2015 Seminars

Hemodynamic forces and autoregulation of cerebral blood flow

Akos Koller, University of Physical Education, Budapest, Szentagothai Res Centre, University of Pecs, Hungary and Department of Physiology, New York Medical College, Valhalla, NY, USA
July 28, 2015, 4:00pm, PAB 4-330


The cerebral vascular network is enclosed in the rigid cranium. Thus any increase in pressure and/or volume could increase intracranial pressure endangering the maintenance of appropriate blood flow to brain tissues. To prevent this however, a very effective autoregulation is present, which is an important feature of the cerebral blood flow (CBF). Many previous studies have investigated this issue and logically assumed that autoregulation is somehow coupled to changes in hemodynamic forces.

Pressure sensitive vasomotor response

For many years, autoregulation of CBF has been primarily explained by the pressure-induced myogenic response of cerebral vessels: the inherent property of vascular smooth muscle to dilate to a decrease and to constrict to an increase in intraluminal pressure. This response of vessels was first described by Bayliss early in the 20th century. Accordingly, when systemic blood pressure increases cerebral vessels constrict, which elevates cerebrovascular resistance. Because flow relates to the 4th power of radius the increased resistance maintains CBF close to the original level, despite elevation in pressure. In contrast, when systemic pressure decreases, dilation of cerebral vessels reduce cerebrovascular resistance, thereby maintaining relatively constant blood flow.

There are two critical mechanisms (Ca2+-dependent and -independent) contributing to the myogenic constriction:
1) Increase in pressure elicits smooth muscle cell stretch, increasing wall tension; this leads to membrane depolarization. Depolarization of the membrane leads to the opening of voltage-gated Ca2+ channels resulting in elevated inward Ca2+ current. The increased intracellular Ca2+ concentration via Ca2+-calmodulin complex leads to myosin light-chain kinase (MLCK) activation. MLCK phosphorylates myosin light chain (MLC20) leading to increased actin-myosin interaction and consequent shortening of smooth muscle cell. Because of the circumferential orientation of the smooth cells shortening is translated into constriction of the vessels.
2) At the same time, Ca2+-independent mechanisms involving protein kinase C (PKC), diacylglycerol and RhoA/Rho kinase regulate the activity of myosin light-chain phosphatase determining the phosphorylated state of MLC20 thus sensitizing actin-myosin proteins to Ca2+.

Flow sensitive vasomotor response

During increases in systemic pressure blood flow changes as well, making it plausible that there is a vascular mechanism which is sensitive to flow changes. Indeed, recent studies support this idea. It was shown in certain cerebral vessels, such as the middle cerebral artery a mechanism exists, which is sensitive for changes in blood flow. In contrast to peripheral arterial vessels, in the presence of constant pressure increases in flow elicit constrictions in this type of vessels. The constrictions are mediated by 20-HETE (20-hydroxieicosatetraenoic acid, a constrictor metabolite of arachidonic acid synthesized by cytochrome P450 hydroxylases) and reactive oxygen species (ROS).

Simultaneous effects of hemodynamic forces

On the basis of above, it is plausible that in the cerebral vascular network, during increases in systemic blood pressure when both pressure and flow changes (for example during exercise) the flow-constriction is superimposed on the pressure-constriction. This double effect can achieve a sufficient decrease in vascular diameter, which substantially increase vascular resistance contributing to the maintenance i.e. “autoregulation” of CBF.


It is important to note here, that the vasomotor tone of cerebral vessels “set” by the pressure- and flow-induced mechanisms can be modulated or overridden by other mechanisms/factors sensitive to the metabolic needs of neural tissues during their increased activity, allowing us to think, once in a while.

Swimming with wobbling bodies: the effect of the cell body on the motility of flagellated bacteria
Bin Liu, University of California, Merced
May 22, 2015, 4:00pm PAB 4-330


The cell body of a flagellated bacterium is often regarded as a passive cargo when describing the cell motility. To study the role of the cell body in bacterial swimming, we have developed a tracking technique with which we can resolve both the 3-d trajectory and the orientation of individual cells over extended times. We have used this technique to study the motility of the uni-flagellated bacterium Caulobacter cresentus and have found that each cell displays two distinct modes of motility, depending on the rotation direction of the flagellar motor. In the “forward” mode with the flagellum pushes the cell, the cell body is tilted and precesses with respect to the direction of swimming, which traces a helical phase.  In the “reverse” mode, the flagellum pulls the cell. In this mode, the precession is much smaller and the cell motility significantly lower.  We show that the helical motion of the cell body can introduce thrust rather than drag and can explain the direction-dependent changes in swimming motility.


Talk title TBA
Jen Hsin, Google Inc.
April 24, 2015, 4:00pm PAB 4-330

Abstract: A cell's survival relies on the coordination of a myriad of moving parts such as genetic materials, proteins, lipids, and signaling molecules.  How do these molecules arrive at the right location in the cell at the right time?  In some cases regulator proteins are involved, but then what factor regulates the regulator proteins?  Recently an elegant framework addressing this problem has emerged: that some molecules might self-organize by locally interacting with their chemical and physical environments.  An example is found in the common soil bacterium B. subtilis, which, when living environment becomes unfavorable, forms a spore encasing its genes and waits until condition improves.  Spore formation is initiated by the small helical protein SpoVM, which is first to attach to the spore membrane and recruits other proteins to coat and protect the spore.  In this talk, I will discuss our efforts to understand how SpoVM arrives at the spore by using its spherical membrane curvature as a physical cue.  We also studied how this curvature detection can be turned on and off by altering one amino acid in SpoVM, which changes the structure of the protein and its interaction with the membrane, subsequently interrupting spore formation.  Our work proposes a biophysical mechanism that explains how the nanometer-scaled SpoVM detects micrometer-scaled membrane curvature, and how the coordination of spore formation is achieved by following this self-organization principle.

Steering affinity maturation to generate cross-reactive antibodies
Shenshen Wang, MIT
April 17, 2015, 4:00pm PAB 4-330

Abstract: The adaptive immune system houses amazingly efficient evolutionary processes to protect higher organisms from diverse invading agents. A key component of effective immune responses is the generation of potent antibodies by a real-time Darwinian process called affinity maturation. However, devastating circumstances are raised by rapidly mutating viruses (e.g. HIV which infects the immune system itself) that can escape antibody recognition. None of the classical vaccination strategies has succeeded to date.

In this talk, I will present an in silico model of affinity maturation driven by multiple antigen variants, a basic problem in cell biology that has not been considered before. I will show that the understanding obtained, using concepts from condensed matter physics, not only explains why the emergence of cross-reactive antibodies is so rare upon natural infection, but also suggests novel strategies to guide their evolution. The proposed vaccination scheme has been shown in mouse experiment to be very effective at inducing cross-reactive antibodies focused on the vulnerable part of the virus.  

Optimal census by quorum sensing
Thibaud Tallifumier, Princeton University
April 10, 2015, 4:00pm PAB 4-330

Abstract: Bacteria regulate gene expression in response to changes in cell density in a process called quorum sensing. To synchronize their gene-expression programs, these bacteria need to glean as much information as possible about their cell density. I will present a physical model for the flow of information in a quorum-sensing microbial community. Combining information theory and the Lagrangian formalism, we find that quorum-sensing systems can improve their information capabilities by tuning circuit feedbacks. At the population level, external feedback adjusts the dynamic range of the shared signal to match that of the detection channel. At the individual level, internal feedback adjusts the response time to optimally balance output noise reduction and signal tracking ability. Our analysis suggests that achieving information benefit via feedback requires dedicated systems to control gene expression noise, such as small RNA-based regulation.

Information, Computation, and Thermodynamics in Cells
Pankaj Mehta, Boston University
April 3, 2015, 4:00pm PAB 4-330

Abstract: Cells live in complex and dynamic environments. Adapting to changing environments often requires cells to perform complex information processing, and cells have developed elaborate signaling networks to accomplish this feat. These biochemical networks are ubiquitous in biology. They range from naturally occurring biochemical networks in bacteria and higher organisms, to sophisticated synthetic cellular circuits that rewire cells to perform complex computations in response to specific inputs. The tremendous advances in our ability to understand and manipulate cellular information processing networks raise fundamental questions about the physics of information processing in living systems. I will discuss recent work in this direction trying to understand the fundamental constraints placed by (nonequilibrium) thermodynamics on the ability of cellular circuits to process information and perform computations and discuss the implications of our results for the emerging field of synthetic biology.

Faculty interview talk TBA
March 27, 2015, 4:00pm PAB 4-330

The dynamics, function and design of cell fate control circuits
Hao Yuan Kueh, California Institute of Technology
March 20, 2015, 4:00pm PAB 4-330

Abstract: Circuits of interacting genes control cell fate specification in multicellular organisms.  While we have determined detailed wiring diagrams for many such circuits, we still lack a basic understanding of the design principles underlying their operation.  To address these questions, I follow and manipulate the behavior of these circuits in single living cells, and analyze their emergent properties using dynamical models.  

Using this approach, I discovered a novel positive feedback circuit for stabilizing macrophage fate identity, where a stable fate-specifying gene induces cell cycle lengthening to promote its own accumulation (Kueh et al., Science 2013).  I also uncovered a remarkably dynamic behavior in the circuit controlling T-cell identity, where a fate-specifying gene turns on intermittently to control commitment.  These studies lay the groundwork for a systems-level understanding of cell fate control in multicellular organisms.

Keeping it together: Organizing the bacterial chromosome for divisionChase Broedersz, Princeton University
March 13, 2015, 4:00pm PAB 4-330

Abstract: Most bacteria contain a single circular chromosome a thousand-fold longer than the bacteria itself. This chromosome is highly condensed and is organized in part by a large amount of associated proteins. Single-molecule experiments revealed that these proteins impact DNA structure by inducing bridging, bending, twisting, looping, or coiling. However, it remains unclear how such DNA-binding proteins collectively organize the bacterial chromosome.  I will focus on what is arguably the most demanding organizational task for the bacterial chromosome: DNA replication and segregation. In many bacteria, chromosome segregation is mediated by the ParABS system. At its heart, this segregation machinery includes a large protein-DNA complex consisting of roughly 1000 ParB proteins. However, the physical organization of ParB proteins on the DNA remains unclear. What controls the formation, localization, and stability of the ParB complex? I developed a simple model for interacting proteins on DNA. This model shows that a combination of 1D spreading bonds and a 3D bridging bond between ParB proteins constitutes a minimal model for condensation of ParB proteins into a 3D ParB-DNA complex. The central predictions of this model directly address recent experiments on ParB-induced gene-silencing and the effect of a DNA ``roadblock'' on ParB localization. Furthermore, my model provides a simple mechanism to explain how a single centromeric parS site on the DNA is both necessary and sufficient for the formation and localization of the ParB-DNA complex.

Faculty interview talk TBA
March 6, 2015, 4:00pm PAB 4-330

Frequency selectivity of the inner ear
Marcel van der Heijden, Erasmus University, Rotterdam, Netherlands
February 27, 2015, 4:00pm PAB 4-330

Abstract: The mammalian inner ear, the cochlea, is a waveguide that mediates sound-induced traveling waves. These waves resemble surface waves in deep water, but have the curious property that their amplitude peaks at a frequency dependent location. This makes the ear a spectral analyzer. The physics behind the peaking is poorly understood. Many current models invoke a complicated combination of resonance and active mechanical feedback ("cochlear amplifier"). This talk explores an alternative explanation that rejects resonance and active feedback, and is based entirely on wave dispersion. When entering its peak region, the wave undergoes a sharp deceleration associated with a transition in which two propagation modes exchange roles. This mode shape swapping is closely related to the phenomenon of avoided crossing in the analysis of eigenmodes, the novel aspect being its application to wave propagation. The resulting waveguide model shows remarkable similarity to the cochlea, both in terms of structure and behavior.

On the modeling of endocytosis in yeast
Jennifer Schwarz, Syracuse University
February 25, 2015, 4:00pm PAB 4-330 

Abstract: The cell membrane deforms during endocytosis to surround extracellular material and draw it into the cell.  Experiments on endocytosis in yeast all agree that (i) actin polymerizes into a network of filaments exerting active forces on the membrane to deform it and (ii) the large scale membrane deformation is tubular in shape. There are three competing proposals, in contrast, for precisely how the actin filament network organizes itself to drive the deformation. I will present a meso-scale model of actin-mediated endocytosis in yeast to address this competition.  The meso-scale model breaks up the invagination process into three stages: (i) initiation, where clathrin interacts with the membrane via adaptor proteins, (ii) elongation, where the membrane is then further deformed by polymerizing actin filaments, followed by (iii) pinch-off.  Not only does the model potentially rule out two of the three competing proposals for the organization of the actin filament network during the elongation stage, it also suggests that the pinch-off mechanism may be assisted by a pearling-like instability.

Noise and competition in gene expression: the biophysics of biological inconveniences
Robert Brewster, Caltech
January 9, 2015, 4:00pm PAB 4-330

Abstract: Resources in the cell are limited and typically shared.  This is especially acute in the process of transcription where the proteins involved often exist in similar copy number to their total number of DNA target sites. This shared demand for and scarcity of protein resources contributes to the difficulty inherent in quantitative predictions for transcription: the cellular environment is noisy and interconnected.   In this talk I'll show how an approach combining rigorous theoretical models with precision measurements made possible by synthetic biology techniques provides a powerful framework for finding the biophysical rules controlling these biological inconveniences and their influence on gene expression.