Kinetochore assembly and heterochromatin formation occur autonomously in Schizosaccharomyces pombe

Kinetochores in multicellular eukaryotes are usually associated with heterochromatin. Whether this heterochromatin simply promotes the cohesion necessary for accurate chromosome segregation at cell division or whether it also has a role in kinetochore assembly is unclear. Schizosaccharomyces pombe is an important experimental system for investigating centromere function, but all of the previous work with this species has exploited a single strain or its derivatives. The laboratory strain and most other S. pombe strains contain three chromosomes, but one recently discovered strain, CBS 2777, contains four. We show that the genome of CBS 2777 is related to that of the laboratory strain by a complex chromosome rearrangement. As a result, two of the kinetochores in CBS 2777 contain the central core sequences present in the laboratory strain centromeres, but lack adjacent heterochromatin. The closest block of heterochromatin to these rearranged kinetochores is ∼100 kb away at new telomeres. Despite lacking large amounts of adjacent heterochromatin, the rearranged kinetochores bind CENP-ACnp1 and CENP-CCnp3 in similar quantities and with similar specificities as those of the laboratory strain. The simplest interpretation of this result is that constitutive kinetochore assembly and heterochromatin formation occur autonomously

Characterizing Signal Loss in the 21 cm Reionization Power Spectrum: A Revised Study of PAPER-64

The Epoch of Reionization (EoR) is an uncharted era in our Universe's history during which the birth of the first stars and galaxies led to the ionization of neutral hydrogen in the intergalactic medium. There are many experiments investigating the EoR by tracing the 21cm line of neutral hydrogen. Because this signal is very faint and difficult to isolate, it is crucial to develop analysis techniques that maximize sensitivity and suppress contaminants in data. It is also imperative to understand the trade-offs between different analysis methods and their effects on power spectrum estimates. Specifically, with a statistical power spectrum detection in HERA's foreseeable future, it has become increasingly important to understand how certain analysis choices can lead to the loss of the EoR signal. In this paper, we focus on signal loss associated with power spectrum estimation. We describe the origin of this loss using both toy models and data taken by the 64-element configuration of the Donald C. Backer Precision Array for Probing the Epoch of Reionization (PAPER). In particular, we highlight how detailed investigations of signal loss have led to a revised, higher 21cm power spectrum upper limit from PAPER-64. Additionally, we summarize errors associated with power spectrum error estimation that were previously unaccounted for. We focus on a subset of PAPER-64 data in this paper; revised power spectrum limits from the PAPER experiment are presented in a forthcoming paper by Kolopanis et al. (in prep.) and supersede results from previously published PAPER analyses.Comment: 25 pages, 18 figures, Accepted by Ap

Towards a common approach to the assessment of the environmental status of deep-sea ecosystems in areas beyond national jurisdiction

Many of the marine policy frameworks developed to protect biodiversity in deep-sea areas, including areas beyond national jurisdiction (ABNJ), include indicators to assess policy objectives. These frameworks often have specific guidance on how the indicators should be applied and interpreted. Selection of indicators is an important process and those with strong scientific underpinnings are more likely to produce the expected outcomes. We reviewed three policy and assessment frameworks which include ABNJ regions or were developed specifically for ABNJ: (1) Oslo and Paris Convention for the Protection of the Marine Environment of the North-East Atlantic (OSPAR) ecosystem assessments, (2) the frameworks adopted to implement the UN General Assembly (UNGA) sustainable fisheries resolutions for the management of bottom fisheries to prevent Significant Adverse Impacts on vulnerable marine ecosystems, and (3) the Aichi Biodiversity Targets adopted by Parties to the Convention on Biological Diversity (CBD). We examined whether an assessment approach based on evaluation of Good Environmental Status (GES) under the European Union's Marine Strategy Framework Directive (MSFD), could be applied to ABNJ. We examined each MSFD descriptor for its applicability to deep-sea habitats considering the work of two European projects concluding that the MSFD could be applied to ABNJ to support OSPAR, UNGA and CBD policy objectives towards a common approach to the assessment of the status of deep-sea ecosystems in ABNJ. In achieving this we also introduce readers outside of Europe to the work conducted within the MSFD

Characteristics of First-Order Vortex Lattice Melting: Jumps in Entropy and Magnetization

We derive expressions for the jumps in entropy and magnetization characterizing the first-order melting transition of a flux line lattice. In our analysis we account for the temperature dependence of the Landau parameters and make use of the proper shape of the melting line as determined by the relative importance of electromagnetic and Josephson interactions. The results agree well with experiments on anisotropic Y$_1$Ba$_2$Cu$_3$O$_{7-\delta}$ and layered Bi$_2$Sr$_2$Ca$_1$Cu$_2$O$_8$ materials and reaffirm the validity of the London model.Comment: 4 pages. We have restructured the paper to emphasize that in the London scaling regime (appropriate for YBCO) our results are essentially exact. We have also emphasized that a major controversy over the relevance of the London model to describe VL melting has been settled by this wor

PAPER-64 Constraints On Reionization II: The Temperature Of The z=8.4 Intergalactic Medium

We present constraints on both the kinetic temperature of the intergalactic medium (IGM) at z=8.4, and on models for heating the IGM at high-redshift with X-ray emission from the first collapsed objects. These constraints are derived using a semi-analytic method to explore the new measurements of the 21 cm power spectrum from the Donald C. Backer Precision Array for Probing the Epoch of Reionization (PAPER), which were presented in a companion paper, Ali et al. (2015). Twenty-one cm power spectra with amplitudes of hundreds of mK^2 can be generically produced if the kinetic temperature of the IGM is significantly below the temperature of the Cosmic Microwave Background (CMB); as such, the new results from PAPER place lower limits on the IGM temperature at z=8.4. Allowing for the unknown ionization state of the IGM, our measurements find the IGM temperature to be above ~5 K for neutral fractions between 10% and 85%, above ~7 K for neutral fractions between 15% and 80%, or above ~10 K for neutral fractions between 30% and 70%. We also calculate the heating of the IGM that would be provided by the observed high redshift galaxy population, and find that for most models, these galaxies are sufficient to bring the IGM temperature above our lower limits. However, there are significant ranges of parameter space that could produce a signal ruled out by the PAPER measurements; models with a steep drop-off in the star formation rate density at high redshifts or with relatively low values for the X-ray to star formation rate efficiency of high redshift galaxies are generally disfavored. The PAPER measurements are consistent with (but do not constrain) a hydrogen spin temperature above the CMB temperature, a situation which we find to be generally predicted if galaxies fainter than the current detection limits of optical/NIR surveys are included in calculations of X-ray heating.Comment: companion paper to Ali et al. (2015), ApJ 809, 61; matches version accepted to ApJ; 11 pages, 7 figure

CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells.

Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor-activity modifying protein (RAMP) associated with CLR we can "re-route" the physiological pathways activated by endogenous agonists calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination