Low-Level HIV-I Replication and the Dynamics of the Resting CD4(+) T Cell Reservoir for HIV-I in the Setting of HAART

In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-I (HIV-I) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4(+) T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-I infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells. Methods: Here we use a mathematical model of T cell dynamics in the setting of HIV-I infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART. Results: By comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model. Conclusion: The intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-I infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.NIH AI 065960, AI 143222, AI 51178Doris Duke Charitable FoundationThe Howard Hughes Medical InstituteIntegrative Biolog

Tradeoff between short-term and long-term adaptation in a changing environment

We investigate the competition dynamics of two microbial or viral strains that live in an environment that switches periodically between two states. One of the strains is adapted to the long-term environment, but pays a short-term cost, while the other is adapted to the short-term environment and pays a cost in the long term. We explore the tradeoff between these alternative strategies in extensive numerical simulations, and present a simple analytic model that can predict the outcome of these competitions as a function of the mutation rate and the time scale of the environmental changes. Our model is relevant for arboviruses, which alternate between different host species on a regular basis.Comment: 9 pages, 3 figures, PRE in pres

Strong magnetoresistance induced by long-range disorder

We calculate the semiclassical magnetoresistivity $\rho_{xx}(B)$ of non-interacting fermions in two dimensions moving in a weak and smoothly varying random potential or random magnetic field. We demonstrate that in a broad range of magnetic fields the non-Markovian character of the transport leads to a strong positive magnetoresistance. The effect is especially pronounced in the case of a random magnetic field where $\rho_{xx}(B)$ becomes parametrically much larger than its B=0 value.Comment: REVTEX, 4 pages, 2 eps figure

Zero-frequency anomaly in quasiclassical ac transport: Memory effects in a two-dimensional metal with a long-range random potential or random magnetic field

We study the low-frequency behavior of the {\it ac} conductivity $\sigma(\omega)$ of a two-dimensional fermion gas subject to a smooth random potential (RP) or random magnetic field (RMF). We find a non-analytic $\propto|\omega|$ correction to ${\rm Re} \sigma$, which corresponds to a $1/t^2$ long-time tail in the velocity correlation function. This contribution is induced by return processes neglected in Boltzmann transport theory. The prefactor of this $|\omega|$-term is positive and proportional to $(d/l)^2$ for RP, while it is of opposite sign and proportional to $d/l$ in the weak RMF case, where $l$ is the mean free path and $d$ the disorder correlation length. This non-analytic correction also exists in the strong RMF regime, when the transport is of a percolating nature. The analytical results are supported and complemented by numerical simulations.Comment: 12 pages, RevTeX, 7 figure

The Error and Repair Catastrophes: A Two-Dimensional Phase Diagram in the Quasispecies Model

This paper develops a two gene, single fitness peak model for determining the equilibrium distribution of genotypes in a unicellular population which is capable of genetic damage repair. The first gene, denoted by $\sigma_{via}$, yields a viable organism with first order growth rate constant $k > 1$ if it is equal to some target ``master'' sequence $\sigma_{via, 0}$. The second gene, denoted by $\sigma_{rep}$, yields an organism capable of genetic repair if it is equal to some target ``master'' sequence $\sigma_{rep, 0}$. This model is analytically solvable in the limit of infinite sequence length, and gives an equilibrium distribution which depends on \mu \equiv L\eps , the product of sequence length and per base pair replication error probability, and \eps_r , the probability of repair failure per base pair. The equilibrium distribution is shown to exist in one of three possible ``phases.'' In the first phase, the population is localized about the viability and repairing master sequences. As \eps_r exceeds the fraction of deleterious mutations, the population undergoes a ``repair'' catastrophe, in which the equilibrium distribution is still localized about the viability master sequence, but is spread ergodically over the sequence subspace defined by the repair gene. Below the repair catastrophe, the distribution undergoes the error catastrophe when $\mu$ exceeds \ln k/\eps_r , while above the repair catastrophe, the distribution undergoes the error catastrophe when $\mu$ exceeds $\ln k/f_{del}$, where $f_{del}$ denotes the fraction of deleterious mutations.Comment: 14 pages, 3 figures. Submitted to Physical Review

Exploring differential effects of an intervention on historical inquiry tasks: a qualitative analysis of 12th-grade students’ progress

Multiple-documents-based (inquiry) tasks are often used to examine historical thinking, as they require students to apply discipline-specific ways of reasoning and writing. Intervention studies using such tasks have often relied on principles from cognitive apprenticeship to make these discipline-specific heuristics explicit to students. While several studies have found positive results, they offer little insight into how and where exactly students’ progress on historical thinking manifests itself, nor into the differential effects of the intervention. Building on essay data gathered during an intervention study on students’ historical inquiry skills, this study explores differential effects of the intervention according to students’ initial historical inquiry ability. To this end, a purposeful sample of students was selected for whom the intervention was particularly effective. The qualitative analysis of students’ essay tasks (pretest and posttest) revealed remarkable differences between students with high and low pretest scores. Although both groups made progress on all aspects of the essay task, they differed in terms of where and how this progress manifested itself: at posttest, students with a high initial score outperformed others in evaluating sources and rebuttals. This study offers insight into patterns of progress in students’ historical inquiry skills which can inform differentiation in instructional practices

Structural evolution drives diversification of the large LRR-RLK gene family

Cells are continuously exposed to chemical signals that they must discriminate between and respond to appropriately. In embryophytes, the leucine‐rich repeat receptor‐like kinases (LRR‐RLKs) are signal receptors critical in development and defense. LRR‐RLKs have diversified to hundreds of genes in many plant genomes. Although intensively studied, a well‐resolved LRR‐RLK gene tree has remained elusive. To resolve the LRR‐RLK gene tree, we developed an improved gene discovery method based on iterative hidden Markov model searching and phylogenetic inference. We used this method to infer complete gene trees for each of the LRR‐RLK subclades and reconstructed the deepest nodes of the full gene family. We discovered that the LRR‐RLK gene family is even larger than previously thought, and that protein domain gains and losses are prevalent. These structural modifications, some of which likely predate embryophyte diversification, led to misclassification of some LRR‐RLK variants as members of other gene families. Our work corrects this misclassification. Our results reveal ongoing structural evolution generating novel LRR‐RLK genes. These new genes are raw material for the diversification of signaling in development and defense. Our methods also enable phylogenetic reconstruction in any large gene family

Re-entrant ferroelectricity in liquid crystals

The ferroelectric (Sm C$^*$) -- antiferroelectric (Sm C$^*_A$) -- reentrant ferroelectric (re Sm C$^*$) phase temperature sequence was observed for system with competing synclinic - anticlinic interactions. The basic properties of this system are as follows (1) the Sm C$^*$ phase is metastable in temperature range of the Sm C$^*_A$ stability (2) the double inversions of the helix handedness at Sm C$^*$ -- Sm C$^*_A$ and Sm C$^*_A$% -- re-Sm C$^*$ phase transitions were found (3) the threshold electric field that is necessary to induce synclinic ordering in the Sm C$^*_A$ phase decreases near both Sm C$^*_A$ -- Sm C$^*$ and Sm C$^*_A$ -- re-Sm C$^*$ phase boundaries, and it has maximum in the middle of the Sm C$^*_A$ stability region. All these properties are properly described by simple Landau model that accounts for nearest neighboring layer steric interactions and quadrupolar ordering only.Comment: 10 pages, 5 figures, submitted to PR

Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART

<p>Abstract</p> <p>Background</p> <p>In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4⁺T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.</p> <p>Methods</p> <p>Here we use a mathematical model of T cell dynamics in the setting of HIV-1 infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART.</p> <p>Results</p> <p>By comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model.</p> <p>Conclusion</p> <p>The intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-1 infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.</p