Seminars

 

Title TBA

Sanjay Dharmavaram, UCLA
September 22, 2017, time and place TBA
 

Encoding of distance, axis of travel, and topology at the juncture of hippocampal and posterior parietal systems for spatial mapping

Douglas Nitz, UC San Diego
June 20 2017, 4pm PAB 1-434

The subiculum and retrosplenial cortex together form a robust connection between hippocampal representations of position in the environment and posterior parietal cortex representations of position in route space. Our recent work examining the spatial firing properties of neurons within subiculum and retrosplenial cortex indicate that, in different ways, these structures encode conjunctions of spatial information concerning route spaces and their positioning and orientation in the larger environment. Furthermore, novel forms of spatial information encoding emerge in each structure. These forms include 'axis-tuning' and encoding of 'spatial analogies' in subiculum, and, in retrosplenial cortex, the encoding of position within route sub-spaces and distances between all route locations. The former are integrated temporally with the hippocampal CA1 sub-region through 'theta phase precession'. The latter, when considered in the context of retrosplenial encoding of head direction, could, in principle, form the basis for knowledge of overall path geometry. The results of these recent findings will be considered with respect to anatomical pathways that appear to represent the transformation of spatial cognition into action. 

 

Formation of two-dimensional DNA films at the air/water interface

Jaime Ruiz-Garcia, Autonomous University of San Luis Potosí, Mexico
May 26, 2017, 4pm PAB 4-330
 
The central dogma in Langmuir monolayers studies is that they are formed when amphiphilic molecules are deposited and spread spontaneously on the water surface to form a monomolecular film. A typical characteristic of these systems is that they are formed by molecules with a hydrophilic head group and a large hydrophobic tail, such as fatty acids, phospholipids, etc. In this talk, we will show that monomolecular films at the air/water interface can also be formed using water soluble molecules. DNA is a highly charged polyelectrolyte and it is considered to be completely soluble in pure water. We show that DNA can be trapped at the air/water interface and does not go back into a water subphase. DNA is trapped in an energy minimum at the interface, much bigger that KBT, that does not permit its return to the water subphase. Once at the interface, DNA molecules condense to form two-dimensional foam-like mesostructures. This condensation occurs without the presence of multivalent cations. At high density, the molecules form a remarkable monomolecular network. At the interface, DNA is only partially immersed in water, which originates that the chains get only partially charged, but the charges are of the same sign. Therefore, this can be considered another case of like-charge attraction, similar to that found in colloids in restricted geometries such as the air/water interface and between glass plates. However, the origin of the attractive part of the interaction potential is unknown. In addition, we found that DNA at the air/water interface can form large 2D tetratic phase domains. Both the DNA monomolecular networks and the tetratic phase domains are interesting from theoretical and application standpoints.

Odd viscosity in chiral active fluids

Anton Sousolv, Leiden University
May 19, 2017, 4pm PAB 4-330

Abstract: Chiral active fluids are materials composed of self-spinning rotors that continuously inject energy and angular momentum at the microscale. Out-of-equilibrium fluids with active-rotor constituents have been experimentally realized using nanoscale biomolecular motors, microscale active colloids, or macroscale driven chiral grains. I will discuss how chiral active fluids break both parity and time-reversal symmetries in their steady states, giving rise to a dissipationless linear-response coefficient called odd (equivalently, Hall) viscosity in their constitutive relations. This odd viscosity provides no energy dissipation, but can give rise to a transverse flow – for example within a hypersonic shock. Such a viscosity term has been previously examined in the context of electron fluids subject to a magnetic field. However, only in active fluids does odd viscosity: (i) arise out of equilibrium, (ii) always come accompanied by an antisymmetric stress, and (iii) become ill-defined in the regime in which active rotations are hindered by interactions. I will examine the origins of odd viscosity and suggest how this property may be exploited to buildmachines powered by active fluids.

Optimizing self-assembly kinetics for biomolecules and complex nanostructures

William Jacobs, Harvard University
April 14, 2017, 4pm PAB 4-330

Abstract: In a heterogeneous self-assembling system, such as a large biomolecule or nanostructure, there is no guarantee that the lowest-free-energy state will form.  Defects and mis-interactions among subunits often arise during a self-assembly reaction, particularly in systems comprising many distinct components.  As a result, if we wish to assemble complex nanostructures reliably, we need to design robust kinetic pathways to the target structures, and not focus  solely on their thermodynamic stabilities.  In this talk, I shall describe a theoretical approach to predicting self-assembly pathways, with applications to both engineered nanostructures and natural biomolecules.  First, I shall discuss design principles that can be used to tune the nucleation and growth rates of DNA 'bricks'.  These principles have crucial implications for low-defect self-assembly and the design of time-dependent experimental protocols.  Then, to highlight the biological importance of self-assembly kinetics, I shall present evidence that evolutionary selection has tuned ribosome translation rates to optimize the folding of globular proteins.

Dynamics of elastic waves on curved planar rods

Jonathan Matthew Kernes, UCLA
4pm PAB 4-330

Abstract: Lower dimensional elastic structures break isotropic symmetry of the material, introducing a preferred coordinate frame. Correspondingly, for an embedded structure the local tangential and normal components deformations respond in a separate but geometrically linked fashion. We exhibit the interaction between normal direction bending undulations, and tangential direction stretching deformations in the simplest case of a rod with local background radius of curvature. Curvature is found to decrease the availble oscillators in our system, as well as restrict the allowed frequencies.

 

Special Joint AMO/CM/CBP Seminar: Biomagnetic sensing with nitrogen vacancies in diamond

John Barry, Harvard University and MIT Lincoln Laboratory
March 3, 2017, 4pm PAB 1-434A

Abstract: Nitrogen vacancy (NV) color centers in diamond are rapidly emerging as a viable technology for quantum sensing. At the smallest scales, single NVs provide angstrom-scale spatial resolution with sensitivity sufficient for individual electron, proton, or protein detection. At much larger scales, bulk magnetometers harnessing large NV ensembles presently exhibit sensitivities surpassed only by SQUIDs and atomic vapor cells. Between these two limiting regimes, shallow surface layers of NVs allow for wide field-of-view magnetic imaging with diffraction-limited performance. The achieved combination of resolution and magnetic sensitivity remain unmatched for non-invasive imaging under ambient conditions, making solid state magnetic imaging favored for future investigations of various physical and biological phenomena. This talk presents progress towards one primary application: magnetic detection and imaging of action potentials from single neurons. We demonstrate this method using excised axons from two invertebrate species, marine worm and squid; and then by single-neuron action potential magnetic sensing exterior to intact, live, opaque marine worms.  Extended-duration magnetic sensing is performed with no adverse effect. We discuss future steps to enable non-invasive imaging of functional mammalian neural networks in real time.

Statistical physics of molecular evolution: from gene regulation to the immune system

Armita Nourmohammad, Princeton University
March 3, 2017, 3pm PAB 4-330

A venerable question in evolutionary biology is: if the tape of life was replayed, would the outcome be the same? We do not know how evolutionary predictability relates to different molecular scales, ranging from genotypes (DNA and amino acids) to molecular phenotypes (functions such as protein activity). I discuss universal properties of molecular phenotypes, encoded by genotypes with large degrees of freedom, which allow for the predictive description of their evolution. Populations are often subject to time-dependent pressure from the environment. I introduce a non-equilibrium framework for adaptive evolution of molecular phenotypes in time-dependent conditions. As an example, I present strong evidence that environmental fluctuations drive the evolution of gene expression levels in Drosophila. Co-evolving populations reciprocally affect the fitness of each other, acting as time-dependent environments with feedback. I show evidence of co-adaptation between interacting cellular populations of HIV viruses and the antibody repertoire of a patient over the course of an infection. In particular, I discuss the conditions for emergence of broadly neutralizing antibodies, which are recognized as critical for designing an effective vaccine against HIV.

Step-by-step shape evolution of tubular solids by defect motion

Daniel Beller, Harvard University
February 24, 2017, 4:00pm PAB 4-330 

Abstract: Two-dimensional crystalline order on surfaces with cylindrical topology gives rise to helical lattices. This type of packing occurs in biology at many scales, from biofilaments to viral capsids to botany, as well as in carbon nanotubes and in colloidal crystals. Shape changes in the tubular surface generally require changes in the crystalline tessellation of the surface. This evolution can be undertaken step-by-step via the motion of elementary defect pairs through the tubular crystal. I will discuss the physics of plastic deformation in tubular crystals by the unbinding and glide separation of dislocation pairs. Through theory and simulation, this work examines how the tube’s radius and helicity affect, and are in turn altered by, the mechanics of dislocation glide. The system’s bending rigidity plays an important role, and can resist, arrest, or even reverse the deformations of tubes with small radii. I will also discuss the equilibrium shapes of tubes containing dislocations, with potential implications for biofilaments such as microtubules. 

Activity, specificity, selectivity: new approaches for micro-assembly

Carl Goodrich, Harvard University
February 10, 2017, 4:00pm PAB 4-330

Abstract: Biology is able to build remarkable machines through a combination of programmable interactions and specific energy input through small molecules (ATP). However, we are largely unable to manufacture artificial structures of comparable complexity at the microscopic scale. The development of specific DNA glues has revolutionized our ability to program interactions, but we have barely scratched the surface of what can be built. I will discuss new approaches for micro-assembly, focusing on the use of self-propelled particles (a potential alternative to ATP) to drive out-of-equilibrium assembly. Under the right conditions, for example, the motion of active colloids can be programmed to pull semiflexible filaments into topological structures such as braids and weaves. I will also discuss how DNA interactions can be used to program a selectively permeable gel. 

Aggregation of proteins: growth of glucagon fibrils and bacterial growth

Andrej Kosmrlj, Princeton University
February 3, 2017, 4:00pm PAB 4-330

Abstract: Misfolding and aggregation of peptides and proteins are the hallmarks of many human diseases. With the advancement of microscopes, it is now possible to observe the kinetics of individual aggregates and fibrils in vitro. Interestingly, in some cases the growth of fibrils is intermittent, where the periods of growth are interrupted by periods of stasis. In this talk I will focus on the intermittent fibrillation of glucagon and I will describe how E. coli bacteria deal with harmful aggregates of misfolded proteins. Glucagon is a peptide hormone that upregulates blood sugar levels and is used to treat diabetic patients in situations of acute hypoglycemia. When dissolved in a fluid state, glucagon can form fibrils and become useless, as the fibrils cannot be absorbed and used by the body. The observed intermittent growth of glucagon fibrils can be explained with a simple model, where fibrils come in two forms, one built entirely from glucagon monomers and one entirely from glucagon trimers. The opposite building blocks act as fibril growth blockers, and this generic model reproduces experimental behavior well. Finally, I will discuss how E. coli bacteria deal with harmful aggregates of misfolded proteins that develop, when bacteria are under heat or antibiotic stress. In order to maximize the fitness of the whole population, bacteria distribute aggregates asymmetrically between their daughters, such that one daughter inherits the whole aggregate, while the other daughter receives none of it. Over time such asymmetric distribution of aggregates produces many “rejuvenated” bacteria with small aggregates that are quickly dividing at the expense of a few bacteria with large aggregates that are dividing very slowly.

 

Central auditory neurons have composite receptive fields and display flexible feature recombination functions

Andrei S. Kozlov, Department of Bioengineering, Imperial College London
November 18, 2016, 4:00pm PAB 4-330

How neurons achieve selectivity and invariance in representation of complex natural stimuli remains poorly understood, in part because standard statistical tools only identify one or two features of stimuli but not complete sets. In this talk, I will show that a set of multiple distinct acoustical features exists in individual auditory neurons in songbirds and that, depending on the stimulus and network state, each neuron can switch between AND-like operations for selectivity and OR-like operations for invariance. This flexibility contrasts with the fixed mapping of computations to neurons in classical pattern-recognition algorithms, but accords with neural-circuit models incorporating divisive normalization. I will then show that an unsupervised neural network trained on birdsong and constrained by two common properties of biological neural circuits, sparseness and divisive normalization, rediscovers the same stimulus features observed in vivo. These results demonstrate that individual high-level auditory neurons respond not to single, but to multiple features of natural stimuli and that they act as flexible logical gates operating in a high dimensional feature space. This property enables a robust, statistically optimal, representation of complex, real-world signals such as birdsong, speech or music.

Identifying vaccine-enhanced viral escape in STEP HIV vaccine trial

Ha Youn Lee, University of Southern California 
November 4, 2016, 4:00pm PAB 4-330

We developed a mathematical model to molecularly date an early HIV infection. From a subject’s single time point sequence sample, our shifted Poisson mixture model concurrently assessed both infection duration and number of transmitted viruses using maximum likelihood estimation. Our model was shown to successfully date early infections, with a statistically significant correlation to estimates of infection duration by Fiebig laboratory staging. Our quantitative approaches for interpreting early HIV genetic diversity guided us to reveal vaccine-enhanced viral escape in the STEP HIV vaccine trial.

An Overview of HIV Modeling: How Mathematics has helped Save Millions of Lives

Alan Perelson, Los Alamos National Laboratory
October 21, 2016 4:00pm PAB 4-330

Dr. Perelson will provide a brief overview of the field of HIV modeling and illustrate how modeling has revealed important insights into HIV pathogenesis and treatment.  In the later part of the talk, he will summarize where we are with respect to curing HIV and show how nonlinear dynamics may play an important role in understanding whether an infected person can control HIV infection without treatment. 

Alan S. Perelson has B.S. degrees in Life Sciences and in Electrical Engineering from MIT, and a Ph.D. in Biophysics from UC Berkeley. He has been an Acting Assistant Professor of Medical Physics at UC Berkeley, an Assistant Professor of Medicine at Brown University, and Group Leader of the Theoretical Biology and Biophysics Group at Los Alamos National Laboratory (LANL). He is now a Senior Fellow at LANL, an external professor at the Santa Fe Institute, and adjunct professor of Bioinformatics at Boston University, an adjunct professor of Biology at the University of New Mexico, and an adjunct professor of Biostatistics at the University of Rochester, School of Medicine. He is a member of the American Academy of Arts and Sciences, a fellow of the American Association for the Advancement of Science (AAAS), a fellow of the Society of Industrial and Applied Mathematics (SIAM) and a fellow of the American Physical Society (APS). He also is the recipient of an NIH MERIT Award and the 2017 Max Delbruck Prize in Biological Physics. He has published over 500 articles that have been cited over 50,000 times. His research focuses on developing models of the immune system and infectious diseases, such as HIV, hepatitis C and influenza.

Chiral twist drives raft formation and organization in membranes composed of rod-like particles

Louis Kang, University of Pennsylvania
August 26, 2016 4:00pm PAB 4-330

Lipid rafts are hypothesized to facilitate protein interaction, tension regulation, and trafficking in biological membranes, but the mechanisms responsible for their formation and maintenance are not clear. Insights into many other condensed matter phenomena have come from colloidal systems, whose micron-scale particles mimic basic properties of atoms and molecules but permit dynamic visualization with single-particle resolution. Recently, experiments showed that bidisperse mixtures of filamentous viruses can self-assemble into colloidal monolayers with thermodynamically-stable rafts exhibiting chiral structure and repulsive interactions. We quantitatively explain these observations by modeling the membrane particles as chiral liquid crystals. Chiral twist promotes the formation of finite-sized rafts and mediates a repulsion that distributes them evenly throughout the membrane. Although this system is composed of filamentous viruses whose aggregation is entropically driven by dextran depletants instead of phospholipids and cholesterol with prominent electrostatic interactions, colloidal and biological membranes share many of the same physical symmetries. Chiral twist can contribute to the behavior of both systems and may account for certain stereospecific effects observed in molecular membranes.

 

 

 

Mini-symposium on membrane biophysics May 27, 2016 4:00-6:00pm

Physical Mechanisms of Membrane Protein Organization and Collective Function

Christoph A. Haselwandter, University of Southern California
May 27, 2016, 4:00pm, PAB 4-330

Abbstract: Cell membranes are one of the fundamental hallmarks of life. For many of their biological functions, cell membranes rely on the collective properties of lattices of interacting membrane proteins. Here we explore the general physical mechanisms and principles underlying supramolecular organization and collective function of membrane proteins, based on three model systems: (1) We show how the interplay between protein-induced lipid bilayer curvature deformations, topological defects in protein packing, and thermal effects can explain the observed symmetry and size of membrane protein polyhedral nanoparticles; (2) We predict that the observed four- and five-fold symmetric states of mechanosensitive ion channels yield characteristic lattice architectures of channel clusters, with distinctive collective gating properties; (3) We show that lipid bilayer-mediated elastic interactions between chemoreceptor trimers provide a physical  mechanism for the observed self-assembly of chemoreceptor lattices, and may contribute to the cooperative signaling response of the chemotaxis system.

The physics of collective cell motility

M. Lisa Manning, Syracuse University
May 27, 2016, 5:00pm, PAB 4-330

Over the past 20 years, active matter models have been developed to explain the behavior of a wide range of nonequilibrium systems where agents inject energy at the smallest scales. An interesting open question is how useful these simple models are for modeling the collective behavior of eukaryotic cells. I will show that even at the lowest densities, standard self-propelled particle models do not capture the behavior of most cell types on 2D substrates, and discuss several model extensions that do capture the observed behaviors. I will then discuss several models for the behavior of motile cells at high densities and describe some of the interesting and biologically relevant features that show up in these systems, such as "swim pressure", cellular streaming, segregation, and fluid-solid transitions.


Dynamics of Neocortical Transverse Micro-electric Fields and Their Ephaptic Coupling

Maryam Ghorbani, Ferdowsi University of Mashhad, Iran
April 29, 2016, 4:00pm, PAB 4-330

Abstract: Neocortical neurons have extensive dendrites that predominantly arborize in the transverse direction and hence could be influenced by local, transverse micro-electric fields (TMF), parallel to the dendritic plane. While the effect of perpendicular electrical fields has been investigated, the TMF have not been studied. Here we measured neocortical TMF chronically in drug free rats in vivo using tetrodes. The four tips of tetrode were ~20um apart, yet TMF across the tips could reach 10mV/mm. The TMF measured between two of the electrodes was largely independent of the TMF measured across the other two tips indicating the extremely local and inhomogeneous nature of TMF. During slow wave sleep TMF was weakly correlated with the local field potential (LFP). Multiunit activity was strongly correlated with the TMF. Further the magnitude of TMF during Up transitions of slow wave sleep was highly predictive of the latency to spiking in that Up state. These results elucidate the dynamics of neocortical transverse micro-electric fields, and their recurrent, ephaptic coupling with spiking activity.

Bridging Fire and Ice: mechanical studies of modified antifreeze proteins

Daniel Cox, Department of Physics, UC Davis
April 22, 2016, 4:00pm, PAB 4-330

Prof. Cox has research interests in protein aggregation diseases, electronic properties of DNA, modelling of transition metal complexes in proteins, and molecular level modelling of biological membranes. His previous background is in the area of strongly correlated electronic metals with transition metal, rare earth, or actinide atoms.

An abstract of his talk is forthcoming.

Mechanical synchronization of active beating within and between cardiomyocytes

Samuel Safran, The Fern and Manfred Steinfeld Professor of Physics, Weizmann Institute of Science, Rehovot, Israel
March 3, 2016, 12:00 noon, 2033 Young Hall

We present theoretical models and predictions of how mechanics due to elastic interactions in actively beating heart cells can lead to synchronization of beating both within single cells and between nearby cells. Our research is motivated by recent experiments that show a correlation between the registry of adjacent muscle fibers and the beating strain of a single, embryonic cardiomyocyte and others that show how a mechanical probe can “pace” the phase and frequency of a nearby heart cell. The theory is generic and analytical in nature and focuses on the role of elastically mediated interactions of oscillating, active force dipoles in these cells. For the single cell, the theory successfully maps the registry data to the strain data.  Similar ideas are used to predict the conditions under which an oscillating mechanical probe will or will not “pace” the beating of a nearby heart cell.

The authors gratefully acknowledge collaborations with experimental groups: Stephanie Majkut and Dennis Discher (University of Pennsylvania, USA) and Shelly Tzlil (Technion, Israel). 

Friction from ion channels’ gating in vibrating hair-cell bundles from the inner ear

Pascal Martin, Institut Marie Curie, Paris
February 19, 2016, 4:00pm, PAB 4-330

Abstract: Hearing starts when sound-evoked mechanical vibrations of the hair-cell bundle activate mechanosensitive ion channels, giving birth to an electrical signal  As for any mechanical system, friction impedes movements of the hair bundle and thus constrains the sensitivity and frequency selectivity of auditory transduction.  We characterized friction by analyzing hysteresis in the force-displacement relation of single hair-cell bundles in response to periodic triangular stimuli.  We found that the opening and closing of the transduction channels produce internal frictional forces that can dominate viscous drag on the micron-sized hair bundle.  A theoretical analysis reveals that channel friction arises from coupling the dynamics of the conformational change associated with channel gating to tension in the tip links that interconnect neighboring stereocilia of the hair bundle.  As a result, varying channel properties affects friction, with faster channels producing smaller friction.  Friction originating from gating of ion channels is a general concept that is relevant to all mechanosensitive channels.  In the context of hearing, this intrinsic source of friction may contribute to the process that sets the hair cell’s characteristic frequency of responsiveness.

Untangling the Mechanics of Entangled Biopolymers
Rae Anderson, Associate Professor and Interim Chair, Department of Physics &  Biophysics, University of San Diego
February 12, 2016, 4:00pm, PAB 4-330

Biology naturally produces a wide range of polymers that are often forced to function in highly entangled and crowded environments within the cell. Such entangled networks display complex and intriguing viscoelastic properties similar to those we find in the squishy materials in and all around us. Our lab uses single-molecule microscopy techniques to elucidate the molecular mechanics underlying the complex viscoelastic properties of entangled and crowded networks of two ubiquitous biopolymers, DNA and actin. Specifically, we use optical tweezers to push and pull microspheres through these networks and measure the force the biopolymers impart on the spheres in response to the microscale strains. We also use fluorescence microscopy to track biopolymer diffusion in these systems to reveal a range of steady-state transport properties and conformational dynamics. By combining these methods, we also track macromolecular deformation imposed by microscale strains. I will discuss three of our recent experiments that highlight these techniques and reveal the fascinating impacts of molecular flexibility, topology and level of entanglement or crowding on biopolymer transport, conformation and nonlinear response to strain.

Making sense of senses: The clever "design" of spider mechanoreceptors

Friedrich G. Barth, Life Sciences, Department of Neurobiology, University of Vienna, Vienna, Austria
February 5, 2016, 4:00pm, PAB 4-330

Abstract: Spider sensors responding to different forms of mechanical energy are chosen to illustrate the power of evolutionary constraints to fine-tune the functional “design” of animal sensors to the specific roles they play in particular behaviors. The application of computational biomechanics and the cooperation between biologists and engineers demonstrate that there are remarkable “technical” tricks to be found by which spider tactile sensors, airflow sensors, and strain sensors are adjusted to their biologically relevant stimulus patterns.  The application of such “tricks” to technical solutions of measuring problems similar to those of the spiders seems both realistic and promising. 

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

Abstract:

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.

Note

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

Abstract:

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.

The problem of self reproduction: from bacteria to artificial cells
Albert Libchaber, The Rockefeller University
October 31, 2014, 4:00pm PAB 4-330

Abstract: Can we synthesize the most elementary cell size compartment that can self-reporduce using genetic information? We will discuss applying high hydrostatic pressure to E. coli bacterium during self reproduction. This is a reversible stress with controlled amplitude.

 

 

DNA confinement drives uncoating of the HIV Virus 
Robijn Bruinsma, UCLA Physics & Astronomy
October 17, 2014, 4:00pm, PAB 4-330

Abstract: The capsid that protects the genome molecule(s) of a virus is in general quite robust against mechanical stress. An outstanding exception is the mature capsid of retroviruses, such as HIV. We present a description of the mature HIV capsid where a key function is not the mechanical protection of the genome but instead a role as a "reactor vessel" for the action of the enzyme reverse transcriptase that converts single-stranded RNA molecules into double-stranded DNA molecules inside mature HIV viral capids. The uncoating of the HIV virus is determined by the fracture force exerted on the capsid wall by the DNA torus that is produced by the reverse transcriptase. 


The interaction between soft colloid particles and an immersed fibrous network
Louis Foucard, UCLA Chemistry & Biochemistry
October 3, 2014, 4:00pm, PAB 4-330

Many colloidal-sized particles encountered in biological and membrane based separation applications can be characterized as soft vesicles such as cells, yeast, viruses and surfactant micelles. The deformation of these vesicles are expected to critically affect permeation by accommodating pore shapes and sizes or enhancing the adhesion with a pore surface. Numerical and theoretical modelings of these processes will be critical to fully understand these processes and thus design novel filtration membranes that target, not only size, but deformability as a selection criterion.

This talk will introduce a multiscale strategy that enables the determination of the permeability of a fibrous network with respect to complex fluids loaded with vesicles. First, a particle-based moving interface method that can be used to characterized the severe deformation of vesicles interacting with an immersed fibrous network is introduced. Second, a homogenization strategy that permits the determination of a network permeability, based on the micromechanisms of vesicle deformation and permeation is presented.

As a proof of concept, the role of vesicle-solvent surface tension on the permeation of both solvent and vesicle through a simple 2D fiber network is investigated.

Pictured at left: Vesicle going through a fibrous network for different capillary numbers.

 

 

 


 

Elegant Mind Seminar: Exploring the origin of life and consciousness through the neural systems of C. elegans
Katsushi Arisaka, UCLA Physics & Astronomy
May 30, 2014, 3:00pm, Kinsey Teaching Pavilion 1200B

“Why are we here? What are we?”  

These fundamental questions, concerning the origin of life and consciousness, are investigated through behavioral analysis of the small nematode organism, C. elegans. The organism is fully sequenced, with an established connectome of 302 neurons. The dynamic functions of the nervous system, however, cannot be addressed from the connectome alone. It remains to be uncovered how these biologic functions are influenced by the environment for adaptation and learning. 100 students in lab focused on understanding such dynamic functions of the C. elegans nervous system, and studied how behavioral functions change through environmental interaction. Topics of study include 2D and 3D navigation under stimulations of E/B-fields, UV/visible lights, and temperature change. This talk presents the students’ findings of amazing and unexpected behaviors. Lastly, an ambitious plan is presented to advance the frontier of science concerning the origin of life and consciousness.

Also please feel free to attend the Elegant Mind Club at UCLA, open house May 30 12 noon to 5:00pm


Simple polymer models of proteins in the unfolded state:  A spherical cow?
Dmitrii E. Makarov, The University of Texas at Austin
May 23, 2014 4:00pm, PAB 4-330 

Contrary to the common misconception that biologically functional proteins always have to adopt well defined 3-dimensional shapes, at least 25% of proteins in our body are completely disordered and many more contain long unstructured segments. Being unstructured has a number of biological advantages and may, for example, speed up proteins’ search for their targets, facilitate protein degradation by the cell machinery, or impart remarkably high toughness to natural elastomeric materials (e.g. spider silk). For those proteins that are found folded under physiological conditions, the time it takes to attain their biologically active state is further controlled by the rate at which the unstructured polypeptide chain can explore its conformational space. 

In this talk, I will describe our efforts to develop very simple yet predictive polymer models of unfolded proteins.  Polymer theory predicts universal scaling laws governing disordered polymer chains, which hold regardless of chemical details as long as the chains in question are long enough. Real proteins, however, are often relatively short and so the use of simple polymer theories may (justifiably) be viewed as studying a spherical cow.  Nevertheless, I hope to convince the audience that rather simple models can quantitatively account for experimental measurements of unfolded proteins (particularly single-molecule FRET and “loop formation” studies) and agree well with arguably more realistic atomistic simulations.  In particular, I will describe recent experimental evidence for “internal friction” in protein dynamics and discuss the molecular origins of this effect. 


Elasticity on the edge of stability: soft matter inspired by the cell 

Fred MacKintosh, VU University, Amsterdam
April 9, 2014 9:00am, PAB 4-330 

Much like the bones in our bodies, the cytoskeleton consisting of stiff protein biopolymers determines the mechanical stability and response of cells. Unlike passive materials, however, living cells are kept far out of equilibrium by metabolic processes and energy-consuming molecular motors that generate forces to drive the machinery behind various cellular processes.

Inspired by such networks, we describe recent theoretical and experimental advances in our understanding of fiber networks in vitro and in vivo. We show that these exhibit a unique state of highly responsive matter near the isostatic point first studied by Maxwell.

For fiber networks, this represents a marginal state of matter with exceptional mechanical properties, including a strongly nonlinear elastic response and zero-temperature critical behavior. We discuss how this can help us to understand long-standing problems in tissue mechanics.  Moreover, the introduction of molecular motor activity can dramatically affect the stability of such systems. 


The Dynamics of Fibrin Gel Formation

James P. Keener, Ph.D., Distinguished Professor of Mathematics, Adjunct Professor of Bioengineering, University of Utah
March 27, 2014, 4:00pm, 13-105 Center for the Health Sciences (CHS)
 
Biogels are complex polymeric networks whose proper function is important to many physiological processes.  For example, the proper function of mucus gel is important for airway clearance, reproduction, digestion, gastric protection, and disease protection and its failure is involved in cystic fibrosis, gastric ulcers, and reproductive dysfunction.  Fibrin clots are crucial for prevention of bleeding after injury but inappropriate formation of clots is implicated in hearts attacks and strokes.
 
There are three phases of biogel dynamics that are important to their biological function.  These are their formation (i.e., blood clotting), degradation (clot dissolution), and swelling/deswelling kinetics (during mucin secretion/exocytosis, for example).
 
The purpose of this talk is to describe recent advances in the study of the dynamics of fibrin clot formation.  In particular, I will derive and discuss features of a new partial differential equation model that describes the growth of fibrin clots as a polymerization/gelation reaction.  The solution of this PDE model gives insight into the branching structure of clots that are formed under various physiological conditions.
 
Host: Tom Chou, Ph.D


Quantitative modeling of nucleic-acid protein interactions

Ralf Bundschuh, Ohio State University
March 14, 2014, 4:00pm - 5:00pm, 4-330 PAB 

The interactions of proteins with nucleic acids are fundamental for gene regulation.  We will discuss two aspects of these interactions where quantitative modeling provides novel insights into biological mechanisms.

The first is the binding of transcription factors to DNA. It is well known that nucleosomes reduce the affinity for transcription factors to binding sites covered by the nucleosome.  It has been assumed that this is due to a reduction in on-rate since a transcription factor can only bind when a rare thermal fluctuation of the nucleosome makes the DNA accessible.  However, recent experimental data surprisingly shows that 
the off-rate of transcription factors is also strongly affected in the presence of a nucleosome.  We demonstrate that this increase in off-rate by several orders of magnitude is a consequence of a competition between partial binding events of dimeric transcription factors and the nucleosome.

Second, we will investigate the interaction between proteins and RNA. Post-transcriptional regulation requires many proteins to bind to RNA. Implementation of combinatorial regulation requires cooperativity between such binding events.  In the case of single-stranded RNA binding proteins, a competition emerges between binding by proteins and formation of intramolecular base pairs of the RNA.  We show that this competition provides a natural mechanism for the required cooperativity between RNA binding proteins.


Polymer mechanics in bacteria - Growth, division, and morphogenesis

Jen Hsin, Stanford University
March 7, 2014, 4:00pm - 5:00pm, 4-330 PAB
 
Polymers assembled by proteins play essential roles in cell physiology.  In this talk I will present our works using realistic physics-based computations (molecular dynamics simulations), in combination with theoretical modeling, to reveal the physical mechanisms of polymers in key cellular processes such as division, growth, and maintaining the correct cell shape.  I will illustrate how a polymer converts chemical energy to mechanical energy, which provides the constrictive force needed for cell division to narrow cell width.  I will then discuss interactions between two polymers, and how their relative mechanical properties such as bending direction and stiffness can determine their cellular architectures.  Lastly, I will consider another major class of polymers that is made of inherently dynamic protein units, and explore the evolutionary significance of employing diverse polymer types to perform different cellular functions.


A physical model of cell-intercalation

Madhav Mani, KITP and UC Santa Barbara
February 28, 2014, 4:00pm - 5:00pm 4-330 PAB

The local rearrangement of cellular neighbors, termed cell-intercalation, results in the alteration of tissue shape and the emergent changes in embryonic form - morphogenesis. Despite our molecular understanding of how the cytoskeleton generates active stresses we lack a physical mechanism that underlies the rearrangement of cellular lattices, in particular accounting for their manifestly collective features. Relying on empirical analyses of live fluorescent microscopy of Drosophila Germ Band Extension (Lecuit Lab, Marseilles) our work makes three key advances: 1) construction of an image-analysis tool that allows a non-destructive measurement of relative tissue stresses, 2) insights into the physics of epithelial tissues that reveals the importance of shear stresses between cells and 3) accounting for the generic features of mechanical feedback on cytoskeletal levels. These ingredients are brought together into a simple mathematical model that provides insight into the observed local and global features of cell-intercalation and, more broadly speaking, into the dynamics of cellular lattices in a wide array of different tissues and animals.


Dynamics of Particles in Soft Matter

Michael Rubenstein, University of North Carolina
February 21, 2014, 4:00pm - 5:00pm

Abstract: Can the properties of materials be deduced from the analysis of the trajectories of probe particles diffusing through them? The anomalous diffusion of a particle in complex media could be due to three fundamental reasons: (1) Viscoelastic response of the medium to the deformation imposed on it by the moving particle; (2) The particle could be attracted to some regions of heterogeneous medium and be temporary localized in these "sticky" regions; (3) The particle is repelled from some regions of the medium and has to go over different energy barriers in order to diffuse through this medium. Can one determine which of these fundamental reasons cause the anomalous diffusion? We propose a method of analyzing particle trajectories to answer this question and to determine the corresponding properties of complex media such as distribution of relaxation times or energy distribution of attractive regions.

We solve activated hopping model in which particle experiences thermally activated jumps between neighboring wells of different energy depths. We find that the particle diffusion is ordinary Brownian (not anomalous) if the width of the distribution of well energies ΔU is smaller than thermal energy kT. In the opposite case (ΔU>kT) we discover the surprising result that although jumps between neighboring wells are completely random and uncorrelated, the particle displacements during consecutive time intervals are correlated. The source of these correlations is that the particle can be located in the same well during both time periods. As the result, while the mean square displacement of the particle is still Brownian, the distribution of displacements is non-Gaussian and is almost exponential. 

We use scaling theory to derive the time dependence of the mean-square displacement <r2(t)> of a probe nanoparticle in polymer solutions and melts. We distinguish several qualitatively different cases depending on the size d of the particle in comparison to solution correlation length ξ and tube diameter a for entangled polymer liquids. We also describe a hopping mechanism for diffusion of particles larger than mesh size of polymer solids (networks and gels).



Elasticity, Geometry, and Buckling

Andrj Kosmrlj, Harvard
February 14, 2014, 4:00pm - 5:00pm 4-330 PAB

Abstract: In this talk I present how geometrical shape affects the mechanical properties of thin solid membranes and how buckling instabilities change the geometry of periodic microstructures in materials. Using methods rooted in statistical physics, we find that random shape fluctuations and thermal excitations of thin solid membranes significantly modify their mechanical properties. Such membranes are much harder to bend, but easier to stretch, compress and shear. Finally, I show how methods from solid state physics can help us deduce the geometry of buckled periodic microstructures. Buckling instabilities can change the microstructure symmetries, including a spontaneous chiral symmetry breaking, which drastically modifies the material properties.


 

A Black Hole of Memory: Cytoskeletal Collapse in Late Stages of Alzheimer’s Disease? *

D.L. Cox, University of California, Davis
February 7, 2014, 4:00pm - 5:00pm

In the late stages of Alzheimer’s disease, the tau proteins that serve to nucleate, stabilize, and crosslink microtubules in the axons of nerve cells are degraded.  The customary view is that the removal of taus can allow for the catastrophic dynamical instability of microtubules in which depolymerization of tubulin monomers overwhelms polymerization and the microtubules vanish.  We offer an alternative perspective, that removal of taus essentially corresponds to a problem of rigidity percolation with the added feature of a depletion force induced by the taus themselves.  We show with a combination of 2D projected simulations and analytic arguments that there is an irreversible first order collapse when too many taus are removed, driven by the attractive depletion force, loosely analogous to gravitational collapse.  The values of tau density and entropic spring constants are such to make this likely dominate over the dynamic instability for a wide range of tau occupancies.  If correct, these arguments point to kinase phosphorylation as the main mechanism of tau degradation.   We discuss possible experimental tests of this on cultured neurons and whether “white matter” volume loss observed by functional MRI in afflicted patients can be attributed to this phenomenon.  Clearly this collapse represents a “Point of No Return” signpost in disease progression and therapeutic intervention. 

*Work supported by US NSF Grants DMR-1207624 and DMR-0844115 in collaboration with A. Sendek, H.R. Fuller, N.E. Hall, and R.R.P. Singh. 


Coupled Oscillators and Arnold Tongues in Cell Dynamics
Mogens H. Jensen, Niels Bohr Institute, Copenhagen, Denmark
January 21, 2014, 4:00pm - 5:00pm

Oscillating genetic patterns have been observed in networks related to the transcription factors NFkB, p53 and Hes1 [1]. We identify the central feed-back loops and found oscillations when time delays due to saturated degradation are present. By applying an external periodic signal, it is sometimes possible to lock the internal oscillation to the external signal. For the NF-kB systems in single cells we have observed that the two signals lock when the ration between the two frequencies is close to basic rational numbers [2]. The resulting response of the cell can be mapped out as Arnold tongues. When the tongues start to overlap we observe a chaotic dynamics of the concentration in NF-kB [2]. Oscillations in some genetic systems can be triggered by noise, i.e. a linearly stable system might oscillate due to a noise induced instability. By applying an external oscillating signal to such systems we predict that it is possible to distinguish a noise induced linear system from a system which oscillates via a limit cycle. In the first case Arnold tongues will
not appear, while in the second subharmonic mode-locking and Arnold tongues are likely [3].

[1] B. Mengel, A. Hunziker, L. Pedersen, A. Trusina, M.H. Jensen and S. Krishna, "Modeling oscillatory control in NF-kB, p53 and Wnt signaling", Current Opinion in Genetics and Development 20, 656-664 (2010).

[2] M.H. Jensen and S. Krishna, "Inducing phase-locking and chaos in cellular oscillators by modulating the driving stimuli", FEBS Letters 586, 1664-1668 (2012).

[3] N. Mitarai, U. Alon and M.H. Jensen, "Entrainment of linear and non-linear systems under noise", Chaos, 23, 023125 (2013).


Sparse codes for speech predict response properties of neurons at various stages of the ascending auditory pathway
Mike DeWeese, UC Berkeley
February 9, 2012,  4:00pm - 5:00pm
Biological Physics Seminar and Group Meeting Series

The natural scenes and sounds we encounter in the world are highly structured. The fact that animals and humans are so efficient at processing these sensory signals compared with the latest algorithms running on the fastest modern computers suggests that our brains can exploit this structure. We have developed a sparse mathematical representation of speech that minimizes the number of active model neurons needed to represent typical speech sounds. The model learns several well-known acoustic features of speech such as harmonic stacks, formants, onsets and terminations, but we also find more exotic structures in the spectrogra representation of sound such as localized checkerboard patterns and frequency-modulated excitatory subregions flanked by suppressive sidebands. Moreover, several of these novel features resemble neuronal receptive fields reported in the Inferior Colliculus (IC), as well as auditory thalamus (MGBv) and primary auditory cortex (A1), and our model neurons exhibit the same tradeoff in spectrotemporal resolution as has been observed in IC. To our knowledge, this is the first demonstration that receptive fields of neurons in the ascending mammalian auditory pathway beyond the auditory nerve can be predicted based on coding principles and the statistical properties of recorded sounds. We have also developed a biologically-inspired neural network model of primary visual cortex (V1) that can learn a sparse representation of natural scenes using spiking neurons and strictly local plasticity rules. The representation learned by our model is in good agreement with measured receptive fields in V1, demonstrating that sparse sensory coding can be achieved in a realistic biological setting.


Allostery in small functional RNAs
Sebastian Doniach, Stanford University
October 26, 2012,  4:00pm - 5:00pm PAB 3-145
Biological Physics Seminar and Group Meeting Series

In addition to the role of RNA as messenger and carrier of amino acids, and its central role in the function of the ribosome, small RNA molecules are becoming increasingly implicated in the machinery for control of gene expression. We will discuss structure-function relationships for a number of small functional RNAs, including riboswitches where binding of a small metabolite molecule induces conformational changes leading to direct control of transcription and/or translation of specific genes. Because of the highly charged phosphate backbone of polynucleotides, the biophysics of allostery in RNA molecules is very different from allostery in proteins, of which the transition between oxy- and deoxy- hemoglobin is a classic example. We will show that allostery in functional RNAs leads to major conformational changes, not just in terms of tertiary structure as is the case for proteins, but also in terms of major changes in the secondary structure hydrogen-bonding motifs. In this sense, it may be argued that allosteric-induced changes in RNA are a more primitive control mechanism than in protein reactions where a fraction of an Angstrom displacement of active groups can make a big difference in function. So RNA biophysics may be said to be closer to the origins of life, as in the hypothetical "RNA world".


Biophysical regulation of axonal transport
Megan T. Valentine, UC Santa Barbara
October 12, 2012, 4:00pm - 5:00pm
Biological Physics Seminar and Group Meeting Series

Axonal transport is an essential process in neurons by which mitochondria, organelles, proteins, and other cargos are transported by motor proteins along microtubules (MTs) from the cell body to the synapse and back. Although intracellular transport is important in a wide variety of cell types, it is particularly important in neurons, whose elongated shape makes them an excellent model system for long-distance transport. The biophysical and biochemical properties of isolated motor proteins, such as kinesin, have been extensively studied at the single-molecule level. However, in cells, kinesins move along microtubules that have been coated with numerous other microtubule-associated proteins (MAPs), and whether and how these MAPs impact axonal transport is still largely unknown. In this talk, I will present an overview of my laboratory’s efforts to better understand the regulation of axonal transport through physical interactions of kinesins, MAPs, and microtubules. Using fluorescence microscopy and optical trapping, we determine how motor speed and travel distance are influenced by the concentration and type of MAP present. We also determine the effects of MAPs on microtubule stiffness using a spectral analysis of the thermal fluctuations of filament shape. In particular, I will present our recent characterization of tau, a MAP that is required for normal neural function and has been implicated in a number of neural diseases, including Alzheimer’s disease.


Cell signaling at the single-cell level
Michael Elowitz, Caltech
November 29, 2012, 4:00 - 5:00pm
Biological Physics Seminar and Group Meeting Series

The cell contains specialized gene circuits that enable it to respond to specific inputs, including extracellular signals and stresses. Despite increasingly comprehensive knowledge of the molecules and interactions that comprise these circuits, it usually remains unclear how a given input is represented dynamically inside the cell, and what capabilities these dynamics provide. In order to address these issues, we are analyzing key circuits dynamically at the level of individual cells, in bacteria, yeast, and mammalian systems. The approach combines quantitative time-lapse microscopy, synthetic biology, mathematical modeling, and synthetic biology. I will discuss the unexpected, often noisy, intracellular dynamics that we have observed in studies of both prokaryotic and eukaryotic cells, and show how they arise from specific features of underlying circuit architectures. I will also discuss how these dynamics enable critical regulatory and developmental functions.


Micro- and mesoscopic blood flow in the brain
David Kleinfeld, UC San Diego
October 18, 2012, 4:00pm - 5:00pm
Biological Physics Seminar and Group Meeting Series