Gregg Duncan, University of Maryland College Park
Hosted by Sergei Sukharev
Title: Microstructural Alterations of Mucus in Obstructive Lung Diseases
Time: 4:00PM - 5:00PM
Date: Monday, January 29, 2018
Abstract
There is a strong clinical need for sensitive biomarkers of disease severity in obstructive lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). The role of airway mucus in the progression of these diseases has yet to be clearly determined and as a result, reliable mucus biomarkers have not been established. Prior assessments of mucus collected from individuals afflicted with these diseases have been limited to determining bulk macroscopic properties. However, these measurements are unable to probe mucus properties on microscopic length scales relevant to key players in the progression of obstructive lung disease such as viruses, bacteria, neutrophils, and eosinophils. In this work, we employed a nanoparticle-based biophysical measurement technique capable of detecting the microstructural properties of mucus and suggest its role in the progression of obstructive lung diseases. Specifically, we use the transport behavior of muco-inert nanoparticle probes within CF mucus produced by cough, known as sputum, as an indication of pore sizes within the sputum mesh network. We mechanistically demonstrate how changes in the biomolecular properties of sputum lead to the alteration of microstructure. Importantly, we found that a reduction in pore sizes within sputum correlates with impairment of lung function in individuals with CF. Our results give new insights into the CF lung airway microenvironment and suggest mucus/sputum microstructure may serve as a non-invasive biomarker for disease severity and outcome measure for new therapies in CF and other related obstructive lung diseases.
Mihaela Mihailescu, Institute for Bioscience and Biotechnology Research/National Institute of Standards and Technology
Hosted by Jeffery Klauda
Title: Exploring the Interplay of Host Defense Mechanisms at Biological Membranes: Insights from studies of antimicrobial Piscidins
Time: 4:00PM - 5:00PM
Date: Monday, February 05, 2018
Abstract
Antimicrobial peptides (AMPs) play an integral role in the fight against invading pathogens. To fully exploit their potential as prototypes for novel antimicrobials the molecular basis of their mechanism of action, which includes disrupting plasma membranes, must be understood. The host-defense peptides piscidin P1 and piscidin P3, that were first isolated from the mast cells of striped bass, display potent antimicrobial activity against a large number of Gram-positive and -negative bacteria, including methicillin-resistant S. aureus (MRSA), viruses such as HIV-1, fungi, yeasts, and cancer cells. The two 22-residue, helical, cationic peptide differ only slightly in amino-acid sequence, but P1 is more potent than P3. Solid state NMR showed that P1 and P3 adopt a very similar helical structure in fluid lipid membranes. However, neutron diffraction with specific deuterium labeling reveal differing conformations of the two peptides in membrane and offer insights on the structural interactions of the peptides with membranes and water, at the molecular level. The contrasting behavior of the two AMP homologues offers a unique opportunity to examine the structure-function relationship of membrane-active peptides.
Igor Aronson, Penn State University
Hosted by Wolfgang Losert
Title: Topological defects in a living nematic
Time: 4:00PM - 5:00PM
Date: Monday, February 12, 2018
Abstract
Living nematic is a realization of an active matter combining a nematic liquid crystal with swimming bacteria [1]. The material exhibits a remarkable tendency towards spatio-temporal self-organization manifested in the formation of dynamic textures of self-propelled half-integer topological defects (disclinations or vortices). The well-established and validated model of nematic liquid crystals coupled to the bacterial dynamics is used to describe intricate properties of such a living nematic. The model yielded a testable prediction on the accumulation of bacteria in the cores of 1/2 topological defects and depletion of bacteria in the cores of -1/2 defects [2]. We also studied of such living nematic near normal inclusions, or tactoids, naturally realized in liquid crystals close to the isotropic-nematic (I-N) phase transition. On the basis of the computational analysis, we have established that tactoid's I-N interface spontaneously acquire negative topological charge which is proportional to the tactoid's size and depends on the concentration of bacteria. The observed negative charging is attributed to the drastic difference in the mobilities of 1/2 and -1/2 topological defects in active systems. The effect is described in the framework of a kinetic theory for point-like weakly-interacting defects with different mobilities. Our dedicated experiments fully confirmed both theoretical predictions. The results hint into new strategies for control of active matter.
Juan Del Alamo, University of California at San Diego
Hosted by Helim Aranda-Espinoza
Title: The mechanics of leukocyte extravasation and subsequent migration through the three-dimensional extracellular matrix
Time: 4:00PM - 5:00PM
Date: Monday, March 12, 2018
Abstract
Leukocyte transmigration across vessel walls is a critical step in the immune response. Upon their activation and firm adhesion to vascular endothelial cells (VECs), leukocytes cross junctional gaps in the endothelial monolayer (paracellular diapedesis). It has been hypothesized that VECs facilitate diapedesis by opening their cell-cell junctions in response to an adhering leukocyte. However, it is unclear how leukocytes interact mechanically with VECs to open the VEC junctions and migrate across the endothelium. We measured the 3D traction stresses generated by the leukocytes and VECs to elucidate the sequence of mechanical events involved in paracellular diapedesis. Decoupling the stresses exerted by the leukocytes and the VECs reveals that the leukocytes actively contract the VECs to open a junctional gap, and then push themselves across the gap by generating strong stresses that push into the matrix. In addition, we found that diapedesis is facilitated when the tension fluctuations in the VEC monolayer were increased by pro-inflammatory agents. Our findings demonstrate that diapedesis can be mechanically regulated by the transmigrating leukocytes and by pro-inflammatory signals that increase VEC contractility. Upon extravasation, leukocytes migrate through fibrous 3-D matrices. To study the mechanics of this process, we are investigating 3-D leukocyte motility in collagen matrices of different concentrations using custom built microfluidic devices. Particle Image Velocimetry and Finite Deformation Theory are used to compute displacement fields in the collagen matrices. Stress fields in the matrices were computed using our E3DFM method. We will present data showing that morphological changes and migratory patterns vary depending on the porosity of the collagen matrices. We will also provide data showing a clear relationship between the aforementioned migratory characteristics and computed displacement and stress fields around migrating leukocytes. The results from our study show that neutrophils migrating in 3-D environments employ distinct mechanical mechanisms that depend on the structure of their mechanical environments.
Gaurav Arya, Duke University
Hosted by Jeffery Klauda
Title: Computational Modeling of DNA Organization: From Nucleosomes to Chromatin Fibers to Chromosomes
Time: 4:00PM - 5:00PM
Date: Monday, April 02, 2018
Abstract
In eukaryotic organisms, the genome is organized into repeating units called nucleosomes consisting of DNA wrapped around an octamer of histone proteins. The array of nucleosomes is folded into a chromatin fiber that undergoes further looping to eventually yield chromosomes. Such hierarchical organization of DNA is critical for the packaging of meters-long DNA into micron-sized cell nuclei and for the regulation of DNA transcription, replication, and recombination processes. This talk will present an overview of the computational approaches we have developed over the years for modeling DNA organization at the different hierarchical levels. At the nucleosome level, we have developed an experimentally-trained coarse-grained model that provides insights into the forced unraveling of nucleosomes. At the level of the chromatin fiber, we have developed a mesoscopic model that reveals its polymorphic architecture and elucidates the role of physiological salt, histone tails, and linker histone in stabilizing its compact state. The model also provides insights into chromatin supercoiling and propagation of torsional stresses in chromatin. At the level of chromosomes, we have developed computational approaches for analyzing contact frequency and sequence data from chromosome conformation capture experiments to recover chromatin 3D conformations and enzyme cleavage fractions.
David Cafiso, University of Virginia
Hosted by Sergei Sukharev
Title: Two-Way Transmembrane Signaling in an Outer-Membrane Transport Protein or why do spectroscopy when we have a crystal structure?
Time: 4:00PM - 5:00PM
Date: Monday, April 23, 2018
Abstract
Proteins execute motion over a wide range of amplitudes and time scales, which may include large amplitude movements between discrete structural substates. A change in the equilibrium distribution of these substates is thought to underlie protein allostery and to play a role in mediating protein-protein recognition. Site-directed spin labeling when combined with EPR spectroscopy is a powerful method to examine conformational exchange and structural heterogeneity in globular, membrane proteins and protein complexes. We will discuss TonB-dependent transporters, which are an important class of outer-membrane transport proteins that function in the uptake of nutrients by Gram negative bacteria. In particular, we will describe the use of EPR spectroscopy to characterize the Escherichia coli vitamin B12 transporter, BtuB, and show that the Ton box (an N-terminal energy coupling motif) and the substrate binding site are allosterically coupled. We will discuss the likely mechanisms of transport in this family of transport proteins, and describe novel methods to achieve efficient spin-labeling and carry out pulse EPR spectroscopy on these proteins in whole bacteria.
Pierre Ronceray, Princeton University
Hosted by Arpita Upadhyaya
Title: The emergence of contractility in biological fiber networks
Time: 4:00PM - 5:00PM
Date: Monday, April 30, 2018
Abstract
Large-scale force generation is essential for biological functions such as cell motility, embryonic development, and muscle contraction. In these processes, active forces generated at the molecular level by motor proteins are transmitted by disordered fiber networks, resulting in large-scale contractile stresses. I will present a comprehensive theoretical study of force transmission in these networks. While the linear response to small forces is remarkably simple, taking into account the nonlinear properties of the filaments yields strikingly counter-intuitive effects such as the reversal of extensile forces into contractile ones. These forces are furthermore amplified as they induce buckling on large scales in the network, resulting in large tensile stresses at the macroscopic scale. Our predictions are quantitatively consistent with experiments on reconstituted tissues and actomyosin networks, and shed light on the role of the network microstructure in shaping active stresses in cells and tissue.
Pablo Sartori Velasco, Rockefeller University
Hosted by Christopher Jarzynski
Title: Dynamics of cilia: mechanical response, chirality and phenotypic variability
Time: 4:00PM - 5:00PM
Date: Monday, May 7, 2018
Abstract
Cilia are model systems for studying how mechanical forces control morphology. Their periodic bending motion is thought to arise from a mechano-chemical feedback: motors generate mechanical forces that bend the cilium, and bending leads to deformations that regulate the motors. Through a combined theoretical and experimental approach we determine that motors respond to the time derivative of the ciliary curvature. Further modeling predicts that the chiral asymmetry of the cilium is a key player in this response mechanism. Ongoing work exploits our model to rationalize the effects of genotypic and phenotypic variability on recorded ciliary wave-forms.