Process Calculi Abstractions for Biology

Several approaches have been proposed to model biological systems by means of the formal techniques and tools available in computer science. To mention just a few of them, some representations are inspired by Petri Nets theory, and some other by stochastic processes. A most recent approach consists in interpreting the living entities as terms of process calculi where the behavior of the represented systems can be inferred by applying syntax-driven rules. A comprehensive picture of the state of the art of the process calculi approach to biological modeling is still missing. This paper goes in the direction of providing such a picture by presenting a comparative survey of the process calculi that have been used and proposed to describe the behavior of living entities. This is the preliminary version of a paper that was published in Algorithmic Bioprocesses. The original publication is available at http://www.springer.com/computer/foundations/book/978-3-540-88868-

Brane Calculi Systems: A Static Preview of their Possible Behaviour

We improve the precision of a previous Control Flow Analysis for Brane Calculi, by adding information on the context and introducing causality information on the membranes. This allows us to prove some biological properties on the behaviour of systems specified in Brane Calculi.Comment: Presented at MeCBIC 201

Types for BioAmbients

The BioAmbients calculus is a process algebra suitable for representing compartmentalization, molecular localization and movements between compartments. In this paper we enrich this calculus with a static type system classifying each ambient with group types specifying the kind of compartments in which the ambient can stay. The type system ensures that, in a well-typed process, ambients cannot be nested in a way that violates the type hierarchy. Exploiting the information given by the group types, we also extend the operational semantics of BioAmbients with rules signalling errors that may derive from undesired ambients' moves (i.e. merging incompatible tissues). Thus, the signal of errors can help the modeller to detect and locate unwanted situations that may arise in a biological system, and give practical hints on how to avoid the undesired behaviour

A Global Occurrence Counting Analysis for Brane Calculi

We propose a polynomial static analysis for Brane Calculi, based on Abstract Interpretation techniques. The analysis provides a description of the possible hierarchical structure of membranes and of the processes possibly associated to each membrane, together with global occurrence counting information. Our analysis can be applied in the biological setting to investigate systems in which the information on the number of membranes occurring in the system plays a crucial role

A Taxonomy of Causality-Based Biological Properties

We formally characterize a set of causality-based properties of metabolic networks. This set of properties aims at making precise several notions on the production of metabolites, which are familiar in the biologists' terminology. From a theoretical point of view, biochemical reactions are abstractly represented as causal implications and the produced metabolites as causal consequences of the implication representing the corresponding reaction. The fact that a reactant is produced is represented by means of the chain of reactions that have made it exist. Such representation abstracts away from quantities, stoichiometric and thermodynamic parameters and constitutes the basis for the characterization of our properties. Moreover, we propose an effective method for verifying our properties based on an abstract model of system dynamics. This consists of a new abstract semantics for the system seen as a concurrent network and expressed using the Chemical Ground Form calculus. We illustrate an application of this framework to a portion of a real metabolic pathway

An assessment of solute kinetics and the application of mathematical modelling in the haemodialysis process

AIM: The aim of this thesis is to enhance knowledge about solute clearance during haemodialysis and to provide insight into factors that may influence dialysis efficiency. By improving the understanding of the kinetics of solute removal the limitations of current dialysis therapy will be better understood, and suggestions can be made for future improvements in the delivery of dialysis.METHODS: The history of dialysis technique and adequacy measurement is detailed. The origin and potential problems with urea kinetic modelling, including the effect of high haematocrit on adequacy, are explored.Mathematical modelling is utilised to provide potential explanations for the clearance characteristics of phosphate and beta2-microglobulin during chronic dialysis. The phosphate model is explored further with studies in acute renal failure and the effect of dialysis on intra-erythrocytic phosphate concentrations is assessed. Diurnal variation in phosphate concentration is explored.The effect of different dialysis modalities on beta2-microgloblin levels and symptoms of dialysis related amyloid is studied. Dialysis related amyloid deposition is investigated by a scintigraphic imaging technique.RESULTS: Haematocrit. High haematocrit is not found to have a significant effect on the clearance of solutes across a wide range of molecular size.Phosphate. A four-pool model that can be applied in both acute and chronic renal failure is proposed to explain the observed kinetic behaviour of phosphate. Studies of intracellular phosphate concentrations fail to demonstrate release of phosphate from erythrocytic stores during dialysis. Diurnal variation in phosphate concentration is demonstrated in subjects with normal renal function and also in advanced chronic kidney disease.Beta2-microglobulin. A multi-pool model explains the kinetic behaviour of beta2- microglobulin during dialysis. Beta-2-microglobulin deposition is assumed to be a staged process with some deposits easily accessible during dialysis and some more resistant to depuration. Patients receiving high-flux dialysis or haemodiafiltration are shown to have lower circulating beta2-microglobulin levels and less symptomatic dialysis related amyloid, but evidence of amyloid deposition is still found when assessed by a scintigraphic imaging technique. Age and duration of dialysis are shown to be the best predictors of symptomatic amyloid deposition.CONCLUSIONS: The results of the studies in this thesis indicate that, for solutes such as phosphate and beta2-microglobulin which have complex intra-dialytic kinetics, current dialysis techniques are insufficient to achieve adequate solute removal. It will be necessary to deliver longer or perhaps more frequent dialysis therapy in order to achieve this goal. Mathematical modelling facilitates understanding of the pathophysiology of the dialysis process and provides a platform for the development and monitoring of improved dialysis strategies

Interactome Analyses Identify Ties of PrPC and Its Mammalian Paralogs to Oligomannosidic N-Glycans and Endoplasmic Reticulum-Derived Chaperones

The physiological environment which hosts the conformational conversion of the cellular prion protein (PrPC) to disease-associated isoforms has remained enigmatic. A quantitative investigation of the PrPC interactome was conducted in a cell culture model permissive to prion replication. To facilitate recognition of relevant interactors, the study was extended to Doppel (Prnd) and Shadoo (Sprn), two mammalian PrPC paralogs. Interestingly, this work not only established a similar physiological environment for the three prion protein family members in neuroblastoma cells, but also suggested direct interactions amongst them. Furthermore, multiple interactions between PrPC and the neural cell adhesion molecule, the laminin receptor precursor, Na/K ATPases and protein disulfide isomerases (PDI) were confirmed, thereby reconciling previously separate findings. Subsequent validation experiments established that interactions of PrPC with PDIs may extend beyond the endoplasmic reticulum and may play a hitherto unrecognized role in the accumulation of PrPSc. A simple hypothesis is presented which accounts for the majority of interactions observed in uninfected cells and suggests that PrPC organizes its molecular environment on account of its ability to bind to adhesion molecules harboring immunoglobulin-like domains, which in turn recognize oligomannose-bearing membrane proteins

Mechanisms of cellular retention of melanin bound drugs : Experiments and computational modeling

Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro and exposure to pigmented eye in vivo has been shown, there is a discrepancy between rapid drug release from melanin particles in vitro and the long in vivo retention in the pigmented tissues. We investigated mechanisms and kinetics of pigment-related drug retention experimentally using isolated melanin particles from porcine retinal pigment epithelium and choroid, isolated porcine eye melanosomes, and re-pigmented ARPE-19 cells in a dynamic flow system. The experimental studies were supplemented with kinetic simulations. Affinity and capacity of levofloxacin, terazosin, papaverine, and timolol binding to melanin revealed Kd values of asymptotic to 50-150 mu M and B-max asymptotic to 40-112 nmol.mg(-1). The drugs were released from melanin in < 1 h (timolol) or in 6-12 h (other drugs). The drugs were released slower from the melanosomes than from melanin; the experimental differences ranged from 1.2-fold (papaverine) to 7.4-fold (timolol). Kinetic simulations supported the role of the melanosomal membrane in slowing down the release of melanin binders. In release studies from the pigmented ARPE-19 cells, drugs were released from the cellular melanin to the extra -cellular space in asymptotic to 1 day (timolol) and asymptotic to 11 days (levofloxacin), i.e., much slower than the release from melanin or melanosomes. Simulations of drug release from pigmented cells in the flow system matched the experimental data and enabled further sensitivity analyses. The simulations demonstrated a significant prolongation of drug retention in the cells as a function of decreasing drug permeability in the melanosomal membranes and increasing melanin content in the cells. Overall, we report the impact of cellular factors in prolonging drug retention and release from melanin-containing cells. These data and simulations will facilitate the design of melanin binding drugs with prolonged ocular actions.Peer reviewe

Bone Mineral Density and Vascular Calcification in Children and Young Adults with Chronic Kidney Disease

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. It is not known if mineral accrual by the growing skeleton protects young people with CKD from extraosseous calcification. My hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: Multicentre longitudinal study in children and young people (5-30 years) with CKD stages 4-5 or on dialysis. Cortical (Cort) and trabecular (Trab) BMD were assessed by peripheral quantitative Computed Tomography and lumbar spine BMD by DXA (Dual Energy X-ray Absorptiometry). Vascular calcification was assessed by cardiac CT for coronary artery calcification (CAC) and ultrasound for carotid intima-media thickness (cIMT). Arterial stiffness was measured by pulse wave velocity (PWV) and carotid distensibility. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed-up after a median of 1.45 years. The cohort had a significant bone and cardiovascular disease burden. 10% suffered at least one previous atraumatic fracture, and 58% reported bone pain affecting activities of daily living. The majority had evidence of vascular calcification and arterial stiffness with increased cIMT and PWV z-scores. 10% had CAC at baseline. Baseline TrabBMD was independently associated with cIMT (R2=0.10, β=0.34, p=0.001). An annualised increase in TrabBMD was an independent predictor of cIMT increase (R2=0.48, β=0.40, p=0.03), with 6-fold greater odds of an increase in ΔcIMT in those with an increase in ΔTrabBMD [(95%CI 1.88 to 18.35), p=0.003]. Young people that demonstrated statural growth (n=33) had attenuated vascular changes compared to those with static growth. Conclusion: These hypothesis generating studies suggest that children and young adults with CKD or on dialysis may develop vascular calcification even as BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraskeletal calcification

Causal static analysis for Brane Calculi

We present here a static analysis, based on Abstract Interpretation, obtained by defining an abstract version of the causal semantics for the Mate/Bud/Drip (MBD) version of Brane Calculi, proposed by Busi. Our analysis statically approximates the dynamic behaviour of MBD systems. More precisely, the analysis is able to describe the essential behaviour of the represented membranes, in terms of their possible interactions. Furthermore, our analysis is able to statically capture the possible causal dependencies among interactions, whose determination can be exploited to better understand the modelled biological phenomena. Finally, we apply our analysis to an abstract specification of the receptor-mediated endocytosis mechanism