1,801 research outputs found
Preadaptation of pandemic GII.4Â noroviruses in unsampled virus reservoirs years before emergence
The control of re-occurring pandemic pathogens requires understanding the origins of new pandemic variants and the factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have hypothesized that new GII.4 pandemic viruses arise when previously circulating pandemic or pre-pandemic variants undergo substitutions in antigenic regions that enable evasion of host population immunity, as described by conventional models of antigenic drift. In contrast, we show here that the acquisition of new genetic and antigenic characteristics cannot be the proximal driver of new pandemics. Pandemic GII.4 viruses diversify and spread over wide geographical areas over several years prior to simultaneous pandemic emergence of multiple lineages, indicating that the necessary sequence changes must have occurred before diversification, years prior to pandemic emergence. We confirm this result through serological assays of reconstructed ancestral virus capsids, demonstrating that by 2003, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics
Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population
Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia
Existence, uniqueness and structure of second order absolute minimisers
Let ⊆ Rn be a bounded open C1,1 set. In this paper we prove the existence
of a unique second order absolute minimiser u∞ of the functional
E∞(u, O) := F(·, u)L∞(O), O ⊆ measurable,
with prescribed boundary conditions for u and Du on ∂ and under natural assumptions
on F. We also show that u∞ is partially smooth and there exists a harmonic
function f∞ ∈ L1() such that
F(x, u∞(x)) = e∞ sgn
f∞(x)
for all x ∈ { f∞ = 0}, where e∞ is the infimum of the global energy
Co-evolution of density and topology in a simple model of city formation
We study the influence that population density and the road network have on
each others' growth and evolution. We use a simple model of formation and
evolution of city roads which reproduces the most important empirical features
of street networks in cities. Within this framework, we explicitely introduce
the topology of the road network and analyze how it evolves and interact with
the evolution of population density. We show that accessibility issues -pushing
individuals to get closer to high centrality nodes- lead to high density
regions and the appearance of densely populated centers. In particular, this
model reproduces the empirical fact that the density profile decreases
exponentially from a core district. In this simplified model, the size of the
core district depends on the relative importance of transportation and rent
costs.Comment: 13 pages, 13 figure
Representation of Time-Varying Stimuli by a Network Exhibiting Oscillations on a Faster Time Scale
Sensory processing is associated with gamma frequency oscillations (30–80 Hz) in sensory cortices. This raises the question whether gamma oscillations can be directly involved in the representation of time-varying stimuli, including stimuli whose time scale is longer than a gamma cycle. We are interested in the ability of the system to reliably distinguish different stimuli while being robust to stimulus variations such as uniform time-warp. We address this issue with a dynamical model of spiking neurons and study the response to an asymmetric sawtooth input current over a range of shape parameters. These parameters describe how fast the input current rises and falls in time. Our network consists of inhibitory and excitatory populations that are sufficient for generating oscillations in the gamma range. The oscillations period is about one-third of the stimulus duration. Embedded in this network is a subpopulation of excitatory cells that respond to the sawtooth stimulus and a subpopulation of cells that respond to an onset cue. The intrinsic gamma oscillations generate a temporally sparse code for the external stimuli. In this code, an excitatory cell may fire a single spike during a gamma cycle, depending on its tuning properties and on the temporal structure of the specific input; the identity of the stimulus is coded by the list of excitatory cells that fire during each cycle. We quantify the properties of this representation in a series of simulations and show that the sparseness of the code makes it robust to uniform warping of the time scale. We find that resetting of the oscillation phase at stimulus onset is important for a reliable representation of the stimulus and that there is a tradeoff between the resolution of the neural representation of the stimulus and robustness to time-warp.
Author Summary
Sensory processing of time-varying stimuli, such as speech, is associated with high-frequency oscillatory cortical activity, the functional significance of which is still unknown. One possibility is that the oscillations are part of a stimulus-encoding mechanism. Here, we investigate a computational model of such a mechanism, a spiking neuronal network whose intrinsic oscillations interact with external input (waveforms simulating short speech segments in a single acoustic frequency band) to encode stimuli that extend over a time interval longer than the oscillation's period. The network implements a temporally sparse encoding, whose robustness to time warping and neuronal noise we quantify. To our knowledge, this study is the first to demonstrate that a biophysically plausible model of oscillations occurring in the processing of auditory input may generate a representation of signals that span multiple oscillation cycles.National Science Foundation (DMS-0211505); Burroughs Wellcome Fund; U.S. Air Force Office of Scientific Researc
Solving Nonlinear Parabolic Equations by a Strongly Implicit Finite-Difference Scheme
We discuss the numerical solution of nonlinear parabolic partial differential
equations, exhibiting finite speed of propagation, via a strongly implicit
finite-difference scheme with formal truncation error . Our application of interest is the spreading of
viscous gravity currents in the study of which these type of differential
equations arise. Viscous gravity currents are low Reynolds number (viscous
forces dominate inertial forces) flow phenomena in which a dense, viscous fluid
displaces a lighter (usually immiscible) fluid. The fluids may be confined by
the sidewalls of a channel or propagate in an unconfined two-dimensional (or
axisymmetric three-dimensional) geometry. Under the lubrication approximation,
the mathematical description of the spreading of these fluids reduces to
solving the so-called thin-film equation for the current's shape . To
solve such nonlinear parabolic equations we propose a finite-difference scheme
based on the Crank--Nicolson idea. We implement the scheme for problems
involving a single spatial coordinate (i.e., two-dimensional, axisymmetric or
spherically-symmetric three-dimensional currents) on an equispaced but
staggered grid. We benchmark the scheme against analytical solutions and
highlight its strong numerical stability by specifically considering the
spreading of non-Newtonian power-law fluids in a variable-width confined
channel-like geometry (a "Hele-Shaw cell") subject to a given mass
conservation/balance constraint. We show that this constraint can be
implemented by re-expressing it as nonlinear flux boundary conditions on the
domain's endpoints. Then, we show numerically that the scheme achieves its full
second-order accuracy in space and time. We also highlight through numerical
simulations how the proposed scheme accurately respects the mass
conservation/balance constraint.Comment: 36 pages, 9 figures, Springer book class; v2 includes improvements
and corrections; to appear as a contribution in "Applied Wave Mathematics II
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