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Seminars 2011

Tuesday, December 13
Dr Dante Romanini, Cornish Lab
Department of Chemistry
"Proteins as Substrates: New Methods for Biomolecule Engineering"

Friday, December 2
Prof Paul Yager
Department of Bioengineering
University of Washington
"Microfluidics 2.0—Making Point-of-Care Testing Extremely Inexpensive, and What That Could Mean for Global Health"

Abstract

The Yager lab has focused on the development of what is now considered "classical" microfluidics for the last 16 years. Since 2008, the Yager lab has shifted to development of instrument-free medical diagnostics based on low-cost 2-dimensional paper networks. These paper networks are based on the principles that underlie simple lateral flow tests (like home pregnancy tests or rapid diagnostic tests for malaria) where the patient provides an unprocessed sample, and shortly thereafter, can read a medically-relevant result. It turns out that when the constraints of a 1D geometry are removed, it becomes possible to “program” the paper devices to perform complex sequences of sample processing, chemical additions, incubations and rinses that are, today, performed by lab technicians or expensive lab robots. This has the potential to allow complex diagnostic tests (like amplified immunoassays or nucleic acid amplification-based testing) to be performed on readily-available fluid samples anytime, anywhere, by untrained individuals, and at extremely low cost.


Tuesday, November 29
Cath Latham, Miller Group
Department of Biological Sciences
"ER membrane asymmetry necessitates Sec13 for COPII vesicle formation"

Tuesday, November 1
Dr Gloria Arriagada, Goff Lab
Department of Microbiology and Immunology
"MuLV Capsid, SUMoylation, and TRIM5α recognition"

Friday, October 7
Dr E. Michael Ostap
Pennsylvania Muscle Institute & Department of Physiology
Perelman School of Medicine, University of Pennsylvania
"Mechanical, Biochemical, and Cellular Control of a Membrane-Associated Molecular Motor"

Abstract

I will discuss our use of biochemical, single-molecule, and cell biological techniques to determine how myosins use the energy stored in ATP to perform mechanical work. Myosins are the widely expressed motor proteins (39 genes in humans) that power contraction of muscle cells and serve as intracellular cargo transporters, cytoskeletal anchors, and signaling molecules in non-muscle cells. Our focus is on the class-1 myosins (8 genes in humans), which are notable for their ability to bind to lipid membranes directly. I will describe our progress in understanding the mechanical and biochemical diversity of myosin-1 motors, and I will discuss our progress in understanding the mechanical properties of myosin-1 interactions with lipid membranes. Our work uses traditional steady-state and transient biochemical techniques, high resolution cell microscopy, and single molecule optical-trap assays.


Tuesday, September 27
Prof Scott Banta
Department of Chemical Engineering
"The beta roll motif as a novel scaffold for engineering biomolcular recognition"

Thursday, September 8
Prof John C. Williams
Molecular Medicine, City of Hope
"Traps, Masks and Meditopes: Development of multivalent reagents for tumor targeting"

Abstract

Using an atoms-up approach, our research efforts have focused on understanding the regulation and activation of biological processes through multivalent interactions. In one line of our investigations, we have developed a series of inducible molecular traps that rapidly antagonize (<mins) molecular interactions involved in endocytosis and cellular trafficking. We have extended the utility of this trapping technology using a photocleavable reagent, allowing us to follow cellular events as they return from acute inhibition. Coupled to microscopy and live cell imaging, these traps provide new insight not currently available with other methods (e.g., siRNA) and will allow us to study molecular events in a single cell in a whole organism. In a second line of investigation, we have developed tumor activated, masked monoclonal antibodies to enhance their efficacy and mitigate their adverse side effects (e.g., cardiac failure). As part of these studies, we have also identified by diffraction methods a novel binding site within a mAb, demonstrated that this interaction does not affect antigen binding, and that this interaction is unique to this specific antibody framework (e.g., does not bind to human mAbs). Collectively, these observations suggest that this interaction can be used as a novel method for drug delivery, imaging, and/or enhance mAb therapeutic efficacy through synergistic coupling. Data will be presented vis-à-vis the design and development of a multivalent imaging agent to realize these goals.


Thursday, August 18
Prof Michael Golub
Tel Aviv University
"Scalar and resonance domain diffractive optical elements and their applications"

Tuesday, August 2
Dr Rene de Jong
DSM Biotechnology Center
"Biotechnology and Sustainability at DSM: Development of a Novel Fermentative Route Towards Pravastatin"

Tuesday, May 24
Margaret Elvekrog, Gonzalez Group
Department of Chemistry
"An IF3 conformational change signals proper initiator tRNA and start codon selection during translation initiation”

Wednesday, May 18
Prof Martha Bulyk
Harvard Medical School
“Transcription factors and cis regulatory elements: cis regulatory codes in DNA”

Abstract

The interactions between sequence-specific transcription factors (TFs) and their DNA binding sites are an integral part of the gene regulatory networks within cells. My group developed highly parallel in vitro microarray technology, termed protein binding microarrays (PBMs), for the characterization of the sequence specificities of DNA-protein interactions at high resolution. Using universal PBMs, we have determined the DNA binding specificities of >500 TFs from a wide range of species. These data have permitted us to identify novel TFs and their DNA binding site motifs, predict the target genes and condition-specific regulatory roles of TFs, predict tissue-specific transcriptional enhancers, investigate functional divergence of paralogous TFs within a TF family, investigate the molecular determinants of TF-DNA ‘recognition’ specificity, and distinguish direct versus indirect TF-DNA interactions in vivo. Further analyses of TFs and cis regulatory elements are likely to reveal features of cis regulatory codes important for driving appropriate gene expression patterns.


Tuesday, April 26
Nicholas Blais, Sheetz Group
Department of Biological Sciences
"Type IV Pilus, a Baterial Swiss Army Knife"

Friday, April 22
Prof Enrique de la Cruz
Yale University
"How Cofilin Severs an Actin Filament"

Abstract

The actin regulatory protein, cofilin, promotes actin assembly dynamics by severing filaments and increasing the number of ends from which subunits add and dissociate. I will present results from biochemical and biophysical studies that yield a thermodynamic, kinetic, structural and mechanical description of cooperative cofilactin binding and actin filament severing. The experimental data are well described by a model in which discontinuities in filament topology, and mechanics generate stress accumulation and promote fracture preferentially at junctions of bare and cofilin-decorated segments along filaments. Computational modeling and simulations indicate an intrinsic coupling between filament bending and twisting elasticity is critical for stress accumulation.


Tuesday, March 29
Prof Gerwald Jogl
Dept of Molecular Biology, Cell Biology and Biochemistry, Brown University
"Crystallographic Approaches to Studying Ribosome Structure and Antibiotic Resistance"

Abstract

The bacterial ribosome is the target of numerous antibiotic compounds and equally numerous antibiotic resistance mutations in ribosomal RNA have been described in the literature. The structural basis for antibiotic resistance due to these mutations has not yet been examined in detail. Similarly, the impact of post-transcriptional rRNA modifications on ribosome structure and the structural basis for antibiotic resistance due to the loss of some of these modifications is currently not well understood. In recent studies, we focused on the KsgA rRNA methyltransferase and studied the enzyme itself as well as the impact of the KsgA modifications on the structure of the 30S ribosomal subunit. Results from this work will be compared to structural data for 30S ribosomal subunits carrying mutations in 16S rRNA that cause resistance to the antibiotic streptomycin.


Friday, March 25
Prof Barbara A. Baird
Cornell University
"Zooming in on Spatial Control of Cellular Responses"

Abstract

At the fundamental level of physiology, cells respond to their physical environment and external stimuli in terms of collective molecular interactions that are regulated in time and space. Small molecules may engage specific receptors to initiate a transmembrane signal, and the system amplifies from this nanoscale to micron scale assemblies within the cell and often to longer length scales involving surrounding tissue and ultimately the whole organism. A striking example of signal integration over multiple length scales is the allergic immune response. IgE receptors (FceRI) on mast cells are the gate keepers of this response, and this system has proven to be a valuable model for investigating receptor-mediated activation of hematopoietic cells. For cellular stimulation, IgE receptors must be clustered on the cell surface, typically by a multivalent ligand (antigen). This causes their phosphorylation within membrane compartments, thus initiating intracellular signaling leading to multiple responses, including degranulation to release mediators of allergies and inflammation. My talk will describe our collaborative efforts that integrate physical, biological, and nanotechnology approaches to examine the spatial orchestration of cellular responses on the length scales at which they occur.


Wednesday, March 23

Prof Thomas Magliery
The Ohio State University
"Information in Protein Sequences Combinatorial and Statistical Protein Design"

Abstract

Both the prediction and design of protein structure, using computational and rational approaches, remain significant challenges in protein chemistry. A major limitation to developing a comprehensive physicochemical model of the protein structure-sequence relationship is the vastness of sequence space and the low-throughput nature of biophysical studies. We are pursuing two avenues to understand better the sequence structure-relationship: sorting large libraries of protein variants for structured proteins, and statistical analysis of ubiquitous protein families for protein redesign. In the combinatorial approach, we have developed a high-throughput cell-based screen for activity of the well-studied four-helix bundle protein Rop. To collect quantitative stability data for large numbers of variants, we have developed a method of high-throughput hydrophobic dye binding called High-Throughput Thermal Scanning (HTTS) which can be applied using automation and a real-time PCR machine 96-wells at a time. This system is being used to directly test the “rules” of protein design, taking those rules as hypotheses and sorting the resulting libraries for structure and stability. We are also interested in the role of correlated occurrences of amino acids in natural protein families. To that end, we have generated a consensus version of triosephosphate isomerase as a host to interrogate the roles of correlated positions by mutagenesis and library methods. Two closely-related consensus variants differ dramatically in their physical properties and activity. Methods for the analysis of pair-wise correlations in protein families, and a proof-of-principle application, will be discussed. Lessons from these approaches have been applied to improving the drug-like properties of the enzyme paraoxonase-1, a possible catalytic bioscavenger of organophosphorus nerve agents.


Thursday, March 10
Dr Andreas Schonle
Max Planck Institute for Biophysical Chemistry, Germany
"Recent Developments in STED Superresolution Microscopy"

Abstract

Stimulated emission depletion (STED) microscopy is one of the most promising superresolution techniques for live cell imaging. It breaks the diffraction limit by bringing the fluorophores back to the ground state in the peripheral of a fluorescently excited point spread function. Dr. Schönle will introduce the most recent advancement of STED microscopy, including high-speed STED, multicolor STED, and STED-FLIM imaging.


Tuesday, February 22

Bharat Reddy, Jia Lab
Department of Biological Sciences
"DeMYSTifying Heterochromatin: the Dark Matter of the Genome"

Friday, February 11
Prof Julie S. Biteen
University of Michigan
"Live-cell single-molecule and superresolution imaging of proteins in bacteria"

Abstract

Single-molecule imaging has extended the resolution of fluorescence microscopy down to the nanometer scale. This superresolution technique is non-invasive, tolerates simple sample preparation, and takes advantage of well-developed labeling schemes. As a result, single-molecule imaging is especially powerful for studying structure and dynamics in live cells. Here, we focus on imaging live bacteria cells, with attention to the particular challenges that they present: these organisms are small, have short cell cycles, live in particular environments, and their organization is relatively poorly understood.


Tuesday, February 1

Scott Dixon, Stockwell Lab
Department of Biological Sciences
"The Varieties of Cell Death Experience: A Study of a Novel Cell Death Phenotype Induced by the Small Molecule Erastin"

Thursday, January 27
Stefan Hell
Max Planck Institute
"Nanoscopy with Focused Light"