Single accessory pathway with multiple insertions?:First-in-human 3D visualization using dipole charge density mapping: a case report

BackgroundAccessory pathways (APs) with multiple atrial insertions are often unrecognized and associated with initial catheter ablation (CA) failure. Recently, a novel dipole charge density mapping (DCDM) system was developed that allows mapping of complex arrhythmias based on a single beat. We aim to present the first-in-human report of 3D visualization of a single AP with two atrial insertion sites using high-resolution DCDM.Case summaryA 43-year-old man with recurrent symptomatic atrioventricular re-entrant tachycardia and previously failed CA attempts underwent repeated CA using DCDM. Dipole charge density mapping identified two quasi-simultaneous early atrial activation sites at the left lateral and left anterolateral atrial aspects of the mitral annulus, suggesting the presence of a single AP with dual atrial insertion sites. Successful radiofrequency CA was performed at the mid-body of the AP.DiscussionThe true prevalence of APs with multiple atrial insertion sites may be higher than currently reported. This is the first-in-human report of 3D visualization of a single AP with two atrial insertion sites using high-resolution DCDM. Dipole charge density mapping allows the accurate localization of APs with multiple insertion sites based on a single beat

Minimally interrupted novel oral anticoagulant versus uninterrupted vitamin K antagonist during atrial fibrillation ablation

The safety and efficacy of a minimally interrupted novel oral anticoagulant (NOAC) strategy at the time of atrial fibrillation (AF) ablation is uncertain. The purpose of this study was to compare rates of bleeding and thromboembolic events between minimally interrupted NOAC and uninterrupted vitamin K antagonist (VKA) in patients undergoing AF ablation.This was a retrospective single-center cohort study of consecutive patients who underwent AF catheter ablation between January 2013 and April 2017. Endpoints included major bleeding, clinically relevant non-major bleeding and systemic thromboembolic event from the time of ablation through 30 days. Bleeding events were defined by the Bleeding Academic Research Consortium (BARC) and International Society on Thrombosis and Haemostasis (ISTH).A total of 637 patients were included in the analysis, 520 patients used uninterrupted VKA and 117 patients minimally interrupted NOAC (dabigatran: n = 68; apixaban: n = 30; rivaroxaban, n = 14; edoxaban, n = 5). The rate of clinically relevant non-major bleeding was lower in the NOAC group in comparison to the VKA group (BARC type 2: 2.6% versus 8.3%, P = 0.03; ISTH: 0% versus 3.8%, P = 0.03). Rates of major bleeding were similar between groups (BARC type 3 to 5: 3.4% versus 4.2%, P = NS; ISTH: 6.0% versus 8.7%, P = NS; for NOAC and VKA groups, respectively). Rates of systemic embolism were 0% with minimally interrupted NOAC, and 0.6% with uninterrupted VKA (P = NS).In patients undergoing AF ablation, anticoagulation with minimally interrupted NOAC was associated with fewer clinically relevant non-major bleeding events in comparison with uninterrupted VKA without compromising thromboembolic safety

Sexually dimorphic gene expression emerges with embryonic genome activation and is dynamic throughout development

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainVKR is supported by grants from the Biotechnology and Biological Sciences Research Council, UK (BB/M012494/1), VKR and CG by (BB/G00711/X/1). MLH is supported by a Research Council UK Academic Fellowship. RL is supported by EU-FP7 BLUEPRINT

Precise Regulation of Gene Expression Dynamics Favors Complex Promoter Architectures

Promoters process signals through recruitment of transcription factors and RNA polymerase, and dynamic changes in promoter activity constitute a major noise source in gene expression. However, it is barely understood how complex promoter architectures determine key features of promoter dynamics. Here, we employ prototypical promoters of yeast ribosomal protein genes as well as simplified versions thereof to analyze the relations among promoter design, complexity, and function. These promoters combine the action of a general regulatory factor with that of specific transcription factors, a common motif of many eukaryotic promoters. By comprehensively analyzing stationary and dynamic promoter properties, this model-based approach enables us to pinpoint the structural characteristics underlying the observed behavior. Functional tradeoffs impose constraints on the promoter architecture of ribosomal protein genes. We find that a stable scaffold in the natural design results in low transcriptional noise and strong co-regulation of target genes in the presence of gene silencing. This configuration also exhibits superior shut-off properties, and it can serve as a tunable switch in living cells. Model validation with independent experimental data suggests that the models are sufficiently realistic. When combined, our results offer a mechanistic explanation for why specific factors are associated with low protein noise in vivo. Many of these findings hold for a broad range of model parameters and likely apply to other eukaryotic promoters of similar structure

Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice

Background There is increasing appreciation for sexually dimorphic effects, but the molecular mechanisms underlying these effects are only partially understood. In the present study, we explored transcriptomics and epigenetic differences in the small intestine and colon of prepubescent male and female mice. In addition, the microbiota composition of the colonic luminal content has been examined. Methods At postnatal day 14, male and female C57BL/6 mice were sacrificed and the small intestine, colon and content of luminal colon were isolated. Gene expression of both segments of the intestine was analysed by microarray analysis. DNA methylation of the promoter regions of selected sexually dimorphic genes was examined by pyrosequencing. Composition of the microbiota was explored by deep sequencing. Results Sexually dimorphic genes were observed in both segments of the intestine of 2-week-old mouse pups, with a stronger effect in the small intestine. Amongst the total of 349 genes displaying a sexually dimorphic effect in the small intestine and/or colon, several candidates exhibited a previously established function in the intestine (i.e. Nts, Nucb2, Alox5ap and Retnlγ). In addition, differential expression of genes linked to intestinal bowel disease (i.e. Ccr3, Ccl11 and Tnfr) and colorectal cancer development (i.e. Wt1 and Mmp25) was observed between males and females. Amongst the genes displaying significant sexually dimorphic expression, nine genes were histone-modifying enzymes, suggesting that epigenetic mechanisms might be a potential underlying regulatory mechanism. However, our results reveal no significant changes in DNA methylation of analysed CpGs within the selected differentially expressed genes. With respect to the bacterial community composition in the colon, a dominant effect of litter origin was found but no significant sex effect was detected. However, a sex effect on the dominance of specific taxa was observed. Conclusions This study reveals molecular dissimilarities between males and females in the small intestine and colon of prepubescent mice, which might underlie differences in physiological functioning and in disease predisposition in the two sexes

Identification of Genes That Promote or Antagonize Somatic Homolog Pairing Using a High-Throughput FISH–Based Screen

The pairing of homologous chromosomes is a fundamental feature of the meiotic cell. In addition, a number of species exhibit homolog pairing in nonmeiotic, somatic cells as well, with evidence for its impact on both gene regulation and double-strand break (DSB) repair. An extreme example of somatic pairing can be observed in Drosophila melanogaster, where homologous chromosomes remain aligned throughout most of development. However, our understanding of the mechanism of somatic homolog pairing remains unclear, as only a few genes have been implicated in this process. In this study, we introduce a novel high-throughput fluorescent in situ hybridization (FISH) technology that enabled us to conduct a genome-wide RNAi screen for factors involved in the robust somatic pairing observed in Drosophila. We identified both candidate “pairing promoting genes” and candidate “anti-pairing genes,” providing evidence that pairing is a dynamic process that can be both enhanced and antagonized. Many of the genes found to be important for promoting pairing are highly enriched for functions associated with mitotic cell division, suggesting a genetic framework for a long-standing link between chromosome dynamics during mitosis and nuclear organization during interphase. In contrast, several of the candidate anti-pairing genes have known interphase functions associated with S-phase progression, DNA replication, and chromatin compaction, including several components of the condensin II complex. In combination with a variety of secondary assays, these results provide insights into the mechanism and dynamics of somatic pairing

Sex Differences in the Brain: A Whole Body Perspective

Most writing on sexual differentiation of the mammalian brain (including our own) considers just two organs: the gonads and the brain. This perspective, which leaves out all other body parts, misleads us in several ways. First, there is accumulating evidence that all organs are sexually differentiated, and that sex differences in peripheral organs affect the brain. We demonstrate this by reviewing examples involving sex differences in muscles, adipose tissue, the liver, immune system, gut, kidneys, bladder, and placenta that affect the nervous system and behavior. The second consequence of ignoring other organs when considering neural sex differences is that we are likely to miss the fact that some brain sex differences develop to compensate for differences in the internal environment (i.e., because male and female brains operate in different bodies, sex differences are required to make output/function more similar in the two sexes). We also consider evidence that sex differences in sensory systems cause male and female brains to perceive different information about the world; the two sexes are also perceived by the world differently and therefore exposed to differences in experience via treatment by others. Although the topic of sex differences in the brain is often seen as much more emotionally charged than studies of sex differences in other organs, the dichotomy is largely false. By putting the brain firmly back in the body, sex differences in the brain are predictable and can be more completely understood

Epigenetics and developmental programming of welfare and production traits in farm animals

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the ‘developmental origins of health and disease’ or ‘DOHaD’ hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems