2,775 research outputs found
Safety and Immunogenicity of a Replication-Defective Adenovirus Type 5 HIV Vaccine in Ad5-Seronegative Persons: A Randomized Clinical Trial (HVTN 054)
BACKGROUND: Individuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses. METHODOLOGY/PRINCIPAL FINDINGS: Volunteers received one dose of vaccine at either 10(10) or 10(11) adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients. CONCLUSIONS/SIGNIFICANCE: This vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119873
Acceleration of generalized hypergeometric functions through precise remainder asymptotics
We express the asymptotics of the remainders of the partial sums {s_n} of the
generalized hypergeometric function q+1_F_q through an inverse power series z^n
n^l \sum_k c_k/n^k, where the exponent l and the asymptotic coefficients {c_k}
may be recursively computed to any desired order from the hypergeometric
parameters and argument. From this we derive a new series acceleration
technique that can be applied to any such function, even with complex
parameters and at the branch point z=1. For moderate parameters (up to
approximately ten) a C implementation at fixed precision is very effective at
computing these functions; for larger parameters an implementation in higher
than machine precision would be needed. Even for larger parameters, however,
our C implementation is able to correctly determine whether or not it has
converged; and when it converges, its estimate of its error is accurate.Comment: 36 pages, 6 figures, LaTeX2e. Fixed sign error in Eq. (2.28), added
several references, added comparison to other methods, and added discussion
of recursion stabilit
Chromatic Illumination Discrimination Ability Reveals that Human Colour Constancy Is Optimised for Blue Daylight Illuminations
The phenomenon of colour constancy in human visual perception keeps surface colours constant, despite changes in their reflected light due to changing illumination. Although colour constancy has evolved under a constrained subset of illuminations, it is unknown whether its underlying mechanisms, thought to involve multiple components from retina to cortex, are optimised for particular environmental variations. Here we demonstrate a new method for investigating colour constancy using illumination matching in real scenes which, unlike previous methods using surface matching and simulated scenes, allows testing of multiple, real illuminations. We use real scenes consisting of solid familiar or unfamiliar objects against uniform or variegated backgrounds and compare discrimination performance for typical illuminations from the daylight chromaticity locus (approximately blue-yellow) and atypical spectra from an orthogonal locus (approximately red-green, at correlated colour temperature 6700 K), all produced in real time by a 10-channel LED illuminator. We find that discrimination of illumination changes is poorer along the daylight locus than the atypical locus, and is poorest particularly for bluer illumination changes, demonstrating conversely that surface colour constancy is best for blue daylight illuminations. Illumination discrimination is also enhanced, and therefore colour constancy diminished, for uniform backgrounds, irrespective of the object type. These results are not explained by statistical properties of the scene signal changes at the retinal level. We conclude that high-level mechanisms of colour constancy are biased for the blue daylight illuminations and variegated backgrounds to which the human visual system has typically been exposed
Lactate signalling regulates fungal β-glucan masking and immune evasion
AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin
Excess Higgs Production in Neutralino Decays
The ATLAS and CMS experiments have recently claimed discovery of a Higgs
boson-like particle at ~5 sigma confidence and are beginning to test the
Standard Model predictions for its production and decay. In a variety of
supersymmetric models, a neutralino NLSP can decay dominantly to the Higgs and
the LSP. In natural SUSY models, a light third generation squark decaying
through this chain can lead to large excess Higgs production while evading
existing BSM searches. Such models can be observed at the 8 TeV LHC in channels
exploiting the rare diphoton decays of the Higgs produced in the cascade decay.
Identifying a diphoton resonance in association with missing energy, a lepton,
or b-tagged jets is a promising search strategy for discovery of these models,
and would immediately signal new physics involving production of a Higgs boson.
We also discuss the possibility that excess Higgs production in these SUSY
decays can be responsible for enhancements of up to 50% over the SM prediction
for the observed rate in the existing inclusive diphoton searches, a scenario
which would likely by the end of the 8 TeV run be accompanied by excesses in
the diphoton + lepton/MET and SUSY multi-lepton/b searches and a potential
discovery in a diphoton + 2b search.Comment: 42 pages, 19 figure
A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines
Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications
P2P Web service based system for supporting decision-making in cellular manufacturing scheduling
With the increase of the Internet and Virtual Enterprises (VEs), interfaces for web systems and automated services are becoming an emergent necessity. In this paper we propose a Peer-to-peer (P2P) web-based decision-support system for enabling access to different manufacturing scheduling methods, which can be remotely available and accessible from a distributed knowledge base. The XML-based modeling and communication is applied to manufacturing scheduling. Therefore, manufacturing scheduling problems and methods are modeled using XML. The proposed P2P web-based system works as web services, under the SOAP protocol. The system’s distributed knowledge base enables sharing information about scheduling problems and corresponding solving methods in a widened search space, through a scheduling community, integrating a VE. Running several methods enables different results for a given problem, consequently, contributing for a better decision-making. An important aspect is that this knowledge base can be easily and continuously updated by any contributor through the VE. Moreover, through this system once suitable available methods, for a given problem, are identified, it enables running one or more of them, for enabling a better manufacturing scheduling support, enhanced though incorporated fuzzy decision-making proceduresAichi Science and Technology Foundation(PTDC/EME-GIN/102143/2008)info:eu-repo/semantics/publishedVersio
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Proteomic analysis of Artemisia annua – towards elucidating the biosynthetic pathways of the antimalarial pro-drug artemisinin
Background: MS-based proteomics was applied to the analysis of the medicinal plant Artemisia annua, exploiting a recently published contig sequence database (Graham et al. (2010) Science 327, 328–331) and other genomic and proteomic sequence databases for comparison. A. annua is the predominant natural source of artemisinin, the precursor for artemisinin-based combination therapies (ACTs), which are the WHO-recommended treatment for P. falciparum malaria.
Results: The comparison of various databases containing A. annua sequences (NCBInr/viridiplantae, UniProt/
viridiplantae, UniProt/A. annua, an A. annua trichome Trinity contig database, the above contig database and
another A. annua EST database) revealed significant differences in respect of their suitability for proteomic analysis, showing that an organism-specific database that has undergone extensive curation, leading to longer contig sequences, can greatly increase the number of true positive protein identifications, while reducing the number of false positives. Compared to previously published data an order-of-magnitude more proteins have been identified from trichome-enriched A. annua samples, including proteins which are known to be involved in the biosynthesis of artemisinin, as well as other highly abundant proteins, which suggest additional enzymatic processes occurring within the trichomes that are important for the biosynthesis of artemisinin.
Conclusions: The newly gained information allows for the possibility of an enzymatic pathway, utilizing
peroxidases, for the less well understood final stages of artemisinin’s biosynthesis, as an alternative to the known non-enzymatic in vitro conversion of dihydroartemisinic acid to artemisinin. Data are available via ProteomeXchange with identifier PXD000703
Asymmetric Origin for Gravitino Relic Density in the Hybrid Gravity-Gauge Mediated Supersymmetry Breaking
We propose the hybrid gravity-gauge mediated supersymmetry breaking where the
gravitino mass is about several GeV. The strong constraints on supersymmetry
viable parameter space from the CMS and ATLAS experiments at the LHC can be
relaxed due to the heavy colored supersymmetric particles, and it is consistent
with null results in the dark matter (DM) direct search experiments such as
XENON100. In particular, the possible maximal flavor and CP violations from the
relatively small gravity mediation may naturally account for the recent LHCb
anomaly. In addition, because the gravitino mass is around the asymmetric DM
mass, we propose the asymmetric origin of the gravitino relic density and solve
the cosmological coincident problem on the DM and baryon densities \Omega_{\rm
DM}:\Omega_{B}\approx 5:1. The gravitino relic density arises from asymmetric
metastable particle (AMP) late decay. However, we show that there is no AMP
candidate in the minimal supersymmetric Standard Model (SM) due to the robust
gaugino/Higgsino mediated wash-out effects. Interestingly, AMP can be realized
in the well motivated supersymmetric SMs with vector-like particles or
continuous U(1)_R symmetry. Especially, the lightest CP-even Higgs boson mass
can be lifted in the supersymmetric SMs with vector-like particles.Comment: RevTex4, 21 pages, 1 figure, minor corrections, JHEP versio
The what and where of adding channel noise to the Hodgkin-Huxley equations
One of the most celebrated successes in computational biology is the
Hodgkin-Huxley framework for modeling electrically active cells. This
framework, expressed through a set of differential equations, synthesizes the
impact of ionic currents on a cell's voltage -- and the highly nonlinear impact
of that voltage back on the currents themselves -- into the rapid push and pull
of the action potential. Latter studies confirmed that these cellular dynamics
are orchestrated by individual ion channels, whose conformational changes
regulate the conductance of each ionic current. Thus, kinetic equations
familiar from physical chemistry are the natural setting for describing
conductances; for small-to-moderate numbers of channels, these will predict
fluctuations in conductances and stochasticity in the resulting action
potentials. At first glance, the kinetic equations provide a far more complex
(and higher-dimensional) description than the original Hodgkin-Huxley
equations. This has prompted more than a decade of efforts to capture channel
fluctuations with noise terms added to the Hodgkin-Huxley equations. Many of
these approaches, while intuitively appealing, produce quantitative errors when
compared to kinetic equations; others, as only very recently demonstrated, are
both accurate and relatively simple. We review what works, what doesn't, and
why, seeking to build a bridge to well-established results for the
deterministic Hodgkin-Huxley equations. As such, we hope that this review will
speed emerging studies of how channel noise modulates electrophysiological
dynamics and function. We supply user-friendly Matlab simulation code of these
stochastic versions of the Hodgkin-Huxley equations on the ModelDB website
(accession number 138950) and
http://www.amath.washington.edu/~etsb/tutorials.html.Comment: 14 pages, 3 figures, review articl
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