Evolution of malaria virulence in cross-generation transmission through selective immune pressure

Theoretical arguments and some mathematical models of host-parasite coevolution (e.g. [1- 6]) suggest host immunity as the driving source for the evolution of parasite virulence. Imperfect vaccines in particular, can play the role and recent work [7] sets to test these ideas experimentally, using the mouse malaria model, Plasmodium chabaudi. To this end the authors evolve parasite lines in immunized and nonimmunized (“naïve”) mice using serial passage of infected blood samples. They find parasite lines evolved in immunized mice become more virulent than those evolved in naive mice. Furthermore, this feature persisted even when the evolved strains were transmitted through mosquitoes. 
Here we develop a mathematical model of parasite dynamics that qualitatively reproduces the experimental results of [7]. Our model accounts for the basic in-host processes: (i) production and depletion of red blood cells (RBC); (ii) immune-modulated parasite growth/ replication, (iii) immune stimulation and clearing of parasite. Besides we introduce multiple parasite strains with variable levels of virulence, and allow random mutations during replication process. The virulence is represented by a single parameter – immune stimulation threshold. So more virulent strains have higher “tolerance levels”, hence increased RBC depletion (anemia). 
Numeric simulations with our model exhibit, as in [7] the overall evolution of virulence in serial passage of parasite strains, and its enhancement through partial (imperfect) immunization

Time-Dependent Vacuum Energy Induced by D-Particle Recoil

We consider cosmology in the framework of a `material reference system' of D particles, including the effects of quantum recoil induced by closed-string probe particles. We find a time-dependent contribution to the cosmological vacuum energy, which relaxes to zero as $\sim 1/ t^2$ for large times $t$. If this energy density is dominant, the Universe expands with a scale factor $R(t) \sim t^2$. We show that this possibility is compatible with recent observational constraints from high-redshift supernovae, and may also respect other phenomenological bounds on time variation in the vacuum energy imposed by early cosmology.Comment: 14 pages LATEX, no figure

Quantum Phase Space from String Solitons

In this paper we view the sigma-model couplings of appropriate vertex operators describing the interaction of string matter with a certain type of string solitons (0-branes) as the quantum phase space of a point particle. The sigma-model is slightly non critical, and therefore one should dress it with a Liouville mode. Quantization is achieved by summing over world-sheet genera (in the pinched approximation). To leading order in the coupling constant expansion, the quantization reproduces the usual quantum mechanical commutator. We attempt to go beyond leading order and we reproduce the generalized string uncertainty principle.Comment: 32 pages LATEX, correction of a minor typo in formula (88

Graviton 1-loop partition function for 3-dimensional massive gravity

The graviton 1-loop partition function in Euclidean topologically massive gravity (TMG) is calculated using heat kernel techniques. The partition function does not factorize holomorphically, and at the chiral point it has the structure expected from a logarithmic conformal field theory. This gives strong evidence for the proposal that the dual conformal field theory to TMG at the chiral point is indeed logarithmic. We also generalize our results to new massive gravity.Comment: 19 pages, v2: major revision, considerably stronger conclusions, added comparison with LCFT partition function, confirmation of LCFT conjecture, added autho

Dynamical Formation of Horizons in Recoiling D Branes

A toy calculation of string/D-particle interactions within a world-sheet approach indicates that quantum recoil effects - reflecting the gravitational back-reaction on space-time foam due to the propagation of energetic particles - induces the appearance of a microscopic event horizon, or `bubble', inside which stable matter can exist. The scattering event causes this horizon to expand, but we expect quantum effects to cause it to contract again, in a `bounce' solution. Within such `bubbles', massless matter propagates with an effective velocity that is less than the velocity of light in vacuo, which may lead to observable violations of Lorentz symmetry that may be tested experimentally. The conformal invariance conditions in the interior geometry of the bubbles select preferentially three for the number of the spatial dimensions, corresponding to a consistent formulation of the interaction of D3 branes with recoiling D particles, which are allowed to fluctuate independently only on the D3-brane hypersurface.Comment: 25 pages LaTeX, 4 eps figures include

Mathematical Modeling of Malaria Infection with Innate and Adaptive Immunity in Individuals and Agent-Based Communities

Background: Agent-based modeling of Plasmodium falciparum infection offers an attractive alternative to the conventional Ross-Macdonald methodology, as it allows simulation of heterogeneous communities subjected to realistic transmission (inoculation patterns). Methodology/Principal Findings: We developed a new, agent based model that accounts for the essential in-host processes: parasite replication and its regulation by innate and adaptive immunity. The model also incorporates a simplified version of antigenic variation by Plasmodium falciparum. We calibrated the model using data from malaria-therapy (MT) studies, and developed a novel calibration procedure that accounts for a deterministic and a pseudo-random component in the observed parasite density patterns. Using the parasite density patterns of 122 MT patients, we generated a large number of calibrated parameters. The resulting data set served as a basis for constructing and simulating heterogeneous agent-based (AB) communities of MT-like hosts. We conducted several numerical experiments subjecting AB communities to realistic inoculation patterns reported from previous field studies, and compared the model output to the observed malaria prevalence in the field. There was overall consistency, supporting the potential of this agent-based methodology to represent transmission in realistic communities. Conclusions/Significance: Our approach represents a novel, convenient and versatile method to model Plasmodiu

Testing A (Stringy) Model of Quantum Gravity

I discuss a specific model of space-time foam, inspired by the modern non-perturbative approach to string theory (D-branes). The model views our world as a three brane, intersecting with D-particles that represent stringy quantum gravity effects, which can be real or virtual. In this picture, matter is represented generically by (closed or open) strings on the D3 brane propagating in such a background. Scattering of the (matter) strings off the D-particles causes recoil of the latter, which in turn results in a distortion of the surrounding space-time fluid and the formation of (microscopic, i.e. Planckian size) horizons around the defects. As a mean-field result, the dispersion relation of the various particle excitations is modified, leading to non-trivial optical properties of the space time, for instance a non-trivial refractive index for the case of photons or other massless probes. Such models make falsifiable predictions, that may be tested experimentally in the foreseeable future. I describe a few such tests, ranging from observations of light from distant gamma-ray-bursters and ultra high energy cosmic rays, to tests using gravity-wave interferometric devices and terrestrial particle physics experients involving, for instance, neutral kaons.Comment: 25 pages LATEX, four figures incorporated, uses special proceedings style. Invited talk at the third international conference on Dark Matter in Astro and Particle Physics, DARK2000, Heidelberg, Germany, July 10-15 200

Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases

Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination ‘as a public health problem’ when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models’ predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020

Genetic Assignment Methods for Gaining Insight into the Management of Infectious Disease by Understanding Pathogen, Vector, and Host Movement

For many pathogens with environmental stages, or those carried by vectors or intermediate hosts, disease transmission is strongly influenced by pathogen, host, and vector movements across complex landscapes, and thus quantitative measures of movement rate and direction can reveal new opportunities for disease management and intervention. Genetic assignment methods are a set of powerful statistical approaches useful for establishing population membership of individuals. Recent theoretical improvements allow these techniques to be used to cost-effectively estimate the magnitude and direction of key movements in infectious disease systems, revealing important ecological and environmental features that facilitate or limit transmission. Here, we review the theory, statistical framework, and molecular markers that underlie assignment methods, and we critically examine recent applications of assignment tests in infectious disease epidemiology. Research directions that capitalize on use of the techniques are discussed, focusing on key parameters needing study for improved understanding of patterns of disease