Clinical Implications of Unmasking Dormant Conduction After Circumferential Pulmonary Vein Isolation in Atrial Fibrillation Using Adenosine: A Systematic Review and Meta-Analysis

Purpose: Circumferential pulmonary vein isolation (CPVI) is a routine ablation strategy of atrial fibrillation (AF). The adenosine test can be used to unmask dormant conduction (DC) of pulmonary veins after CPVI, thereby demonstrating possible pulmonary vein re-connection and the need for further ablation. However, whether adenosine test could help improve the long term successful rate of CPVI is still controversial. This systemic review and meta-analysis was to determine the clinical utility of the adenosine test.Methods: PubMed, EMBASE, Web of Science and Cochrane Library database were searched through July 2016 to identify relevant studies using the keywords “dormant pulmonary vein conduction,” “adenosine test,” “circumferential pulmonary vein isolation,” and “atrial fibrillation.” A random-effects model was used to compare pooled outcomes and tested for heterogeneity.Results: A total of 17 studies including 5,169 participants were included in the final meta-analysis. Two groups of comparisons were classified: (1) Long-term successful rate in those AF patients underwent CPVI with and without adenosine test [Group A (+) and Group A (−)]; (2) Long-term successful rate in those patients who had adenosine test with and without dormant conduction [Group DC (+) and Group DC (−)]. The overall meta-analysis showed that no significant difference can be observed between Group A (+) and Group A (−) (RR 1.08; 95% CI 0.97–1.19; P = 0.16; I2 = 66%) and between Group DC (+) and Group DC (−) (RR 1.01; 95% CI 0.91–1.12; P = 0.88; I2 = 60%).Conclusion: Pooled meta-analysis suggested adenosine test may not improve long-term successful rate in AF patients underwent CPVI. Furthermore, AF recurrence may not be decreased by eliminating DC provoked by adenosine, even though adenosine test was applied after CPVI

Unlocking the mystery of the hard-to-sequence phage genome: PaP1 methylome and bacterial immunity

BACKGROUND: Whole-genome sequencing is an important method to understand the genetic information, gene function, biological characteristics and survival mechanisms of organisms. Sequencing large genomes is very simple at present. However, we encountered a hard-to-sequence genome of Pseudomonas aeruginosa phage PaP1. Shotgun sequencing method failed to complete the sequence of this genome. RESULTS: After persevering for 10 years and going over three generations of sequencing techniques, we successfully completed the sequence of the PaP1 genome with a length of 91,715 bp. Single-molecule real-time sequencing results revealed that this genome contains 51 N-6-methyladenines and 152 N-4-methylcytosines. Three significant modified sequence motifs were predicted, but not all of the sites found in the genome were methylated in these motifs. Further investigations revealed a novel immune mechanism of bacteria, in which host bacteria can recognise and repel modified bases containing inserts in a large scale. This mechanism could be accounted for the failure of the shotgun method in PaP1 genome sequencing. This problem was resolved using the nfi(-) mutant of Escherichia coli DH5α as a host bacterium to construct a shotgun library. CONCLUSIONS: This work provided insights into the hard-to-sequence phage PaP1 genome and discovered a new mechanism of bacterial immunity. The methylome of phage PaP1 is responsible for the failure of shotgun sequencing and for bacterial immunity mediated by enzyme Endo V activity; this methylome also provides a valuable resource for future studies on PaP1 genome replication and modification, as well as on gene regulation and host interaction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-803) contains supplementary material, which is available to authorized users

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Causal associations between modifiable risk factors and pancreatitis: A comprehensive Mendelian randomization study

BackgroundThe pathogenesis of pancreatitis involves diverse environmental risk factors, some of which have not yet been clearly elucidated. This study systematically investigated the causal effects of genetically predicted modifiable risk factors on pancreatitis using the Mendelian randomization (MR) approach.MethodsGenetic variants associated with 30 exposure factors were obtained from genome-wide association studies. Summary-level statistical data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were obtained from FinnGen consortia. Univariable and multivariable MR analyses were performed to identify causal risk factors for pancreatitis.ResultsGenetic predisposition to smoking (OR = 1.314, P = 0.021), cholelithiasis (OR = 1.365, P = 1.307E-19) and inflammatory bowel disease (IBD) (OR = 1.063, P = 0.008) as well as higher triglycerides (OR = 1.189, P = 0.016), body mass index (BMI) (OR = 1.335, P = 3.077E-04), whole body fat mass (OR = 1.291, P = 0.004) and waist circumference (OR = 1.466, P = 0.011) were associated with increased risk of AP. The effect of obesity traits on AP was attenuated after correcting for cholelithiasis. Genetically-driven smoking (OR = 1.595, P = 0.005), alcohol consumption (OR = 3.142, P = 0.020), cholelithiasis (OR = 1.180, P = 0.001), autoimmune diseases (OR = 1.123, P = 0.008), IBD (OR = 1.066, P = 0.042), type 2 diabetes (OR = 1.121, P = 0.029), and higher serum calcium (OR = 1.933, P = 0.018), triglycerides (OR = 1.222, P = 0.021) and waist-to-hip ratio (OR = 1.632, P = 0.023) increased the risk of CP. Cholelithiasis, triglycerides and the waist-to-hip ratio remained significant predictors in the multivariable MR. Genetically predicted alcohol drinking was associated with increased risk of AAP (OR = 15.045, P = 0.001) and ACP (OR = 6.042, P = 0.014). After adjustment of alcohol drinking, genetic liability to IBD had a similar significant causal effect on AAP (OR = 1.137, P = 0.049), while testosterone (OR = 0.270, P = 0.002) a triglyceride (OR = 1.610, P = 0.001) and hip circumference (OR = 0.648, P = 0.040) were significantly associated with ACP. Genetically predicted higher education and household income levels could lower the risk of pancreatitis.ConclusionsThis MR study provides evidence of complex causal associations between modifiable risk factors and pancreatitis. These findings provide new insights into potential therapeutic and prevention strategies

Dynamics of the Lipid Droplet Proteome of the Oleaginous Yeast Rhodosporidium toruloides

Lipid droplets (LDs) are ubiquitous organelles that serve as a neutral lipid reservoir and a hub for lipid metabolism. Manipulating LD formation, evolution, and mobilization in oleaginous species may lead to the production of fatty acid-derived biofuels and chemicals. However, key factors regulating LD dynamics remain poorly characterized. Here we purified the LDs and identified LD-associated proteins from cells of the lipid-producing yeast Rhodosporidium toruloides cultured under nutrient-rich, nitrogen-limited, and phosphorus-limited conditions. The LD proteome consisted of 226 proteins, many of which are involved in lipid metabolism and LD formation and evolution. Further analysis of our previous comparative transcriptome and proteome data sets indicated that the transcription level of 85 genes and protein abundance of 77 proteins changed under nutrient-limited conditions. Such changes were highly relevant to lipid accumulation and partially confirmed by reverse transcription-quantitative PCR. We demonstrated that the major LD structure protein Ldp1 is an LD marker protein being upregulated in lipid-rich cells. When overexpressed in Saccharomyces cerevisiae, Ldp1 localized on the LD surface and facilitated giant LD formation, suggesting that Ldp1 plays an important role in controlling LD dynamics. Our results significantly advance the understanding of the molecular basis of lipid overproduction and storage in oleaginous yeasts and will be valuable for the development of superior lipid producers

Transcriptomic and Metabolomic Analysis Revealed Multifaceted Effects of Phage Protein Gp70.1 on Pseudomonas aeruginosa

The impact of phage infection on the host cell is severe. In order to take over the cellular machinery, some phage proteins were produced to shut off the host biosynthesis early in the phage infection. The discovery and identification of these phage-derived inhibitors have a significant prospect of application in antibacterial treatment. This work presented a phage protein, gp70.1, with nonspecific inhibitory effects on Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli). Gp70.1 was encoded by early gene – orf 70.1 from P. aeruginosa phage PaP3. The P. aeruginosa with a plasmid encoding gp70.1 showed with delayed growth and had the appearance of a small colony. The combination of multifaceted analysis including microarray-based transcriptomic analysis, RT-qPCR, nuclear magnetic resonance (NMR) spectroscopy-based metabolomics and phenotype experiments were performed to investigate the effects of gp70.1 on P. aeruginosa. A total of 178 genes of P. aeruginosa mainly involved in extracellular function and metabolism were differentially expressed in the presence of gp70.1 at 3 examined time points. Furthermore, our results indicated that gp70.1 had an extensive impact on the extracellular phenotype of P. aeruginosa, such as motility, pyocyanin, extracellular protease, polysaccharide, and cellulase. For the metabolism of P. aeruginosa, the main effect of gp70.1 was the reduction of amino acid consumption. Finally, the RNA polymerase sigma factor RpoS was identified as a potential cellular target of gp70.1. Gp70.1 was the first bacterial inhibitor identified from Pseudomonas aeruginosa phage PaP3. It was also the first phage protein that interacted with the global regulator RpoS of bacteria. Our results indicated the potential value of gp70.1 in antibacterial applications. This study preliminarily revealed the biological function of gp70.1 and provided a reference for the study of other phage genes sharing similarities with orf70.1

Utilization Trend and Comparison of Different Radiotherapy Modes for Patients with Early-Stage High-Intermediate-Risk Endometrial Cancer: A Real-World, Multi-Institutional Study

This study aimed to compare the outcomes of RT modalities among patients who met different HIR criteria based on multicentric real-world data over 15 years. The enrolled patients, who were diagnosed with FIGO I-II EC from 13 medical institutes and treated with hysterectomy and RT, were reclassified into HIR groups according to the criteria of GOG-249, PORTEC-2, and ESTRO-ESMO-ESGO, respectively. The trends in RT modes utilization were reviewed using the Man-Kendall test. The rate of VBT alone increased from zero in 2005 to 50% in 2015, which showed a significant upward trend (p p > 0.05). There were no significant differences in OS, DFS, LRFS, and DMFS between VBT alone and EBRT ± VBT in three HIR cohorts. Subgroup analyses in the GOG-249 HIR cohort showed that EBRT ± VBT had higher 5-year DFS, DMFS, and LRFS than VBT alone for patients without lymph node dissection (p < 0.05). Thus, VBT could be regarded as a standard adjuvant radiation modality for HIR patients. EBRT should be administrated to selected HIR patients who meet the GOG-249 criteria and did not undergo lymph node dissection

Genomic and Proteomic Analyses of the Terminally Redundant Genome of the <i>Pseudomonas aeruginosa</i> Phage PaP1: Establishment of Genus PaP1-Like Phages

<div><p>We isolated and characterized a new <i>Pseudomonas aeruginosa</i> myovirus named PaP1. The morphology of this phage was visualized by electron microscopy and its genome sequence and ends were determined. Finally, genomic and proteomic analyses were performed. PaP1 has an icosahedral head with an apex diameter of 68–70 nm and a contractile tail with a length of 138–140 nm. The PaP1 genome is a linear dsDNA molecule containing 91,715 base pairs (bp) with a G+C content of 49.36% and 12 tRNA genes. A strategy to identify the genome ends of PaP1 was designed. The genome has a 1190 bp terminal redundancy. PaP1 has 157 open reading frames (ORFs). Of these, 143 proteins are homologs of known proteins, but only 38 could be functionally identified. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance liquid chromatography-mass spectrometry allowed identification of 12 ORFs as structural protein coding genes within the PaP1 genome. Comparative genomic analysis indicated that the <i>Pseudomonas aeruginosa</i> phage PaP1, JG004, PAK_P1 and vB_PaeM_C2-10_Ab1 share great similarity. Besides their similar biological characteristics, the phages contain 123 core genes and have very close phylogenetic relationships, which distinguish them from other known phage genera. We therefore propose that these four phages be classified as PaP1-like phages, a new phage genus of <i>Myoviridae</i> that infects <i>Pseudomonas aeruginosa</i>.</p></div