B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation

Altres ajuts: We thank CERCA Programme/Generalitat de Catalunya for institutional support. [...] BMJ is a Ramon y Cajal fellow (RYC-2016-19655). This work was supported by the Health Department PERIS-project no. SLT/002/16/00374 and [...]; and CIBERONC CB16/12/00312 and CB16/12/00489; [...]; the Cellex Foundation; and "la Caixa" Bank Foundation (LCF/PR/GN18/51140001). We thank Dr Thomas Graf for providing the transdifferentiation model.Altres ajuts: MEFP/FPU17-0242

Influence of socioeconomic factors on pregnancy outcome in women with structural heart disease

OBJECTIVE: Cardiac disease is the leading cause of indirect maternal mortality. The aim of this study was to analyse to what extent socioeconomic factors influence the outcome of pregnancy in women with heart disease.  METHODS: The Registry of Pregnancy and Cardiac disease is a global prospective registry. For this analysis, countries that enrolled ≥10 patients were included. A combined cardiac endpoint included maternal cardiac death, arrhythmia requiring treatment, heart failure, thromboembolic event, aortic dissection, endocarditis, acute coronary syndrome, hospitalisation for cardiac reason or intervention. Associations between patient characteristics, country characteristics (income inequality expressed as Gini coefficient, health expenditure, schooling, gross domestic product, birth rate and hospital beds) and cardiac endpoints were checked in a three-level model (patient-centre-country).  RESULTS: A total of 30 countries enrolled 2924 patients from 89 centres. At least one endpoint occurred in 645 women (22.1%). Maternal age, New York Heart Association classification and modified WHO risk classification were associated with the combined endpoint and explained 37% of variance in outcome. Gini coefficient and country-specific birth rate explained an additional 4%. There were large differences between the individual countries, but the need for multilevel modelling to account for these differences disappeared after adjustment for patient characteristics, Gini and country-specific birth rate.  CONCLUSION: While there are definite interregional differences in pregnancy outcome in women with cardiac disease, these differences seem to be mainly driven by individual patient characteristics. Adjustment for country characteristics refined the results to a limited extent, but maternal condition seems to be the main determinant of outcome

Morphology, Genome Plasticity, and Phylogeny in the Genus Ostreococcus Reveal a Cryptic Species, O. mediterraneus sp. nov. (Mamiellales, Mamiellophyceae)

Coastal marine waters in many regions worldwide support abundant populations of extremely small (1-3 μm diameter) unicellular eukaryotic green algae, dominant taxa including several species in the class Mamiellophyceae. Their diminutive size conceals surprising levels of genetic diversity and defies classical species’ descriptions. We present a detailed analysis within the genus Ostreococcus and show that morphological characteristics cannot be used to describe diversity within this group. Karyotypic analyses of the best-characterized species O. tauri show it to carry two chromosomes that vary in size between individual clonal lines, probably an evolutionarily ancient feature that emerged before species’ divergences within the Mamiellales. By using a culturing technique specifically adapted to members of the genus Ostreococcus, we purified >30 clonal lines of a new species, Ostreococcus mediterraneus sp. nov., previously known as Ostreococcus clade D, that has been overlooked in several studies based on PCR-amplification of genetic markers from environment-extracted DNA. Phylogenetic analyses of the S-adenosylmethionine synthetase gene, and of the complete small subunit ribosomal RNA gene, including detailed comparisons of predicted ITS2 (internal transcribed spacer 2) secondary structures, clearly support that this is a separate species. In addition, karyotypic analyses reveal that the chromosomal location of its ribosomal RNA gene cluster differs from other Ostreococcus clades

CNVassoc: Association analysis of CNV data using R

Background: Copy number variants (CNV) are a potentially important component of the genetic contribution to risk of common complex diseases. Analysis of the association between CNVs and disease requires that uncertainty in CNV copy-number calls, which can be substantial, be taken into account; failure to consider this uncertainty can lead to biased results. Therefore, there is a need to develop and use appropriate statistical tools. To address this issue, we have developed CNVassoc, an R package for carrying out association analysis of common copy number variants in population-based studies. This package includes functions for testing for association with different classes of response variables (e.g. class status, censored data, counts) under a series of study designs (case-control, cohort, etc) and inheritance models, adjusting for covariates. The package includes functions for inferring copy number (CNV genotype calling), but can also accept copy number data generated by other algorithms (e.g. CANARY, CGHcall, IMPUTE). Results: Here we present a new R package, CNVassoc, that can deal with different types of CNV arising from different platforms such as MLPA o aCGH. Through a real data example we illustrate that our method is able to incorporate uncertainty in the association process. We also show how our package can also be useful when analyzing imputed data when analyzing imputed SNPs. Through a simulation study we show that CNVassoc outperforms CNVtools in terms of computing time as well as in convergence failure rate. Conclusions: We provide a package that outperforms the existing ones in terms of modelling flexibility, power, convergence rate, ease of covariate adjustment, and requirements for sample size and signal quality. Therefore, we offer CNVassoc as a method for routine use in CNV association studiesThis work has been supported by the Spanish Ministry of Science and Innovation (MTM2008-02457 to JRG, BIO2009-12458 to RD-U and statistical genetics network MTM2010-09526-E (subprograma MTM) to JRG, IS, GL and RD-U). GL is supported by the Juan de la Cierva Program of the Spanish Ministry of Science and Innovation

Efficacy and safety of a hexanic extract of Serenoa repens (Permixon (R)) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies

Objectives To comprehensively evaluate the efficacy and safety of the hexanic extract of Serenoa repens (HESr, Permixon (R); Pierre Fabre Medicament, Castres, France), at a dose of 320 mg daily, as monotherapy for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). Materials and methods We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies in patients with LUTS/BPH identified through searches in Medline, Web of Knowledge (Institute for Scientific Information), Scopus, the Cochrane Library, and bibliographic references up to March 2017. Articles studying S. repens extracts other than Permixon were excluded. Data were collected on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), nocturia, quality of life, prostate volume, sexual function, and adverse drug reactions (ADRs). Data obtained from RCTs and observational studies were analysed jointly and separately using a random effects model. A sub-group analysis was performed of studies that included patients on longer-term treatment (= 1 year). Results Data from 27 studies (15 RCTs and 12 observational studies) were included for meta-analysis (total N = 5 800). Compared with placebo, the HESr was associated with 0.64 (95% confidence interval [CI] -0.98 to -0.31) fewer voids/ night (P < 0.001) and an additional mean increase in Q(max) of 2.75 mL/s (95% CI 0.57 to 4.93; P = 0.01). When compared with a-blockers, the HESr showed similar improvements on IPSS (weighted mean difference [WMD] 0.57, 95% CI -0.27 to 1.42; P = 0.18) and a comparable increase in Q(max) to tamsulosin (WMD -0.02, 95% CI -0.71 to 0.66; P = 0.95). Efficacy assessed using the IPSS was similar after 6 months of treatment between the HESr and 5a-reductase inhibitors (5ARIs). Analysis of all available published data for the HESr showed a mean improvement in IPSS from baseline of -5.73 points (95% CI -6.91 to -4.54; P < 0.001). HESr did not negatively affect sexual function and no clinically relevant effect was observed on prostate-specific antigen. Prostate volume decreased slightly. Similar efficacy results were seen in patients treated for = 1 year (n = 447). The HESr had a favourable safety profile, with gastrointestinal disorders being the most frequent ADR (mean incidence of 3.8%). Conclusion The present meta-analysis, which includes all available RCTs and observational studies, shows that the HESr (Permixon) reduced nocturia and improved Q(max) compared with placebo and had a similar efficacy to tamsulosin and short-term 5ARI in relieving LUTS. HESr (Permixon) appears to be an efficacious and well-tolerated therapeutic option for the longterm medical treatment of LUTS/BPH

Crystal Structure of a Complex of DNA with One AT-Hook of HMGA1

We present here for the first time the crystal structure of an AT-hook domain. We show the structure of an AT-hook of the ubiquitous nuclear protein HMGA1, combined with the oligonucleotide d(CGAATTAATTCG)2, which has two potential AATT interacting groups. Interaction with only one of them is found. The structure presents analogies and significant differences with previous NMR studies: the AT-hook forms hydrogen bonds between main-chain NH groups and thymines in the minor groove, DNA is bent and the minor groove is widened

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Amphioxus functional genomics and the origins of vertebrate gene regulation

Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that—in vertebrates—over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations