60 research outputs found
Responsibility modelling for civil emergency planning
This paper presents a new approach to analysing and understanding civil emergency planning based on the notion of responsibility modelling combined with HAZOPS-style analysis of information requirements. Our goal is to represent complex contingency plans so that they can be more readily understood, so that inconsistencies can be highlighted and vulnerabilities discovered. In this paper, we outline the framework for contingency planning in the United Kingdom and introduce the notion of responsibility models as a means of representing the key features of contingency plans. Using a case study of a flooding emergency, we illustrate our approach to responsibility modelling and suggest how it adds value to current textual contingency plans
Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.
A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.We would like to thank the EPSRC (SVL, grant nº EP/K0099494/1 and nº EP/K039520/1) for financial support.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ml500507v
Limits on the ultra-bright Fast Radio Burst population from the CHIME Pathfinder
We present results from a new incoherent-beam Fast Radio Burst (FRB) search
on the Canadian Hydrogen Intensity Mapping Experiment (CHIME) Pathfinder. Its
large instantaneous field of view (FoV) and relative thermal insensitivity
allow us to probe the ultra-bright tail of the FRB distribution, and to test a
recent claim that this distribution's slope, , is quite small. A 256-input incoherent beamformer was
deployed on the CHIME Pathfinder for this purpose. If the FRB distribution were
described by a single power-law with , we would expect an FRB
detection every few days, making this the fastest survey on sky at present. We
collected 1268 hours of data, amounting to one of the largest exposures of any
FRB survey, with over 2.4\,\,10\,deg\,hrs. Having seen no
bursts, we have constrained the rate of extremely bright events to
\,sky\,day above \,220 Jy\,ms
for between 1.3 and 100\,ms, at 400--800\,MHz. The non-detection also
allows us to rule out with 95 confidence, after
marginalizing over uncertainties in the GBT rate at 700--900\,MHz, though we
show that for a cosmological population and a large dynamic range in flux
density, is brightness-dependent. Since FRBs now extend to large
enough distances that non-Euclidean effects are significant, there is still
expected to be a dearth of faint events and relative excess of bright events.
Nevertheless we have constrained the allowed number of ultra-intense FRBs.
While this does not have significant implications for deeper, large-FoV surveys
like full CHIME and APERTIF, it does have important consequences for other
wide-field, small dish experiments
A high-quality bonobo genome refines the analysis of hominid evolution
The divergence of chimpanzee and bonobo provides one of the few examples of recent hominid speciation1,2. Here we describe a fully annotated, high-quality bonobo genome assembly, which was constructed without guidance from reference genomes by applying a multiplatform genomics approach. We generate a bonobo genome assembly in which more than 98% of genes are completely annotated and 99% of the gaps are closed, including the resolution of about half of the segmental duplications and almost all of the full-length mobile elements. We compare the bonobo genome to those of other great apes1,3,4,5 and identify more than 5,569 fixed structural variants that specifically distinguish the bonobo and chimpanzee lineages. We focus on genes that have been lost, changed in structure or expanded in the last few million years of bonobo evolution. We produce a high-resolution map of incomplete lineage sorting and estimate that around 5.1% of the human genome is genetically closer to chimpanzee or bonobo and that more than 36.5% of the genome shows incomplete lineage sorting if we consider a deeper phylogeny including gorilla and orangutan. We also show that 26% of the segments of incomplete lineage sorting between human and chimpanzee or human and bonobo are non-randomly distributed and that genes within these clustered segments show significant excess of amino acid replacement compared to the rest of the genome
Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin
By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies
The Atacama Cosmology Telescope: DR6 Gravitational Lensing Map and Cosmological Parameters
We present cosmological constraints from a gravitational lensing mass map
covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama
Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO
measurements (from SDSS and 6dF), we obtain the amplitude of matter
fluctuations at 1.8% precision,
and the Hubble
constant at
1.6% precision. A joint constraint with CMB lensing measured by the Planck
satellite yields even more precise values: ,
and . These measurements agree
well with CDM-model extrapolations from the CMB anisotropies measured
by Planck. To compare these constraints to those from the KiDS, DES, and HSC
galaxy surveys, we revisit those data sets with a uniform set of assumptions,
and find from all three surveys are lower than that from ACT+Planck
lensing by varying levels ranging from 1.7-2.1. These results motivate
further measurements and comparison, not just between the CMB anisotropies and
galaxy lensing, but also between CMB lensing probing on
mostly-linear scales and galaxy lensing at on smaller scales. We
combine our CMB lensing measurements with CMB anisotropies to constrain
extensions of CDM, limiting the sum of the neutrino masses to eV (95% c.l.), for example. Our results provide independent
confirmation that the universe is spatially flat, conforms with general
relativity, and is described remarkably well by the CDM model, while
paving a promising path for neutrino physics with gravitational lensing from
upcoming ground-based CMB surveys.Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological
likelihood data is here:
https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood
software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also
see companion papers Qu et al and MacCrann et al. Mass maps will be released
when papers are publishe
A global phylogeny of butterflies reveals their evolutionary history, ancestral hosts and biogeographic origins
Butterflies are a diverse and charismatic insect group that are thought to have evolved with plants and dispersed throughout the world in response to key geological events. However, these hypotheses have not been extensively tested because a comprehensive phylogenetic framework and datasets for butterfly larval hosts and global distributions are lacking. We sequenced 391 genes from nearly 2,300 butterfly species, sampled from 90 countries and 28 specimen collections, to reconstruct a new phylogenomic tree of butterflies representing 92% of all genera. Our phylogeny has strong support for nearly all nodes and demonstrates that at least 36 butterfly tribes require reclassification. Divergence time analyses imply an origin similar to 100 million years ago for butterflies and indicate that all but one family were present before the K/Pg extinction event. We aggregated larval host datasets and global distribution records and found that butterflies are likely to have first fed on Fabaceae and originated in what is now the Americas. Soon after the Cretaceous Thermal Maximum, butterflies crossed Beringia and diversified in the Palaeotropics. Our results also reveal that most butterfly species are specialists that feed on only one larval host plant family. However, generalist butterflies that consume two or more plant families usually feed on closely related plants
The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth
We present new measurements of cosmic microwave background (CMB) lensing over
sq. deg. of the sky. These lensing measurements are derived from the
Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which
consists of five seasons of ACT CMB temperature and polarization observations.
We determine the amplitude of the CMB lensing power spectrum at
precision ( significance) using a novel pipeline that minimizes
sensitivity to foregrounds and to noise properties. To ensure our results are
robust, we analyze an extensive set of null tests, consistency tests, and
systematic error estimates and employ a blinded analysis framework. The
baseline spectrum is well fit by a lensing amplitude of
relative to the Planck 2018 CMB power spectra
best-fit CDM model and relative to
the best-fit model. From our lensing power
spectrum measurement, we derive constraints on the parameter combination
of
from ACT DR6 CMB lensing alone and
when combining ACT DR6 and Planck NPIPE
CMB lensing power spectra. These results are in excellent agreement with
CDM model constraints from Planck or
CMB power spectrum measurements. Our lensing measurements from redshifts
-- are thus fully consistent with CDM structure growth
predictions based on CMB anisotropies probing primarily . We find no
evidence for a suppression of the amplitude of cosmic structure at low
redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see
companion papers Madhavacheril et al and MacCrann et a
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