2010-2011 Colloquia

October 11, 2010 2:30 - 3:30PM
Abstract
Bacterial cells come in a wide variety of shapes and sizes, with the peptidoglycan cell wall as the primary stress-bearing structure that dictates cell shape. In recent years, cell shape has been shown to play a critical role in regulating many important biological functions including attachment, dispersal, motility, polar differentiation, predation, and cellular differentiation. How much control does a cell have over its shape, and can we tap into control mechanisms to synthetically engineer new morphologies? Though many molecular details of the composition and assembly of the cell wall components are known, how the peptidoglycan network organizes to give the cell shape during normal growth, and how it reorganizes in response to damage or environmental forces have been relatively unexplored. We have introduced a quantitative mechanical model of the bacterial cell wall that predicts the response of cell shape to peptidoglycan damage in the rod-shaped Gram-negative bacterium Escherichia coli. We have verified some of our predictions regarding morphological response to antibiotics using time-lapse imaging, suggesting that mechanical modelling of the cell wall can inform our understanding of cellular physiology. Our simulations based on our physical model also suggest a surprising robustness of cell shape to damage, allowing cells to grow and maintain their shape even under conditions that limit crosslinking. Our current research focuses on identifying the molecular factors responsible for cell shape determination and characterizing their phylogenetic diversity. In particular, we demonstrate that a small set of physical rules determines the cell's shape and the ability of the cell to maintain that shape, and we have used these rules to systematically alter the dimensions of rod-shaped bacteria. Our work has shown that many common bacterial cell shapes can be realized within both our model and in experiments via simple spatial patterning of the cytoplasm and cell wall, suggesting that subtle patterning changes could underlie the great diversity of shapes observed in the bacterial kingdom.
October 18, 2010 2:30 - 3:30PM
Abstract
In numerous applications in the biological and engineering sciences, one encounters inverse problems where the uncertainty and/or variability in parameters and mechanisms to be modeled are a fundamental part of the problem formulation. This is in addition to the data-driven uncertainty that arises naturally in most inverse problems. We discuss a theoretical framework and an associated computational methodology for such problems. In statistical inverse problem formulations these problems are usually discussed in the context of "mixing distributions", but the mathematical foundations can be found in much earlier work on relaxed controls (sliding regimes, chattering controls) of Young, Filippov, Warga,...., the early treatment of two player non-cooperative differential games, and more recently in the treatment of Preisach hysteresis in smart materials. In this expository lecture we outline these connections and present results from our recent efforts using these ideas in several applications in biology.
November 08, 2010 2:30 - 3:30PM
Abstract
The first step in RNA processing is the addition of an inverted GMP nucleotide, called a 'cap', onto the 5' end of the first transcribed nucleotide. In the nucleus this is bound by CBP80, which interacts with the processing machinery to coordinate intron splicing and addition of the poly(A) tail at the 3' end. The newly-processed mRNA is exported through the nuclear pore complex cap-end first, where CBP80 is replaced by eIF4E to begin the process of its translation into protein. The cap is removed as one of the first steps in the overall process of mRNA decay, and it was generally thought that loss of the cap results in rapid degradation by an exonuclease acting on the unprotected end.

In the dogma of molecular biology cap addition only occurs in the nucleus and its loss in the cytoplasm is irreversible. There are numerous reasons why this made sense, the most compelling of which is the concentration of the responsible protein (capping enzyme( in the nucleus and the biochemistry of cap addition, which requires a substrate with 2 phosphate groups, not the single phosphate that is left after the cap is removed. I will present work from my lab describing a new mechanism by which the cap can be restored onto cytoplasmic mRNAs after it has been removed by decapping or endonuclease cleavage. This work began with re-examination of results published in 1992 and never followed up describing a cap or cap-like structure on decay products of Ÿ-globin mRNA in patients with Ÿ-thalassemia (Cooley's anemia), a fatal disorder of hemoglobin production that is caused by inheriting two copies of this gene with a premature termination codon. I will describe how we validated those results, some of the basic biochemistry behind the re-capping process, and the identification and properties of a cytoplasmic complex that contains the enzymes that are responsible for mRNA re-capping. The loss of the cap is one of the key steps by which microRNAs repress translation and silence gene expression, and my talk will cover the cycle by which cytoplasmic re-capping may function in re-activating these silenced mRNAs. I will also touch on the possible links between cytoplasmic capping and the activation of neuronal or maternal mRNAs that must be kept in a silenced state until their translation is required. Although at this point it is highly speculative, cytoplasmic capping may also expand the proteome by enabling the translation of different forms of a protein from mRNAs that have lost the cap and sequences from their 5' ends, and the challenges the complexity of this process presents for bioinformatics, molecular and cell biology.
November 15, 2010 2:30 - 3:30PM
Abstract
Selection is weak, so evolutionary change is slow. That's the classical picture. But over the last 25 years we've learned that it's often very wrong, and ecologically important traits can change markedly in just a few generations. I will talk about experimental work using aquatic predator-prey microcosms as a model system to study rapid evolution; general theory motivated by those experiments; and methods that we have been developing to apply these ideas to field data, to quantify the importance of evolutionary change and non-heritable trait changes for ecological dynamics. This is joint work with many colleagues, postdocs, and students.
November 22, 2010 2:30 - 3:30PM
Abstract
At the cellular level, the detection, amplification, and processing of external chemical signals is affected by random fluctuations that arise within signaling pathways. In the case of the bacterial chemotaxis system we now have enough experimental data to go beyond ensemble averages. I will talk about our recent experimental and theoretical efforts to examine how the network design and spatial arrangement of this model signaling pathway shape the information processing and chemotactic capabilities of the single cell. An interesting result that emerges from this individual cell perspective is a molecular understanding of how cells resolve the compromise between the essential but likely competing behavioral modes of sensing and exploring.
January 24, 2011 2:30 - 3:30PM
Abstract
Structures and dynamics of proteins and their complexes are revealed in great details by NMR methods. In contrast to crystallography, no requirement for crystallization, or for low temperature. So processes are closer to physiological conditions. New in-cell methods make this more of a reality.

The experimental process is very slow because of

Intrinsic low sensitivity of method

Buggy whip approaches to data analysis and use of prior known information -over-focus on graphical interfaces and link to spectroscopy

There is no 'master equation'

Need improved, faster methods which incorporate chemical information appropriately, use probability methods in an integrated way, and make reasonable assumptions about averaging and motions.

Incorporate known information into experiment design for assignment and data collection
Break separation of assignment and structure calculation
Identify region of conformational spaces available from NMR data
Complete the loop of analysis and place complete analysis in a proper statistical framework

Use predictive power of integrated approach for

Speed up for structural genomics
Synthetic reconstruction and analysis of muilti-domain/ complexes for therapeutic target evaluation
Predictive structure/ function relationships for newly engineered systems (including de novo biology)
January 31, 2011 2:30 - 3:30PM
Abstract
The National Science foundation has funded many groups to assemble a framework phylogeny, or Tree of Life, for all major lineages of life. This effort requires large teams working across institutions and disciplines. In 2011, The Ohio State University has joined with nine other institutions to contribute the Echinoderm branch to the Tree of Life. The tree of life is incomplete without inclusion of the diverse marine animal phylum Echinodermata. The Echinodermata includes familiar organisms such as starfish and sea urchins as well as a wide array of extinct forms stretching back to the Cambrian Period. Echinoderms share a recent common ancestor with other deuterostomes, including chordates, and provide a crucial link to understanding the tree of life as a whole and the history of our species. However, understanding echinoderm phylogeny presents unique challenges. Whereas echinoderms are bilaterian animals, they have diverged considerably from this form. Most living echinoderms have five-sided symmetry. Moreover, the five living echinoderm classes are only a fraction of the diversity of Echinodermata (total class diversity is 21). Thus much of echinoderm diversity is known only from fossils. In recognition of these challenges, we have built a team to consider the fossil and the living echinoderms together. This work brings together experts from around the world within paleontology, genomics, informatics, developmental biology, anatomy, and phylogenetics. I will discuss our first results and the challenges that lay ahead. For more info see http://www.osu.edu/watch/45s4Ay5-vzIV8
February 07, 2011 2:30 - 3:30PM
Abstract

Despite more than 50 years of research, the etiology of depressive illness remains unknown. A hypothesis that has been central to much work in pharmacology and electrophysiology is that depression is caused by dysfunction in the serotonergic signaling system. In recent work, with Janet Best (OSU) and H. Frederik Nijhout (Duke), a mathematical model of a serotonergic synapse was created to study regulatory mechanisms in the serotonin system. After an introduction to the serotonin system, the model will be described as well as comparisons to experimental results. We will discuss why it is so difficult to understand the mechanism of efficacy of selective serotonin reuptake inhibitors (SSRIs). We will present predictions of the model as well as a new hypothesis for the mechanism of action of the SSRIs.

February 28, 2011 2:30 - 3:30PM
Abstract
Antigenically variable RNA viruses are significant contributors to the burden of infectious disease worldwide. Although control of these viruses is becoming increasingly effective through improvements in vaccine strain selection, predicting the antigenic characteristics of new viral variants remains an exceptionally difficult task. A complementary approach to disease control would be to guide the dynamics of a virus into an evolutionary regime that could be more effectively managed. This approach seems plausible as different viruses exhibit different evolutionary patterns and these patterns appear to be shaped, at least in part, by modifiable ecological factors. However, the feasibility of this approach is currently limited because we lack an understanding of which factors are key to shaping these evolutionary differences. With this as an overarching goal, I will present a theoretical framework that probabilistically anticipates patterns of viral antigenic diversification. This framework is based on a dimensionless number, whose value depends on epidemiological parameters. While similar in spirit to the basic reproduction number, which quantifies a pathogen's reproductive potential, our dimensionless number quantifies an antigenically variable virus's evolutionary potential. As such, it offers new perspectives on viral evolution by linking well-known ecological factors to the less well understood, long-term changes in viral antigenic diversity. I further detail how this framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study.
March 07, 2011 2:30 - 3:30PM
Abstract
Binocular rivalry is a fascinating phenomenon in which presentation of incompatible images to the two eyes results in a perceptual oscillations between the two monocular views. After demonstrating the phenomenon to the audience, the nonlinear dynamics underlying rivalry, rivalry memory, and traveling waves in rivalry will be discussed. Analogous traveling waves also arise during migraine auras, and the dynamics underlying these will also be developed using a simplified two-dimensional cortical model incorporating diffusion.
March 28, 2011 2:30 - 3:30PM
Abstract
In addition to responding to mechanical stimuli, the hair cell's transduction apparatus mediates active hair-bundle motility, one mechanism underlying the active process that increases responsiveness to sound, sharpens frequency selectivity, compresses the dynamic range of hearing, and even causes spontaneous otoacoustic emissions. In non-mammalian tetrapods-and perhaps in mammals as well-mechanical amplification is accomplished by active hair-bundle motility, which results from the interaction of negative hair-bundle stiffness with the myosin 1c motors that underlie adaptation. The operation of the active process near a Hopf bifurcation explains many of the characteristics of hearing. In particular, the dependence of response amplitude on stimulus force is expected to follow a power law with an exponent of one-third, as is measured experimentally. Operation near a Hopf bifurcation additionally produces distortion products with the level dependence observed for human hearing. Finally, a critical oscillator can become unstable, providing a natural explanation for spontaneous otoacoustic emissions.
April 11, 2011 2:30 - 3:30PM
Abstract
The maintenance of cellular homeostasis in the face of rapidly changing environmental conditions has been the focus of our research for the past five years. Specifically, we have studied the relationship between the growth rate, which we can control directly by setting the dilution rate in chemostats, and the initiation of cell division cycle, response to environmental stress, and metabolism. We have exploited high-throughput methods, some of our own devising, to follow gene expression, metabolite levels, and relative fitness of mutants on a comprehensive scale in order to obtain a view of the integration of these functions at the system level.

The results of these studies, which have involved collaborations with many other laboratories in the Lewis-Sigler Institute, include the following:

1) Expression of a substantial fraction (ca. 1/4) of the yeast genes is strongly correlated with the growth rate regardless of the limiting nutrient. Some genes are expressed more as growth rate increases (positive slope) and others are expressed more as the growth rate decreases (negative slope). These slopes are related to the periodic expression of the same genes in the metabolic cycle, which we have shown, by counting individual mRNAs by fluorescence in situ hybridization (FISH), is an intrinsic feature of yeast cell metabolism.

2) The levels of intracellular metabolites, in contrast, depend strongly on the limiting nutrient and relatively little on the growth rate. Only two (glutathione and trehalose) show strong negative slopes and a handful (e.g. ribose phosphate and fructose bis-phosphate) show strong positive slopes.

3) Starvation for phosphorus, sulfur or nitrogen ("natural nutrients") results in cell-cycle arrest, long-term (weeks) survival and sparing of residual glucose. Starvation, in auxotrophs, for leucine, uracil or histidine, in contrast, fail to arrest the cell cycle promptly, die much more rapidly and waste residual glucose. The glucose wasting is reminiscent of the Warburg effect seen in tumor cells.

4) Mutants that suppress starvation lethality and glucose wasting appear in genes already implicated in nutrient sensing. Genome-scale assessment of fitness during starvation provides a quantitative assessment of the contribution of each of the non-essential yeast genes to nutrient sensing and/or starvation survival.

It seems to us that much of what has been described as "stress response" would better be described as the consequence of slowing growth. The metabolic cycle, which separates oxidative and fermentative metabolism, appears to play a central role in growth-rate regulation. We are testing models in which metabolite levels, position in the metabolic cycle, external nutrient sensing as well as cell size are used to gate entry into the S-phase of the cell division cycle.
April 18, 2011 2:30 - 3:30PM
Abstract

In this talk, we will first introduce a new quantity called Signed Activation Time (SAT), which is found to be critical in determining noise attenuation capability of a feedback system. We will next study how noise amplification rates of several biological examples may depend on SAT and investigate strategies for noise attenuation in systems involving both extra-cellular and intra-cellular components. In particular, we will study boundary sharpening during Zebrafish embryonic development.


May 09, 2011 2:30 - 3:30PM
Abstract

We discuss diffuse interface (phase field) models of both single-component and multi-component vesicle membranes. We also consider models for the interactions of vesicles with an adhesive substrate and those with a background fluid. We present the mathematical derivations and compare results of numerical simulations with experimental findings.


May 23, 2011 2:30 - 3:30PM
Abstract

I will first present recent developments on the Dissipative particle Dynamics (DPD) -- a Lagrangian method that bridges the gap between continuum and atomistic scales. In particular, I will first discuss theoretical foundations of DPD, its relation to molecular dynamics (MD), and its use in modeling seamlessly blood flow interacting with blood cells (platelets, white cells and red blood cells (RBCs). Specific examples will be given for cerebral malaria and sickle cell anemia.


This work is supported by NIH and by the DOE/INCITE program and NSF/NICS for computations.