Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

<p>Abstract</p> <p>Background</p> <p>CC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions.</p> <p>In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events.</p> <p>Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML) were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (<it>CCR</it>) gene family. The results of neutral vs. adaptive evolution (positive selection) hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω) >1.</p> <p>Results</p> <p>Of the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only <it>CCR2 </it>and <it>CCR3 </it>contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive selection code for amino acid residues located in extracellular domains of the receptor protein products.</p> <p>Conclusions</p> <p>These results suggest that amino acid residues present in intracellular and membrane-bound domains are more selectively constrained for functional signal transduction and homo- or heterodimerization, whereas amino acid residues in extracellular domains of these receptor proteins evolve more quickly, perhaps due to heightened selective pressure resulting from ligand-binding and pathogen interactions of extracellular domains.</p

Structural and magnetic properties of an InGaAs/Fe3_3Si superlattice in cylindrical geometry

The structure and the magnetic properties of an InGaAs/Fe3Si superlattice in a cylindrical geometry are investigated by electron microscopy techniques, x-ray diffraction and magnetometry. To form a radial superlattice, a pseudomorphic InGaAs/Fe3As bilayer has been released from its substrate self-forming into a rolled-up microtube. Oxide-free interfaces as well as areas of crystalline bonding are observed and an overall lattice mismatch between succeeding layers is determined. The cylindrical symmetry of the final radial superlattice shows a significant effect on the magnetization behavior of the rolled-up layers

Influence of HiPIMS pulse widths on the deposition behaviour and properties of CuAgZr compositionally graded films

In this work, the influence of different pulse widths (25, 50 and 100 μs) during high power impulse magnetron sputtering (HiPIMS) of copper, silver and zirconium was investigated in terms of plasma properties and properties of combinatorial composition gradient CuAgZr film libraries. In situ plasma diagnostics via optical emission spectroscopy (OES), time-of-flight mass spectrometry (TOFMS), and modified quartz crystal microbalance (m-QCM), followed by film ex situ X-ray diffraction (XRD) and scanning electron microscopy (SEM) investigations allowed to determine the effect of deposition parameters on the thin films' microstructural changes. Changing the pulse width, while keeping the duty cycle constant, modified the discharge composition in the target region and the ionised fraction of the sputtered species in the substrate region. The maximum Cu ionised fraction (19 %) was found for 50 μs, resulting in compact and smooth morphology for Cu-rich films, whereas short 25 μs pulses provided porous columnar films with rough surfaces, as the result from Ar+ bombardment. For Ag-rich films, Ag segregation allowed the deposition of dense layers, regardless of the used pulse width. Furthermore, low Ag (<10 at.%) CuAgZr films produced via HiPIMS and direct-current magnetron sputtering (DCMS) were compared in terms of structural and mechanical property changes as a function of Zr contents. For the studied chemical composition range, a linear relationship between Zr content, XRD phase shift and mechanical properties was observed for HiPIMS films, in contrast to DCMS's more abrupt transitions. An increase in hardness and elastic modulus (up to 44 % and 22 %, respectively) was found for the HiPIMS films compared to DCMS ones. The obtained results highlight HiPIMS's flexibility in providing a wide range of tailoring possibilities to meet specific application requirements, such as crystalline microstructure, density and associated mechanical properties

Electromagnetic Counterparts of Compact Object Mergers Powered by the Radioactive Decay of R-process Nuclei

The most promising astrophysical sources of kHz gravitational waves (GWs) are the inspiral and merger of binary neutron star(NS)/black hole systems. Maximizing the scientific return of a GW detection will require identifying a coincident electro-magnetic (EM) counterpart. One of the most likely sources of isotropic EM emission from compact object mergers is a supernova-like transient powered by the radioactive decay of heavy elements synthesized in ejecta from the merger. We present the first calculations of the optical transients from compact object mergers that self-consistently determine the radioactive heating by means of a nuclear reaction network; using this heating rate, we model the light curve with a one dimensional Monte Carlo radiation transfer calculation. For an ejecta mass ~1e-2 M_sun[1e-3 M_sun] the resulting light curve peaks on a timescale ~ 1 day at a V-band luminosity nu L_nu ~ 3e41[1e41] ergs/s (M_V = -15[-14]); this corresponds to an effective "f" parameter ~3e-6 in the Li-Paczynski toy model. We argue that these results are relatively insensitive to uncertainties in the relevant nuclear physics and to the precise early-time dynamics and ejecta composition. Due to the rapid evolution and low luminosity of NS merger transients, EM counterpart searches triggered by GW detections will require close collaboration between the GW and astronomical communities. NS merger transients may also be detectable following a short-duration Gamma-Ray Burst or "blindly" with present or upcoming optical transient surveys. Because the emission produced by NS merger ejecta is powered by the formation of rare r-process elements, current optical transient surveys can directly constrain the unknown origin of the heaviest elements in the Universe.Comment: 14 pages, 7 figures; accepted to MNRAS; title changed to highlight r-process connection and new figure added

Electromagnetic counterparts of compact object mergers powered by the radioactive decay of r-process nuclei

The most promising astrophysical sources of kHz gravitational waves (GWs) are the inspiral and merger of binary neutron star(NS)/black hole systems. Maximizing the scientific return of a GW detection will require identifying a coincident electromagnetic (EM) counterpart. One of the most likely sources of isotropic EM emission from compact object mergers is a supernova-like transient powered by the radioactive decay of heavy elements synthesized in ejecta from the merger. We present the first calculations of the optical transients from compact object mergers that self-consistently determine the radioactive heating by means of a nuclear reaction network; using this heating rate, we model the light curve with a one-dimensional Monte Carlo radiation transfer calculation. For an ejecta mass ∼10−2 M⊙ (10−3 M⊙) the resulting light-curve peaks on a time-scale ∼1 d at a V-band luminosity νLν∼ 3 × 1041 (1041) erg s−1[MV=−15(−14)]; this corresponds to an effective ‘f' parameter ∼3 × 10−6 in the Li-Paczynski toy model. We argue that these results are relatively insensitive to uncertainties in the relevant nuclear physics and to the precise early-time dynamics and ejecta composition. Since NS merger transients peak at a luminosity that is a factor of ∼103 higher than a typical nova, we propose naming these events ‘kilo-novae'. Because of the rapid evolution and low luminosity of NS merger transients, EM counterpart searches triggered by GW detections will require close collaboration between the GW and astronomical communities. NS merger transients may also be detectable following a short-duration gamma-ray burst or ‘blindly' with present or upcoming optical transient surveys. Because the emission produced by NS merger ejecta is powered by the formation of rare r-process elements, current optical transient surveys can directly constrain the unknown origin of the heaviest elements in the Univers

A Detailed Observational Analysis of V1324 Sco, the Most Gamma-Ray Luminous Classical Nova to Date

It has recently been discovered that some, if not all, classical novae emit GeV gamma rays during outburst, but the mechanisms involved in the production of the gamma rays are still not well understood. We present here a comprehensive multi-wavelength dataset---from radio to X-rays---for the most gamma-ray luminous classical nova to-date, V1324 Sco. Using this dataset, we show that V1324 Sco is a canonical dusty Fe-II type nova, with a maximum ejecta velocity of 2600 km s$^{-1}$ and an ejecta mass of few $\times 10^{-5}$ M$_{\odot}$. There is also evidence for complex shock interactions, including a double-peaked radio light curve which shows high brightness temperatures at early times. To explore why V1324~Sco was so gamma-ray luminous, we present a model of the nova ejecta featuring strong internal shocks, and find that higher gamma-ray luminosities result from higher ejecta velocities and/or mass-loss rates. Comparison of V1324~Sco with other gamma-ray detected novae does not show clear signatures of either, and we conclude that a larger sample of similarly well-observed novae is needed to understand the origin and variation of gamma rays in novae.Comment: 26 pages, 13 figure

Skeletal levels of bisphosphonate in the setting of chronic kidney disease are independent of remodeling rate and lower with fractionated dosing

Background Chronic kidney disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher acute skeletal accumulation of fluorescently-tagged zoledronate (ZOL) in the setting of CKD but how this accumulation is retained/lost over time is unclear. Furthermore, it is unknown if alternative dosing approaches can modulate accumulation in the setting of CKD. Methods To address these two questions normal (NL) and Cy/+ (CKD) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), a single dose of non-labelled zoledronate (ZOL) or ten weekly doses of FAM-ZOL each at 1/10th the dose of the single dose group. Half of the CKD animals in each group were provided water with 3% calcium in drinking water (CKD + Ca) to suppress PTH and remodeling. At 30 or 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected and subjected to assessment methods including biochemistry, dynamic histomorphometry and multi-spectral fluorescence levels (using IVIS SpectrumCT). Results FAM-ZOL did not significantly reduce bone remodeling in either NL or CKD animals while Ca supplementation in CKD produced remodeling levels comparable to NL. At five- and ten-weeks post-dosing, both CKD and CKD + Ca groups had higher levels of FAM-ZOL in most, but not all, skeletal sites compared to NL with no difference between the two CKD groups suggesting that the rate of remodeling did not affect skeletal retention of FAM-ZOL. Fractionating the FAM-ZOL into ten weekly doses led to 20–32% less (p < 0.05) accumulation/retention of compound in the vertebra, radius, and ulna compared to administration as a single dose. Conclusions The rate of bone turnover does not have significant effects on levels of FAM-ZOL accumulation/retention in animals with CKD. A lower dose/more frequent administration paradigm results in lower levels of accumulation/retention over time. These data provide information that could better inform the use of bisphosphonates in the setting of CKD in order to combat the dramatic increase in fracture risk

Experiences of refugees and asylum seekers in general practice: a qualitative study

Background: There has been much debate regarding the refugee health situation in the UK. However most of the existing literature fails to take account of the opinions of refugees themselves. This study was established to determine the views of asylum seekers and refugees on their overall experiences in primary care and to suggest improvements to their care. Methods: Qualitative study of adult asylum seekers and refugees who had entered the UK in the last 10 years. The study was set in Barnet Refugee Walk in Service, London. 11 Semi structured interviews were conducted and analysed using framework analysis. Results: Access to GPs may be more difficult for failed asylum seekers and those without support from refugee agencies or family. There may be concerns amongst some in the refugee community regarding the access to and confidentiality of professional interpreters. Most participants stated their preference for GPs who offered advice rather than prescriptions. The stigma associated with refugee status in the UK may have led to some refugees altering their help seeking behaviour. Conclusion: The problem of poor access for those with inadequate support may be improved by better education and support for GPs in how to provide for refugees. Primary Care Trusts could also supply information to newly arrived refugees on how to access services. GPs should be aware that, in some situations, professional interpreters may not always be desired and that instead, it may be advisable to reach a consensus as to who should be used as an interpreter. A better doctor-patient experience resulting from improvements in access and communication may help to reduce the stigma associated with refugee status and lead to more appropriate help seeking behaviour. Given the small nature of our investigation, larger studies need to be conducted to confirm and to quantify these results