Hari Shroff, NIH/NIBIB
Hosted by Giuliano Scarcelli
Title: Biological Imaging at High Spatiotemporal Resolution
Time: 4:00PM - 5:00PM
Date: Monday, September 17, 2018

Abstract

I will discuss our latest attempts to improve fluorescence microscopy techniques for following biological phenomena at high spatiotemporal resolution. Emphasis will be given to structured illumination microscopy (SIM) and light-sheet microscopy (LSFM) techniques. SIM1 doubles the spatial resolution of light microscopy, requiring lower light intensities and acquisition times than other super-resolution techniques. I will present SIM implementations that enable resolution doubling in live volumes > 10-20x thicker2-4 than possible with conventional SIM, as well as hardware modifications that enable effectively ‘instant’ SIM3,5 imaging at rates 10-100x faster than other SIM. New applications of instant SIM, including combination with total internal reflection (TIRF) and with adaptive optics6 will also be discussed. The second half of the talk will focus on the development of inverted selective plane illumination microscopy (iSPIM), and subsequent application to the noninvasive study of neurodevelopment in nematodes7. I will discuss progress that quadruples the axial resolution of iSPIM by utilizing a second specimen view, thus enabling imaging with isotropic spatial resolution (dual-view iSPIM, or diSPIM8,9). Newer multiview results with more objectives10 and more views11, further improving spatial resolution, will also be shown. Applications of these technologies will be presented, including computational methods for untwisting worm embryos12, with the goal of building a neurodevelopmental atlas with subcellular resolution13. Time permitting, I will also discuss 3 new and unpublished research projects in my lab: (1) rapid, sensor-less adaptive optics for use in SIM and LSFM; (2) 3D orientation sensing via multi-view fluorescence polarization; (3) structured illumination microcopy with ~5-fold improvement in axial resolution.

Sridhar Hannenhalli, University of Maryland at College Park
Hosted by Sergei Sukharev
Title: Transcriptional Enhancers – Looking out for the genes and each other
Time: 4:00PM - 5:00PM
Date: Monday, September 24, 2018

Abstract

The ENCODE project, via generation of unprecedented transcriptomic and epigenomic profiles, has revealed a complex layer of transcriptional regulation mediated by distal regulatory enhancers distributed throughout the human genome. These data open up more questions than they answer. We will discuss their nuclear organization, how they can be used for better genotype-phenotype associations and their potential emergent properties by virtue of their spatial proximity.

Suren Tatulian, University of Central Florida
Hosted by Sergei Sukharev
Title: Structure, Aggregation, and Cytotoxicity of Amyloid Beta Peptide
Time: 3:00PM - 4:00PM
Date: Monday, October 1, 2018

Abstract

The amyloid β (Aβ) peptide plays a major role in Alzheimer's disease (AD) and occurs in multiple forms, including pyroglutamylated Aβ (AβpE). Identification and characterization of the most cytotoxic Aβ species is necessary for advancement in AD diagnostics and therapeutics. While in brain tissue multiple Aβ species act in combination, structure/toxicity studies and immunotherapy trials have been focused on individual forms of Aβ. As a result, the molecular composition and the structural features of "toxic Aβ oligomers" have remained unresolved. Here, we have used a novel approach, hydration from gas phase coupled with isotope-edited Fourier transform infrared (FTIR) spectroscopy, to identify the prefibrillar assemblies formed by Aβ and AβpE and to resolve the structures of both peptides in combination. The peptides form unusual β-sheet oligomers stabilized by intramolecular H-bonding as opposed to intermolecular H-bonding in the fibrils. Time-dependent morphological changes in peptide assemblies have been visualized by atomic force microscopy and transmission electron microscopy. Furthermore, Aβ/AβpE hetero-oligomers exert unsurpassed cytotoxic effect on PC12 cells as compared to oligomers of individual peptides or fibrils. These findings lead to a novel concept that Aβ/AβpE hetero-oligomers, not just Aβ or AβpE oligomers, constitute the main neurotoxic species. The hetero-oligomers thus present a new biomarker that may be targeted for development of more efficient diagnostic and immunotherapeutic strategies to combat AD.

Tom Kurtzman, Lehman College NY
Hosted by Pratyush Tiwary
Title: Exploiting active site water and thermodynamics to improve the discovery and design of new pharmaceutical compounds
Time: 4:00PM - 5:00PM
Date: Monday, October 22, 2018

Abstract

Understanding the underlying physics of the binding of small-molecule drugs to protein active sites is a key objective of computational chemistry and biology. The displacement and reorganization of water molecules from the active site upon the binding of a ligand is a principal, and often dominant, source of binding free energy. We will discuss how statistical mechanics and molecular dynamics simulations help characterize the solvation of protein active sites and how this information may be incorporated into computational tools aimed at aiding early stage drug discovery and design efforts.

Elijah Roberts, Johns Hopkins University
Hosted by Dorothy Beckett
Title: Understanding the Complex Networks Driving Cellular Decisions
Time: 4:00PM - 5:00PM
Date: Monday, October 29, 2018

Abstract

Cellular phenotypes are intricate phenomena created by complex gene regulatory networks. Rather than remaining fixed in a given phenotypic state, cells move along a rough epigenetic landscape. Mapping back and forth between regulatory networks and epigenetic landscapes is a grand challenge for biological physics. I will present results from two studies of these networks in microbes. First, I will discuss a potential new source of epigenetic information in bacteria. Using a model that combines molecular thermodynamics with mass-action kinetics, we have shown that the build up of supercoiling due to transcription can introduce gene expression correlations within DNA topological domains. These correlations may give rise to a new layer of weak interactions in the bacterial regulatory network. Second, I will discuss recent results in understanding how the cell processes and stores information about gradients. Using a multiscale model of the yeast-mating pathway, we have shown how the bistable architecture of the mating pathway plays a crucial role in integrating directional information. We also hypothesize that the cell uses the cytoskeleton to actively store information about spatial direction.​

Sujit Datta, Princeton University
Hosted by Gregg Duncan
Title: Stressing cells and gels: exploiting gradients in two different systems
Time: 4:00PM - 5:00PM
Date: Monday, November 5, 2018

Abstract

Diverse applications, ranging from actuation to drug delivery to bioremediation, rely on how biological systems respond to environmental gradients. In this talk, I will present two examples, in two very different settings, of how we use gradients to direct behavior. First, I will describe our work using highly-resolved imaging and soft materials engineering to study how nutrient gradients impact bacterial motion in three-dimensional porous media. Our measurements reveal how gradient-induced motility depends sensitively on pore-scale confinement. Second, I will describe how we combine experiments and poroelasticity theory to investigate the influence of osmotic stresses in hydrogel packings. In some cases, the stresses that develop cause packings to crack. We show how cracking behavior depends on gradients in the stress profile, suggesting a way to control material behavior in this complex system. Ultimately, our work stimulates new findings and questions at the interface of Physics, Biology, Materials Science, and Engineering.

Lillian Chong, University of Pittsburgh
Hosted by Pratyush Tiwary
Title: The "Art of Possibility": Weighted Ensembles of Trajectories
Time: 4:00PM - 5:00PM
Date: Monday, November 19, 2018

Abstract

The weighted ensemble (WE) path sampling strategy orchestrates quasi-independent parallel simulations that are run with intermittent communication to enhance sampling of rare events such as large protein conformational transitions, protein folding, and protein binding. Trajectories are pruned or replicated in a way that encourages sampling of under-explored regions without biasing the dynamics. The WE strategy has been demonstrated to be orders of magnitude more efficient than standard simulations in generating complete pathways and rate constants for rare events of numerous benchmark systems. I will present advances in both WE methodology and software that have enabled applications to complex processes such as protein-protein binding along with challenges that remain.

Alexey Onufriev, Virginia Tech
Hosted by Garegin Papoian
Title: The nucleosome: from structure to function through physics
Time: 4:00PM - 5:00PM
Date: Monday, December 3, 2018

Abstract

The nucleosome, a complex of 147 base-pairs of DNA with eight histone proteins, must protect its DNA, but, at the same time, allow on-demand access to it when needed by the cell. The exact mechanism of the control remain unclear. A simplified electrostatic model of the nucleosome reveals that at physiological conditions the complex is close to the phase boundary separating it from the “unwrapped" states where the DNA is more accessible. A small drop in the positive charge (e.g. through acetylation of a lysine) of the globular histone core can significantly lower the DNA affinity to the core, and thus increase DNA accessibility. The findings suggest that charge-altering post-translational modifications in the histone core might be utilized by the cell to modulate accessibility to its DNA at the nucleosome level. A connection to higher order states of chromatin is made. A follow-up, detailed multi-state atomistic model of the nucleosome explores virtually all possible charge-altering post-translational modifications (PTMs) in the globular histone core. The model reveals a rich and nuanced picture: the effect of PTMs varies greatly depending on location, including counter-intuitive trends such as decrease of DNA accessibility for some lysine acetylations in the core. A detailed connection to transcription regulation in-vivo is made.

Michael Naughton, Boston College
Hosted by Wolfgang Losert
Title: Nanocoax: A Device Architecture for Bioelectronic Investigations
Time: 4:00PM - 5:00PM
Date: Monday, December 10, 2018

Abstract

We discuss a nanoscale coaxial architecture with potential utility in nanophotonics, photovoltaics, neuroprosthetics, and bioelectronic, chemical and neuro sensing. As subwavelength optical waveguides, these nanostructures can be used in a range of nanoscale manipulations of light, including optical nanoscopy and lithography, high efficiency solar cells, high electrode-density neuro-implants and discrete optical metamedia. A modification of the basic structure enables the fabrication of highly sensitive molecular sensors and high resolution bioelectronic probes, including optoelectronic neurostimulators/sensors (optrodes). We will report on aspects of these applications, including radial p-n junction solar cells, and bio, electrochemical and neuro sensing.