Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients.

Naturally acquired blood-stage infections of the malaria parasite Plasmodium falciparum typically harbour multiple haploid clones. The apparent number of clones observed in any single infection depends on the diversity of the polymorphic markers used for the analysis, and the relative abundance of rare clones, which frequently fail to be detected among PCR products derived from numerically dominant clones. However, minority clones are of clinical interest as they may harbour genes conferring drug resistance, leading to enhanced survival after treatment and the possibility of subsequent therapeutic failure. We deployed new generation sequencing to derive genome data for five non-propagated parasite isolates taken directly from 4 different patients treated for clinical malaria in a UK hospital. Analysis of depth of coverage and length of sequence intervals between paired reads identified both previously described and novel gene deletions and amplifications. Full-length sequence data was extracted for 6 loci considered to be under selection by antimalarial drugs, and both known and previously unknown amino acid substitutions were identified. Full mitochondrial genomes were extracted from the sequencing data for each isolate, and these are compared against a panel of polymorphic sites derived from published or unpublished but publicly available data. Finally, genome-wide analysis of clone multiplicity was performed, and the number of infecting parasite clones estimated for each isolate. Each patient harboured at least 3 clones of P. falciparum by this analysis, consistent with results obtained with conventional PCR analysis of polymorphic merozoite antigen loci. We conclude that genome sequencing of peripheral blood P. falciparum taken directly from malaria patients provides high quality data useful for drug resistance studies, genomic structural analyses and population genetics, and also robustly represents clonal multiplicity

Relative sea-level change in northeastern Florida (USA) during the last ~8.0 ka

An existing database of relative sea-level (RSL) reconstructions from the U.S. Atlantic coast lacked valid sea-level index points from Georgia and Florida. This region lies on the edge of the collapsing forebulge of the former Laurentide Ice Sheet making it an important location for understanding glacio-isostatic adjustment and the history of ice-sheet melt. To address the paucity of data, we reconstruct RSL in northeastern Florida (St. Marys) over the last ∼8.0 ka from samples of basal salt-marsh sediment that minimize the influence of compaction. The analogy between modern salt-marsh foraminifera and their fossil counterparts preserved in the sedimentary record was used to estimate paleomarsh surface elevation. Sample ages were determined by radiocarbon dating of identifiable and in-situ plant macrofossils. This approach yielded 25 new sea-level index points that constrain a ∼5.7 m rise in RSL during the last ∼8.0 ka. The record shows that no highstand in sea level occurred in this region over the period of the reconstruction. We compared the new reconstruction to Earth-ice models ICE 6G-C VM5a and ICE 6G-C VM6. There is good fit in the later part of the Holocene with VM5a and for a brief time in the earlier Holocene with VM6. However, there are discrepancies in model-reconstruction fit in the early to mid Holocene in northeastern Florida and elsewhere along the Atlantic coast at locations with early Holocene RSL reconstructions. The most pronounced feature of the new reconstruction is a slow down in the rate of RSL rise from approximately 5.0 to 3.0 ka. This trend may reflect a significant contribution from local-scale processes such as tidal-range change and/or change in base flow of the St. Marys River in response to paleoclimate changes. However, the spatial expression (local vs. regional) of this slow down is undetermined and corroborative records are needed to establish its geographical extent

Predictive coding and representationalism

According to the predictive coding theory of cognition (PCT), brains are predictive machines that use perception and action to minimize prediction error, i.e. the discrepancy between bottom–up, externally-generated sensory signals and top–down, internally-generated sensory predictions. Many consider PCT to have an explanatory scope that is unparalleled in contemporary cognitive science and see in it a framework that could potentially provide us with a unified account of cognition. It is also commonly assumed that PCT is a representational theory of sorts, in the sense that it postulates that our cognitive contact with the world is mediated by internal representations. However, the exact sense in which PCT is representational remains unclear; neither is it clear that it deserves such status—that is, whether it really invokes structures that are truly and nontrivially representational in nature. In the present article, I argue that the representational pretensions of PCT are completely justified. This is because the theory postulates cognitive structures—namely action-guiding, detachable, structural models that afford representational error detection—that play genuinely representational functions within the cognitive system

Search for Dark Matter Annihilation in the Galactic Center with IceCube-79

The Milky Way is expected to be embedded in a halo of dark matter particles, with the highest density in the central region, and decreasing density with the halo-centric radius. Dark matter might be indirectly detectable at Earth through a flux of stable particles generated in dark matter annihilations and peaked in the direction of the Galactic Center. We present a search for an excess flux of muon (anti-) neutrinos from dark matter annihilation in the Galactic Center using the cubic-kilometer-sized IceCube neutrino detector at the South Pole. There, the Galactic Center is always seen above the horizon. Thus, new and dedicated veto techniques against atmospheric muons are required to make the southern hemisphere accessible for IceCube. We used 319.7 live-days of data from IceCube operating in its 79-string configuration during 2010 and 2011. No neutrino excess was found and the final result is compatible with the background. We present upper limits on the self-annihilation cross-section, \left, for WIMP masses ranging from 30 GeV up to 10 TeV, assuming cuspy (NFW) and flat-cored (Burkert) dark matter halo profiles, reaching down to $\simeq 4 \cdot 10^{-24}$ cm$^3$ s$^{-1}$, and $\simeq 2.6 \cdot 10^{-23}$ cm$^3$ s$^{-1}$ for the $\nu\overline{\nu}$ channel, respectively.Comment: 14 pages, 9 figures, Submitted to EPJ-C, added references, extended limit overvie

The IceCube Neutrino Observatory - Contributions to ICRC 2015 Part II: Atmospheric and Astrophysical Diffuse Neutrino Searches of All Flavors

Papers on atmospheric and astrophysical diffuse neutrino searches of all flavors submitted to the 34th International Cosmic Ray Conference (ICRC 2015, The Hague) by the IceCube Collaboration.Comment: 66 pages, 36 figures, Papers submitted to the 34th International Cosmic Ray Conference, The Hague 2015, v2 has a corrected author lis

A combined maximum-likelihood analysis of the high-energy astrophysical neutrino flux measured with IceCube

Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for neutrino events with deposited energies $\gtrsim30$ TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, $\nu_\mu$-induced tracks from the Northern hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index $-2.50\pm0.09$ and a flux at 100 TeV of $\left(6.7_{-1.2}^{+1.1}\right)\cdot10^{-18}\,\mathrm{GeV}^{-1}\mathrm{s}^{-1}\mathrm{sr}^{-1}\mathrm{cm}^{-2}$. Under the same assumptions, an unbroken power law with index $-2$ is disfavored with a significance of 3.8 $\sigma$ ($p=0.0066\%$) with respect to the best fit. This significance is reduced to 2.1 $\sigma$ ($p=1.7\%$) if instead we compare the best fit to a spectrum with index $-2$ that has an exponential cut-off at high energies. Allowing the electron neutrino flux to deviate from the other two flavors, we find a $\nu_e$ fraction of $0.18\pm0.11$ at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay dominated sources, is rejected with a significance of 3.6 $\sigma$ ($p=0.014\%$).Comment: 16 pages, 10 figures; accepted for publication in The Astrophysical Journal; updated one referenc

The IceCube Neutrino Observatory: Instrumentation and Online Systems

The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.Comment: 83 pages, 50 figures; updated with minor changes from journal review and proofin

Characterization of the Atmospheric Muon Flux in IceCube

Muons produced in atmospheric cosmic ray showers account for the by far dominant part of the event yield in large-volume underground particle detectors. The IceCube detector, with an instrumented volume of about a cubic kilometer, has the potential to conduct unique investigations on atmospheric muons by exploiting the large collection area and the possibility to track particles over a long distance. Through detailed reconstruction of energy deposition along the tracks, the characteristics of muon bundles can be quantified, and individual particles of exceptionally high energy identified. The data can then be used to constrain the cosmic ray primary flux and the contribution to atmospheric lepton fluxes from prompt decays of short-lived hadrons. In this paper, techniques for the extraction of physical measurements from atmospheric muon events are described and first results are presented. The multiplicity spectrum of TeV muons in cosmic ray air showers for primaries in the energy range from the knee to the ankle is derived and found to be consistent with recent results from surface detectors. The single muon energy spectrum is determined up to PeV energies and shows a clear indication for the emergence of a distinct spectral component from prompt decays of short-lived hadrons. The magnitude of the prompt flux, which should include a substantial contribution from light vector meson di-muon decays, is consistent with current theoretical predictions.Comment: 36 pages, 39 figure