487 research outputs found
Structure-inspired design of ÎČ-arrestin-biased ligands for aminergic GPCRs
Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into ÎČ-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and ÎČ-arrestin signaling, respectively, and targeted those residues to develop biased ligands. For these ligands, we found that bias is conserved at other aminergic GPCRs that retain similar residues at TM5 and EL2. Our approach provides a template for generating arrestin-biased ligands by modifying predicted ligand interactions that block TM5 interactions and promote EL2 interactions. This strategy may facilitate the structure-guided design of arrestin-biased ligands at other GPCRs, including polypharmacological biased ligands
Proton Elastic and Inelastic Scattering at Intermediate Energies from Isotopes of Oxygen and 9-Be as Part of a Unified Study of These Nuclei
This work was supported by National Science Foundation Grants PHY 76-84033A01, PHY 78-22774, and Indiana Universit
Population genomics of a predatory mammal reveals patterns of decline and impacts of exposure to toxic toads
Mammal declines across northern Australia are one of the major biodiversity loss events occurring globally. There has been no regional assessment of the implications of these species declines for genomic diversity. To address this, we conducted a species-wide assessment of genomic diversity in the northern quoll (Dasyurus hallucatus), an Endangered marsupial carnivore. We used next generation sequencing methods to genotype 10,191 single nucleotide polymorphisms (SNPs) in 352 individuals from across a 3220-km length of the continent, investigating patterns of population genomic structure and diversity, and identifying loci showing signals of putative selection. We found strong heterogeneity in the distribution of genomic diversity across the continent, characterized by (i) biogeographical barriers driving hierarchical population structure through long-term isolation, and (ii) severe reductions in diversity resulting from population declines, exacerbated by the spread of introduced toxic cane toads (Rhinella marina). These results warn of a large ongoing loss of genomic diversity and associated adaptive capacity as mammals decline across northern Australia. Encouragingly, populations of the northern quoll established on toad-free islands by translocations appear to have maintained most of the initial genomic diversity after 16âyears. By mapping patterns of genomic diversity within and among populations, and investigating these patterns in the context of population declines, we can provide conservation managers with data critical to informed decision-making. This includes the identification of populations that are candidates for genetic management, the importance of remnant island and insurance/translocated populations for the conservation of genetic diversity, and the characterization of putative evolutionarily significant units
Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets
The spins of ten stellar black holes have been measured using the
continuum-fitting method. These black holes are located in two distinct classes
of X-ray binary systems, one that is persistently X-ray bright and another that
is transient. Both the persistent and transient black holes remain for long
periods in a state where their spectra are dominated by a thermal accretion
disk component. The spin of a black hole of known mass and distance can be
measured by fitting this thermal continuum spectrum to the thin-disk model of
Novikov and Thorne; the key fit parameter is the radius of the inner edge of
the black hole's accretion disk. Strong observational and theoretical evidence
links the inner-disk radius to the radius of the innermost stable circular
orbit, which is trivially related to the dimensionless spin parameter a_* of
the black hole (|a_*| < 1). The ten spins that have so far been measured by
this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95.
The robustness of the method is demonstrated by the dozens or hundreds of
independent and consistent measurements of spin that have been obtained for
several black holes, and through careful consideration of many sources of
systematic error. Among the results discussed is a dichotomy between the
transient and persistent black holes; the latter have higher spins and larger
masses. Also discussed is recently discovered evidence in the transient sources
for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to
appear in hard cover in the Space Sciences Series of ISSI "The Physics of
Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2,
6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405)
who find no evidence for a correlation between the power of ballistic jets
and black hole spi
Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer : An International Multidisciplinary Systematic Review
Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.Peer reviewedPostprin
Extreme magnification of an individual star at redshift 1.5 by a galaxy-cluster lens
Galaxy-cluster gravitational lenses can magnify background galaxies by a total factor of up to ~50. Here we report an image of an individual star at redshift zâ=â1.49 (dubbed MACS J1149 Lensed Star 1) magnified by more than Ă2,000. A separate image, detected briefly 0.26âł from Lensed Star 1, is probably a counterimage of the first star demagnified for multiple years by an object of âł3 solar masses in the cluster. For reasonable assumptions about the lensing system, microlensing fluctuations in the starsâ light curves can yield evidence about the mass function of intracluster stars and compact objects, including binary fractions and specific stellar evolution and supernova models. Dark-matter subhaloes or massive compact objects may help to account for the two imagesâ long-term brightness ratio
Attrition among families of divorce: Patterns in an outpatient psychiatric population
The accelerated divorce rate has greatly increased the number of children of divorce. In addition, the children and families of divorce are proportionately overrepresented in populations seeking child guidance and psychiatric services. However, the patterns in the use of such services by these families has been unexamined. In our study we find no differences in the use of outpatient psychiatric services between families where both biological parents are present and families of divorce. A closer look at the divorced families reveals that recently divorced mother-headed families more frequently interrupt both the evaluation and treatment phases of clinic contact. Several clinical patterns are described which help explain the finding and it is suggested that the traditional child guidance model may not be the most suitable intervention modality in working with these families.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44293/1/10591_2004_Article_BF00927093.pd
America's Rural Hospitals: A Selective Review of 1980s Research
We review 1980s research on American rural hospitals within the context of a decade of increasing restrictiveness in the reimbursement and operating environments. Areas addressed include rural hospital definitions, organizational and financial performance, and strategic management activities. The latter category consists of hospital closure, diversification and vertical integration, swing-bed conversion, sole community provider designation, horizontal integration and multihospital system affiliation, marketing, and patient retention. The review suggests several research needs, including: developing more meaningful definitions of rural hospitals, engaging in methodologically sound work on the effects of innovative programs and strategic management activitiesâincluding conversion of the facility itselfâon rural hospital performance, and completing studies of the effects of rural hospital closure or conversion on the health of the communities served.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74857/1/j.1748-0361.1990.tb00682.x.pd
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