396 research outputs found
Stevin numbers and reality
We explore the potential of Simon Stevin's numbers, obscured by shifting
foundational biases and by 19th century developments in the arithmetisation of
analysis.Comment: 22 pages, 4 figures. arXiv admin note: text overlap with
arXiv:1104.0375, arXiv:1108.2885, arXiv:1108.420
Viral population estimation using pyrosequencing
The diversity of virus populations within single infected hosts presents a
major difficulty for the natural immune response as well as for vaccine design
and antiviral drug therapy. Recently developed pyrophosphate based sequencing
technologies (pyrosequencing) can be used for quantifying this diversity by
ultra-deep sequencing of virus samples. We present computational methods for
the analysis of such sequence data and apply these techniques to pyrosequencing
data obtained from HIV populations within patients harboring drug resistant
virus strains. Our main result is the estimation of the population structure of
the sample from the pyrosequencing reads. This inference is based on a
statistical approach to error correction, followed by a combinatorial algorithm
for constructing a minimal set of haplotypes that explain the data. Using this
set of explaining haplotypes, we apply a statistical model to infer the
frequencies of the haplotypes in the population via an EM algorithm. We
demonstrate that pyrosequencing reads allow for effective population
reconstruction by extensive simulations and by comparison to 165 sequences
obtained directly from clonal sequencing of four independent, diverse HIV
populations. Thus, pyrosequencing can be used for cost-effective estimation of
the structure of virus populations, promising new insights into viral
evolutionary dynamics and disease control strategies.Comment: 23 pages, 13 figure
Crystallographic reconstruction study of the effects of finish rolling temperature on the variant selection during bainite transformation in C-Mn high-strength steels
The effect of finish rolling temperature (FRT) on the austenite- ()
to-bainite () phase transformation is quantitatively investigated in
high-strength C-Mn steels. In particular, the present study aims to clarify the
respective contributions of the conditioning during the hot rolling and the
variant selection (VS) during the phase transformation to the inherited
texture. To this end, an alternative crystallographic reconstruction procedure,
which can be directly applied to experimental electron backscatter diffraction
(EBSD) mappings, is developed by combining the best features of the existing
models: the orientation relationship (OR) refinement, the local pixel-by-pixel
analysis and the nuclei identification and spreading strategy. The
applicability of this method is demonstrated on both quenching and partitioning
(Q&P) and as-quenched lath-martensite steels. The results obtained on the C-Mn
steels confirm that the sample finish rolled at the lowest temperature
(829{\deg}C) exhibits the sharpest transformation texture. It is shown that
this sharp texture is exclusively due to a strong VS from parent brass
{110}, S {213} and Goss {110} grains, whereas the VS from the
copper {112} grains is insensitive to the FRT. In addition, a
statistical VS analysis proves that the habit planes of the selected variants
do not systematically correspond to the predicted active slip planes using the
Taylor model. In contrast, a correlation between the Bain group to which the
selected variants belong and the FRT is clearly revealed, regardless of the
parent orientation. These results are discussed in terms of polygranular
accommodation mechanisms, especially in view of the observed development in the
hot-rolled samples of high-angle grain boundaries with misorientation axes
between and
Ten Misconceptions from the History of Analysis and Their Debunking
The widespread idea that infinitesimals were "eliminated" by the "great
triumvirate" of Cantor, Dedekind, and Weierstrass is refuted by an
uninterrupted chain of work on infinitesimal-enriched number systems. The
elimination claim is an oversimplification created by triumvirate followers,
who tend to view the history of analysis as a pre-ordained march toward the
radiant future of Weierstrassian epsilontics. In the present text, we document
distortions of the history of analysis stemming from the triumvirate ideology
of ontological minimalism, which identified the continuum with a single number
system. Such anachronistic distortions characterize the received interpretation
of Stevin, Leibniz, d'Alembert, Cauchy, and others.Comment: 46 pages, 4 figures; Foundations of Science (2012). arXiv admin note:
text overlap with arXiv:1108.2885 and arXiv:1110.545
Prototype Tests for the CELESTE Solar Array Gamma--Ray Telescope
The CELESTE experiment will be an Atmospheric Cherenkov detector designed to
bridge the gap in energy sensitivity between current satellite and ground-based
gamma-ray telescopes, 20 to 300 GeV. We present test results made at the former
solar power plant, Themis, in the French Pyrenees. The tests confirm the
viability of using a central tower heliostat array for Cherenkov wavefront
sampling.Comment: LaTeX2e,30 pages including 14 figures, accepted for publication by
Nuclear Instruments & Methods Section
High-Resolution Functional Mapping of the Venezuelan Equine Encephalitis Virus Genome by Insertional Mutagenesis and Massively Parallel Sequencing
We have developed a high-resolution genomic mapping technique that combines transposon-mediated insertional mutagenesis with either capillary electrophoresis or massively parallel sequencing to identify functionally important regions of the Venezuelan equine encephalitis virus (VEEV) genome. We initially used a capillary electrophoresis method to gain insight into the role of the VEEV nonstructural protein 3 (nsP3) in viral replication. We identified several regions in nsP3 that are intolerant to small (15 bp) insertions, and thus are presumably functionally important. We also identified nine separate regions in nsP3 that will tolerate small insertions at low temperatures (30°C), but not at higher temperatures (37°C, and 40°C). Because we found this method to be extremely effective at identifying temperature sensitive (ts) mutations, but limited by capillary electrophoresis capacity, we replaced the capillary electrophoresis with massively parallel sequencing and used the improved method to generate a functional map of the entire VEEV genome. We identified several hundred potential ts mutations throughout the genome and we validated several of the mutations in nsP2, nsP3, E3, E2, E1 and capsid using single-cycle growth curve experiments with virus generated through reverse genetics. We further demonstrated that two of the nsP3 ts mutants were attenuated for virulence in mice but could elicit protective immunity against challenge with wild-type VEEV. The recombinant ts mutants will be valuable tools for further studies of VEEV replication and virulence. Moreover, the method that we developed is applicable for generating such tools for any virus with a robust reverse genetics system
Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
Background
Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs.
Methods
Samples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain.
Results
We cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC50 to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure.
Conclusions
Here we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally
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