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Using a combined spiking and secretion model to investigate osmotic signal encoding and hormone secretion response in hypothalamic vasopressin neurons

 Duncan MacGregor and Gareth Leng

    Date: Friday, 21 June 2013
Time:  16H00
Venue: McIntyre Medical Building Room 1101

Dr. Duncan MacGregor, PhD

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

Abstract :

The magnocellular vasopressin neurons of the supraoptic nucleus and the paraventricular nucleus of the hypothalamus project axonal terminals to the posterior pituitary, where they secrete vasopressin hormone into the blood, acting at the kidneys to reduce water loss, as part of the homeostatic system regulating osmotic pressure. Experiments show a robust linear relationship between osmotic pressure and vasopressin secretion, despite spike generating and secretion mechanisms that are both highly non-linear. The neurons respond to synaptic input and depolarising currents generated by osmotic pressure, with increasing activity generating a distinctive phasic firing pattern, consisting of long bursts and silences lasting tens of seconds. We have previously modelled this phasic spike firing mechanism (1), and have now integrated our spike model with a model of the spike triggered calcium driven secretion mechanism.

The secretion mechanism is highly non-linear, subject to both frequency facilitation and fatigue effects, and we have used simple representations of the hypothesised underlying mechanisms to simulate these. Frequency facilitation uses activity dependent spike broadening, opposed by Ca2+ dependent Ca2+ channel inactivation. Fatigue uses a hyperpolarising Ca2+ dependent K+ current, which makes spikes progressively less effective at invading the axonal terminals. We match the results showing that a phasic spiking pattern produces the optimal secretion response, based on secretion per spike, but we also show that phasic spiking produces a highly non-linear secretion response to increasing stimulus in a single cell. However, we show that using a heterogeneous population of model cells, with varied rates of input activity, produces a much more linear summed population output, matching the linear response observed experimentally. We also show, using a simulated releasable pool and reserve store to test the effects of hormone depletion, that the fatigue mechanism acts to maintain this linear secretion response during chronic stimulation. The combined model demonstrates the importance of considering secretion as well as spike activity when investigating the functional properties of neural networks.

(1) MacGregor DJ and Leng G. Phasic firing in vasopressin cells: understanding its functional significance through computational models.  PLoS Comput. Biol. 2012; 8:e1002740.

Ultrasensitivity by multisite phosphorylation with application to the T cell antigen receptor

Date: Thursday, 6 June 2013
Time:  16H00
Venue: McIntyre Medical Building Room 1101

Dr. Omer Dushek, PhD

Sir Henry Dale Fellow, University Research Lecturer, Sir William Dunn School of Pathology, Oxford, UK

Abstract :

Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. Many receptors, including immune receptors, often contain multiple phosphorylation sites that are modified by membrane-confined enzymes but mechanistic models of how their phosphorylation is regulated are presently missing. Ultrasensitive or switchlike responses in their phosphorylation state are not expected because the modifying enzymes are in excess. In this talk I will present a novel mechanism of ultrasensitivity that is exhibited by membrane-anchored, but not cytosolic, multisite proteins. The model framework will be applied to the specific case of the T cell antigen receptor.

For more information, visit his personal website or http://www.path.ox.ac.uk/dirsci/immunology/dushek

Computational Neuroscience Workshop (CAMBAM)

Restoration of normal cardiac function in patients with ventricular assist devices. How far is it from reality?

Date: Thursday, 25 April 2013
Time:  16H00
Venue: McIntyre Medical Building Room 1101

Prof. Francesco Moscato, PhD

Center for Medical Physics and Biomedical Engineering,

Medical University of Vienna

Abstract :

In recent years the progress in the treatment of heart failure has led to impressive results, significantly reducing morbidity/mortality. Clinical studies have also shown that current heart failure treatment, especially by ventricular assist devices (VADs), lead to a renormalization of structural, cellular and molecular factors otherwise deranged during heart failure (reverse-remodeling). Despite reverse-remodeling a complete remission from heart failure (myocardial recovery) has been observed only in a minority of patients.

This fact highlights a major unknown: It is unclear which processes involved in reverse-remodeling are necessary for the achievement of myocardial recovery. On the one hand, it is impossible to continuously track cardiac function and its eventual recovery in VAD patients by using conventional diagnostic means such as cardiac ultrasound, which can be performed only infrequently. On the other hand there is an urgent need for innovative experimental tools as well as theoretical approaches, which could shed some light on the cardiac remodeling and recovery processes.

In this talk methods and tools developed at the Medical University of Vienna will be presented. In the first part, algorithms for continuous monitoring of the cardiac function during mechanical assistance with minimal sensor requirements will be addressed. In the second part, a large-animal isolated heart setup will be presented, which is used to investigate the hemodynamic interaction of VAD and the native heart. In the last part of the talk, considerations about limits and speculations about the chances of current and future theoretical approaches to reverse-remodeling and recovery will be introduced for discussion.

For more information - please visit Web-Page: http://www.zmpbmt.meduniwien.ac.at/index.php?id=161

Optimal performance of the tryptophan operon of E. coli in terms of low biochemical noise, fast response time to nutritional shifts, and economic regulatory mechanisms

Date:           Tuesday, 23 April 2013

Time:          16H00

Venue:          McIntyre Medical Building Room 1101

Speaker:        Prof. Moisés Santillán, Biomedical Engineering and Physics, Centro de Investigación y Estudios Avanzados del IPN at Monterrey, México


Abstract :

 In this work we develop a detailed, stochastic, dynamical, mathematical model for the tryptophan operon of E. coli, paying special attention to estimating of all of the model parameters from reported experimental data. We further employ the model to study the amount of biochemical noise in all of the system variables, the system response time to nutritional shifts, the amount of repression molecules necessary to maintain an adequate level of repression, as well as the dependence of these performance characteristics on the model parameter values. In particular, we found that the level of cooperativity achieved by repressor molecules bound to the first two operators in the trp promoter affects all of the above enlisted performance characteristics, and that the cooperativity level found in the wild-type strain optimizes a cost benefit function involving low biochemical noise in the tryptophan level, fast response time to nutritional shifts, and low number of regulatory molecules.


Optimality of a Time-Dependent Treatment Profile during an Influenza Epidemic

Date:           Friday, 22 March 2013
Time:          14H00
Venue:          McIntyre Medical Building Room 1034
Speaker:       Dr. Majid JaberiCenter for Nonlinear Dynamics, McGill University, MITACS NCE Postdoctoral Research Fellow, Centre for Disease Modelling, York University, PhD in Applied Mathematics, Université Laval, Quebec

The emergence and spread of drug resistance is one of the most challenging public health issues in the treatment of some infectious diseases. The objective of this work is to investigate whether the effect of resistance can be contained through a time-dependent treatment strategy during the epidemic subject to an isoperimetric constraint. We apply control theory to a population dynamical model of influenza infection with drug sensitive and drug resistant strains, and solve the associated control problem to find the optimal treatment profile that minimizes the cumulative number of infections (i.e., the epidemic final size). We consider the problem under the assumption of limited drug stockpile, and show that as the size of stockpile increases, a longer delay in start of treatment is required to minimize the total number of infections. Our findings show that the amount of drugs used to minimize the total number of infections depends on the rate of de novo resistance regardless of the initial size of drug stockpile. We demonstrate that both the rate of resistance emergence and the relative transmissibility of the resistant strain play important roles in determining the optimal timing and level of treatment profile.

Workshop: Biodiversity in a Changing World / Biodiversité dans un monde en mouvement

22-26 July 2013
Location: CRM, CAMBAM, Montréal, Canada.

Organizers: Frédéric Guichard (McGill), Frithjof Lutscher (Ottawa)


Biodiversity describes the manifestations of life through its many forms at the molecular level and across ecosystems. Biodiversity has always been the main topic of study for ecologists and evolutionary biologists since it remains a paradox ...

... hope is to advance the mechanistic understanding of observed relationships between biodiversity and ecosystem services.

For more information: Mathematics of Planet Earth 2013 - Pan-Canadian Thematic Program - Biodiversity in a Changing World

Conference - In honour of Michael Mackey's 70th birthday

Michael Mackey's 70th birthday

in Lyon, in Rhone-Alpes, France 

from 3-6 June 2013

For more information please visit :

1.   http://mathbio2013.sciencesconf.org/resource/page?id=4 (Eng)

2.   http://mathbio2013.sciencesconf.org/resource/page?id=10 (French)

Perhaps, there is still some financial support available.  Hence if you are interested go to the link # 1.

Looking forward to seeing you at the Events.

Mathematics behind stream population dynamics

Date:      Friday, 15th February 2013, 9:30 a.m.
Venue:    Stewart Biology W4/12
Speaker:  Prof. MARK Lewis, CRC Mathematical Biology, University of Alberta


Human activites change the natural flow regimes in streams and rivers and this impacts ecosystems. In this talk I will mathematically investigate the impact of changes in water flow on biological populations.  The approach I will take is to develop process-oriented advection-diffusion-reaction equations that couple hydraulic flow to population growth, and then to analyze the equations so as to assess the effect of impacts of water flow on population dynamics. The mathematical framework is based on new theory for the net reproductive rate $R_0$ as applied to advection-diffusion-reaction equations. I will then connect the theory to populations in rivers under various flow regimes.

This work lays the groundwork for connecting $R_0$ to more complex models of spatially structured and interacting populations, as well as more detailed habitat and hydrological data. This is achieved through explicit numerical simulation of two dimensional depth-averaged models for river population dynamics.

For more information: Lewis Research Group

Mathematical Models for Territorial Interactions

Date:      Thursday, 14th February 2013, 3:00 p.m.
Venue:    Redpath auditorium
Speaker:  Prof. MARK Lewis, CRC Mathematical Biology, University of Alberta

Note: The talk will be preceded by coffee and snacks in the Redpath lobby, around 2:30p.m.

Mathematical models can help us understand the formation of complex spatial patterns, including the territories of wolves and coyotes. Here scent marks provide important cues regarding the use of space. In this talk I will show how biologically-based mechanistic rules can be put into a mathematical model which predicts the process of territorial formation as individuals create and respond to scent marks. The model predicts complex spatial patterns which are seen in nature, such stable `buffer zones' between territories which act as refuges for prey such as deer. The mathematical work is supported by detailed radio-tracking studies of animals. I will also employ the approach of game theory, where each pack attempts to maximize its fitness by increasing intake of prey (deer) and while decreasing interactions with hostile neighboring packs. Here the predictions are compared with radio-tracking data for wolves and coyotes. Finally I will show how a version of the territorial model has been applied to human populations in understanding spatial patterns arising from conflict between urban gangs.

 Figure 1. ...Green: ligand dynamics, & blue signaling pathway output


Date:      Thursday, 17th January 2013, 15:30 p.m.
Venue:    Ernest Rutherford Physics Building, R.E. Bell Conference Room (room 103)
Speaker:  Aryeh Warmflash, Rockefeller University

During embryonic development, signaling pathways convey positional information in order to pattern the embryo. Although the timing of  signaling exerts an important influence on patterning, the dynamical properties of developmental signaling pathways remain largely unexplored. The TGF-beta pathway plays a vital role in embryonic patterning and has been shown to act as a morphogen inducing cell fate in a concentration-dependent manner. We used integrated automated microfludic cell-culture and time-lapse microscopy to probe t he dynamics of the signaling pathway under a variety of time courses of ligand stimulation that mimic those seen during embryonic development. We show that the pathway responds transiently and adaptively to a step in ligand stimulation and as a consequence of this adaptation: 1) pathway throughput is maximized by pulsatile stimulation and 2) the response to increasing ligand concentration depends strongly on the rate at which the ligand is presented. Mathematical modeling suggests that in an embryonic context, an adaptive pathway can extract positional information as ligand spreads dynamically from a source thereby providing an alternative to the static morphogen model. Thus, the rate of ligand presentation may be an important instructive signal for patterning.

- This seminar will be followed by coffee and conversation with the Dr. Warmflash
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