Mathematical models for kidney function focusing on clinical interest.

We give an overview of mathematical models of renal physiology and anatomy with the clinician in mind. Beyond the past focus on issues of local transport mechanisms along the nephron and the urine concentrating mechanism, recent models have brought insight into difficult problems such as renal ischemia (oxygen and CO diffusion in the medulla) or calcium and potassium homeostasis. They have also provided revealing 3D reconstructions of the full trajectories of families of nephrons and collecting ducts through cortex and medulla.

A small-molecule activator of kinesin-1 drives remodeling of the microtubule network.

The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood.

SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain.

The molecular interplay between cargo recognition and regulation of the activity of the kinesin-1 microtubule motor is not well understood. Using the lysosome adaptor SKIP (also known as PLEKHM2) as model cargo, we show that the kinesin heavy chains (KHCs), in addition to the kinesin light chains (KLCs), can recognize tryptophan-acidic-binding determinants on the cargo when presented in the context of an extended KHC-interacting domain. Mutational separation of KHC and KLC binding shows that both interactions are important for SKIP-kinesin-1 interaction and that KHC binding is important for lysosome transport However, in the absence of KLCs, SKIP can only bind to KHC when autoinhibition is relieved, suggesting that the KLCs gate access to the KHCs.

Mathematical Model of Ammonia Handling in the Rat Renal Medulla.

The kidney is one of the main organs that produces ammonia and release it into the circulation. Under normal conditions, between 30 and 50% of the ammonia produced in the kidney is excreted in the urine, the rest being absorbed into the systemic circulation via the renal vein. In acidosis and in some pathological conditions, the proportion of urinary excretion can increase to 70% of the ammonia produced in the kidney.

Implementation of a model of bodily fluids regulation.

The classic model of blood pressure regulation by Guyton et al. (Annu Rev Physiol 34:13-46, 1972a; Ann Biomed Eng 1:254-281, 1972b) set a new standard for quantitative exploration of physiological function and led to important new insights, some of which still remain the focus of debate, such as whether the kidney plays the primary role in the genesis of hypertension (Montani et al. in Exp Physiol 24:41-54, 2009a; Exp Physiol 94:382-388, 2009b; Osborn et al.

Representing kidney development using the gene ontology.

Gene Ontology (GO) provides dynamic controlled vocabularies to aid in the description of the functional biological attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org).

A vision and strategy for the virtual physiological human: 2012 update.

European funding under Framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for 5 years. The VPH Network of Excellence (NoE) has been set up to help develop common standards, open source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also working to coordinate the many clinically targeted projects that have been funded under the FP7 calls.

A formin-g role during development and disease.

Several different protein families were shown to be involved in the regulation of actin filament formation and have been studied extensively in processes such as cell migration. Among them are members of the formin family, which tend to promote the formation of linear actin filaments. Studies in recent years, often using loss of function animal models, have indicated that formin family members play roles beyond cell motility in vitro and are involved in processes ranging from tissue morphogenesis and cell differentiation to diseases such as cancer and cardiomyopathy.

Delineation of the TRAK binding regions of the kinesin-1 motor proteins.

Understanding specific cargo distribution in differentiated cells is a major challenge. Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes.

Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis.

We present a lumped-nephron model that explicitly represents the main features of the underlying physiology, incorporating the major hormonal regulatory effects on both tubular and vascular function, and that accurately simulates hormonal regulation of renal salt and water excretion. This is the first model to explicitly couple glomerulovascular and medullary dynamics, and it is much more detailed in structure than existing whole organ models and renal portions of multiorgan models. In contrast to previous medullary models, which have only considered the antidiuretic state, our model is able to regulate water and sodium excretion over a variety of experimental conditions in good agreement with data from experimental studies of the rat.

A model of calcium transport along the rat nephron.

We developed a mathematical model of calcium (Ca(2+)) transport along the rat nephron to investigate the factors that promote hypercalciuria. The model is an extension of the flat medullary model of Hervy and Thomas (Am J Physiol Renal Physiol 284: F65-F81, 2003). It explicitly represents all the nephron segments beyond the proximal tubules and distinguishes between superficial and deep nephrons.

Virtual patients and sensitivity analysis of the Guyton model of blood pressure regulation: towards individualized models of whole-body physiology.

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model.

Integration of detailed modules in a core model of body fluid homeostasis and blood pressure regulation.

This paper presents a contribution to the definition of the interfaces required to perform heterogeneous model integration in the context of integrative physiology. A formalization of the model integration problem is proposed and a coupling method is presented. The extension of the classic Guyton model, a multi-organ, integrated systems model of blood pressure regulation, is used as an example of the application of the proposed method.

The global risk approach should be better applied in French hypertensive patients: a comparison between simulation and observation studies.

Background: The prediction of the public health impact of a preventive strategy provides valuable support for decision-making. International guidelines for hypertension management have introduced the level of absolute cardiovascular risk in the definition of the treatment target population. The public health impact of implementing such a recommendation has not been measured.

The Virtual Kidney: an eScience interface and Grid portal.

The Virtual Kidney uses a web interface and distributed computing to provide experimental scientists and analysts with access to computational simulations and knowledge databases hosted in geographically separated laboratories. Users can explore a variety of complex models without requiring the specific programming environment in which applications have been developed. This initiative exploits high-bandwidth communication networks for collaborative research and for shared access to knowledge resources.

SAPHIR: a physiome core model of body fluid homeostasis and blood pressure regulation.

We present the current state of the development of the SAPHIR project (a Systems Approach for PHysiological Integration of Renal, cardiac and respiratory function). The aim is to provide an open-source multi-resolution modelling environment that will permit, at a practical level, a plug-and-play construction of integrated systems models using lumped-parameter components at the organ/tissue level while also allowing focus on cellular- or molecular-level detailed sub-models embedded in the larger core model. Thus, an in silico exploration of gene-to-organ-to-organism scenarios will be possible, while keeping computation time manageable.

Robert Rosen in the age of systems biology.

The widespread use of the term Systems Biology (SB) signals a welcome recognition that organisms must be understood as integrated systems. Although just what this is taken to mean varies from one group to another, it generally implies a focus on biological functions and processes rather than on biological parts and a reliance on mathematical modeling to arrive at an understanding of these biological processes based on biological observations or measurements. SB, thus, falls directly in the line of reflection carried out by Robert Rosen throughout his work.

QxDB: a generic database to support mathematical modelling in biology.

QxDB (quantitative x-modelling database) is a web-based generic database package designed especially to house quantitative and structural information. Its development was motivated by the need for centralized access to such results for development of mathematical models, but its usefulness extends to the general research community of both modellers and experimentalists. Written in PHP (Hyper Preprocessor) and MYSQL, the database is easily adapted to new fields of research and ported to Apache-based web servers.

The microbial experience of environmental phosphate fluctuations. An essay on the possibility of putting intentions into cell biochemistry.

We present a model of microbial information processing that contains characteristic features of the phenomenon of physiological adaptation. The backbone of the model is the "adaptive event" in which energy-converting subsystems of the cell interact with the changing environment. In this process, the subsystems pass, via an adaptive operation mode, from one adapted state to the next.

Inner medullary lactate production and urine-concentrating mechanism: a flat medullary model.

We used a mathematical model to explore the possibility that metabolic production of net osmoles in the renal inner medulla (IM) may participate in the urine-concentrating mechanism. Anaerobic glycolysis (AG) is an important source of energy for cells of the IM, because this region of the kidney is hypoxic. AG is also a source of net osmoles, because it splits each glucose into two lactate molecules, which are not metabolized within the IM.