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MBI Emphasis Year on Systems Physiology Tutorials
September 2006 - August 2007

Tutorial on the Heart
(September 18-20, 2006)

Monday, September 18
9:00-10:00am Jim Keener: Introduction to Cardiac Electrophysiology
10:30-11:30am Jim Keener: Introduction to Cardiac Electrophysiology
Tuesday, September 19
1:30-2:30pm Rai Winslow: Integrative Models of the Heart
3:00-4:00pm Rai Winslow: Integrative Models of the Heart
Wednesday, September 20
1:00-3:00pm Roy Kerckhoffs: Cardiac Muscle and Organ Mechanics
AVI1, AVI2, AVI3, AVI4
Friday, September 22
10:00-12:00pm Jose Puglisi: Cardiac Cell Contraction

Tutorial on the Lung
(October 18, 2006)

Organizer: Jason Bates

The assessment of respiratory mechanics has evolved in recent years into a fairly exact science. Accordingly, the measurement of quantities pertaining to the mechanical properties of the respiratory system (most often gas pressures and flows) can now be done with such precision and temporal resolution that their full exploitation entails the use of mathematical models and computer-based signal processing. The front line of investigation into respiratory mechanics has thus become more the domain of the biomedical engineer than the classically trained physiologist. This is especially true of the so-called "oscillation mechanics" of the respiratory system, which is likely to hold the future both for improved means of patient diagnosis and for bronchopharmacologic studies in animals. In this seminar, a model-based approach to the subject of lung mechanics will be taken by proceeding from one mathematical model to the next, in ascending order of complexity. The goal will be to cover some of the key mathematical models that embody our current view of how the lung works from a mechanical perspective, and how these models are currently being used to investigate mice that have been manipulated to exhibit certain lung diseases. Experimental methods used to determine lung mechanical function in humans and animals will also be discussed.

Wednesday, October 18
9:00-10:00am Jason Bates: The Assessment and Physiological Interpretation of Lung Mechanics
10:30-11:30am Jason Bates: The Assessment and Physiological Interpretation of Lung Mechanics
1:30-2:30pm Jason Bates: The Assessment and Physiological Interpretation of Lung Mechanics
Presentation materials: PPT1, PPT2, PPT3, PPT4, PPT5

Tutorial on Microcirculation
(January 19, 2007)

Wednesday, October 18
9:00-10:00am Tim Secomb: Microcirculation: structure and oxygen transport
The function of the circulatory system is to transport materials throughout the body. Blood flows through an extensive branching network of tubes, driven by the pumping action of the heart. Transport of oxygen from the lungs to other parts of the body is a crucial task of the circulatory system. The solubility of oxygen in water is relatively low, but the presence of a high volume fraction (40-45%) of red blood cells in blood greatly increases its oxygen carrying capacity. Hemoglobin molecules within red blood cells take up oxygen in the lungs and release it in the body. A further consequence of the low solubility of oxygen in water is that the distance that oxygen can diffuse into an oxygen-consuming tissue is relatively short, typically of order 20-100 µm. The circulatory system must therefore deliver blood within a short distance of every point in the tissue, and so all oxygen-consuming tissues are supplied with a dense network of very narrow blood vessels, ranging in diameter from a few hundred µm to about 4 µm, known as the microcirculation. Theoretical models have provided important insights into the mechanics of blood flow in the microvascular networks, and relationship between microvascular structure and oxygen tissue oxygenation.
10:30-11:30am Daniel Beard - Simulation of blood-tissue exchange and metabolism
11:30-2:00pm Lunch break, hands-on use of simulation models
2:00-2:45pm Tim Secomb: Microcirculation: structural adaptation and angiogenesis
The circulatory system is a dynamic structure. Blood vessels grow or regress during development and in a variety of normal and disease states, over time scales of hours, days and longer. Under normal conditions, these structural changes ensure that all parts of the tissue are supplied with blood, and that the network structure is well organized and efficient with regard both to the volume of blood needed and the energy required to drive the flow. In the arteries and arterioles, the relationship between blood flow rate and vessel diameter is found experimentally to be approximately cubic on average. This relationship can be predicted based on an optimality principle (Murray's law) in which a linear combination of blood volume and energy dissipation is minimized. The cubic relationship implies fixed fluid shear stress acting on all vessel walls, and this led to the proposal that each vessel continuously adjusts its diameter to maintain a fixed level of shear stress. However, such a mechanism would lead to instability, and would not adequately meet the functional needs of tissues. Theoretical models have been used to investigate how other factors, including tension in vessel walls, metabolic needs and information transfer along vessel walls, also play a role in structural adaptation. The simulation of angiogenesis (new vessel growth) has been addressed using various theoretical approaches, particularly in the contexts of wound healing and tumor growth.
3:15-4:00pm Tim Secomb: Microcirculation: regulation of blood flow
The circulatory system is capable of rapidly controlling blood flow, on time scales of seconds, minutes and longer, by active contraction and dilation of smooth muscle cells in vessel walls, particularly in the arterioles. This allows localized short-term flow regulation in response to changing conditions and tissue needs. Two major modes of flow regulation are autoregulation, in which flow to a given tissue is held almost constant independent of changes in blood pressure, and metabolic regulation, in which blood flow can be modulated over a wide range in response to changing metabolic demands, and particularly to changes in oxygen consumption. Regulation of blood flow is achieved by a number of mechanisms, in which individual vessel segments respond to mechanical and metabolic stimuli. In the myogenic response, an increase in wall tension causes vascular contraction. In the shear-dependent response, and increase in wall-shear stress causes dilation. Several metabolic stimuli, including levels of oxygen, potassium ions, adenosine triphosphate and nitric oxide, cause alterations in arteriole diameter. With regard to metabolic regulation of blood flow, the sensing of metabolic status must occur at downstream locations (capillaries and venules), after oxygen has been extracted from the blood, but the controllers are the arterioles. Information is transferred upstream along vessel walls by conducted responses, which involve electrical coupling of the cells making up the walls. Theoretical models provide a means to integrate information about these multiple processes and gain a quantitative understanding of blood flow regulation.

Tutorial on RAxML
(March 5-9, 2007)

Tuesday, March 6
10:00-10:45am Alexandros Stamatakis: A Program for Maximum Likelihood-based Phylogenetic Analyses with Thousands of Taxa and Mixed Models: How it works and how to use it
RAxML-VI is a program for Maximum Likelihood-based inference of huge single-gene and multi-gene DNA and AA phylogenies with up to several thousands of sequences. This talk will cover the basic functionality and the usage of RAxML-VI for real-world biological studies on single and multiple genes. Moreover, the potential of using the CAT model of rate heterogeneity as a work-around for the significantly more compute- and memory-intensive GAMMA model on huge data will be discussed. In addition, it will include a recent performance comparison with other popular ML programs. Finally, the installation and usage of RAxML on High Performance Computing platforms will be described. Availability: Related papers (PDF) and software (open source code for Mac/Linux) available at icwww.epfl.ch/~stamatak.
1:30-2:15pm Alexandros Stamatakis: Models, Algorithms, and High Performance Computing for Phylogeny Reconstruction: Current State and Future Challenges
Recent years have witnessed significant improvements in Maximum Likelihood (ML) based phylogenetic search algorithms. Nonetheless, the amount of available data grows at a higher rate than algorithms are getting faster. In this talk I will briefly review the current state of research and address upcoming challenges as well as potential solutions in three main areas: Search algorithms including faster approaches to compute support values and an experimental implementation of a likelihood ratchet in RAxML, which surprisingly did not yield improved results. Modeling issues which mainly concern a more efficient accommodation of rate heterogeneity and potential new models to handle "gappy" multi-gene alignments. High performance computing issues regarding the exploitation of the intrinsic multi-grain parallelism inherent to ML-based and to a lesser degree Maximum Parsimony-based inferences. I will outline two current projects which deal with the adaptation of RAxML to the IBM CELL and IBM BlueGene architectures. In addition, I will show how standard high performance computing techniques can be deployed to accelerate programs for host-parasite co-evolution analysis by factor 40-57 while reducing the memory footprint by factor 2.5 at the same time. Finally, I will present some preliminary ideas on how simultaneous alignment and tree building could be efficiently conducted within an ML framework. Availability: Related papers (PDF) and software (open source code for Mac/Linux) available at icwww.epfl.ch/~stamatak.
Wednesday, March 7
10:00-12:00pm Alexandros Stamatakis: Using RAxML (hands on tutorial)
Presentation materials: PDF

Tutorial for Workshop 7: Cellular and Organism Models for Glucose Homeostasis and Diabetes
(May 18, 2007)

Organizers: Richard Bertram and Arthur Sherman

We will review of the biological background on insulin secretion and insulin action and their relation to Type 2 Diabetes, highlighting past successes and current issues. Models for electrical activity of pancreatic beta-cells (ion channels/calcium stores/metabolism), insulin signaling (receptor kinetics/signaling cascades), and whole-body glucose homeostasis (compartmental models/diagnostic tools for beta-cell function and insulin resistance) will be discussed.

Friday, May 18
9:00-10:00am Richard Bertram: Electrophysiology of Pancreatic Islets
Topics: relaxation oscillators and classical bursting, fast-slow decomposition, role of the ER, phantom bursting, modulation by G-protein signaling, electrical coupling
10:00-11:00pm Break and informal discussion
11:00-12:00pm Richard Bertram: Glucose Metabolism in the Beta-Cell
Topics: glycolysis, citric acid cycle, oxidative phosphorylation, models for metabolic oscillations
12:00-1:00pm Lunch break
1:00-2:00pm Arthur Sherman: Insulin Secretion
Topics: triggering and amplifying pathways, exocytosis, models for secretion, whole-body pulsatility and synchrony
2:00-3:00pm Break and informal discussion
3:00-4:00pm Arthur Sherman: Whole-Body Metabolism and Disease
Topics: insulin resistance, beta-cell function, beta-cell mass, models for assessing insulin resistance and beta-cell function