Genomic features and computational identification of human microRNAs under long-range developmental regulation

<p>Abstract</p> <p>Background</p> <p>Recent functional studies have demonstrated that many microRNAs (miRNAs) are expressed by RNA polymerase II in a specific spatiotemporal manner during the development of organisms and play a key role in cell-lineage decisions and morphogenesis. They are therefore functionally related to a number of key protein coding developmental genes, that form genomic regulatory blocks (GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning as long-range enhancers that collaboratively regulate the expression of their target genes. Given this functional similarity as well as recent zebrafish transgenesis assays showing that the miR-9 family is indeed regulated by HCNEs with enhancer activity, we hypothesized that this type of miRNA regulation is prevalent. In this paper, we therefore systematically investigate the regulatory landscape around conserved self-transcribed miRNAs (ST miRNAs), with their own known or computationally inferred promoters, by analyzing the hallmarks of GRB target genes. These include not only the density of HCNEs in their vicinity but also the presence of large CpG islands (CGIs) and distinct patterns of histone modification marks associated with developmental genes.</p> <p>Results</p> <p>Our results show that a subset of the conserved ST miRNAs we studied shares properties similar to those of protein-coding GRB target genes: they are located in regions of significantly higher HCNE/enhancer binding density and are more likely to be associated with CGIs. Furthermore, their putative promoters have both activating as well as silencing histone modification marks during development and differentiation. Based on these results we used both an elevated HCNE density in the genomic vicinity as well as the presence of a bivalent promoter to identify 29 putative GRB target miRNAs/miRNA clusters, over two-thirds of which are known to play a role during development and differentiation. Furthermore these predictions include miRNAs of the miR-9 family, which are the only experimentally verified GRB target miRNAs.</p> <p>Conclusions</p> <p>A subset of the conserved miRNA loci we investigated exhibits typical characteristics of GRB target genes, which may partially explain their complex expression profiles during development.</p

Lineage-Specific Biology Revealed by a Finished Genome Assembly of the Mouse

A finished clone-based assembly of the mouse genome reveals extensive recent sequence duplication during recent evolution and rodent-specific expansion of certain gene families. Newly assembled duplications contain protein-coding genes that are mostly involved in reproductive function

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Planetary Migration in Protoplanetary Disks

The known exoplanet population displays a great diversity of orbital architectures, and explaining the origin of this is a major challenge for planet formation theories. The gravitational interaction between young planets and their protoplanetary disks provides one way in which planetary orbits can be shaped during the formation epoch. Disk-planet interactions are strongly influenced by the structure and physical processes that drive the evolution of the protoplanetary disk. In this review we focus on how disk-planet interactions drive the migration of planets when different assumptions are made about the physics of angular momentum transport, and how it drives accretion flows in protoplanetary disk models. In particular, we consider migration in discs where: (i) accretion flows arise because turbulence diffusively transports angular momentum; (ii) laminar accretion flows are confined to thin, ionised layers near disk surfaces and are driven by the launching of magneto-centrifugal winds, with the midplane being completely inert; (iii) laminar accretion flows pervade the full column density of the disc, and are driven by a combination of large scale horizontal and vertical magnetic fields

Standard Model Physics at the HL-LHC and HE-LHC

The successful operation of the Large Hadron Collider (LHC) and the excellent performance of the ATLAS, CMS, LHCb and ALICE detectors in Run-1 and Run-2 with $pp$ collisions at center-of-mass energies of 7, 8 and 13 TeV as well as the giant leap in precision calculations and modeling of fundamental interactions at hadron colliders have allowed an extraordinary breadth of physics studies including precision measurements of a variety physics processes. The LHC results have so far confirmed the validity of the Standard Model of particle physics up to unprecedented energy scales and with great precision in the sectors of strong and electroweak interactions as well as flavour physics, for instance in top quark physics. The upgrade of the LHC to a High Luminosity phase (HL-LHC) at 14 TeV center-of-mass energy with 3 ab$^{-1}$ of integrated luminosity will probe the Standard Model with even greater precision and will extend the sensitivity to possible anomalies in the Standard Model, thanks to a ten-fold larger data set, upgraded detectors and expected improvements in the theoretical understanding. This document summarises the physics reach of the HL-LHC in the realm of strong and electroweak interactions and top quark physics, and provides a glimpse of the potential of a possible further upgrade of the LHC to a 27 TeV $pp$ collider, the High-Energy LHC (HE-LHC), assumed to accumulate an integrated luminosity of 15 ab$^{-1}$

Endoscopic perductal electrolytic ablation of the pancreas: Experimental studies of morbidity and mortality

© KargerBackgroundPalliation of pancreatic cancer remains the only option for the majority of patients. Palliative techniques such as surgical bypass and endoscopic retrograde cholangiopancreatography (ERCP) with stenting are not ideal. The 'ideal' palliative technique would combine the efficacy of surgery with the minimal complications of an endoscopic procedure. Endoscopically delivered perductal electrolytic ablation of pancreatic lesions has the potential to meet these criteria.MethodsFifteen pigs were used. The pancreatic duct was cannulated with an electrolysis catheter. Animals were randomised to either: controls, treatment 2-week survivor or treatment 8-week survivor. An electrolytic dose was administered to the treatment animals. Post-operatively, serum amylase and leucocyte count were assessed. Pancreata were histologically examined to detect evidence of acute pancreatitis.ResultsElectrolysis was well tolerated. There was no difference in post-operative hyperamylasaemia and leucocyte count between the groups. Histological examination showed inflammation at the ablation site at 2 weeks, by 8 weeks this was replaced by scarring.ConclusionThe results of this study suggest that endoscopic perductal electrolytic ablation of the pancreas is feasible and safe. Biochemical and histological findings indicate self-limiting localised inflammation of the pancreas. This technique may have a role in the palliation of pancreatic cancer and warrants further investigation.C.P. Morrison, F.G. Court, B.D. Teague, M.S. Metcalfe, S.A. Wemyss-Holden, M. Texler, A.R. Dennison and G.J. Madder