159 research outputs found
Tapping Environmental History to Recreate America’s Colonial Hydrology
To properly remediate, improve, or predict how hydrological systems behave, it is vital to establish their histories. However, modern-style records, assembled from instrumental data and remote sensing platforms, hardly exist back more than a few decades. As centuries of data is preferable given multidecadal fluxes of both meteorology/climatology and demographics, building such a history requires resources traditionally considered only useful in the social sciences and humanities. In this Feature, Pastore et al. discuss how they have undertaken the synthesis of historical records and modern techniques to understand the hydrology of the Northeastern U.S. from Colonial times to modern day. Such approaches could aid studies in other regions that may require heavier reliance on qualitative narratives. Further, a better insight as to how historical changes unfolded could provide a “past is prologue” methodology to increase the accuracy of predictive environmental models
Preclinical antimalarial combination studies: the case of M5717, a P. falciparum elongation factor 2 inhibitor and pyronaridine, a hemozoin formation inhibitor
Antimalarial drug resistance in the; Plasmodium falciparum; parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing the targeted parasitological and clinical profile of the final drug product. Here, we have studied the combination of M5717, a; P. falciparum; translation elongation factor 2 inhibitor, and pyronaridine, an inhibitor of hemozoin formation. Our test cascade consisted of; in vitro; isobolograms as well as; in vivo; studies in the; P. falciparum; severe combined immunodeficient (SCID) mouse model. We also analyzed pharmacokinetic and pharmacodynamic parameters, including genomic sequencing of recrudescent parasites. We observed no pharmacokinetic interactions with the combination of M5717 and pyronaridine. M5717 did not negatively impact the rate of kill of the faster-acting pyronaridine, and the latter was able to suppress the selection of M5717-resistant mutants, as well as significantly delay the recrudescence of parasites both with suboptimal and optimal dosing regimens
Cincinnati Knee Rating System, and Short Form 36 in Patients With Focal Articular Cartilage Defects Comparison to the Western Ontario and McMaster Universities Osteoarthritis Index, Modified Responsiveness of the International Knee Documentation Committee
General Approach for Combining Diverse Rare Variant Association Tests Provides Improved Robustness Across a Wider Range of Genetic Architectures
The widespread availability of genome sequencing data made possible by way of next-generation technologies has yielded a flood of different gene-based rare variant association tests. Most of these tests have been published because they have superior power for particular genetic architectures. However, for applied researchers it is challenging to know which test to choose in practice when little is known a priori about genetic architecture. Recently, tests have been proposed which combine two particular individual tests (one burden and one variance components) to minimize power loss while improving robustness to a wider range of genetic architectures. In our analysis we propose an expansion of these approaches, yielding a general method that works for combining any number of individual tests. We demonstrate that running multiple different tests on the same dataset and using a Bonferroni correction for multiple testing is never better than combining tests using our general method. We also find that using a test statistic that is highly robust to the inclusion of non-causal variants (Joint-infinity) together with a previously published combined test (SKAT-O) provides improved robustness to a wide range of genetic architectures and should be considered for use in practice. Software for this approach is supplied. We support the increased use of combined tests in practice-- as well as further exploration of novel combined testing approaches using the general framework provided here--to maximize robustness of rare-variant testing strategies against a wide range of genetic architectures
Tidal Signatures in the Faintest Milky Way Satellites: The Detailed Properties of Leo V, Pisces II and Canes Venatici II
We present deep wide-field photometry of three recently discovered faint
Milky Way satellites: Leo V, Pisces II, and Canes Venatici II. Our main goals
are to study the structure and star formation history of these dwarfs; we also
search for signs of tidal disturbance. The three satellites have similar
half-light radii ( pc) but a wide range of ellipticities. Both Leo
V and CVn II show hints of stream-like overdensities at large radii. An
analysis of the satellite color-magnitude diagrams shows that all three objects
are old ( 10 Gyr) and metal-poor ([Fe/H] ), though neither the
models nor the data have sufficient precision to assess when the satellites
formed with respect to cosmic reionization. The lack of an observed younger
stellar population (\la 10 Gyr) possibly sets them apart from the other
satellites at Galactocentric distances \ga 150 kpc. We present a new
compilation of structural data for all Milky Way satellite galaxies and use it
to compare the properties of classical dwarfs to the ultra-faints. The
ellipticity distribution of the two groups is consistent at the
2- level. However, the faintest satellites tend to be more
aligned toward the Galactic center, and those satellites with the highest
ellipticity (\ga 0.4) have orientations () in the range
. This latter
observation is in rough agreement with predictions from simulations of dwarf
galaxies that have lost a significant fraction of their dark matter halos and
are being tidally stripped.Comment: 25 pages, 7 figures, ApJ accepted; version updated to match ApJ
accepte
Astrophysical Tests of Dark Matter with Maunakea Spectroscopic Explorer
We discuss how astrophysical observations with the Maunakea Spectroscopic
Explorer (MSE), a high-multiplexity (about 4300 fibers), wide field-of-view
(1.5 square degree), large telescope aperture (11.25 m) facility, can probe the
particle nature of dark matter. MSE will conduct a suite of surveys that will
provide critical input for determinations of the mass function, phase-space
distribution, and internal density profiles of dark matter halos across all
mass scales. N-body and hydrodynamical simulations of cold, warm, fuzzy and
self-interacting dark matter suggest that non-trivial dynamics in the dark
sector could have left an imprint on structure formation. Analysed within these
frameworks, the extensive and unprecedented datasets produced by MSE will be
used to search for deviations away from cold and collisionless dark matter
model. MSE will provide an improved estimate of the local density of dark
matter, critical for direct detection experiments, and will improve estimates
of the J-factor for indirect searches through self-annihilation or decay into
Standard Model particles. MSE will determine the impact of low mass
substructures on the dynamics of Milky Way stellar streams in velocity space,
and will allow for estimates of the density profiles of the dark matter halos
of Milky Way dwarf galaxies using more than an order of magnitude more tracers.
In the low redshift Universe, MSE will provide critical redshifts to pin down
the luminosity functions of vast numbers of satellite systems, and MSE will be
an essential component of future strong lensing measurements to constrain the
halo mass function. Across nearly all mass scales, the improvements offered by
MSE, in comparison to other facilities, are such that the relevant analyses are
limited by systematics rather than statistics.Comment: 44 pages, 19 figures. To appear as a chapter for "The Detailed
Science Case for the Maunakea Spectroscopic Explorer, 2019
Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe
Towards a Muon Collider
A muon collider would enable the big jump ahead in energy reach that is
needed for a fruitful exploration of fundamental interactions. The challenges
of producing muon collisions at high luminosity and 10 TeV centre of mass
energy are being investigated by the recently-formed International Muon
Collider Collaboration. This Review summarises the status and the recent
advances on muon colliders design, physics and detector studies. The aim is to
provide a global perspective of the field and to outline directions for future
work.Comment: 118 pages, 103 figure
Towards a muon collider
A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work
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