Genetic variation and recent positive selection in worldwide human populations: Evidence from nearly 1 million SNPs

BACKGROUND: Genome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world. METHODOLOGY: We genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level. CONCLUSIONS: Our analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature

Direct imaging of a massive dust cloud around R Coronae Borealis

We present recent polarimetric images of the highly variable star R CrB using ExPo and archival WFPC2 images from the HST. We observed R CrB during its current dramatic minimum where it decreased more than 9 mag due to the formation of an obscuring dust cloud. Since the dust cloud is only in the line-of-sight, it mimics a coronograph allowing the imaging of the star's circumstellar environment. Our polarimetric observations surprisingly show another scattering dust cloud at approximately 1.3" or 2000 AU from the star. We find that to obtain a decrease in the stellar light of 9 mag and with 30% of the light being reemitted at infrared wavelengths (from R CrB's SED) the grains in R CrB's circumstellar environment must have a very low albedo of approximately 0.07%. We show that the properties of the dust clouds formed around R CrB are best fitted using a combination of two distinct populations of grains size. The first are the extremely small 5 nm grains, formed in the low density continuous wind, and the second population of large grains (~0.14 {\mu}m) which are found in the ejected dust clouds. The observed scattering cloud, not only contains such large grains, but is exceptionally massive compared to the average cloud.Comment: 8 pages, 7 figures published in A&

The Ever Changing Circumstellar Nebula Around UW Centauri

We present new images of the reflection nebula surrounding the R Coronae Borealis Star, UW Cen. This nebula, first detected in 1990, has changed its appearance significantly. At the estimated distance of UW Cen, this nebula is approximately 0.6 ly in radius so the nebula cannot have physically altered in only 8 years. Instead, the morphology of the nebula appears to change as different parts are illuminated by light from the central star modulated by shifting thick dust clouds near its surface. These dust clouds form and dissipate at irregular intervals causing the well-known declines in the R Coronae Borealis (RCB) stars. In this way, the central star acts like a lighthouse shining through holes in the dust clouds and lighting up different portions of the nebula. The existence of this nebula provides clues to the evolutionary history of RCB stars possibly linking them to the Planetary Nebulae and the final helium shell flash stars.Comment: To be published in ApJ Letters. 5 pages, 3 figures (2 in color

Spectropolarimetry of R Coronae Borealis in 1998--2003: Discovery of Transient Polarization at Maximum Brightness

We present an extended optical spectropolarimetry of R CrB from 1998 January to 2003 September. The polarization was almost constant in the phase of maximum brightness, being consistent with past observations. We detected, however, temporal changes of polarization ($\sim 0.5$ %) in 2001 March and August, which were the first detection of large polarization variability in R CrB near maximum brightness. The amplitude and the position angle of the `transient polarization' were almost constant with wavelength in both two events. There was a difference by about 20 degrees in the position angle between the two events. Each event could be explained by light scattering due to short-lived dust puff occasionally ejected off the line of sight. The flatness of the polarization against the wavelength suggests that the scatterer is a mixture of dust grains having various sizes. The rapid growth and fading of the transient polarization favors the phenomenological model of dust formation near the stellar photosphere (e.g., within two stellar radii) proposed for the time evolution of brightness and chromospheric emission lines during deeply declining periods, although the fading timescale can hardly be explained by a simple dispersal of expanding dust puff with a velocity of $\sim 200-350$ km s $^{-1}$. Higher expansion velocity or some mechanism to destroy the dust grains should be needed.Comment: 22 pages, 10 figures, accepted for publication in A

Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats.

Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC = 0.1 microg/ml), antibiotic was administered at 12- or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED(50) (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED(90) of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy

Feasibility studies of the time-like proton electromagnetic form factor measurements with PANDA at FAIR

The possibility of measuring the proton electromagnetic form factors in the time-like region at FAIR with the \PANDA detector is discussed. Detailed simulations on signal efficiency for the annihilation of $\bar p +p$ into a lepton pair as well as for the most important background channels have been performed. It is shown that precision measurements of the differential cross section of the reaction $\bar p +p \to e^++ e^-$ can be obtained in a wide angular and kinematical range. The individual determination of the moduli of the electric and magnetic proton form factors will be possible up to a value of momentum transfer squared of $q^2\simeq 14$ (GeV/c)$^2$. The total $\bar p +p\to e^++e^-$ cross section will be measured up to $q^2\simeq 28$ (GeV/c)$^2$. The results obtained from simulated events are compared to the existing data. Sensitivity to the two photons exchange mechanism is also investigated.Comment: 12 pages, 4 tables, 8 figures Revised, added details on simulations, 4 tables, 9 figure

Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use

Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a “resistant” variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching

Feasibility studies of time-like proton electromagnetic form factors at PANDA at FAIR

Simulation results for future measurements of electromagnetic proton form factors at \PANDA (FAIR) within the PandaRoot software framework are reported. The statistical precision with which the proton form factors can be determined is estimated. The signal channel $\bar p p \to e^+ e^-$ is studied on the basis of two different but consistent procedures. The suppression of the main background channel, $\textit{i.e.}$ $\bar p p \to \pi^+ \pi^-$, is studied. Furthermore, the background versus signal efficiency, statistical and systematical uncertainties on the extracted proton form factors are evaluated using two different procedures. The results are consistent with those of a previous simulation study using an older, simplified framework. However, a slightly better precision is achieved in the PandaRoot study in a large range of momentum transfer, assuming the nominal beam conditions and detector performance

Two HIV-1 Variants Resistant to Small Molecule CCR5 Inhibitors Differ in How They Use CCR5 for Entry

HIV-1 variants resistant to small molecule CCR5 inhibitors recognize the inhibitor-CCR5 complex, while also interacting with free CCR5. The most common genetic route to resistance involves sequence changes in the gp120 V3 region, a pathway followed when the primary isolate CC1/85 was cultured with the AD101 inhibitor in vitro, creating the CC101.19 resistant variant. However, the D1/86.16 escape mutant contains no V3 changes but has three substitutions in the gp41 fusion peptide. By using CCR5 point-mutants and gp120-targeting agents, we have investigated how infectious clonal viruses derived from the parental and both resistant isolates interact with CCR5. We conclude that the V3 sequence changes in CC101.19 cl.7 create a virus with an increased dependency on interactions with the CCR5 N-terminus. Elements of the CCR5 binding site associated with the V3 region and the CD4-induced (CD4i) epitope cluster in the gp120 bridging sheet are more exposed on the native Env complex of CC101.19 cl.7, which is sensitive to neutralization via these epitopes. However, D1/86.16 cl.23 does not have an increased dependency on the CCR5 N-terminus, and its CCR5 binding site has not become more exposed. How this virus interacts with the inhibitor-CCR5 complex remains to be understood