowledge graph analysis into the system multivariate analysis, the process of event explorations in SocioPedia+ can be significantly enhanced and thus enabling system capability on performing full required tasks of visual analytics and social event explorations. Furthermore, SocioPedia+ has been optimized for visualizing event analysis on different levels from macroscopic (events level) to microscopic (knowledge level). The system is then implemented and investigated with a detailed case study for evaluating its usefulness and visualization effectiveness for the application of event explorations., Competing Interests: The authors declare there are no competing interests., (©2023 Nguyen et al.)

A series of novel peripherally tetra- and octa-substituted copper phthalocyanines (CuPcs) bearing various aminophenoxy groups was designed and synthesized for detecting strong Brønsted acids. Octa-(diethyl-aminophenoxy)-substituted CuPc 5 exhibited excellent HCl detection capability with high sensitivity (limit of detection: 240 ppb), rapid (<2s), and selectivity for strong acids in versatile conditions including solution, solid, and dyed fabric. Furthermore, CuPc 5 noted reusability in recyclable tests with HCl and NH 3 , demonstrating its great potential for practical detection of HCl and ammonia gas leak under various environments. Based on systemic characterizations based on UV-Vis absorption spectra and NMR, we suggest that the proton of HCl associated with the N atom of CuPc 5, and the proton sensing abilities are directly related to the dissociation constants of the amine groups. The steric hindrance of alkyl chains and molar absorption coefficient of the CuPc species in THF solvent, as well as the H 2 O content of the solvent system, also affected the sensing performance. Due to less bulky nature of diethyl-amino groups having higher pK a and stronger basicity, CuPc 5 featured effective recognition of strong acids with pK a value less than -2.0 (K a  > 100). To the best of our knowledge, this is the first demonstration of pKa-sensitive colorimetric chemosensor using CuPc backbone, in particular for distinguishing strong Brønsted acids such as HCl., (Copyright © 2022. Published by Elsevier B.V.)

With the global trend toward an aging population, the increasing number of dementia patients and elderly living alone has emerged as a serious social issue in South Korea. The assessment of activities of daily living (ADL) is essential for diagnosing dementia. However, since the assessment is based on the ADL questionnaire, it relies on subjective judgment and lacks objectivity. Seven healthy seniors and six with early-stage dementia participated in the study to obtain ADL data. The derived ADL features were generated by smart home sensors. Statistical methods and machine learning techniques were employed to develop a model for auto-classifying the normal controls and early-stage dementia patients. The proposed approach verified the developed model as an objective ADL evaluation tool for the diagnosis of dementia. A random forest algorithm was used to compare a personalized model and a non-personalized model. The comparison result verified that the accuracy (91.20%) of the personalized model was higher than that (84.54%) of the non-personalized model. This indicates that the cognitive ability-based personalization showed encouraging performance in the classification of normal control and early-stage dementia and it is expected that the findings of this study will serve as important basic data for the objective diagnosis of dementia.

Dementia is a cognitive impairment that poses a global threat. Current dementia treatments slow the progression of the disease. The timing of starting such treatment markedly affects the effectiveness of the treatment. Some experts mentioned that the optimal timing for starting the currently available treatment in order to delay progression to dementia is the mild cognitive impairment stage, which is the prior stage of dementia. However, medical records are typically only available at a later stage, i.e., from the early or middle stage of dementia. In order to address this limitation, this study developed a model using national health information data from 5 years prior, to predict dementia development 5 years in the future. The Senior Cohort Database, comprising 550,000 samples, were used for model development. The F-measure of the model predicting dementia development after a 5-year incubation period was 77.38%. Models for a 1- and 3-year incubation period were also developed for comparative analysis of dementia risk factors. The three models had some risk factors in common, but also had unique risk factors, depending on the stage. For the common risk factors, a difference in disease severity was confirmed. These findings indicate that the diagnostic criteria and treatment strategy for dementia should differ depending on the timing. Furthermore, since the results of this study present new dementia risk factors that have not been reported previously, this study may also contribute to identification of new dementia risk factors.

Squarylium-based colorimetric hydrogen sulfide (H 2 S) chemosensors (SQ1, SQ2, and SQ3) were developed, and their detection properties were systematically characterized. SQ1 exhibited rapid and high resolution H 2 S sensing properties through significant color changes detectable by naked-eye with limit of detection as low as 7.2 ppb. SQ1 also showed excellent selectivity for H 2 S detection over other relevant anions and nucleophiles. Sensing mechanisms of SQ1 were investigated based on spectroscopic and 1 H NMR analyses with quantum calculations. Furthermore, SQ1 showed an efficient response to H2S under versatile conditions in the solution, solid, and dyed fabric states, which suggests applicability of SQ1 to simple, low-cost, and practical H 2 S sensors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Globally, one of the biggest problems with the increase in the elderly population is dementia. However, dementia still has no fundamental cure. Therefore, it is important to predict and prevent dementia early. For early prediction of dementia, it is crucial to find dementia risk factors that increase a person's risk of developing dementia. In this paper, the subject of dementia risk factor analysis and discovery studies were limited to gender, because it is assumed that the difference in the prevalence of dementia in men and women will lead to differences in the risk factors for dementia among men and women. This study analyzed the Korean National Health Information System-Senior Cohort using machine-learning techniques. By using the machine-learning technique, it was possible to reveal a very small causal relationship between data that are ignored using existing statistical techniques. By using the senior cohort, it was possible to analyze 6000 data that matched the experimental conditions out of 558,147 sample subjects over 14 years. In order to analyze the difference in dementia risk factors between men and women, three machine-learning-based dementia risk factor analysis models were constructed and compared. As a result of the experiment, it was found that the risk factors for dementia in men and women are different. In addition, not only did the results include most of the known dementia risk factors, previously unknown candidates for dementia risk factors were also identified. We hope that our research will be helpful in finding new dementia risk factors.

A novel compound named 'kanakugiol' was recently isolated from Lindera erythrocarpa and showed free radical-scavenging and antifungal activities. However, the details of the anticancer effect of kanakugiol on breast cancer cells remain unclear. We investigated the effect of kanakugiol on the growth of MCF-7 human breast cancer cells. Kanakugiol affected cell cycle progression, and decreased cell viability in MCF-7 cells in a dose-dependent manner. It also enhanced PARP cleavage (50 kDa), whereas DNA laddering was not induced. FACS analysis with annexin V-FITC/PI staining showed necrosis induction in kanakugiol-treated cells. Caspase-9 cleavage was also induced. Expression of death receptors was not altered. However, Bcl-2 expression was suppressed, and mitochondrial membrane potential collapsed, indicating limited apoptosis induction by kanakugiol. Immunofluorescence analysis using α-tubulin staining revealed mitotic exit without cytokinesis (4N cells with two nuclei) due to kanakugiol treatment, suggesting that mitotic catastrophe may have been induced via microtubule destabilization. Furthermore, cell cycle analysis results also indicated mitotic catastrophe after cell cycle arrest in MCF-7 cells due to kanakugiol treatment. These findings suggest that kanakugiol inhibits cell proliferation and promotes cell death by inducing mitotic catastrophe after cell cycle arrest. Thus, kanakugiol shows potential for use as a drug in the treatment of human breast cancer.

One of the omega-3 essential fatty acids, docosahexaenoic acid (DHA), is a significant constituent of the cell membrane and the precursor of several potent lipid mediators. These mediators are considered to be important in preventing or treating several diseases. Resolvin D5, an oxidized lipid mediator derived from DHA, has been known to exert anti-inflammatory effects. However, the detailed mechanism underlying these effects has not yet been elucidated in human monocytic THP-1 cells. In the present study, we investigated the effects of resolvin D5 on inflammation-related signaling pathways, including the extracellular signal-regulated kinase (ERK)-nuclear factor (NF)-κB signaling pathway. Resolvin D5 downregulated the production of interleukin (IL)-6 and chemokine (C-C motif) ligand 5 (CCL5). Additionally, these inhibitory effects were found to be modulated by mitogen-activated protein kinase (MAPK) and NF-κB in lipopolysaccharide (LPS)-treated THP-1 cells. Resolvin D5 inhibited the LPS-stimulated phosphorylation of ERK and translocation of p65 and p50 into the nucleus, resulting in the inhibition of IL-6 and CCL5 production. These results revealed that resolvin D5 exerts anti-inflammatory effects in LPS-treated THP-1 cells by regulating the phosphorylation of ERK and nuclear translocation of NF-kappaB.

Epimagnolin A is a lignan obtained from the flower buds of Magnolia fargesii, which is traditionally used in Asian medicine for treating headache and nasal congestion. A herbal compound fargesin obtained from M. fargesii, has exerted anti-inflammatory effects in human monocytic THP-1 cells in the previous study. The anti-inflammatory effects of epimagnolin A, however, have been not elucidated yet. In this study, it was demonstrated that epimagnolin A reduced phorbol-12-myristate-13-acetate (PMA)-induced IL-6 promoter activity and IL-6 production in human monocytic THP-1 cells. Furthermore, it was investigated the modulating effects of epimagnolin A on mitogen-activated protein kinase, nuclear factor-kappa B (NF-κB), and activator protein 1 (AP-1) activities. Phosphorylation of p38 and nuclear translocation of p50 and c-Jun were down-regulated by epimagnolin A in the PMA-stimulated THP-1 cell. The results revealed that epimagnolin A attenuated the binding affinity of NF-κB and AP-1 transcription factors to IL-6 promoter and IL-6 production through p38/NF-kB and AP-1 signaling pathways in the PMA-stimulated THP-1 cells. These results suggest that epimagnolin A can be a useful drug for the treatment of inflammatory diseases., (© 2019 Wiley Periodicals, Inc.)

Programmed cell death ligand 1 (PD-L1) is an essential immune checkpoint protein implicated in immune evasion by malignant tumors. Overexpression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 is associated with poor prognosis in various types of cancer. Recently, multiple advances have occurred in the area of cancer immunotherapy. Inhibiting the ligation of PD-1 by PD-L1 has been the major focus of anti-tumor immunotherapy. In diagnostic pathology, it has become crucial to detect PD-L1 + tumor cases using a validated immunohistochemistry (IHC) approach. Preliminary data demonstrate that C-MET promotes survival of some (e.g., renal) cancer types through regulation of PD-L1. However, C-MET expression, and its association with PD-L1, has not been well-characterized in the context of hepatocellular carcinoma (HCC), and no anti-HCC immunotherapy is currently available in Korea. Therefore, it is crucial to investigate the expression of C-MET and PD-L1, and their association with clinicopathologic factors, to facilitate the development of targeted treatments for HCC. PD-L1 expression was examined in tumor cells (TC) and immune cells (IC) of 70 patient-derived HCC specimens using IHC. Two anti-PD-L1 monoclonal antibodies (MAbs), SP263 and SP142, were utilized. Additionally, TC C-MET expression was assessed. Correlations between PD-L1 expression (as identified by both MAbs), C-MET expression and clinicopathologic factors were assessed. More PD-L1 + cases were identified via SP263 than via SP142 when assessing both TC and IC; in the former group, SP236 identified 14/70 positive cases, while SP142 identified only 2/70. In the latter group, SP236 identified 49/70 positive cases, while SP142 identified 30/70. Both MAbs demonstrated a higher frequency of PD-L1 expression by IC than TC. The Edmondson-Steiner grade statistically correlated with a higher frequency of SP236-detected TC PD-L1 expression. C-MET was significantly associated with advanced tumor size and was positively correlated with SP263-detected PD-L1 expression in TC. These results suggest that C-MET may serve a role in regulating PD-L1 expression in HCC. Furthermore, while SP263 generally exhibited a higher sensitivity for PD-L1 detection, concordance in PD-L1 + case detection between the two different MAbs was generally good. These background data may be helpful in the development of targeted anti-HCC immunotherapy focused on PD-L1 or C-MET, and in evaluating selection criteria for target populations best suited to such treatments.

Interest in research involving health-medical information analysis based on artificial intelligence, especially for deep learning techniques, has recently been increasing. Most of the research in this field has been focused on searching for new knowledge for predicting and diagnosing disease by revealing the relation between disease and various information features of data. These features are extracted by analyzing various clinical pathology data, such as EHR (electronic health records), and academic literature using the techniques of data analysis, natural language processing, etc. However, still needed are more research and interest in applying the latest advanced artificial intelligence-based data analysis technique to bio-signal data, which are continuous physiological records, such as EEG (electroencephalography) and ECG (electrocardiogram). Unlike the other types of data, applying deep learning to bio-signal data, which is in the form of time series of real numbers, has many issues that need to be resolved in preprocessing, learning, and analysis. Such issues include leaving feature selection, learning parts that are black boxes, difficulties in recognizing and identifying effective features, high computational complexities, etc. In this paper, to solve these issues, we provide an encoding-based Wave2vec time series classifier model, which combines signal-processing and deep learning-based natural language processing techniques. To demonstrate its advantages, we provide the results of three experiments conducted with EEG data of the University of California Irvine, which are a real-world benchmark bio-signal dataset. After converting the bio-signals (in the form of waves), which are a real number time series, into a sequence of symbols or a sequence of wavelet patterns that are converted into symbols, through encoding, the proposed model vectorizes the symbols by learning the sequence using deep learning-based natural language processing. The models of each class can be constructed through learning from the vectorized wavelet patterns and training data. The implemented models can be used for prediction and diagnosis of diseases by classifying the new data. The proposed method enhanced data readability and intuition of feature selection and learning processes by converting the time series of real number data into sequences of symbols. In addition, it facilitates intuitive and easy recognition, and identification of influential patterns. Furthermore, real-time large-capacity data analysis is facilitated, which is essential in the development of real-time analysis diagnosis systems, by drastically reducing the complexity of calculation without deterioration of analysis performance by data simplification through the encoding process., Competing Interests: The authors declare no conflict of interest.

The carcinogenicity of chemicals in the environment is a major concern. Recently, numerous studies have attempted to develop methods for predicting carcinogenicity, including rodent and cell-based approaches. However, rodent carcinogenicity tests for evaluating the carcinogenic potential of a chemical to humans are time-consuming and costly. This study focused on the development of an alternative method for predicting carcinogenicity using quantitative PCR (qPCR) and colon cancer stem cells. A toxicogenomic method, mRNA profiling, is useful for predicting carcinogenicity. Using microarray analysis, we optimized 16 predictive gene sets from five carcinogens (azoxymethane, 3,2'-dimethyl-4-aminobiphenyl, N -ethyl- n -nitrosourea, metronidazole, 4-( n -methyl- n -nitrosamino)-1-(3-pyridyl)-1-butanone) used to treat colon cancer stem cell samples. The 16 genes were evaluated by qPCR using 23 positive and negative carcinogens in colon cancer stem cells. Among them, six genes could differentiate between positive and negative carcinogens with a p -value of < or =0.05. Our qPCR-based prediction system for colon carcinogenesis using colon cancer stem cells is cost- and time-efficient. Thus, this qPCR-based prediction system is an alternative to in vivo carcinogenicity screening assays.

The issue of public health in Korea has attracted significant attention given the aging of the country's population, which has created many types of social problems. The approach proposed in this article aims to address dementia, one of the most significant symptoms of aging and a public health care issue in Korea. The Korean National Health Insurance Service Senior Cohort Database contains personal medical data of every citizen in Korea. There are many different medical history patterns between individuals with dementia and normal controls. The approach used in this study involved examination of personal medical history features from personal disease history, sociodemographic data, and personal health examinations to develop a prediction model. The prediction model used a support-vector machine learning technique to perform a 10-fold cross-validation analysis. The experimental results demonstrated promising performance (80.9% F-measure). The proposed approach supported the significant influence of personal medical history features during an optimal observation period. It is anticipated that a biomedical "big data"-based disease prediction model may assist the diagnosis of any disease more correctly., Competing Interests: The authors declare no conflict of interest.

It has been found that abnormal activation of the hedgehog (Hh) signaling pathway is involved in the occurrence, invasion and metastasis of malignant tumors. In addition, epithelial-mesenchymal transition (EMT) also performs an important function in the invasion and metastasis of malignant tumors. However, the significance of the Hh signaling pathway and EMT in hepatocellular carcinoma (HCC) remains unknown. In the present study, the expression of Gli family zinc finger 1 (Gli-1) and Gli family zinc finger 2 (Gli-2), which are key transcriptional factors in the Hh signaling pathway, and Twist and E-cadherin, which are two factors involved in EMT, was examined in 42 patients with HCC and 20 cases of non-tumorous liver (NTL) tissue by immunohistochemistry. Clinicopathological information was collected in order to analyze the correlation of the Hh signaling pathway with EMT. The present study aimed to examine the difference in the expression of Gli-1, Gli-2, E-cadherin and Twist in HCC and NTL to assess the diagnostic value of these factors in HCC. Additionally, the present study aimed to elucidate the correlation between those proteins and other clinicopathological parameters. Whether abnormal activation of the Hh signaling pathway is closely associated with EMT was also evaluated. Gli-1 and Twist expression was found to be significantly increased and E-cadherin expression was found to be decreased in HCC in contrast to NTL (Gli-1, P=0.019; Twist, P=0.003; E-cadherin, P<0.001). Increased Twist expression was associated with the tumor size (P=0.043), and loss of or decreased E-cadherin expression was associated with the histological type of HCC (P=0.021). There was an inverse association between the expression of Twist and E-cadherin (P=0.006). These results showed that Twist overexpression by induction of EMT changes is involved in the occurrence and progression of HCC. However, the role of Hh signaling pathway-associated proteins in HCC may require elucidation by additional studies using additional materials in the future.

Background: Thyroid incidentalomas detected by 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) have been reported in 1% to 4% of the population, with a risk of malignancy of 27.8% to 74%. We performed a retrospective review of FDG-avid thyroid incidentalomas in cancer screening subjects and patients with nonthyroid cancer. The risk of malignancy in thyroid incidentaloma and its association with the maximal standardized uptake value (SUVmax) in 18F-FDG PET/CT were evaluated to define the predictor variables in assessing risk of malignancy., Methods: A total of 2,584 subjects underwent 18F-FDG PET/CT for metastatic evaluation or cancer screening from January 2005 to January 2010. Among them, 36 subjects with FDG-avid thyroid incidentalomas underwent further diagnostic evaluation (thyroid ultrasonography-guided fine needle aspiration cytology [FNAC] or surgical resection). We retrospectively reviewed the database of these subjects., Results: Of the 2,584 subjects who underwent 18F-FDG PET/CT (319 for cancer screening and 2,265 for metastatic evaluation), 52 (2.0%) were identified as having FDG-avid thyroid incidentaloma and cytologic diagnosis was obtained by FNAC in 36 subjects. Of the subjects, 15 were proven to have malignant disease: 13 by FNAC and two by surgical resection. The positive predictive value of malignancy in FDG-avid thyroid incidentaloma was 41.7%. Median SUVmax was higher in malignancy than in benign lesions (4.7 [interquartile range (IQR), 3.4 to 6.0] vs. 2.8 [IQR, 2.6 to 4.0], P=0.001)., Conclusion: Thyroid incidentalomas found on 18F-FDG PET/CT have a high risk of malignancy, with a positive predictive value of 41.7%. FDG-avid thyroid incidentalomas with higher SUVmax tended to be malignant.

Motivation: Epistasis is the interactions among multiple genetic variants. It has emerged to explain the 'missing heritability' that a marginal genetic effect does not account for by genome-wide association studies, and also to understand the hierarchical relationships between genes in the genetic pathways. The Fisher's geometric model is common in detecting the epistatic effects. However, despite the substantial successes of many studies with the model, it often fails to discover the functional dependence between genes in an epistasis study, which is an important role in inferring hierarchical relationships of genes in the biological pathway., Results: We justify the imperfectness of Fisher's model in the simulation study and its application to the biological data. Then, we propose a novel generic epistasis model that provides a flexible solution for various biological putative epistatic models in practice. The proposed method enables one to efficiently characterize the functional dependence between genes. Moreover, we suggest a statistical strategy for determining a recessive or dominant link among epistatic expression quantitative trait locus to enable the ability to infer the hierarchical relationships. The proposed method is assessed by simulation experiments of various settings and is applied to human brain data regarding schizophrenia., Availability and Implementation: The MATLAB source codes are publicly available at: http://biomecis.uta.edu/epistasis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Since their introduction in 2009, the BioNLP Shared Task events have been instrumental in advancing the development of methods and resources for the automatic extraction of information from the biomedical literature. In this paper, we present the Cancer Genetics (CG) and Pathway Curation (PC) tasks, two event extraction tasks introduced in the BioNLP Shared Task 2013. The CG task focuses on cancer, emphasizing the extraction of physiological and pathological processes at various levels of biological organization, and the PC task targets reactions relevant to the development of biomolecular pathway models, defining its extraction targets on the basis of established pathway representations and ontologies., Results: Six groups participated in the CG task and two groups in the PC task, together applying a wide range of extraction approaches including both established state-of-the-art systems and newly introduced extraction methods. The best-performing systems achieved F-scores of 55% on the CG task and 53% on the PC task, demonstrating a level of performance comparable to the best results achieved in similar previously proposed tasks., Conclusions: The results indicate that existing event extraction technology can generalize to meet the novel challenges represented by the CG and PC task settings, suggesting that extraction methods are capable of supporting the construction of knowledge bases on the molecular mechanisms of cancer and the curation of biomolecular pathway models. The CG and PC tasks continue as open challenges for all interested parties, with data, tools and resources available from the shared task homepage.

The drug reaction with eosinophilia and systemic symptom (DRESS) syndrome is a severe adverse drug-induced reaction which includes a severe skin eruption, fever, hematologic abnormalities (eosinophilia or atypical lymphocytes) and internal organ involvement. The most frequently reported drug was anticonvulsants. The diagnosis of DRESS syndrome is challenging because the pattern of cutaneous eruption and the types of organs involved are various. The treatments for DRESS syndrome are culprit drug withdrawal and corticosteroids. Here we report a 71-year-old man with skin eruption with eosinophilia and hepatic and renal involvement that appeared 4 weeks after he had taken anti-tuberculosis drugs (isoniazid, ethambutol, rifampicin, and pyrazinamide), and resolved after stopping anti-tuberculosis drugs and the administration of systemic corticosteroids. DRESS recurred after re-challenging isoniazid, we identified isoniazid was causative drug.

Background: BioHackathon 2010 was the third in a series of meetings hosted by the Database Center for Life Sciences (DBCLS) in Tokyo, Japan. The overall goal of the BioHackathon series is to improve the quality and accessibility of life science research data on the Web by bringing together representatives from public databases, analytical tool providers, and cyber-infrastructure researchers to jointly tackle important challenges in the area of in silico biological research., Results: The theme of BioHackathon 2010 was the 'Semantic Web', and all attendees gathered with the shared goal of producing Semantic Web data from their respective resources, and/or consuming or interacting those data using their tools and interfaces. We discussed on topics including guidelines for designing semantic data and interoperability of resources. We consequently developed tools and clients for analysis and visualization., Conclusion: We provide a meeting report from BioHackathon 2010, in which we describe the discussions, decisions, and breakthroughs made as we moved towards compliance with Semantic Web technologies - from source provider, through middleware, to the end-consumer.

Background: Bio-molecular event extraction from literature is recognized as an important task of bio text mining and, as such, many relevant systems have been developed and made available during the last decade. While such systems provide useful services individually, there is a need for a meta-service to enable comparison and ensemble of such services, offering optimal solutions for various purposes., Results: We have integrated nine event extraction systems in the U-Compare framework, making them intercompatible and interoperable with other U-Compare components. The U-Compare event meta-service provides various meta-level features for comparison and ensemble of multiple event extraction systems. Experimental results show that the performance improvements achieved by the ensemble are significant., Conclusions: While individual event extraction systems themselves provide useful features for bio text mining, the U-Compare meta-service is expected to improve the accessibility to the individual systems, and to enable meta-level uses over multiple event extraction systems such as comparison and ensemble.

Background: The interaction between biological researchers and the bioinformatics tools they use is still hampered by incomplete interoperability between such tools. To ensure interoperability initiatives are effectively deployed, end-user applications need to be aware of, and support, best practices and standards. Here, we report on an initiative in which software developers and genome biologists came together to explore and raise awareness of these issues: BioHackathon 2009., Results: Developers in attendance came from diverse backgrounds, with experts in Web services, workflow tools, text mining and visualization. Genome biologists provided expertise and exemplar data from the domains of sequence and pathway analysis and glyco-informatics. One goal of the meeting was to evaluate the ability to address real world use cases in these domains using the tools that the developers represented. This resulted in i) a workflow to annotate 100,000 sequences from an invertebrate species; ii) an integrated system for analysis of the transcription factor binding sites (TFBSs) enriched based on differential gene expression data obtained from a microarray experiment; iii) a workflow to enumerate putative physical protein interactions among enzymes in a metabolic pathway using protein structure data; iv) a workflow to analyze glyco-gene-related diseases by searching for human homologs of glyco-genes in other species, such as fruit flies, and retrieving their phenotype-annotated SNPs., Conclusions: Beyond deriving prototype solutions for each use-case, a second major purpose of the BioHackathon was to highlight areas of insufficiency. We discuss the issues raised by our exploration of the problem/solution space, concluding that there are still problems with the way Web services are modeled and annotated, including: i) the absence of several useful data or analysis functions in the Web service "space"; ii) the lack of documentation of methods; iii) lack of compliance with the SOAP/WSDL specification among and between various programming-language libraries; and iv) incompatibility between various bioinformatics data formats. Although it was still difficult to solve real world problems posed to the developers by the biological researchers in attendance because of these problems, we note the promise of addressing these issues within a semantic framework.

Web services have become a key technology for bioinformatics, since life science databases are globally decentralized and the exponential increase in the amount of available data demands for efficient systems without the need to transfer entire databases for every step of an analysis. However, various incompatibilities among database resources and analysis services make it difficult to connect and integrate these into interoperable workflows. To resolve this situation, we invited domain specialists from web service providers, client software developers, Open Bio* projects, the BioMoby project and researchers of emerging areas where a standard exchange data format is not well established, for an intensive collaboration entitled the BioHackathon 2008. The meeting was hosted by the Database Center for Life Science (DBCLS) and Computational Biology Research Center (CBRC) and was held in Tokyo from February 11th to 15th, 2008. In this report we highlight the work accomplished and the common issues arisen from this event, including the standardization of data exchange formats and services in the emerging fields of glycoinformatics, biological interaction networks, text mining, and phyloinformatics. In addition, common shared object development based on BioSQL, as well as technical challenges in large data management, asynchronous services, and security are discussed. Consequently, we improved interoperability of web services in several fields, however, further cooperation among major database centers and continued collaborative efforts between service providers and software developers are still necessary for an effective advance in bioinformatics web service technologies.

Here we report the new features and improvements in our latest release of the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/), a comprehensive annotation resource for human genes and transcripts. H-InvDB, originally developed as an integrated database of the human transcriptome based on extensive annotation of large sets of full-length cDNA (FLcDNA) clones, now provides annotation for 120 558 human mRNAs extracted from the International Nucleotide Sequence Databases (INSD), in addition to 54 978 human FLcDNAs, in the latest release H-InvDB&#95;4.6. We mapped those human transcripts onto the human genome sequences (NCBI build 36.1) and determined 34 699 human gene clusters, which could define 34 057 (98.1%) protein-coding and 642 (1.9%) non-protein-coding loci; 858 (2.5%) transcribed loci overlapped with predicted pseudogenes. For all these transcripts and genes, we provide comprehensive annotation including gene structures, gene functions, alternative splicing variants, functional non-protein-coding RNAs, functional domains, predicted sub cellular localizations, metabolic pathways, predictions of protein 3D structure, mapping of SNPs and microsatellite repeat motifs, co-localization with orphan diseases, gene expression profiles, orthologous genes, protein-protein interactions (PPI) and annotation for gene families. The current H-InvDB annotation resources consist of two main views: Transcript view and Locus view and eight sub-databases: the DiseaseInfo Viewer, H-ANGEL, the Clustering Viewer, G-integra, the TOPO Viewer, Evola, the PPI view and the Gene family/group.