Lilit Yeghiazarian

Immune Activation, Cd4+ T Cell Counts, and Viremia Exhibit Oscillatory Patterns over Time in Patients with Highly Resistant HIV Infection

The rates of immunologic and clinical progression are lower in patients with drug-resistant HIV compared to wild-type HIV. This difference is not fully explained by viral load. It has been argued that reductions in T cell activation and/or viral fitness might result in preserved target cells and an altered relationship between the level of viremia and the rate of CD4+ T cell loss. We tested this hypothesis over time in a cohort of patients with highly resistant HIV. Fifty-four antiretroviral-treated patients with multi-drug resistant HIV and detectable plasma HIV RNA were followed longitudinally. CD4+ T cell counts and HIV RNA levels were measured every 4 weeks and T cell activation (CD38/HLA-DR) was measured every 16 weeks. We found that the levels of CD4+ T cell activation over time were a strong independent predictor of CD4+ T cell counts while CD8+ T cell activation was more strongly associated with viremia. Using spectral analysis, we found strong evidence for oscillatory (or cyclic) behavior in CD4+ T cell counts, HIV RNA levels, and T cell activation. Each of the cell populations exhibited an oscillatory behavior with similar frequencies. Collectively, these data suggest that there may be a mechanistic link between T cell activation, CD4+ T cell counts, and viremia and lends support for the hypothesis of altered predator-prey dynamics as a possible explanation of the stability of CD4+ T cell counts in the presence of sustained multi-drug resistant viremia.

A screening-level modeling approach to estimate nitrogen loading and standard exceedance risk, with application to the Tippecanoe River watershed, Indiana

This paper presents a screening-level modeling approach that can be used to rapidly estimate nutrient loading, assess numerical nutrient standard exceedance risk of surface waters leading to potential classification as impaired for designated use, and explore best management practice (BMP) implementation to reduce loading with a relatively low data requirement. The modeling framework uses a hybrid statistical and process based approach to estimate source of pollutants, their transport and decay in the terrestrial and aquatic parts of watersheds. The framework is developed in the ArcGIS environment and is based on the total maximum daily load (TMDL) balance model. Nitrogen (N) is currently addressed in the framework, referred to as WQM-TMDL-N. Loading for each catchment includes non-point sources (NPS) and point sources (PS). The probability of a nutrient load to exceed a target load is evaluated using probabilistic risk assessment, by including the uncertainty associated with export coefficients of various land uses. In an application of this modeling approach to the Tippecanoe River watershed in Indiana, USA, total nitrogen (TN) loading, confidence interval and risk of standard exceedance leading to potential impairment were estimated. Model results suggest that decay coefficients decrease, and delivery fractions increase with increasing stream order. The spatial distribution pattern of delivered incremental TN yield shows a trend similar to that of the delivery fraction in this watershed. The target TN exceedance risk increases considerably when switching from Indiana draft-N benchmark to far lower EPA-proposed TN criteria, suggesting that load reduction to meet the latter criteria may benefit from BMP implementation through source control and delivery reduction.

Markov model of sex-linked recessive trait transmission

A Markov model of sex-linked recessive trait transmission is developed with genotypes viewed as the states of the transmission process and the changes of generations considered to occur at discrete moments of time. Gender and a linked recessive gene are considered simultaneously, and in contrast to conventional approaches, mating is not confined to the offspring of the same couple but is random and permitted among all the members of the population. Recessive gene inherited diseases haemophilia A and Duchenne muscular dystrophy are used to illustrate the model, and direct calculations from a case study of a mild haemophilia A pedigree which includes about 10% of Greek haemophiliacs showed good agreement with the results of model calculations.

A Stochastic Multi-Scale Model of HIV-1 Transmission for Decision-Making: Application to a MSM Population

Background In the absence of an effective vaccine against HIV-1, the scientific community is presented with the challenge of developing alternative methods to curb its spread. Due to the complexity of the disease, however, our ability to predict the impact of various prevention and treatment strategies is limited. While ART has been widely accepted as the gold standard of modern care, its timing is debated. Objectives To evaluate the impact of medical interventions at the level of individuals on the spread of infection across the whole population. Specifically, we investigate the impact of ART initiation timing on HIV-1 spread in an MSM (Men who have Sex with Men) population. Design and Methods A stochastic multi-scale model of HIV-1 transmission that integrates within a single framework the in-host cellular dynamics and their outcomes, patient health states, and sexual contact networks. The model captures disease state and progression within individuals, and allows for simulation of therapeutic strategies. Results Early ART initiation may substantially affect disease spread through a population. Conclusions Our model provides a multi-scale, systems-based approach to evaluate the broader implications of therapeutic strategies.

A Feasibility Study of the Pore Topology Method (PTM), A Medial Surface-Based Approach to Multi-phase Flow Simulation in Porous Media

Computationally efficient microscale models designed to simulate multi-phase flow and characterize low-porosity media are challenged in thin, highly porous materials, primarily due to large, irregular pore spaces and inability to satisfy representative elementary volume requirements. In this article, we describe the pore topology method (PTM) and explore its capabilities to characterize a set of isotropic fibrous materials and to simulate multi-phase flow. PTM is a fast, algorithmically simple method that reduces the complexity of the 3-D void space geometry to its topologically consistent medial surface and uses it as a solution domain for single- and multi-phase flow simulations. Our results in permeability calculations, pore size distribution, and quasi-static drainage and imbibition simulations are in very good agreement with other numerical methods and analytical solutions. We expect that incorporating detailed spatial information about the porous media structure into the medial surface will enable a more accurate representation of the void space structure and of physical phenomena involved in multi-phase flow, thus expanding the applicability of PTM to a broader range of porous media, including non-fibrous materials.

Field Calibration and Verification of a Pathogen Transport Model

Outbreaks of cryptosporidiosis throughout the world, especially the massive outbreak in Milwakee in 1993 drew public attention to the quality of drinking water supplies and to the efficiency of water treatment methods. Cryptosporidiosis is a severe gastrointestinal disease caused by the transmissive form of Cryptosporidium parvum protozoan – its oocysts. Digestion of as few as 30 oocysts may be fatal to infants, elderly and immunocompromized persons. C. parvum oocysts are ubiquitous in untreated water and extremely resistant to harsh environmental conditions including standard water treatment procedures. We have developed an integrated modeling strategy to quantify the risk of surface drinking water contamination by water borne pathogens, in particular the oocysts of C. parvum, from agricultural non-point pollution sources. This project is comprised of both a modeling and an experimental effort. The main experimental effort focused on the measurement of C. parvum oocysts partitioning in the soil/water systems with the objective of parameterizing the transport model. This title belongs to WERF Research Report Series ISBN: 9781780404271 (eBook) ISBN: 9781843397113 (Print)

Role of temperature in quanta mechanisms of facilitation in the frog neuromuscular junction

Abstract The results of computer simulations on the Double Barrier Synapse (DBS) model are presented which quantify the relationship between the synapse parameters and the quanta transfer process. The DBS model is applicable to a variety of states of synaptic activity, and by changing the synapse parameters it is possible to simulate various conditions of quanta transmission. The influence of the bathing solution temperature change on the synaptic parameters under different conditions of transmitter release in the frog neuromuscular junction is investigated. Simulations demonstrate that several synaptic parameters, including the parameters of the presynaptic membrane, are not affected by the temperature change. It is shown that a stimulation frequency exists at which the steady-state level of facilitation during a long train of stimuli is the same for a wide range of temperatures.

Incorporation of the Water Erosion Prediction Project (WEPP) in the Modeling of Transport of Pathogenic Microorganisms From Non-Point Sources of Pollution

High intensity agriculture such as cattle feedlots and land application of manure is a significant source of Cryptosporidium parvum oocysts and other pathogens in drinking water supplies. Our research concentrates on the development of a mathematical model of pathogen transport and interactions in the overland flow. The transport of microorganisms is considered in two broad categories: microorganisms attached to mineral or organic substrates in suspended sediment; and unattached microorganisms suspended in overland flow. The strength of attachment of microorganisms to soil particles is determined by the chemical characteristics of soils which are highly correlated with the particle size. The particle size class distribution in the suspended sediment is predicted by the WEPP. The model is based on the deterministic analog of the Chapman-Kolmogorov equations. The parameters of the process can be random or deterministic depending on the mechanism of transfer of microorganisms from one phase to another. The solutions provide the temporal and spatial distribution of microorganisms in solid and aqueous phase as a function of hydrological, soil and microorganism properties.