Ensembl regulation resources

New experimental techniques in epigenomics allow researchers to assay a diversity of highly dynamic features such as histone marks, DNA modifications or chromatin structure. The study of their fluctuations should provide insights into gene expression regulation, cell differentiation and disease. The Ensembl project collects and maintains the Ensembl regulation data resources on epigenetic marks, transcription factor binding and DNA methylation for human and mouse, as well as microarray probe mappings and annotations for a variety of chordate genomes. From this data, we produce a functional annotation of the regulatory elements along the human and mouse genomes with plans to expand to other species as data becomes available. Starting from well-studied cell lines, we will progressively expand our library of measurements to a greater variety of samples. Ensembl's regulation resources provide a central and easy-to-query repository for reference epigenomes. As with all Ensembl data, it is freely available at http://www.ensembl.org, from the Perl and REST APIs and from the public Ensembl MySQL database server at ensembldb.ensembl.org.Database URL: http://www.ensembl.org.Wellcome Trust grant: (WT098051); National Human Genome Research Institute grants: (U41HG007234, 1U01 HG004695); Biotechnology and Biological Sciences Research Council grant: (BB/L024225/1); European Molecular Biology Laboratory; European Union’s Seventh Framework Programme; European Research Council

Epac1 mediates protein kinase A–independent mechanism of forskolin-activated intestinal chloride secretion

Intestinal Cl− secretion is stimulated by cyclic AMP (cAMP) and intracellular calcium ([Ca2+]i). Recent studies show that protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) are downstream targets of cAMP. Therefore, we tested whether both PKA and Epac are involved in forskolin (FSK)/cAMP-stimulated Cl− secretion. Human intestinal T84 cells and mouse small intestine were used for short circuit current (Isc) measurement in response to agonist-stimulated Cl− secretion. FSK-stimulated Cl− secretion was completely inhibited by the additive effects of the PKA inhibitor, H89 (1 µM), and the [Ca2+]i chelator, 1,2-bis-(o-aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM; 25 µM). Both FSK and the Epac activator 8-pCPT-2’-O-Me-cAMP (50 µM) elevated [Ca2+]i, activated Ras-related protein 2, and induced Cl− secretion in intact or basolateral membrane–permeabilized T84 cells and mouse ileal sheets. The effects of 8-pCPT-2’-O-Me-cAMP were completely abolished by BAPTA-AM, but not by H89. In contrast, T84 cells with silenced Epac1 had a reduced Isc response to FSK, and this response was completely inhibited by H89, but not by the phospholipase C inhibitor U73122 or BAPTA-AM. The stimulatory effect of 8-pCPT-2’-O-Me-cAMP on Cl− secretion was not abolished by cystic fibrosis transmembrane conductance (CFTR) inhibitor 172 or glibenclamide, suggesting that CFTR channels are not involved. This was confirmed by lack of effect of 8-pCPT-2’-O-Me-cAMP on whole cell patch clamp recordings of CFTR currents in Chinese hamster ovary cells transiently expressing the human CFTR channel. Furthermore, biophysical characterization of the Epac1-dependent Cl− conductance of T84 cells mounted in Ussing chambers suggested that this conductance was hyperpolarization activated, inwardly rectifying, and displayed a Cl−>Br−>I− permeability sequence. These results led us to conclude that the Epac-Rap-PLC-[Ca2+]i signaling pathway is involved in cAMP-stimulated Cl− secretion, which is carried by a novel, previously undescribed Cl− channel

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Loss of coral reef growth capacity to track future increases in sea level

Water-depths above coral reefs is predicted to increase due to global sea-level rise (SLR). As ecological degradation inhibits the vertical accretion of coral reefs, it is likely that coastal wave exposure will increase but there currently exists a lack of data in projections concerning local rates of reef growth and local SLR. In this study we have aggregated ecological data of more than 200 tropical western Atlantic and Indian Ocean reefs and calculated their vertical growth which we have then compared with recent and projected rates of SLR across different Representative Concentration Pathway (RCP) scenarios. While many reefs currently show vertical growth that would be sufficient to keep-up with recent historic SLR, future projections under scenario RCP4.5 reveal that without substantial ecological recovery many reefs will not have the capacity to track SLR. Under RCP8.5, we predict that mean water depth will increase by over half a metre by 2100 across the majority of reefs. We found that coral cover strongly predicted whether a reef could track SLR, but that the majority of reefs had coral cover significantly lower than that required to prevent reef submergence. To limit reef submergence, and thus the impacts of waves and storms on adjacent coasts, climate mitigation and local impacts that reduce coral cover (e.g., local pollution and physical damage through development land reclamation) will be necessary

Large Area Precision Cathode Boards for ATLAS Muon Upgrades

The largest phase-1 upgrade project for the ATLAS Muon System is the replacement of the present first station in the forward regions with the so-called New Small Wheels (NSWs) during the long-LHC shutdown in 2019/20. The NSWs will be equipped with eight layers of small-strip thin gap chambers (sTGC) arranged in multilayers of two quadruplets, for a total active surface area of more than 2500 m^2. Large area circuit boards for the sTGC quadruplets have trapezoidal shapes with surface areas up to 2 m^2. To retain the good precision tracking and trigger capabilities in the high background environment of the high luminosity LHC, each sTGC plane must achieve a spatial resolution better than 100 μm to allow the Level-1 trigger track segments to be reconstructed with an angular resolution of approximately 1 mrad. The precision cathode plane has strips with a 3.2 mm pitch for the precision coordinate and the cathode plane on the other side has large area pads for triggering. The position of each strip must be known with an accuracy of 40 µm along the precision coordinate and 80 µm along the beam. On such large area detectors, the mechanical precision is a key point and then must be controlled and monitored all along the process of construction and integration into quadruplets and wedges. The cathode boards are produced in industry by either CNC machining or chemical etching of copper plated FR4 boards. An insulating pre-preg layer is pressed on top of the copper readout elements. Material flow of the underlying FR4 boards during the cathode board manufacturing processes of CNC machining or etching and pressing have been found to have significant impact on the placement of the copper read-out elements. Production of the sTGC detectors is well underway, including the assembly of the 3 metre long wedges maintaining 100 μm position accuracy for installation into ATLAS. We will describe the technological innovations, production challenges in industry and sTGC construction sites, measuring and tracking the dimensional precision of the circuit boards, and alignment of the chambers in ATLAS

Double Empathy

The double empathy problem (DEP) refers to a “disjuncture in reciprocity between two differently disposed social actors” who hold different norms and expectations of each other, such as is common in autistic to non-autistic social interactions (Milton 2012: 884). With different dispositional outlooks and personal conceptual understandings, interactions involving autistic and non-autistic people are susceptible to frequent misunderstandings. It is a “double problem” as both people experience it, and so it is not a singular problem located in any one person. However “the disjuncture may be more severe for the non-autistic disposition as it is experienced as unusual, while for the ‘autistic person’ it is a common experience.” (Milton 2012: 885)

Slowly rotating black holes in quartic generalized quasi-topological gravity

Abstract We study slowly rotating black hole solutions in the six independent theories of Quartic Generalized Quasi-topological Gravity in four dimensions. Unlike in the static case for which all six theories yield the same solution, for rotating black holes we obtain distinct results for five out of the six theories. Working to leading order in the rotation parameter, we find that the equations characterizing these black holes can be reduced to second order for each theory, similar to what has already been done for Einstein Cubic Gravity. We construct approximate and numerical solutions to these equations, and study how physical properties of the solutions such as the angular velocity, photon sphere, black hole shadow, and innermost stable circular orbit are modified, working to leading order in the coupling constant.</jats:p

Slowly rotating black holes in quartic generalized quasi-topological gravity

Abstract We study slowly rotating black hole solutions in the six independent theories of Quartic Generalized Quasi-topological Gravity in four dimensions. Unlike in the static case for which all six theories yield the same solution, for rotating black holes we obtain distinct results for five out of the six theories. Working to leading order in the rotation parameter, we find that the equations characterizing these black holes can be reduced to second order for each theory, similar to what has already been done for Einstein Cubic Gravity. We construct approximate and numerical solutions to these equations, and study how physical properties of the solutions such as the angular velocity, photon sphere, black hole shadow, and innermost stable circular orbit are modified, working to leading order in the coupling constant

Slowly rotating black holes in quartic generalized quasi-topological gravity

We study slowly rotating black hole solutions in the six independent theories of Quartic Generalized Quasi-topological Gravity in four dimensions. Unlike in the static case for which all six theories yield the same solution, for rotating black holes we obtain distinct results for five out of the six theories. Working to leading order in the rotation parameter, we find that the equations characterizing these black holes can be reduced to second order for each theory, similar to what has already been done for Einstein Cubic Gravity. We construct approximate and numerical solutions to these equations, and study how physical properties of the solutions such as the angular velocity, photon sphere, black hole shadow, and innermost stable circular orbit are modified, working to leading order in the coupling constant