jakehofman.com

current work

my current work involves applications of machine learning and statistical inference techniques to network data, mostly as applied to problems in social science.

publications

A Bayesian Approach to Network Modularity abstract: We present an efficient, principled, and interpretable technique for inferring module assignments and for identifying the optimal number of modules in a given network. We show how several existing methods for finding modules can be described as variant, special, or limiting cases of our work, and how the method overcomes the resolution limit problem, accurately recovering the true number of modules. Our approach is based on Bayesian methods for model selection which have been used with success for almost a century, implemented using a variational technique developed only in the past decade. We apply the technique to synthetic and real networks and outline how the method naturally allows selection among competing models.
Jake M. Hofman, Chris H. Wiggins
Phys. Rev. Lett. 100, 258701 (2008) code
preprint: arXiv: 0709.3512 (2007)

Quantification of Cell Edge Velocities and Traction Forces Reveals Distinct Motility Modules during Cell Spreading abstract: Actin-based cell motility and force generation are central to immune response, tissue development, and cancer metastasis, and understanding actin cytoskeleton regulation is a major goal of cell biologists. Cell spreading is a commonly used model system for motility experiments -- fibroblasts exhibit stereotypic, spatially-isotropic edge dynamics during a reproducible sequence of functional phases: 1) During early spreading, cells form initial contacts with the surface. 2) The middle spreading phase exhibits rapidly increasing attachment area. 3) Late spreading is characterized by periodic contractions and stable adhesions formation. While differences in cytoskeletal regulation between phases are known, a global analysis of the spatial and temporal coordination of motility and force generation is missing. Implementing improved algorithms for analyzing edge dynamics over the entire cell periphery, we observed that a single domain of homogeneous cytoskeletal dynamics dominated each of the three phases of spreading. These domains exhibited a unique combination of biophysical and biochemical parameters -- a motility module. Biophysical characterization of the motility modules revealed that the early phase was dominated by periodic, rapid membrane blebbing; the middle phase exhibited continuous protrusion with very low traction force generation; and the late phase was characterized by global periodic contractions and high force generation. Biochemically, each motility module exhibited a different distribution of the actin-related protein VASP, while inhibition of actin polymerization revealed different dependencies on barbed-end polymerization. In addition, our whole-cell analysis revealed that many cells exhibited heterogeneous combinations of motility modules in neighboring regions of the cell edge. Together, these observations support a model of motility in which regions of the cell edge exhibit one of a limited number of motility modules that, together, determine the overall motility function. Our data and algorithms are publicly available to encourage further exploration.
Benjamin J. Dubin-Thaler, Jake M. Hofman, Yunfei Cai, Harry Xenias, Ingrid Spielman, Anna V. Shneidman, Lawrence A. David, Hans-Gunther Dobereiner, Chris H. Wiggins, Michael P. Sheetz
PLoS ONE 3(11): e3735 (2008) pdf

Opposing Effects of PKC{theta} and WASp on Symmetry Breaking and Relocation of the Immunological Synapse abstract: The immunological synapse (IS) is a junction between the T cell and antigen-presenting cell and is composed of supramolecular activation clusters (SMACs). No studies have been published on naive T cell IS dynamics. Here, we find that IS formation during antigen recognition comprises cycles of stable IS formation and autonomous naive T cell migration. The migration phase is driven by PKC{theta}, which is localized to the F-actin-dependent peripheral (p)SMAC. PKC-/- T cells formed hyperstable IS in vitro and in vivo and, like WT cells, displayed fast oscillations in the distal SMAC, but they showed reduced slow oscillations in pSMAC integrity. IS reformation is driven by the Wiscott Aldrich Syndrome protein (WASp). WASp-/- T cells displayed normal IS formation but were unable to reform IS after migration unless PKC{theta} was inhibited. Thus, opposing effects of PKC? and WASp control IS stability through pSMAC symmetry breaking and reformation.
Tasha N. Sims, Timothy J. Soos, Harry S. Xenias, Benjamin Dubin-Thaler, Jake M. Hofman, Janelle C. Waite, Thomas O. Cameron, V. Kaye Thomas, Rajat Varma, Chris H. Wiggins, Michael P. Sheetz, Dan R. Littman, and Michael L. Dustin
Cell 129:773-785 (2007) pdf

Nonmuscle Myosin IIA-dependent Force Inhibits Cell Spreading and Drives F-actin Flow abstract: Nonmuscle myosin IIA (NMM-IIA) is involved in the formation of focal adhesions and neurite retraction. However, the role of NMM-IIA in these functions remains largely unknown. Using RNA interference (RNAi) as a tool to decrease NMM-IIA expression, we have found that NMM-IIA is the major myosin involved in traction force generation and retrograde F-actin flow in mouse embryonic fibroblast (MEF) cells. Quantitative analyses revealed that ~60% of traction force on fibronectin-coated surfaces is contributed by NMM-IIA and ~30% by NMM-IIB. The retrograde F-actin flow decreased dramatically in NMM-IIA-depleted cells, but seemed unaffected by NMM-IIB deletion. In addition, we found that depletion of NMM-IIA caused cells to spread at a higher rate and to a greater area on fibronectin substrates during the early spreading period, whereas deletion of NMM-IIB appeared to have no effect on spreading. The distribution of NMM-IIA was concentrated on the dorsal surface and approached the ventral surface in the periphery whereas NMM-IIB was primarily concentrated around the nucleus and to a lesser extent at the ventral surface. Our results suggest that NMM-IIA is involved in generating a coherent cytoplasmic contractile force from one side of the cell to the other through the crosslinking and the contraction of dorsal actin filaments.
Yunfei Cai, Nicolas Biais, Gregory Giannone, Monica Tanase, Benoit Ladoux, Jake M. Hofman, Chris H. Wiggins and Michael P. Sheetz
Biophysical Journal, 91:3907-3920 (2006) pdf

Lateral Membrane Waves Constitute a Universal Dynamic Pattern of Motile Cells abstract: We have monitored active movements of the cell circumference on specifically coated substrates for a variety of cells including mouse embryonic fibroblasts and T cells, as well as wing disk cells from fruit flies. Despite having different functions and being from multiple phyla, these cell types share a common spatiotemporal pattern in their normal membrane velocity; we show that protrusion and retraction events are organized in lateral waves along the cell membrane. These wave patterns indicate both spatial and temporal long-range periodic correlations of the actomyosin gel.
Hans-Guenther Dobereiner, Benjamin J. Dubin-Thaler, Jake M. Hofman, Harry S. Xenias, Tasha N. Sims, Gregory Giannone, Michael L. Dustin, Chris H. Wiggins, and Michael P. Sheetz
Phys. Rev. Lett. 97:038102 (2006) pdf

The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLC{epsilon} abstract: R-Ras, an atypical member of the Ras subfamily of small GTPases, enhances integrin-mediated adhesion and signaling through a poorly understood mechanism. Dynamic analysis of cell spreading by total internal reflection fluorescence (TIRF) microscopy demonstrated that active R-Ras lengthened the duration of initial membrane protrusion, and promoted the formation of a ruffling lamellipod, rich in branched actin structures and devoid of filopodia. By contrast, dominant-negative R-Ras enhanced filopodia formation. Moreover, RNA interference (RNAi) approaches demonstrated that endogenous R-Ras contributed to cell spreading. These observations suggest that R-Ras regulates membrane protrusions through organization of the actin cytoskeleton. Our results suggest that phospholipase C{epsilon} (PLC{epsilon}) is a novel R-Ras effector mediating the effects of R-Ras on the actin cytoskeleton and membrane protrusion, because R-Ras was co-precipitated with PLC{epsilon} and increased its activity. Knockdown of PLC{epsilon} with siRNA reduced the formation of the ruffling lamellipod in R-Ras cells. Consistent with this pathway, inhibitors of PLC activity, or chelating intracellular Ca2+ abolished the ability of R-Ras to promote membrane protrusions and spreading. Overall, these data suggest that R-Ras signaling regulates the organization of the actin cytoskeleton to sustain membrane protrusion through the activity of PLC{epsilon}.
Aude S. Ada-Nguema, Harry Xenias, Jake M. Hofman, Chris H. Wiggins, Michael P. Sheetz and Patricia J. Keely
Journal of Cell Science 119:1307-1319 (2006) pdf

selected talks

2008.07.04: "inferring the structure and scale of modular networks", mlg 2008: slides as pdf, video
2008.03.12: "a bayesian approach to network modularity", aps march meeting: slides as pdf
2007.12.08: "a bayesian approach to network modularity", nips 2007 workshop: slides as pdf or quicktime
2007.10.31: "simple math for a complex world: random walks in biology and finance": slides, notes, movies
2007.10.19: "a bayesian approach to network modularity", apam: slides as pdf or quicktime
2007.09.28: "using time wisely in research: computer tools for keeping up + collborating": slides
2007.07.18: "machine learning tutorial", boulder summer school: slides, demos

links

chris wiggins, phd advisor, associate professor of applied mathematics in dept of applied physics and applied mathematics at columbia
the sheetz lab, collaborators; cell biology lab at columbia
the gonzalez lab, collaborators; single-molecule lab in columbia's chemistry department