927 research outputs found
Pre-existence and emergence of drug resistance in a generalized model of intra-host viral dynamics
AbstractUnderstanding the source of drug resistance emerging within a treated patient is an important problem, from both clinical and basic evolutionary perspectives. Resistant mutants may arise de novo either before or after treatment is initiated, with different implications for prevention. Here we investigate this problem in the context of chronic viral diseases, such as human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV and HCV). We present a unified model of viral population dynamics within a host, which can capture a variety of viral life cycles. This allows us to identify which results generalize across various viral diseases, and which are sensitive to the particular virus's life cycle. Accurate analytical approximations are derived that allow for a solid understanding of the parameter dependencies in the system. We find that the mutation-selection balance attained prior to treatment depends on the step at which mutations occur and the viral trait that incurs the cost of resistance. Life cycle effects and key parameters, including mutation rate, infected cell death rate, cost of resistance, and drug efficacy, play a role in determining when mutations arising during treatment are important relative to those pre-existing
Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe
Objective To assess the association between pandemic influenza A (H1N1) 2009 vaccine and Guillain-Barré syndrome
Error Thresholds on Dynamic Fittness-Landscapes
In this paper we investigate error-thresholds on dynamics fitness-landscapes.
We show that there exists both lower and an upper threshold, representing
limits to the copying fidelity of simple replicators. The lower bound can be
expressed as a correction term to the error-threshold present on a static
landscape. The upper error-threshold is a new limit that only exists on dynamic
fitness-landscapes. We also show that for long genomes on highly dynamic
fitness-landscapes there exists a lower bound on the selection pressure needed
to enable effective selection of genomes with superior fitness independent of
mutation rates, i.e., there are distinct limits to the evolutionary parameters
in dynamic environments.Comment: 5 page
Coordinated optimization of visual cortical maps (I) Symmetry-based analysis
In the primary visual cortex of primates and carnivores, functional
architecture can be characterized by maps of various stimulus features such as
orientation preference (OP), ocular dominance (OD), and spatial frequency. It
is a long-standing question in theoretical neuroscience whether the observed
maps should be interpreted as optima of a specific energy functional that
summarizes the design principles of cortical functional architecture. A
rigorous evaluation of this optimization hypothesis is particularly demanded by
recent evidence that the functional architecture of OP columns precisely
follows species invariant quantitative laws. Because it would be desirable to
infer the form of such an optimization principle from the biological data, the
optimization approach to explain cortical functional architecture raises the
following questions: i) What are the genuine ground states of candidate energy
functionals and how can they be calculated with precision and rigor? ii) How do
differences in candidate optimization principles impact on the predicted map
structure and conversely what can be learned about an hypothetical underlying
optimization principle from observations on map structure? iii) Is there a way
to analyze the coordinated organization of cortical maps predicted by
optimization principles in general? To answer these questions we developed a
general dynamical systems approach to the combined optimization of visual
cortical maps of OP and another scalar feature such as OD or spatial frequency
preference.Comment: 90 pages, 16 figure
Chronic y-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures
The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer’s disease (AD). Amyloid bpeptide (Ab), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APPswe/PS1L166P)–green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type g-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug
Explicit kinetic heterogeneity: mechanistic models for interpretation of labeling data of heterogeneous cell populations
Estimation of division and death rates of lymphocytes in different conditions
is vital for quantitative understanding of the immune system. Deuterium, in the
form of deuterated glucose or heavy water, can be used to measure rates of
proliferation and death of lymphocytes in vivo. Inferring these rates from
labeling and delabeling curves has been subject to considerable debate with
different groups suggesting different mathematical models for that purpose. We
show that the three models that are most commonly used are in fact
mathematically identical and differ only in their interpretation of the
estimated parameters. By extending these previous models, we here propose a
more mechanistic approach for the analysis of data from deuterium labeling
experiments. We construct a model of "kinetic heterogeneity" in which the total
cell population consists of many sub-populations with different rates of cell
turnover. In this model, for a given distribution of the rates of turnover, the
predicted fraction of labeled DNA accumulated and lost can be calculated. Our
model reproduces several previously made experimental observations, such as a
negative correlation between the length of the labeling period and the rate at
which labeled DNA is lost after label cessation. We demonstrate the reliability
of the new explicit kinetic heterogeneity model by applying it to artificially
generated datasets, and illustrate its usefulness by fitting experimental data.
In contrast to previous models, the explicit kinetic heterogeneity model 1)
provides a mechanistic way of interpreting labeling data; 2) allows for a
non-exponential loss of labeled cells during delabeling, and 3) can be used to
describe data with variable labeling length
Theory of nuclear spin conversion in ethylene
First theoretical analysis of the nuclear spin conversion in ethylene
molecules (13^CCH4) has been performed. The conversion rate was found equal
approx. 3x10^{-4} 1/s*Torr, which is in qualitative agreement with the recently
obtained experimental value. It was shown that the ortho-para mixing in 13^CCH4
is dominated by the spin-rotation coupling. Mixing of only two pairs of
ortho-para levels were found to contribute significantly to the spin
conversion.Comment: 20 pages, 5 eps figure
Defining forgiveness: Christian clergy and general population perspectives.
The lack of any consensual definition of forgiveness is a serious weakness in the research literature (McCullough, Pargament & Thoresen, 2000). As forgiveness is at the core of Christianity, this study returns to the Christian source of the concept to explore the meaning of forgiveness for practicing Christian clergy. Comparisons are made with a general population sample and social science definitions of forgiveness to ensure that a shared meaning of forgiveness is articulated. Anglican and Roman Catholic clergy (N = 209) and a general population sample (N = 159) completed a postal questionnaire about forgiveness. There is agreement on the existence of individual differences in forgiveness. Clergy and the general population perceive reconciliation as necessary for forgiveness while there is no consensus within psychology. The clergy suggests that forgiveness is limitless and that repentance is unnecessary while the general population suggests that there are limits and that repentance is necessary. Psychological definitions do not conceptualize repentance as necessary for forgiveness and the question of limits has not been addressed although within therapy the implicit assumption is that forgiveness is limitless.</p
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